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Sample records for brain glucose homeostasis

  1. Exercise, Energy Intake, Glucose Homeostasis, and the Brain

    OpenAIRE

    Van Praag, Henriette; Fleshner, Monika; Schwartz, Michael W.; Mattson, Mark P.

    2014-01-01

    Here we summarize topics covered in an SFN symposium that considered how and why exercise and energy intake affect neuroplasticity and, conversely, how the brain regulates peripheral energy metabolism. This article is not a comprehensive review of the subject, but rather a view of how the authors' findings fit into a broader context. Emerging findings elucidate cellular and molecular mechanisms by which exercise and energy intake modify the plasticity of neural circuits in ways that affect br...

  2. Pancreatic regulation of glucose homeostasis.

    Science.gov (United States)

    Röder, Pia V; Wu, Bingbing; Liu, Yixian; Han, Weiping

    2016-01-01

    In order to ensure normal body function, the human body is dependent on a tight control of its blood glucose levels. This is accomplished by a highly sophisticated network of various hormones and neuropeptides released mainly from the brain, pancreas, liver, intestine as well as adipose and muscle tissue. Within this network, the pancreas represents a key player by secreting the blood sugar-lowering hormone insulin and its opponent glucagon. However, disturbances in the interplay of the hormones and peptides involved may lead to metabolic disorders such as type 2 diabetes mellitus (T2DM) whose prevalence, comorbidities and medical costs take on a dramatic scale. Therefore, it is of utmost importance to uncover and understand the mechanisms underlying the various interactions to improve existing anti-diabetic therapies and drugs on the one hand and to develop new therapeutic approaches on the other. This review summarizes the interplay of the pancreas with various other organs and tissues that maintain glucose homeostasis. Furthermore, anti-diabetic drugs and their impact on signaling pathways underlying the network will be discussed. PMID:26964835

  3. Brain iron homeostasis.

    Science.gov (United States)

    Moos, Torben

    2002-11-01

    Iron is essential for virtually all types of cells and organisms. The significance of the iron for brain function is reflected by the presence of receptors for transferrin on brain capillary endothelial cells. The transport of iron into the brain from the circulation is regulated so that the extraction of iron by brain capillary endothelial cells is low in iron-replete conditions and the reverse when the iron need of the brain is high as in conditions with iron deficiency and during development of the brain. Whereas there is good agreement that iron is taken up by means of receptor-mediated uptake of iron-transferrin at the brain barriers, there are contradictory views on how iron is transported further on from the brain barriers and into the brain extracellular space. The prevailing hypothesis for transport of iron across the BBB suggests a mechanism that involves detachment of iron from transferrin within barrier cells followed by recycling of apo-transferrin to blood plasma and release of iron as non-transferrin-bound iron into the brain interstitium from where the iron is taken up by neurons and glial cells. Another hypothesis claims that iron-transferrin is transported into the brain by means of transcytosis through the BBB. This thesis deals with the topic "brain iron homeostasis" defined as the attempts to maintain constant concentrations of iron in the brain internal environment via regulation of iron transport through brain barriers, cellular iron uptake by neurons and glia, and export of iron from brain to blood. The first part deals with transport of iron-transferrin complexes from blood to brain either by transport across the brain barriers or by uptake and retrograde axonal transport in motor neurons projecting beyond the blood-brain barrier. The transport of iron and transport into the brain was examined using radiolabeled iron-transferrin. Intravenous injection of [59Fe-125]transferrin led to an almost two-fold higher accumulation of 59Fe than of

  4. Leptin therapy, insulin sensitivity, and glucose homeostasis

    OpenAIRE

    Gilberto Paz-Filho; Claudio Mastronardi; Ma-Li Wong; Julio Licinio

    2012-01-01

    Glucose homeostasis is closely regulated not only by insulin, but also by leptin. Both hormones act centrally, regulating food intake and adiposity in humans. Leptin has several effects on the glucose-insulin homeostasis, some of which are independent of body weight and adiposity. Those effects of leptin are determined centrally in the hypothalamus and peripherally in the pancreas, muscles and liver. Leptin has beneficial effects on the glucose-insulin metabolism, by decreasing glycemia, insu...

  5. Leptin therapy, insulin sensitivity, and glucose homeostasis

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    Gilberto Paz-Filho

    2012-01-01

    Full Text Available Glucose homeostasis is closely regulated not only by insulin, but also by leptin. Both hormones act centrally, regulating food intake and adiposity in humans. Leptin has several effects on the glucose-insulin homeostasis, some of which are independent of body weight and adiposity. Those effects of leptin are determined centrally in the hypothalamus and peripherally in the pancreas, muscles and liver. Leptin has beneficial effects on the glucose-insulin metabolism, by decreasing glycemia, insulinemia and insulin resistance. The understanding of the effects of leptin on the glucose-insulin homeostasis will lead to the development of leptin-based therapies against diabetes and other insulin resistance syndromes. In these review, we summarize the interactions between leptin and insulin, and their effects on the glucose metabolism.

  6. Bitter taste receptors influence glucose homeostasis.

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    Cedrick D Dotson

    Full Text Available TAS1R- and TAS2R-type taste receptors are expressed in the gustatory system, where they detect sweet- and bitter-tasting stimuli, respectively. These receptors are also expressed in subsets of cells within the mammalian gastrointestinal tract, where they mediate nutrient assimilation and endocrine responses. For example, sweeteners stimulate taste receptors on the surface of gut enteroendocrine L cells to elicit an increase in intracellular Ca(2+ and secretion of the incretin hormone glucagon-like peptide-1 (GLP-1, an important modulator of insulin biosynthesis and secretion. Because of the importance of taste receptors in the regulation of food intake and the alimentary responses to chemostimuli, we hypothesized that differences in taste receptor efficacy may impact glucose homeostasis. To address this issue, we initiated a candidate gene study within the Amish Family Diabetes Study and assessed the association of taste receptor variants with indicators of glucose dysregulation, including a diagnosis of type 2 diabetes mellitus and high levels of blood glucose and insulin during an oral glucose tolerance test. We report that a TAS2R haplotype is associated with altered glucose and insulin homeostasis. We also found that one SNP within this haplotype disrupts normal responses of a single receptor, TAS2R9, to its cognate ligands ofloxacin, procainamide and pirenzapine. Together, these findings suggest that a functionally compromised TAS2R receptor negatively impacts glucose homeostasis, providing an important link between alimentary chemosensation and metabolic disease.

  7. Hormones and the Autonomic Nervous System are Involved in Suprachiasmatic Nucleus Modulation of Glucose Homeostasis

    NARCIS (Netherlands)

    Ruiter, M.; Buijs, R.M.; Kalsbeek, A.

    2006-01-01

    Glucose is one of the most important energy sources for the body in general, and the brain in particular. It is essential for survival to keep glucose levels within strict boundaries. Acute disturbances of glucose homeostasis are rapidly corrected by hormonal and neuronal mechanisms. Furthermore, ch

  8. Glucose is necessary to maintain neurotransmitter homeostasis during synaptic activity in cultured glutamatergic neurons

    DEFF Research Database (Denmark)

    Bak, Lasse K; Schousboe, Arne; Sonnewald, Ursula;

    2006-01-01

    Glucose is the primary energy substrate for the adult mammalian brain. However, lactate produced within the brain might be able to serve this purpose in neurons. In the present study, the relative significance of glucose and lactate as substrates to maintain neurotransmitter homeostasis was inves...

  9. The role of biological clock in glucose homeostasis 

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    Piotr Chrościcki

    2013-06-01

    Full Text Available The mechanism of the biological clock is based on a rhythmic expression of clock genes and clock-controlled genes. As a result of their transcripto-translational associations, endogenous rhythms in the synthesis of key proteins of various physiological and metabolic processes are created. The major timekeeping mechanism for these rhythms exists in the central nervous system. The master circadian clock, localized in suprachiasmatic nucleus (SCN, regulates multiple metabolic pathways, while feeding behavior and metabolite availability can in turn regulate the circadian clock. It is also suggested that in the brain there is a food entrainable oscillator (FEO or oscillators, resulting in activation of both food anticipatory activity and hormone secretion that control digestion processes. Moreover, most cells and tissues express autonomous clocks. Maintenance of the glucose homeostasis is particularly important for the proper function of the body, as this sugar is the main source of energy for the brain, retina, erythrocytes and skeletal muscles. Thus, glucose production and utilization are synchronized in time. The hypothalamic excited orexin neurons control energy balance of organism and modulate the glucose production and utilization. Deficiency of orexin action results in narcolepsy and weight gain, whereas glucose and amino acids can affect activity of the orexin cells. Large-scale genetic studies in rodents and humans provide evidence for the involvement of disrupted clock gene expression rhythms in the pathogenesis of obesity and type 2 diabetes. In general, the current lifestyle of the developed modern societies disturbs the action of biological clock. 

  10. The effect of altitude hypoxia on glucose homeostasis in men

    DEFF Research Database (Denmark)

    Larsen, J J; Hansen, J M; Olsen, Niels Vidiendal;

    1997-01-01

    1. Exposure to altitude hypoxia elicits changes in glucose homeostasis with increases in glucose and insulin concentrations within the first few days at altitude. Both increased and unchanged hepatic glucose production (HGP) have previously been reported in response to acute altitude hypoxia...

  11. Insulin Signaling in the Control of Glucose and Lipid Homeostasis.

    Science.gov (United States)

    Saltiel, Alan R

    2016-01-01

    A continuous supply of glucose is necessary to ensure proper function and survival of all organs. Plasma glucose levels are thus maintained in a narrow range around 5 mM, which is considered the physiological set point. Glucose homeostasis is controlled primarily by the liver, fat, and skeletal muscle. Following a meal, most glucose disposals occur in the skeletal muscle, whereas fasting plasma glucose levels are determined primarily by glucose output from the liver. The balance between the utilization and production of glucose is primarily maintained at equilibrium by two opposing hormones, insulin and glucagon. In response to an elevation in plasma glucose and amino acids (after consumption of a meal), insulin is released from the beta cells of the islets of Langerhans in the pancreas. When plasma glucose falls (during fasting or exercise), glucagon is secreted by α cells, which surround the beta cells in the pancreas. Both cell types are extremely sensitive to glucose concentrations, can regulate hormone synthesis, and are released in response to small changes in plasma glucose levels. At the same time, insulin serves as the major physiological anabolic agent, promoting the synthesis and storage of glucose, lipids, and proteins and inhibiting their degradation and release back into the circulation. This chapter will focus mainly on signal transduction mechanisms by which insulin exerts its plethora of effects in liver, muscle, and fat cells, focusing on those pathways that are crucial in the control of glucose and lipid homeostasis. PMID:26721672

  12. Roles of the Gut in Glucose Homeostasis.

    Science.gov (United States)

    Holst, Jens Juul; Gribble, Fiona; Horowitz, Michael; Rayner, Chris K

    2016-06-01

    The gastrointestinal tract plays a major role in the regulation of postprandial glucose profiles. Gastric emptying is a highly regulated process, which normally ensures a limited and fairly constant delivery of nutrients and glucose to the proximal gut. The subsequent digestion and absorption of nutrients are associated with the release of a set of hormones that feeds back to regulate subsequent gastric emptying and regulates the release of insulin, resulting in downregulation of hepatic glucose production and deposition of glucose in insulin-sensitive tissues. These remarkable mechanisms normally keep postprandial glucose excursions low, regardless of the load of glucose ingested. When the regulation of emptying is perturbed (e.g., pyloroplasty, gastric sleeve or gastric bypass operation), postprandial glycemia may reach high levels, sometimes followed by profound hypoglycemia. This article discusses the underlying mechanisms. PMID:27222546

  13. [Regulation of bone homeostasis by glucose].

    Science.gov (United States)

    Fukasawa, Kazuya; Hinoi, Eiichi

    2016-08-01

    Synthesis of type Ⅰ collagen, a major component of the bone matrix, precedes the expression of Runt-related transcription factor 2(Runx2), a master regulator in osteoblast differentiation. Thus, a direct link between osteoblast differentiation and bone formation is seemingly absent, and how these are maintained in a coordinated matter remains unclear. It was recently demonstrated that osteoblasts depend on glucose, which glucose transporter type 1(GLUT1)takes up as an energy source, and it was found that glucose uptake promotes osteoblast differentiation and bone formation via AMP-activated protein kinase. It was also shown that Runx2 upregulates GLUT1 expression, and this Runx2-GLUT1 feedforward regulation integrates and coordinates osteoblast differentiation and bone formation throughout life. These previous findings revealed that the energy metabolism balance in osteoblasts integrates the differentiation and function of osteoblasts, and re-emphasized the importance of crosstalk between bone and sugar metabolism. PMID:27461500

  14. Taurine supplementation modulates glucose homeostasis and islet function.

    Science.gov (United States)

    Carneiro, Everardo M; Latorraca, Marcia Q; Araujo, Eliana; Beltrá, Marta; Oliveras, Maria J; Navarro, Mónica; Berná, Genoveva; Bedoya, Francisco J; Velloso, Licio A; Soria, Bernat; Martín, Franz

    2009-07-01

    Taurine is a conditionally essential amino acid for human that is involved in the control of glucose homeostasis; however, the mechanisms by which the amino acid affects blood glucose levels are unknown. Using an animal model, we have studied these mechanisms. Mice were supplemented with taurine for 30 d. Blood glucose homeostasis was assessed by intraperitoneal glucose tolerance tests (IPGTT). Islet cell function was determined by insulin secretion, cytosolic Ca2+ measurements and glucose metabolism from isolated islets. Islet cell gene expression and translocation was examined via immunohistochemistry and quantitative real-time polymerase chain reaction. Insulin signaling was studied by Western blot. Islets from taurine-supplemented mice had: (i) significantly higher insulin content, (ii) increased insulin secretion at stimulatory glucose concentrations, (iii) significantly displaced the dose-response curve for glucose-induced insulin release to the left, (iv) increased glucose metabolism at 5.6 and 11.1-mmol/L concentrations; (v) slowed cytosolic Ca2+ concentration ([Ca2+]i) oscillations in response to stimulatory glucose concentrations; (vi) increased insulin, sulfonylurea receptor-1, glucokinase, Glut-2, proconvertase and pancreas duodenum homeobox-1 (PDX-1) gene expression and (vii) increased PDX-1 expression in the nucleus. Moreover, taurine supplementation significantly increased both basal and insulin stimulated tyrosine phosphorylation of the insulin receptor in skeletal muscle and liver tissues. Finally, taurine supplemented mice showed an improved IPGTT. These results indicate that taurine controls glucose homeostasis by regulating the expression of genes required for glucose-stimulated insulin secretion. In addition, taurine enhances peripheral insulin sensitivity. PMID:18708284

  15. Brain Glucose Metabolism Controls Hepatic Glucose and Lipid Production

    OpenAIRE

    Lam, Tony K.T.

    2007-01-01

    Brain glucose-sensing mechanisms are implicated in the regulation of feeding behavior and hypoglycemic-induced hormonal counter-regulation. This commentary discusses recent findings indicating that the brain senses glucose to regulate both hepatic glucose and lipid production.

  16. Dietary fructose and glucose differentially affect lipid and glucose homeostasis

    Science.gov (United States)

    Absorbed glucose and fructose differ in that glucose largely escapes first pass removal by the liver, whereas fructose does not, resulting in different metabolic effects of these two monosaccharides. In short-term controlled feeding studies, dietary fructose significantly increases postprandial trig...

  17. Brown adipose tissue regulates glucose homeostasis and insulin sensitivity

    OpenAIRE

    Stanford, Kristin I.; Middelbeek, Roeland J.W.; Townsend, Kristy L.; An, Ding; Nygaard, Eva B.; Hitchcox, Kristen M.; Markan, Kathleen R.; Nakano, Kazuhiro; Hirshman, Michael F.; Tseng, Yu-Hua; Goodyear, Laurie J.

    2012-01-01

    Brown adipose tissue (BAT) is known to function in the dissipation of chemical energy in response to cold or excess feeding, and also has the capacity to modulate energy balance. To test the hypothesis that BAT is fundamental to the regulation of glucose homeostasis, we transplanted BAT from male donor mice into the visceral cavity of age- and sex-matched recipient mice. By 8–12 weeks following transplantation, recipient mice had improved glucose tolerance, increased insulin sensitivity, lowe...

  18. The effect of metformin on glucose homeostasis during moderate exercise

    DEFF Research Database (Denmark)

    Hansen, Merethe; Palsøe, Marie K.; Helge, Jørn Wulff;

    2015-01-01

    OBJECTIVE: We investigated the role of metformin on glucose kinetics during moderate exercise. RESEARCH DESIGN AND METHODS: Before, during, and after a 45-min bout of exercise at 60% VO2max, glucose kinetics were determined by isotope tracer technique in patients with type 2 diabetes mellitus wit....... CONCLUSIONS: Metformin has a positive effect on glucose homeostasis during exercise.......OBJECTIVE: We investigated the role of metformin on glucose kinetics during moderate exercise. RESEARCH DESIGN AND METHODS: Before, during, and after a 45-min bout of exercise at 60% VO2max, glucose kinetics were determined by isotope tracer technique in patients with type 2 diabetes mellitus...... with metformin treatment (DM2+Met) or without metformin treatment (DM2) and in healthy control subjects (CON) matched for BMI and age. Glucoregulatory hormones and metabolites were measured throughout the study. RESULTS: Plasma glucose concentration was unchanged during exercise in CON but decreased in DM2...

  19. nfluence of antidepressants on glucose homeostasis : effects and mechanisms

    NARCIS (Netherlands)

    Derijks, H.J.

    2009-01-01

    Depression has shown to be a common morbidity in patients with diabetes mellitus and comorbid depression in diabetes mellitus patients is frequently treated with antidepressants. It has been postulated that antidepressants may interfere with glucose homeostasis and that the interference of antidepre

  20. Microbiota-Produced Succinate Improves Glucose Homeostasis via Intestinal Gluconeogenesis

    DEFF Research Database (Denmark)

    De Vadder, Filipe; Kovatcheva-Datchary, Petia; Zitoun, Carine;

    2016-01-01

    Beneficial effects of dietary fiber on glucose and energy homeostasis have long been described, focusing mostly on the production of short-chain fatty acids by the gut commensal bacteria. However, bacterial fermentation of dietary fiber also produces large amounts of succinate and, to date...

  1. Exploring the role of glucagon in glucose homeostasis

    NARCIS (Netherlands)

    Dongen, Maria Gertrud Jobina van

    2015-01-01

    The aim of this thesis was to gain further insight into the role of glucagon in glucose homeostasis in healthy volunteers and type 2 diabetes mellitus (T2DM) patients, and to explore the novel antisense glucagon receptor antagonist. Chapter 2 showed that the effect of meal replacers containing prote

  2. Influence of glucose homeostasis on maturation and ontogenesis of fetus

    Directory of Open Access Journals (Sweden)

    Grujić Zorica

    2011-01-01

    Full Text Available Introduction. The aim of the paper is to examine the incidence and the rate of cardio respiratory disorders in mothers of newborns with diabetes mellitus in pregnancy as well as their influence on the perinatal outcome. Material and methods. A prospective and random study included 102 newborns, 31 newborns of mothers with glucose homeostasis disorder (group I and 71 newborns of healthy mothers (group II. The average age, body height, body weight, body mass index, parity and illness duration of the pregnant women were recorded as well as the delivery method. Every newborn underwent physical examination in order to determine the Apgar score, body weight and length. Electrocardiogram, brain ultrasound and the basic hematology biochemical and microbiological analysis were done as well. Results. The average weight and obesity incidence were higher in diabetic women than in the control group and their newborns were heavier and of lower gestational age.Heart failures were diagnosed in 5 (1612% newborns of diabetic mothers and in 1 (1.4% of a healthy pregnant woman (p<0.01. Respiratory disorders were diagnosed in 48.4% of newborns of diabetic mothers and 12.64% of healthy mothers (p<0.01. Additional oxygen was needed by 42% of newborns of diabetic mothers and 19.7% of newborns of healthy mothers. Conclusion. Congenital anomalies of cardiovascular system and respiratory disorders were 6-8 times more frequent in newborns of diabetic mothers than in newborns of healthy mothers.

  3. Microbiota-Produced Succinate Improves Glucose Homeostasis via Intestinal Gluconeogenesis.

    Science.gov (United States)

    De Vadder, Filipe; Kovatcheva-Datchary, Petia; Zitoun, Carine; Duchampt, Adeline; Bäckhed, Fredrik; Mithieux, Gilles

    2016-07-12

    Beneficial effects of dietary fiber on glucose and energy homeostasis have long been described, focusing mostly on the production of short-chain fatty acids by the gut commensal bacteria. However, bacterial fermentation of dietary fiber also produces large amounts of succinate and, to date, no study has focused on the role of succinate on host metabolism. Here, we fed mice a fiber-rich diet and found that succinate was the most abundant carboxylic acid in the cecum. Dietary succinate was identified as a substrate for intestinal gluconeogenesis (IGN), a process that improves glucose homeostasis. Accordingly, dietary succinate improved glucose and insulin tolerance in wild-type mice, but those effects were absent in mice deficient in IGN. Conventional mice colonized with the succinate producer Prevotella copri exhibited metabolic benefits, which could be related to succinate-activated IGN. Thus, microbiota-produced succinate is a previously unsuspected bacterial metabolite improving glycemic control through activation of IGN. PMID:27411015

  4. Dopaminergic drugs in type 2 diabetes and glucose homeostasis.

    Science.gov (United States)

    Lopez Vicchi, Felicitas; Luque, Guillermina Maria; Brie, Belen; Nogueira, Juan Patricio; Garcia Tornadu, Isabel; Becu-Villalobos, Damasia

    2016-07-01

    The importance of dopamine in central nervous system function is well known, but its effects on glucose homeostasis and pancreatic β cell function are beginning to be unraveled. Mutant mice lacking dopamine type 2 receptors (D2R) are glucose intolerant and have abnormal insulin secretion. In humans, administration of neuroleptic drugs, which block dopamine receptors, may cause hyperinsulinemia, increased weight gain and glucose intolerance. Conversely, treatment with the dopamine precursor l-DOPA in patients with Parkinson's disease reduces insulin secretion upon oral glucose tolerance test, and bromocriptine improves glycemic control and glucose tolerance in obese type 2 diabetic patients as well as in non diabetic obese animals and humans. The actions of dopamine on glucose homeostasis and food intake impact both the autonomic nervous system and the endocrine system. Different central actions of the dopamine system may mediate its metabolic effects such as: (i) regulation of hypothalamic noradrenaline output, (ii) participation in appetite control, and (iii) maintenance of the biological clock in the suprachiasmatic nucleus. On the other hand, dopamine inhibits prolactin, which has metabolic functions; and, at the pancreatic beta cell dopamine D2 receptors inhibit insulin secretion. We review the evidence obtained in animal models and clinical studies that posited dopamine receptors as key elements in glucose homeostasis and ultimately led to the FDA approval of bromocriptine in adults with type 2 diabetes to improve glycemic control. Furthermore, we discuss the metabolic consequences of treatment with neuroleptics which target the D2R, that should be monitored in psychiatric patients to prevent the development in diabetes, weight gain, and hypertriglyceridemia. PMID:26748034

  5. Glucose homeostasis in pregnant rats submitted to dietary protein restriction.

    Science.gov (United States)

    de Mello, Maria Alice Rostom; Luciano, Eliete; Carneiro, Everardo Magalhães; Latorraca, Márcia Queiroz; Machado de Oliveira, Camnila Aparecida; Boschero, Antonio Carlos

    2003-01-01

    In the present work, we examined the effects of feeding a low protein diet during pregnancy on glucose-induced insulin secretion and glucose homeostasis in rats. Young (60 days), pregnant (P) or non-pregnant (NP) rats were fed during pregnancy or for 21 days (the NP) a normal (17%) or a low (6%) protein diet. Serum glucose and insulin levels and pancreas insulin content in the fed state; total area under serum glucose curve (AG) after a glucose load and serum glucose disappearance rate (Kitt) after insulin administration; as well as 86Rb outflow, 45Ca uptake and insulin secretion by isolated pancreatic islets in response to glucose were evaluated. Serum glucose was lower in 17%-P (12%) and 6%-P (27%) than in corresponding NP-rats. Serum insulin was higher in 17%-P (153%) and 6%-P (77%) compared to the corresponding NP-rats. Pancreatic insulin was higher in 6%-rats (55%) than in 17%-rats. No differences were found in AG among the groups whereas Kitt was lower in 6%-NP and higher in 6%-P than in the equivalent 17% rats. Increasing glucose concentration from 2.8 to 16.7 mmol/l, reduced 86Rb outflow from isolated islets from all groups. Increasing glucose concentration from 2.8 to 16.7 mmol/l elevated 45Ca uptake by 17%-NP (47%), 17%-P (40%) and 6%-P (214%) islets but not by 6%-NP ones. The increase in 45Ca uptake was followed by an increase in insulin release by the 17%-NP (2767%), 17%-P (2850%) and 6%-P (1200%) islets. In conclusion, 6%-P rats show impaired glucose induced insulin secretion related to reduced calcium uptake by pancreatic islets. However, the poor insulin secretion did not fully compensate the high peripheral sensitivity to the hormone, resulting in hypoglycemia. PMID:15686122

  6. Hormones and the autonomic nervous system are involved in suprachiasmatic nucleus modulation of glucose homeostasis.

    Science.gov (United States)

    Ruiter, Marieke; Buijs, Ruud M; Kalsbeek, Andries

    2006-05-01

    Glucose is one of the most important energy sources for the body in general, and the brain in particular. It is essential for survival to keep glucose levels within strict boundaries. Acute disturbances of glucose homeostasis are rapidly corrected by hormonal and neuronal mechanisms. Furthermore, changes in energy expenditure associated with the light-dark cycle induce variations in the plasma glucose concentration that are more gradual. Organisms take advantage of adapting their internal physiology to the predictable daily changes in energy expenditure, because it enables them to anticipate these changes and to prevent unnecessary disturbance of homeostasis. The hypothalamic biological clock, located in the suprachiasmatic nucleus (SCN), receives light information from the eyes and transmits this information to the rest of the body to synchronize physiology to the environment. Here we review several studies providing evidence for biological clock control of the daily variation in several aspects of glucose metabolism. Although both hormones and the autonomic nervous system can stimulate glucose uptake or production by organs in the periphery, we have shown that the biological clock control of glucose metabolism mostly occurs through the autonomic nervous system. The critical involvement of the biological clock is also indicated by several studies, indicating that disturbance of the biological clock is often associated with metabolic diseases, such as obesity, diabetes mellitus and hypertension.

  7. Brain glycogen and its role in supporting glutamate and GABA homeostasis in a type 2 diabetes rat model

    DEFF Research Database (Denmark)

    Sickmann, Helle Mark; Waagepetersen, Helle S.; Schousboe, Arne;

    2012-01-01

    diabetic state. Also, our objective was to elucidate the contribution of glycogen to support neurotransmitter glutamate and GABA homeostasis. A glycogen phosphorylase (GP) inhibitor was administered to Sprague-Dawley (SprD) and Zucker Diabetic Fatty (ZDF) rats in vivo and after one day of treatment [1......-(13)C]glucose was used to monitor metabolism. Brain levels of (13)C labeling in glucose, lactate, alanine, glutamate, GABA, glutamine and aspartate were determined. Our results show that inhibition of brain glycogen metabolism reduced the amounts of glutamate in both the control and type 2 diabetes......The number of people suffering from diabetes is hastily increasing and the condition is associated with altered brain glucose homeostasis. Brain glycogen is located in astrocytes and being a carbohydrate reservoir it contributes to glucose homeostasis. Furthermore, glycogen has been indicated to be...

  8. Common genetic determinants of glucose homeostasis in healthy children

    DEFF Research Database (Denmark)

    Kelliny, Clara; Ekelund, Ulf; Andersen, Lars Bo;

    2009-01-01

    OBJECTIVE: The goal of this study was to investigate whether the effects of common genetic variants associated with fasting glucose in adults are detectable in healthy children. RESEARCH DESIGN AND METHODS: Single nucleotide polymorphisms in MTNR1B (rs10830963), G6PC2 (rs560887), and GCK (rs4607517......) were genotyped in 2,025 healthy European children aged 9-11 and 14-16 years. Associations with fasting glucose, insulin, homeostasis model assessment (HOMA)-insulin resistance (IR) and HOMA-B were investigated along with those observed for type 2 diabetes variants available in this study (CDKN2A/B, IGF...... glucose (0.033 mmol/l [0.01-0.06], P = 0.01). Calculating a genetic predisposition score adding the number of risk alleles of G6PC2, MTNR1B, GCK, and SLC30A8 showed that glucose levels were successively higher in children carrying a greater number of risk alleles (P = 7.1 x 10(-17)), with mean levels of 5...

  9. Regulation of glucose homeostasis by KSR1 and MARK2.

    Directory of Open Access Journals (Sweden)

    Paula J Klutho

    Full Text Available Protein scaffolds control the intensity and duration of signaling and dictate the specificity of signaling through MAP kinase pathways. KSR1 is a molecular scaffold of the Raf/MEK/ERK MAP kinase cascade that regulates the intensity and duration of ERK activation. Relative to wild-type mice, ksr1⁻/⁻ mice are modestly glucose intolerant, but show a normal response to exogenous insulin. However, ksr1⁻/⁻ mice also demonstrate a three-fold increase in serum insulin levels in response to a glucose challenge, suggesting a role for KSR1 in insulin secretion. The kinase MARK2 is closely related to C-TAK1, a known regulator of KSR1. Mice lacking MARK2 have an increased rate of glucose disposal in response to exogenous insulin, increased glucose tolerance, and are resistant to diet-induced obesity. mark2⁻/⁻ksr1⁻/⁻ (DKO mice were compared to wild type, mark2⁻/⁻, and ksr1⁻/⁻ mice for their ability to regulate glucose homeostasis. Here we show that disruption of KSR1 in mark2⁻/⁻ mice reverses the increased sensitivity to exogenous insulin resulting from MARK2 deletion. DKO mice respond to exogenous insulin similarly to wild type and ksr1⁻/⁻ mice. These data suggest a model whereby MARK2 negatively regulates insulin sensitivity in peripheral tissue through inhibition of KSR1. Consistent with this model, we found that MARK2 binds and phosphorylates KSR1 on Ser392. Phosphorylation of Ser392 is a critical regulator of KSR1 stability, subcellular location, and ERK activation. These data reveal an unexpected role for the molecular scaffold KSR1 in insulin-regulated glucose metabolism.

  10. Glucagon-like peptide-1 inhibits blood-brain glucose transfer in humans

    DEFF Research Database (Denmark)

    Lerche, Susanne; Brock, Birgitte; Rungby, Jørgen;

    2008-01-01

    demonstrated that a hormone involved in postprandial glucose regulation also limits glucose delivery to brain tissue and hence provides a possible regulatory mechanism for the link between plasma glucose and brain glucose. Because GLP-1 reduces glucose uptake across the intact blood-brain barrier at normal...... glycemia, GLP-1 may also protect the brain by limiting intracerebral glucose fluctuation when plasma glucose is increased.......OBJECTIVE: Glucagon-like peptide-1 (GLP-1) has many effects on glucose homeostasis, and GLP-1 receptors are broadly represented in many tissues including the brain. Recent research in rodents suggests a protective effect of GLP-1 on brain tissue. The mechanism is unknown. We therefore tested...

  11. Astragalus polysaccharides alleviates glucose toxicity and restores glucose homeostasis in diabetic states via activation of AMPK

    OpenAIRE

    Zou, Feng; Mao, Xian-qing; Wang, Nian; Liu, Jian; Ou-Yang, Jing-ping

    2009-01-01

    Aim: To establish the mechanism underlying the improvement of glucose toxicity by Astragalus polysaccharide (APS), which occurred via an AMP activated protein kinase (AMPK)-dependent pathway. Methods: In vivo and in vitro effects of APS on glucose homeostasis were examined in a type 2 diabetes mellitus (T2DM) rat model. The T2DM rat model was duplicated by a high-fat diet (58% fat, 25.6% carbohydrate, and 16.4% protein) and a small dose of streptozotocin (STZ, 25 mg/kg, ip). After APS therapy...

  12. The role of gut hormone peptide YY in energy and glucose homeostasis: twelve years on.

    Science.gov (United States)

    Manning, Sean; Batterham, Rachel L

    2014-01-01

    Although the role of peptide YY (PYY) as a regulator of energy homeostasis was first highlighted only in 2002, our understanding of the physiological role of PYY has since rapidly advanced. In recent years, insights from mechanistic studies in patients undergoing bariatric surgery, from pancreatic islet research, from functional neuroimaging studies, and from exercise research have greatly added to the field, and these areas provide the focus of discussion for this narrative review. We critically discuss recent findings relating to the role of PYY in mediating the beneficial effects of bariatric surgery, the role of PYY in glucose homeostasis, the role of hepatoportal PYY in mediating its central physiological effects, the specific modulation of brain regions by PYY, and the exercise-induced PYY response. PMID:24188711

  13. Revisiting "Vegetables" to combat modern epidemic of imbalanced glucose homeostasis.

    Science.gov (United States)

    Tiwari, Ashok Kumar

    2014-04-01

    Vegetables have been part of human food since prehistoric times and are considered nutritionally necessary and good for health. Vegetables are rich natural resource of biological antioxidants and possess capabilities of maintaining glucose homeostasis. When taken before starch-rich diet, juice also of vegetables such as ridge gourd, bottle gourd, ash gourd, chayote and juice of leaves of vegetables such as radish, Indian Dill, ajwain, tropical green amaranth, and bladder dock are reported to arrest significantly the rise in postprandial blood glucose level. Juice of vegetables such as ash gourd, squash gourd, and tropical green amaranth leaves are observed to tone-down sweet-beverages such as sucrose, fructose, and glucose-induced postprandial glycemic excursion. On the other hand, juice of egg-plant and juice of leaves of Ceylon spinach, Joyweed, and palak are reported to augment starch-induced postprandial glycemic excursion; and juice of leaves of Ceylon spinach, Joyweed, and radish supplement to the glucose-induced postprandial glycemia. Vegetables possess multifaceted antihyperglycemic activities such as inhibition of pancreatic α-amylase and intestinal α-glucosidase, inhibition of protein-tyrosine phosphatase 1β in liver and skeletal muscles, and insulin mimetic and secretagogue activities. Furthermore, they are also reported to influence polyol pathway in favor of reducing development of oxidative stress, and consequently the development of diabetic complications. In the wake of emergence of modern maladaptive diet-induced hyperglycemic epidemic therefore, vegetables may offer cost-effective dietary regimen to control diet-induced glycemic over load and future development of diabetes mellitus. However, for vegetables have been reported to do both, mitigate as well as supplement to the diet-induced postprandial glycemic load, care is required in selection of vegetables when considered as medicament. PMID:24991093

  14. Revisiting "Vegetables" to combat modern epidemic of imbalanced glucose homeostasis

    Directory of Open Access Journals (Sweden)

    Ashok Kumar Tiwari

    2014-01-01

    Full Text Available Vegetables have been part of human food since prehistoric times and are considered nutritionally necessary and good for health. Vegetables are rich natural resource of biological antioxidants and possess capabilities of maintaining glucose homeostasis. When taken before starch-rich diet, juice also of vegetables such as ridge gourd, bottle gourd, ash gourd, chayote and juice of leaves of vegetables such as radish, Indian Dill, ajwain, tropical green amaranth, and bladder dock are reported to arrest significantly the rise in postprandial blood glucose level. Juice of vegetables such as ash gourd, squash gourd, and tropical green amaranth leaves are observed to tone-down sweet-beverages such as sucrose, fructose, and glucose-induced postprandial glycemic excursion. On the other hand, juice of egg-plant and juice of leaves of Ceylon spinach, Joyweed, and palak are reported to augment starch-induced postprandial glycemic excursion; and juice of leaves of Ceylon spinach, Joyweed, and radish supplement to the glucose-induced postprandial glycemia. Vegetables possess multifaceted antihyperglycemic activities such as inhibition of pancreatic α-amylase and intestinal α-glucosidase, inhibition of protein-tyrosine phosphatase 1β in liver and skeletal muscles, and insulin mimetic and secretagogue activities. Furthermore, they are also reported to influence polyol pathway in favor of reducing development of oxidative stress, and consequently the development of diabetic complications. In the wake of emergence of modern maladaptive diet-induced hyperglycemic epidemic therefore, vegetables may offer cost-effective dietary regimen to control diet-induced glycemic over load and future development of diabetes mellitus. However, for vegetables have been reported to do both, mitigate as well as supplement to the diet-induced postprandial glycemic load, care is required in selection of vegetables when considered as medicament.

  15. Sleep duration and sleep quality are associated differently with alterations of glucose homeostasis

    DEFF Research Database (Denmark)

    Byberg, Stine; Hansen, Anne-Louise Smidt; Christensen, Dirk Lund;

    2012-01-01

    Abstract Aims  Studies suggest that inadequate sleep duration and poor sleep quality increase the risk of impaired glucose regulation and diabetes. However, associations with specific markers of glucose homeostasis are less well explained. The objective of this study was to explore possible...... associations of sleep duration and sleep quality with markers of glucose homeostasis and glucose tolerance status in a healthy population-based study sample. Methods  The study comprised 771 participants from the Danish, population-based cross-sectional ‘Health2008’ study. Sleep duration and sleep quality were......), the homeostasis model assessment of β-cell function and glucose tolerance status. Associations of sleep duration and sleep quality with markers of glucose homeostasis and tolerance were analysed by multiple linear and logistic regression. Results  A 1-h increment in sleep duration was associated with a 0.3 mmol...

  16. The effect of hepatectomy on glucose homeostasis in pig and in man

    DEFF Research Database (Denmark)

    Lauritsen, Torsten Leif Bunk; Grunnet, Niels; Rasmussen, Allan;

    2002-01-01

    muscle) to the glucose homeostasis in the anhepatic pig and in man during the anhepatic phase of human liver transplantations. METHODS: Blood glucose and lactate were monitored in the anhepatic phase in 46 patients undergoing liver transplantation. Arterial-venous differences of lactate, glucose...

  17. Lack of glucagon receptor signaling and its implications beyond glucose homeostasis.

    Science.gov (United States)

    Charron, Maureen J; Vuguin, Patricia M

    2015-03-01

    Glucagon action is transduced by a G protein-coupled receptor located in liver, kidney, intestinal smooth muscle, brain, adipose tissue, heart, pancreatic β-cells, and placenta. Genetically modified animal models have provided important clues about the role of glucagon and its receptor (Gcgr) beyond glucose control. The PubMed database was searched for articles published between 1995 and 2014 using the key terms glucagon, glucagon receptor, signaling, and animal models. Lack of Gcgr signaling has been associated with: i) hypoglycemic pregnancies, altered placentation, poor fetal growth, and increased fetal-neonatal death; ii) pancreatic glucagon cell hyperplasia and hyperglucagonemia; iii) altered body composition, energy state, and protection from diet-induced obesity; iv) impaired hepatocyte survival; v) altered glucose, lipid, and hormonal milieu; vi) altered metabolic response to prolonged fasting and exercise; vii) reduced gastric emptying and increased intestinal length; viii) altered retinal function; and ix) prevention of the development of diabetes in insulin-deficient mice. Similar phenotypic findings were observed in the hepatocyte-specific deletion of Gcgr. Glucagon action has been involved in the modulation of sweet taste responsiveness, inotropic and chronotropic effects in the heart, satiety, glomerular filtration rate, secretion of insulin, cortisol, ghrelin, GH, glucagon, and somatostatin, and hypothalamic signaling to suppress hepatic glucose production. Glucagon (α) cells under certain conditions can transdifferentiate into insulin (β) cells. These findings suggest that glucagon signaling plays an important role in multiple organs. Thus, treatment options designed to block Gcgr activation in diabetics may have implications beyond glucose homeostasis.

  18. The Role of Glucose Transporters in Brain Disease: Diabetes and Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    Thomas Abbruscato

    2012-10-01

    Full Text Available The occurrence of altered brain glucose metabolism has long been suggested in both diabetes and Alzheimer’s diseases. However, the preceding mechanism to altered glucose metabolism has not been well understood. Glucose enters the brain via glucose transporters primarily present at the blood-brain barrier. Any changes in glucose transporter function and expression dramatically affects brain glucose homeostasis and function. In the brains of both diabetic and Alzheimer’s disease patients, changes in glucose transporter function and expression have been observed, but a possible link between the altered glucose transporter function and disease progress is missing. Future recognition of the role of new glucose transporter isoforms in the brain may provide a better understanding of brain glucose metabolism in normal and disease states. Elucidation of clinical pathological mechanisms related to glucose transport and metabolism may provide common links to the etiology of these two diseases. Considering these facts, in this review we provide a current understanding of the vital roles of a variety of glucose transporters in the normal, diabetic and Alzheimer’s disease brain.

  19. Obesity and type 2 diabetes in rats are associated with altered brain glycogen and amino-acid homeostasis

    DEFF Research Database (Denmark)

    Sickmann, Helle M; Waagepetersen, Helle S; Schousboe, Arne;

    2010-01-01

    Obesity and type 2 diabetes have reached epidemic proportions; however, scarce information about how these metabolic syndromes influence brain energy and neurotransmitter homeostasis exist. The objective of this study was to elucidate how brain glycogen and neurotransmitter homeostasis are affected...... by these conditions. [1-(13)C]glucose was administered to Zucker obese (ZO) and Zucker diabetic fatty (ZDF) rats. Sprague-Dawley (SprD), Zucker lean (ZL), and ZDF lean rats were used as controls. Several brain regions were analyzed for glycogen levels along with (13)C-labeling and content of glutamate, glutamine...... of glutamine and glutamate were decreased in the cerebellum of the ZO and the ZDF rats. Glycogen levels were also lower in this region. These results suggest that the obese and type 2 diabetic models were associated with lower brain glucose metabolism. Glucose metabolism through the TCA cycle was more...

  20. Role of Snf3 in glucose homeostasis of Saccharomyces cerevisiae (review)

    DEFF Research Database (Denmark)

    Kielland-Brandt, Morten

    signal pathways in directions opposite to those caused by extracellular nutrients (6,7), a phenomenon predicted to contribute to intracellular nutrient homeostasis. Although significant, the influence of intracellular leucine on signaling from Ssy1 is relatively modest (6), whereas the conditions with...... enhanced intracellular glucose concentrations (7) caused a strong decrease in signaling from Snf3, suggesting an important role of Snf3 in intracellular glucose homeostasis. Strategies for studies of this role will be discussed....

  1. Emerging role of the brain in the homeostatic regulation of energy and glucose metabolism.

    Science.gov (United States)

    Roh, Eun; Song, Do Kyeong; Kim, Min-Seon

    2016-01-01

    Accumulated evidence from genetic animal models suggests that the brain, particularly the hypothalamus, has a key role in the homeostatic regulation of energy and glucose metabolism. The brain integrates multiple metabolic inputs from the periphery through nutrients, gut-derived satiety signals and adiposity-related hormones. The brain modulates various aspects of metabolism, such as food intake, energy expenditure, insulin secretion, hepatic glucose production and glucose/fatty acid metabolism in adipose tissue and skeletal muscle. Highly coordinated interactions between the brain and peripheral metabolic organs are critical for the maintenance of energy and glucose homeostasis. Defective crosstalk between the brain and peripheral organs contributes to the development of obesity and type 2 diabetes. Here we comprehensively review the above topics, discussing the main findings related to the role of the brain in the homeostatic regulation of energy and glucose metabolism. PMID:26964832

  2. Minireview: Finding the Sweet Spot: Peripheral Versus Central Glucagon-Like Peptide 1 Action in Feeding and Glucose Homeostasis

    OpenAIRE

    Williams, Diana L.

    2009-01-01

    Glucagon-like peptide 1 (GLP-1) is both a gut-derived hormone and a neurotransmitter synthesized in the brain. Early reports suggested that GLP-1 acts in the periphery to promote insulin secretion and affect glucose homeostasis, whereas central GLP-1 reduces food intake and body weight. However, current research indicates that in fact, GLP-1 in each location plays a role in these functions. This review summarizes the evidence for involvement of peripheral and brain GLP-1 in food intake regula...

  3. Implications of Hydrogen Sulfide in Glucose Regulation: How H2S Can Alter Glucose Homeostasis through Metabolic Hormones

    Science.gov (United States)

    Pichette, Jennifer

    2016-01-01

    Diabetes and its comorbidities continue to be a major health problem worldwide. Understanding the precise mechanisms that control glucose homeostasis and their dysregulation during diabetes are a major research focus. Hydrogen sulfide (H2S) has emerged as an important regulator of glucose homeostasis. This is achieved through its production and action in several metabolic and hormone producing organs including the pancreas, liver, and adipose. Of importance, H2S production and signaling in these tissues are altered during both type 1 and type 2 diabetes mellitus. This review first examines how H2S is produced both endogenously and by gastrointestinal microbes, with a particular focus on the altered production that occurs during obesity and diabetes. Next, the action of H2S on the metabolic organs with key roles in glucose homeostasis, with a particular focus on insulin, is described. Recent work has also suggested that the effects of H2S on glucose homeostasis goes beyond its role in insulin secretion. Several studies have demonstrated important roles for H2S in hepatic glucose output and adipose glucose uptake. The mechanism of H2S action on these metabolic organs is described. In the final part of this review, future directions examining the roles of H2S in other metabolic and glucoregulatory hormone secreting tissues are proposed. PMID:27478532

  4. Neuro-endocrine basis for altered plasma glucose homeostasis in the Fragile X mouse

    Directory of Open Access Journals (Sweden)

    El Idrissi Abdeslem

    2010-08-01

    Full Text Available Abstract Background The fragile X mouse model shows an increase in seizure susceptibility, indicating an involvement of the GABAergic system via an alteration in cellular excitability. In the brain, we have previously described a reduction in GABAA receptor expression as a likely basis for this susceptibility. In the brains of fragile X mice, this reduction in receptor expression culminates with a concomitant increase in the expression of glutamic acid decarboxylase (GAD, the enzyme responsible for GABA synthesis. Further, voltage-sensitive calcium channel expression is reduced in the pancreas of the fragile X mouse. Since there are considerable similarities in the GABAergic system in the brain and pancreas, we evaluated the protective role of taurine in pancreatic islet development in both wild type (WT and fragile X mice (KO. Methods One-month-old FVB/NJ males or age-matched fmr1-knockout (KO mice were supplemented with taurine in drinking water (0.05% w/v for four weeks. Age-matched controls were fed water only for the same duration. At four weeks, mice were sacrificed and pancreases processed for histology and immunohistochemical studies on changes of insulin, glucagon and somatostatin expression. Additional mice were subjected to a glucose tolerance test. Results Taurine treatment resulted in a significant increase in the number and size of islets. WT taurine-fed mice, slightly hypoglycemic prior to glucose injection, showed significantly reduced plasma glucose at 30 min post-injection when compared to control mice. KO mice had normal baseline plasma glucose concentration; however, following glucose injection they had higher plasma glucose levels at 30 min when compared to controls. Supplementation of taurine to KO mice resulted in reduced baseline levels of plasma glucose. After glucose injection, the taurine-fed KO mice had reduced plasma glucose at 30 min compared to KO. Concomitant with the increased islets size and glucose tolerance

  5. Brown Adipose Tissue Improves Whole-Body Glucose Homeostasis and Insulin Sensitivity in Humans

    OpenAIRE

    Chondronikola, Maria; Volpi, Elena; Børsheim, Elisabet; Porter, Craig; Annamalai, Palam; Enerbäck, Sven; Lidell, Martin E.; Saraf, Manish K.; Sebastien M Labbe; Hurren, Nicholas M; Yfanti, Christina; Chao, Tony; Andersen, Clark R.; Cesani, Fernando; Hawkins, Hal

    2014-01-01

    Brown adipose tissue (BAT) has attracted scientific interest as an antidiabetic tissue owing to its ability to dissipate energy as heat. Despite a plethora of data concerning the role of BAT in glucose metabolism in rodents, the role of BAT (if any) in glucose metabolism in humans remains unclear. To investigate whether BAT activation alters whole-body glucose homeostasis and insulin sensitivity in humans, we studied seven BAT-positive (BAT+) men and five BAT-negative (BAT−) men under thermon...

  6. Role of changes in insulin and glucagon in glucose homeostasis in exercise.

    OpenAIRE

    Wolfe, R R; Nadel, E. R.; Shaw, J H; Stephenson, L A; Wolfe, M H

    1986-01-01

    This experiment was performed to determine if plasma glucose homeostasis is maintained in normal human volunteers during light exercise (40% maximal oxygen consumption [VO2 max]) when changes in insulin and glucagon are prevented. Hormonal control was achieved by the infusion of somatostatin, insulin, and glucagon. Glucose kinetics and oxidation rates were determined with stable isotopic tracers of glucose, and by indirect calorimetry. Two different rates of replacement of insulin and glucago...

  7. SGLT2 Deletion Improves Glucose Homeostasis and Preserves Pancreatic β-Cell Function

    OpenAIRE

    Jurczak, Michael J.; Lee, Hui-Young; Birkenfeld, Andreas L; Jornayvaz, Francois R.; Frederick, David W.; Pongratz, Rebecca L.; Zhao, Xiaoxian; Moeckel, Gilbert W.; Samuel, Varman T.; Whaley, Jean M.; Shulman, Gerald I.; Kibbey, Richard G

    2011-01-01

    OBJECTIVE Inhibition of the Na+-glucose cotransporter type 2 (SGLT2) is currently being pursued as an insulin-independent treatment for diabetes; however, the behavioral and metabolic consequences of SGLT2 deletion are unknown. Here, we used a SGLT2 knockout mouse to investigate the effect of increased renal glucose excretion on glucose homeostasis, insulin sensitivity, and pancreatic β-cell function. RESEARCH DESIGN AND METHODS SGLT2 knockout mice were fed regular chow or a high-fat diet (HF...

  8. Lactate, Glucose and Oxygen Uptake in Human Brain During Recovery from Maximal Exercise

    DEFF Research Database (Denmark)

    Kojiro, I.; Schmalbruch, I.K.; Quistorff, B.;

    1999-01-01

    Skeletal muscle, brain lactate uptake, brain oxygen uptake, energy metabolism, brain glucose uptake......Skeletal muscle, brain lactate uptake, brain oxygen uptake, energy metabolism, brain glucose uptake...

  9. Glucose Homeostasis Variables in Pregnancy versus Maternal and Infant Body Composition

    Directory of Open Access Journals (Sweden)

    Pontus Henriksson

    2015-07-01

    Full Text Available Intrauterine factors influence infant size and body composition but the mechanisms involved are to a large extent unknown. We studied relationships between the body composition of pregnant women and variables related to their glucose homeostasis, i.e., glucose, HOMA-IR (homeostasis model assessment-insulin resistance, hemoglobin A1c and IGFBP-1 (insulin-like growth factor binding protein-1, and related these variables to the body composition of their infants. Body composition of 209 women in gestational week 32 and of their healthy, singleton and full-term one-week-old infants was measured using air displacement plethysmography. Glucose homeostasis variables were assessed in gestational week 32. HOMA-IR was positively related to fat mass index and fat mass (r2 = 0.32, p < 0.001 of the women. Maternal glucose and HOMA-IR values were positively (p ≤ 0.006 associated, while IGFBP-1was negatively (p = 0.001 associated, with infant fat mass. HOMA-IR was positively associated with fat mass of daughters (p < 0.001, but not of sons (p = 0.65 (Sex-interaction: p = 0.042. In conclusion, glucose homeostasis variables of pregnant women are related to their own body composition and to that of their infants. The results suggest that a previously identified relationship between fat mass of mothers and daughters is mediated by maternal insulin resistance.

  10. Blood-Brain Glucose Transfer: Repression in Chronic Hyperglycemia

    Science.gov (United States)

    Gjedde, Albert; Crone, Christian

    1981-10-01

    Diabetic patients with increased plasma glucose concentrations may develop cerebral symptoms of hypoglycemia when their plasma glucose is rapidly lowered to normal concentrations. The symptoms may indicate insufficient transport of glucose from blood to brain. In rats with chronic hyperglycemia the maximum glucose transport capacity of the blood-brain barrier decreased from 400 to 290 micromoles per 100 grams per minute. When plasma glucose was lowered to normal values, the glucose transport rate into brain was 20 percent below normal. This suggests that repressive changes of the glucose transport mechanism occur in brain endothelial cells in response to increased plasma glucose.

  11. Chronic Sleep Disturbance Impairs Glucose Homeostasis in Rats

    NARCIS (Netherlands)

    Barf, R. Paulien; Meerlo, Peter; Scheurink, Anton J. W.

    2010-01-01

    Epidemiological studies have shown an association between short or disrupted sleep and an increased risk for metabolic disorders. To assess a possible causal relationship, we examined the effects of experimental sleep disturbance on glucose regulation in Wistar rats under controlled laboratory condi

  12. Effects of ethanol ingestion on maternal and fetal glucose homeostasis

    Energy Technology Data Exchange (ETDEWEB)

    Singh, S.P.; Snyder, A.K.; Singh, S.K.

    1984-08-01

    Carbohydrate metabolism has been studied in the offspring of rats fed liqiud diet containing ethanol during gestation (EF group). Weight-matched control dams were given liquid diet either by the pair-fed technique (PF group) or ad libitum (AF group). EF and PF dams showed reduced food consumption and attenuated gain in body weight during the gestation period compared with the AF group. Blood glucose, liver glycogen, and plasma insulin levels were significantly reduced in EF and PF dams. Ethanol ingestion resulted in a significant decrease in litter survival and fetal body weight. At term, EF pups on average showed a 30% decrease in blood glucose levels and 40% decrease in plasma insulin levels compared with AF pups. One hour after birth, EF pups exhibited a marked increase in blood sugar level compared with either control group. Fetal hyperinsulinemia disappeared shortly after delivery in control pups, as expected; however, in EF pups, the fall in plasma insulin level was gradual. Fetal and neonatal plasma glucagon levels were not altered by ethanol exposure in utero. Blood glucose levels remained significantly low at 2 days of age in EF pups, but reached near control values at 4 days of age. Plasma insulin and glucagon were nearly equal in EF and control pups at 2 and 4 days of age. These results show aberrations in blood glucose, plasma insulin, and liver glycogen levels in offspring exposed to ethanol in utero.

  13. BMAL1 and CLOCK, two essential components of the circadian clock, are involved in glucose homeostasis.

    Directory of Open Access Journals (Sweden)

    R Daniel Rudic

    2004-11-01

    Full Text Available Circadian timing is generated through a unique series of autoregulatory interactions termed the molecular clock. Behavioral rhythms subject to the molecular clock are well characterized. We demonstrate a role for Bmal1 and Clock in the regulation of glucose homeostasis. Inactivation of the known clock components Bmal1 (Mop3 and Clock suppress the diurnal variation in glucose and triglycerides. Gluconeogenesis is abolished by deletion of Bmal1 and is depressed in Clock mutants, but the counterregulatory response of corticosterone and glucagon to insulin-induced hypoglycaemia is retained. Furthermore, a high-fat diet modulates carbohydrate metabolism by amplifying circadian variation in glucose tolerance and insulin sensitivity, and mutation of Clock restores the chow-fed phenotype. Bmal1 and Clock, genes that function in the core molecular clock, exert profound control over recovery from insulin-induced hypoglycaemia. Furthermore, asynchronous dietary cues may modify glucose homeostasis via their interactions with peripheral molecular clocks.

  14. Glucagon-like peptide-1: glucose homeostasis and beyond.

    Science.gov (United States)

    Cho, Young Min; Fujita, Yukihiro; Kieffer, Timothy J

    2014-01-01

    Glucagon-like peptide-1 (GLP-1), an incretin hormone secreted primarily from the intestinal L-cells in response to meals, modulates nutrient homeostasis via actions exerted in multiple tissues and cell types. GLP-1 and its analogs, as well as compounds that inhibit endogenous GLP-1 breakdown, have become an effective therapeutic strategy for many subjects with type 2 diabetes. Here we review the discovery of GLP-1; its synthesis, secretion, and elimination from the circulation; and its multiple pancreatic and extrapancreatic effects. Finally, we review current options for GLP-1-based diabetes therapy, including GLP-1 receptor agonism and inhibition of GLP-1 breakdown, as well as the benefits and drawbacks of different modes of therapy and the potential for new therapeutic avenues. PMID:24245943

  15. Caffeine and glucose homeostasis during rest and exercise in diabetes mellitus.

    Science.gov (United States)

    Zaharieva, Dessi P; Riddell, Michael C

    2013-08-01

    Caffeine is a substance that has been used in our society for generations, primarily for its effects on the central nervous system that causes wakefulness. Caffeine supplementation has become increasingly more popular as an ergogenic aid for athletes and considerable scientific evidence supports its effectiveness. Because of their potential to alter energy metabolism, the effects of coffee and caffeine on glucose metabolism in diabetes have also been studied both epidemiologically and experimentally. Predominantly targeting the adenosine receptors, caffeine causes alterations in glucose homeostasis by decreasing glucose uptake into skeletal muscle, thereby causing elevations in blood glucose concentration. Caffeine intake has also been proposed to increase symptomatic warning signs of hypoglycemia in patients with type 1 diabetes and elevate blood glucose levels in patients with type 2 diabetes. Other effects include potential increases in glucose counterregulatory hormones such as epinephrine, which can also decrease peripheral glucose disposal. Despite these established physiological effects, increased coffee intake has been associated with reduced risk of developing type 2 diabetes in large-scale epidemiological studies. This review paper highlights the known effects of caffeine on glucose homeostasis and diabetes metabolism during rest and exercise. PMID:23855268

  16. Glucose homeostasis and safety in patients with acromegaly converted from long-acting octreotide to pegvisomant

    NARCIS (Netherlands)

    A.L. Barkan (Ariel); P. Burman (Pia); D.R. Clemmons (David); M.T. Drake (Marcus); R.F. Gagel (Robert); P.E. Harris (Philip); P. Trainer; A-J. van der Lely (Aart-Jan); M.L. Vance

    2005-01-01

    textabstractContext: In clinical practice, patients with acromegaly may be switched from therapy with long-acting somatostatin analogs to pegvisomant. The effect of changing therapies on glucose homeostasis and safety has not been reported. Objectives: The objectives of this study were to monitor ch

  17. Serotonin 2c receptors in pro-opiomelanocortin neurons regulate energy and glucose homeostasis

    Science.gov (United States)

    Energy and glucose homeostasis are regulated by central serotonin 2C receptors. These receptors are attractive pharmacological targets for the treatment of obesity; however, the identity of the serotonin 2C receptor-expressing neurons that mediate the effects of serotonin and serotonin 2C receptor a...

  18. Farnesoid X Receptor Deficiency Improves Glucose Homeostasis in Mouse Models of Obesity

    NARCIS (Netherlands)

    Prawitt, Janne; Abdelkarim, Mouaadh; Stroeve, Johanna H. M.; Popescu, Iuliana; Duez, Helene; Velagapudi, Vidya R.; Dumont, Julie; Bouchaert, Emmanuel; van Dijk, Theo H.; Lucas, Anthony; Dorchies, Emilie; Daoudi, Mehdi; Lestavel, Sophie; Gonzalez, Frank J.; Oresic, Matej; Cariou, Bertrand; Kuipers, Folkert; Caron, Sandrine; Staels, Bart

    2011-01-01

    OBJECTIVE-Bile acids (BA) participate in the maintenance of metabolic homeostasis acting through different signaling pathways. The nuclear BA receptor farnesoid X receptor (FXR) regulates pathways in BA, lipid, glucose, and energy metabolism, which become dysregulated in obesity. However, the role o

  19. Actions of prolonged ghrelin infusion on gastrointestinal transit and glucose homeostasis in humans

    DEFF Research Database (Denmark)

    Falkén, Y; Hellström, P M; Sanger, G J;

    2010-01-01

    Ghrelin is produced by enteroendocrine cells in the gastric mucosa and stimulates gastric emptying in healthy volunteers and patients with gastroparesis in short-term studies. The aim of this study was to evaluate effects of intravenous ghrelin on gastrointestinal motility and glucose homeostasis...... during a 6-h infusion in humans....

  20. Loss of sugar detection by GLUT2 affects glucose homeostasis in mice.

    Directory of Open Access Journals (Sweden)

    Emilie Stolarczyk

    Full Text Available BACKGROUND: Mammals must sense the amount of sugar available to them and respond appropriately. For many years attention has focused on intracellular glucose sensing derived from glucose metabolism. Here, we studied the detection of extracellular glucose concentrations in vivo by invalidating the transduction pathway downstream from the transporter-detector GLUT2 and measured the physiological impact of this pathway. METHODOLOGY/PRINCIPAL FINDINGS: We produced mice that ubiquitously express the largest cytoplasmic loop of GLUT2, blocking glucose-mediated gene expression in vitro without affecting glucose metabolism. Impairment of GLUT2-mediated sugar detection transiently protected transgenic mice against starvation and streptozotocin-induced diabetes, suggesting that both low- and high-glucose concentrations were not detected. Transgenic mice favored lipid oxidation, and oral glucose was slowly cleared from blood due to low insulin production, despite massive urinary glucose excretion. Kidney adaptation was characterized by a lower rate of glucose reabsorption, whereas pancreatic adaptation was associated with a larger number of small islets. CONCLUSIONS/SIGNIFICANCE: Molecular invalidation of sugar sensing in GLUT2-loop transgenic mice changed multiple aspects of glucose homeostasis, highlighting by a top-down approach, the role of membrane glucose receptors as potential therapeutic targets.

  1. Bayesian model discrimination for glucose-insulin homeostasis

    DEFF Research Database (Denmark)

    Andersen, Kim Emil; Brooks, Stephen P.; Højbjerre, Malene

    In this paper we analyse a set of experimental data on a number of healthy and diabetic patients and discuss a variety of models for describing the physiological processes involved in glucose absorption and insulin secretion within the human body. We adopt a Bayesian approach which facilitates...... the reformulation of existing deterministic models as stochastic state space models which properly accounts for both measurement and process variability. The analysis is further enhanced by Bayesian model discrimination techniques and model averaged parameter estimation which fully accounts for model as well...

  2. SRC-2 orchestrates polygenic inputs for fine-tuning glucose homeostasis.

    Science.gov (United States)

    Fleet, Tiffany; Zhang, Bin; Lin, Fumin; Zhu, Bokai; Dasgupta, Subhamoy; Stashi, Erin; Tackett, Bryan; Thevananther, Sundararajah; Rajapakshe, Kimal I; Gonzales, Naomi; Dean, Adam; Mao, Jianqiang; Timchenko, Nikolai; Malovannaya, Anna; Qin, Jun; Coarfa, Cristian; DeMayo, Francesco; Dacso, Clifford C; Foulds, Charles E; O'Malley, Bert W; York, Brian

    2015-11-01

    Despite extensive efforts to understand the monogenic contributions to perturbed glucose homeostasis, the complexity of genetic events that fractionally contribute to the spectrum of this pathology remain poorly understood. Proper maintenance of glucose homeostasis is the central feature of a constellation of comorbidities that define the metabolic syndrome. The ability of the liver to balance carbohydrate uptake and release during the feeding-to-fasting transition is essential to the regulation of peripheral glucose availability. The liver coordinates the expression of gene programs that control glucose absorption, storage, and secretion. Herein, we demonstrate that Steroid Receptor Coactivator 2 (SRC-2) orchestrates a hierarchy of nutritionally responsive transcriptional complexes to precisely modulate plasma glucose availability. Using DNA pull-down technology coupled with mass spectrometry, we have identified SRC-2 as an indispensable integrator of transcriptional complexes that control the rate-limiting steps of hepatic glucose release and accretion. Collectively, these findings position SRC-2 as a major regulator of polygenic inputs to metabolic gene regulation and perhaps identify a previously unappreciated model that helps to explain the clinical spectrum of glucose dysregulation. PMID:26487680

  3. Glucose homeostasis and insulin sensitivity in growth hormone-transgenic mice: a cross-sectional analysis.

    Science.gov (United States)

    Boparai, Ravneet K; Arum, Oge; Khardori, Romesh; Bartke, Andrzej

    2010-10-01

    In contrast to its stimulatory effects on musculature, bone, and organ development, and its lipolytic effects, growth hormone (GH) opposes insulin effects on glucose metabolism. Chronic GH overexposure is thought to result in insulin insensitivity and decreased blood glucose homeostatic control. Yet, despite the importance of this concept for basic biology, as well as human conditions of GH excess or deficiency, no systematic assessment of the impact of GH over- expression on glucose homeostasis and insulin sensitivity has been conducted. We report that male and female adult GH transgenic mice have enhanced glucose tolerance compared to littermate controls and this effect is not dependent on age or on the particular heterologous GH transgene used. Furthermore, increased glucose-stimulated insulin secretion, augmented insulin sensitivity, and muted gluconeogenesis were also observed in bovine GH overexpressing mice. These results show that markedly increased systemic GH concentration in GH-transgenic mice exerts unexpected beneficial effects on glucose homeostasis, presumably via a compensatory increase in insulin release. The counterintuitive nature of these results challenges previously held presumptions of the physiology of these mice and other states of GH overexpression or suppression. In addition, they pose intriguing queries about the relationships between GH, endocrine control of metabolism, and aging. PMID:20707609

  4. TCF7L2 involvement in estradiol- and progesterone-modulated islet and hepatic glucose homeostasis.

    Science.gov (United States)

    Dong, Fengqin; Ling, Qi; Ye, Dan; Zhang, Zhe; Shu, Jing; Chen, Guoping; Fei, Yang; Li, Chengjiang

    2016-01-01

    To evaluate the role of TCF7L2, a key regulator of glucose homeostasis, in estradiol (E2) and progesterone (P4)-modulated glucose metabolism, mouse insulinoma cells (MIN6) and human liver cancer cells (hepG2 and HUH7) were treated with physiological concentrations of E2 or P4 in the up- and down-regulation of TCF7L2. Insulin/proinsulin secretion was measured in MIN6 cells, while glucose uptake and production were evaluated in liver cancer cells. E2 increased insulin/proinsulin secretion under both basal and stimulated conditions, whereas P4 increased insulin/proinsulin secretion only under glucose-stimulated conditions. An antagonistic effect, possibly concentration-dependent, of E2 and P4 on the regulation of islet glucose metabolism was observed. After E2 or P4 treatment, secretion of insulin/proinsulin was positively correlated with TCF7L2 protein expression. When TCF7L2 was silenced, E2- or P4-promoted insulin/proinsulin secretion was significantly weakened. Under glucotoxicity conditions, overexpression of TCF7L2 increased insulin secretion and processing. In liver cancer cells, E2 or P4 exposure elevated TCF7L2 expression, enhanced the activity of insulin signaling (pAKT/pGSK), reduced PEPCK expression, subsequently increased insulin-stimulated glucose uptake, and decreased glucose production. Silencing TCF7L2 eliminated effects of E2 or P4. In conclusion, TCF7L2 regulates E2- or P4-modulated islet and hepatic glucose metabolism. The results have implications for glucose homeostasis in pregnancy. PMID:27108846

  5. Oxygen glucose deprivation in rat hippocampal slice cultures results in alterations in carnitine homeostasis and mitochondrial dysfunction.

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    Thomas F Rau

    Full Text Available Mitochondrial dysfunction characterized by depolarization of mitochondrial membranes and the initiation of mitochondrial-mediated apoptosis are pathological responses to hypoxia-ischemia (HI in the neonatal brain. Carnitine metabolism directly supports mitochondrial metabolism by shuttling long chain fatty acids across the inner mitochondrial membrane for beta-oxidation. Our previous studies have shown that HI disrupts carnitine homeostasis in neonatal rats and that L-carnitine can be neuroprotective. Thus, this study was undertaken to elucidate the molecular mechanisms by which HI alters carnitine metabolism and to begin to elucidate the mechanism underlying the neuroprotective effect of L-carnitine (LCAR supplementation. Utilizing neonatal rat hippocampal slice cultures we found that oxygen glucose deprivation (OGD decreased the levels of free carnitines (FC and increased the acylcarnitine (AC: FC ratio. These changes in carnitine homeostasis correlated with decreases in the protein levels of carnitine palmitoyl transferase (CPT 1 and 2. LCAR supplementation prevented the decrease in CPT1 and CPT2, enhanced both FC and the AC∶FC ratio and increased slice culture metabolic viability, the mitochondrial membrane potential prior to OGD and prevented the subsequent loss of neurons during later stages of reperfusion through a reduction in apoptotic cell death. Finally, we found that LCAR supplementation preserved the structural integrity and synaptic transmission within the hippocampus after OGD. Thus, we conclude that LCAR supplementation preserves the key enzymes responsible for maintaining carnitine homeostasis and preserves both cell viability and synaptic transmission after OGD.

  6. Bone morphogenetic proteins in inflammation, glucose homeostasis and adipose tissue energy metabolism

    DEFF Research Database (Denmark)

    Grgurevic, Lovorka; Christensen, Gitte Lund; Schulz, Tim J;

    2016-01-01

    implicated in pancreas development as well as control of adult glucose homeostasis. Lastly, we review the recently recognized role of BMPs in brown adipose tissue formation and their consequences for energy expenditure and adiposity. In summary, BMPs play a pivotal role in metabolism beyond their role...... homeostasis (anaemia, hemochromatosis) and oxidative damage. The second and third parts of this review focus on BMPs in the development of metabolic pathologies such as type-2 diabetes mellitus and obesity. The pancreatic beta cells are the sole source of the hormone insulin and BMPs have recently been...... in skeletal homeostasis. However, increased understanding of these pleiotropic functions also highlights the necessity of tissue-specific strategies when harnessing BMP action as a therapeutic target....

  7. INSIG2 SNPS ASSOCIATED WITH OBESITY & GLUCOSE HOMEOSTASIS TRAITS IN HISPANICS: THE IRAS FAMILY STUDY

    OpenAIRE

    Talbert, Matthew E.; Langefeld, Carl D.; Ziegler, Julie; Haffner, Steven M.; Norris, Jill M.; Donald W Bowden

    2009-01-01

    The genome-wide association study by Herbert and colleagues identified the INSIG2 single nucleotide polymorphism (SNP) rs7566605 as contributing to increased BMI in ethnically distinct cohorts. The present study sought to further clarify by testing whether SNPs of INSIG2 influenced quantitative adiposity or glucose homeostasis traits in Hispanics of the Insulin Resistance Atherosclerosis Family Study (IRASFS). Using a tagging SNP approach, rs7566605 and 31 additional SNPs were genotyped in 14...

  8. Revisiting “Vegetables” to combat modern epidemic of imbalanced glucose homeostasis

    OpenAIRE

    Ashok Kumar Tiwari

    2014-01-01

    Vegetables have been part of human food since prehistoric times and are considered nutritionally necessary and good for health. Vegetables are rich natural resource of biological antioxidants and possess capabilities of maintaining glucose homeostasis. When taken before starch-rich diet, juice also of vegetables such as ridge gourd, bottle gourd, ash gourd, chayote and juice of leaves of vegetables such as radish, Indian Dill, ajwain, tropical green amaranth, and bladder dock are reported to ...

  9. Perk gene dosage regulates glucose homeostasis by modulating pancreatic β-cell functions.

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    Rong Wang

    Full Text Available Insulin synthesis and cell proliferation are under tight regulation in pancreatic β-cells to maintain glucose homeostasis. Dysfunction in either aspect leads to development of diabetes. PERK (EIF2AK3 loss of function mutations in humans and mice exhibit permanent neonatal diabetes that is characterized by insufficient β-cell mass and reduced proinsulin trafficking and insulin secretion. Unexpectedly, we found that Perk heterozygous mice displayed lower blood glucose levels.Longitudinal studies were conducted to assess serum glucose and insulin, intracellular insulin synthesis and storage, insulin secretion, and β-cell proliferation in Perk heterozygous mice. In addition, modulation of Perk dosage specifically in β-cells showed that the glucose homeostasis phenotype of Perk heterozygous mice is determined by reduced expression of PERK in the β-cells.We found that Perk heterozygous mice first exhibited enhanced insulin synthesis and secretion during neonatal and juvenile development followed by enhanced β-cell proliferation and a substantial increase in β-cell mass at the adult stage. These differences are not likely to entail the well-known function of PERK to regulate the ER stress response in cultured cells as several markers for ER stress were not differentially expressed in Perk heterozygous mice.In addition to the essential functions of PERK in β-cells as revealed by severely diabetic phenotype in humans and mice completely deficient for PERK, reducing Perk gene expression by half showed that intermediate levels of PERK have a profound impact on β-cell functions and glucose homeostasis. These results suggest that an optimal level of PERK expression is necessary to balance several parameters of β-cell function and growth in order to achieve normoglycemia.

  10. Leptin Is Required for Glucose Homeostasis after Roux-en-Y Gastric Bypass in Mice.

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    Mohamad Mokadem

    Full Text Available Leptin, the protein product of the ob gene, increases energy expenditure and reduces food intake, thereby promoting weight reduction. Leptin also regulates glucose homeostasis and hepatic insulin sensitivity via hypothalamic proopiomelanocortin neurons in mice. Roux-en-Y gastric bypass (RYGB induces weight loss that is substantial and sustained despite reducing plasma leptin levels. In addition, patients who fail to undergo diabetes remission after RYGB are hypoletinemic compared to those who do and to lean controls. We have previously demonstrated that the beneficial effects of RYGB in mice require the melanocortin-4 receptor, a downstream effector of leptin action. Based on these observations, we hypothesized that leptin is required for sustained weight reduction and improved glucose homeostasis observed after RYGB.To investigate this hypothesis, we performed RYGB or sham operations on leptin-deficient ob/ob mice maintained on regular chow. To investigate whether leptin is involved in post-RYGB weight maintenance, we challenged post-surgical mice with high fat diet.RYGB reduced total body weight, fat and lean mass and caused reduction in calorie intake in ob/ob mice. However, it failed to improve glucose tolerance, glucose-stimulated plasma insulin, insulin tolerance, and fasting plasma insulin. High fat diet eliminated the reduction in calorie intake observed after RYGB in ob/ob mice and promoted weight regain, although not to the same extent as in sham-operated mice. We conclude that leptin is required for the effects of RYGB on glucose homeostasis but not body weight or composition in mice. Our data also suggest that leptin may play a role in post-RYGB weight maintenance.

  11. Sugar for the brain: the role of glucose in physiological and pathological brain function

    OpenAIRE

    Mergenthaler, Philipp; Lindauer, Ute; Dienel, Gerald A; Meisel, Andreas

    2013-01-01

    The mammalian brain depends upon glucose as its main source of energy, and tight regulation of glucose metabolism is critical for brain physiology. Consistent with its critical role for physiological brain function, disruption of normal glucose metabolism as well as its interdependence with cell death pathways forms the pathophysiological basis for many brain disorders. Here, we review recent advances in understanding how glucose metabolism sustains basic brain physiology. We aim at synthesiz...

  12. CD14 deficiency impacts glucose homeostasis in mice through altered adrenal tone.

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    James L Young

    Full Text Available The toll-like receptors comprise one of the most conserved components of the innate immune system, signaling the presence of molecules of microbial origin. It has been proposed that signaling through TLR4, which requires CD14 to recognize bacterial lipopolysaccharide (LPS, may generate low-grade inflammation and thereby affect insulin sensitivity and glucose metabolism. To examine the long-term influence of partial innate immune signaling disruption on glucose homeostasis, we analyzed knockout mice deficient in CD14 backcrossed into the diabetes-prone C57BL6 background at 6 or 12 months of age. CD14-ko mice, fed either normal or high-fat diets, displayed significant glucose intolerance compared to wild type controls. They also displayed elevated norepinephrine urinary excretion and increased adrenal medullary volume, as well as an enhanced norepinephrine secretory response to insulin-induced hypoglycemia. These results point out a previously unappreciated crosstalk between innate immune- and sympathoadrenal- systems, which exerts a major long-term effect on glucose homeostasis.

  13. Heritability of phenotypes associated with glucose homeostasis and adiposity in a rural area of Brazil.

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    Pena, Geórgia G; Dutra, Míriam Santos; Gazzinelli, Andrea; Corrêa-Oliveira, Rodrigo; Velasquez-Melendez, Gustavo

    2014-01-01

    We aimed to estimate the heritability and genetic correlation between glucose homeostasis and adiposity traits in a population in a rural community in Brazil. The Jequitinhonha Community Family Study cohort consists of subjects aged ≥18 years residing in rural areas in Brazil. The data on the following traits were assembled for 280 individuals (51.7% women): body mass index (BMI), body fat percentage, waist and mid-upper arm circumferences, triceps skinfold, conicity index, insulin, glucose, high-density lipoprotein cholesterol (HDLc), triglycerides and C-reactive protein. Extended pedigrees were constructed up to the third generation of individuals using the data management software PEDSYS. The heritability and genetic correlations were estimated using a variance component method. The age- and sex-adjusted heritability values estimated for insulin (h(2) = 52%), glucose (h(2) = 51%), HDLc (h(2) = 58%), and waist circumference (WC; h(2) = 49%) were high. Significantly adjusted genetic correlations were observed between insulin paired with each of the following phenotypes; (BMI; ρg = 0.48), WC (ρg = 0.47) and HDLc (ρg = -0.47). The homeostasis model assessment of insulin resistance (HOMA-IR) was genetically correlated with BMI (ρg = 0.53) and HDLc (ρg = -0.58). The adjusted genetic correlations between traits were consistently higher compared with the environmental correlations. In conclusion, glucose metabolism and adiposity traits are highly heritable and share common genetic effects with body adiposity traits. PMID:24359477

  14. Heritability of phenotypes associated with glucose homeostasis and adiposity in a rural area of Brazil.

    Science.gov (United States)

    Pena, Geórgia G; Dutra, Míriam Santos; Gazzinelli, Andrea; Corrêa-Oliveira, Rodrigo; Velasquez-Melendez, Gustavo

    2014-01-01

    We aimed to estimate the heritability and genetic correlation between glucose homeostasis and adiposity traits in a population in a rural community in Brazil. The Jequitinhonha Community Family Study cohort consists of subjects aged ≥18 years residing in rural areas in Brazil. The data on the following traits were assembled for 280 individuals (51.7% women): body mass index (BMI), body fat percentage, waist and mid-upper arm circumferences, triceps skinfold, conicity index, insulin, glucose, high-density lipoprotein cholesterol (HDLc), triglycerides and C-reactive protein. Extended pedigrees were constructed up to the third generation of individuals using the data management software PEDSYS. The heritability and genetic correlations were estimated using a variance component method. The age- and sex-adjusted heritability values estimated for insulin (h(2) = 52%), glucose (h(2) = 51%), HDLc (h(2) = 58%), and waist circumference (WC; h(2) = 49%) were high. Significantly adjusted genetic correlations were observed between insulin paired with each of the following phenotypes; (BMI; ρg = 0.48), WC (ρg = 0.47) and HDLc (ρg = -0.47). The homeostasis model assessment of insulin resistance (HOMA-IR) was genetically correlated with BMI (ρg = 0.53) and HDLc (ρg = -0.58). The adjusted genetic correlations between traits were consistently higher compared with the environmental correlations. In conclusion, glucose metabolism and adiposity traits are highly heritable and share common genetic effects with body adiposity traits.

  15. Transcriptional activation of glutathione pathways and role of glucose homeostasis during copper imbalance.

    Science.gov (United States)

    Quiroz, Natalia; Rivas, Nicole; del Pozo, Talía; Burkhead, Jason; Suazo, Miriam; González, Mauricio; Latorre, Mauricio

    2015-04-01

    Copper is an essential micronutrient for organism health. Dietary changes or pathologies linked to this metal induce changes in intracellular glutathione concentrations. Here, we studied the transcriptional activation of glutathione pathways in Jurkat cell lines, analyzing the effect of change in glucose homeostasis during a physiological and supra-physiological copper exposure. An immortalized line of human T lymphocyte cell line (Jurkat) was exposed to different copper and glucose conditions to mimic concentrations present in human blood. We applied treatments for 6 (acute) and 24 h (sustained) to 2 µM (physiological) or 20 µM (supra-physiological, Wilson disease scenario) of CuSO4 in combination with 25 mg/dL (hypoglycemia), 100 mg/dL (normal) and 200 mg/dL (hyperglycemia, diabetes scenario) of glucose. The results indicate that a physiological concentration of copper exposure does not induce transcriptional changes in the glutathione synthesis pathway after 6 or 24 h. The G6PDH gene (regeneration pathway), however, is induced during a supra-physiological copper condition. This data was correlated with the viability assays, where fluctuation in both glucose conditions (hypo and hyperglycemia scenario) affected Jurkat proliferation when 20 µM of CuSO4 was added to the culture media. Under a copper overload condition, the transcription of a component of glutathione regeneration pathway (G6PDH gene) is activated in cells chronically exposed to a hyperglycemia scenario, indicating that fluctuations in glucose concentration impact the resistance against the metal. Our findings illustrate the importance of glucose homeostasis during copper excess.

  16. Interactive effects of neonatal exposure to monosodium glutamate and aspartame on glucose homeostasis

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    Collison Kate S

    2012-06-01

    Full Text Available Abstract Background Recent evidence suggests that the effects of certain food additives may be synergistic or additive. Aspartame (ASP and Monosodium Glutamate (MSG are ubiquitous food additives with a common moiety: both contain acidic amino acids which can act as neurotransmitters, interacting with NMDA receptors concentrated in areas of the Central Nervous System regulating energy expenditure and conservation. MSG has been shown to promote a neuroendocrine dysfunction when large quantities are administered to mammals during the neonatal period. ASP is a low-calorie dipeptide sweetener found in a wide variety of diet beverages and foods. However, recent reports suggest that ASP may promote weight gain and hyperglycemia in a zebrafish nutritional model. Methods We investigated the effects of ASP, MSG or a combination of both on glucose and insulin homeostasis, weight change and adiposity, in C57BL/6 J mice chronically exposed to these food additives commencing in-utero, compared to an additive-free diet. Pearson correlation analysis was used to investigate the associations between body characteristics and variables in glucose and insulin homeostasis. Results ASP alone (50 mg/Kgbw/day caused an increase in fasting blood glucose of 1.6-fold, together with reduced insulin sensitivity during an Insulin Tolerance Test (ITT P  Conclusions Aspartame exposure may promote hyperglycemia and insulin intolerance. MSG may interact with aspartame to further impair glucose homeostasis. This is the first study to ascertain the hyperglycemic effects of chronic exposure to a combination of these commonly consumed food additives; however these observations are limited to a C57BL/6 J mouse model. Caution should be applied in extrapolating these findings to other species.

  17. Helicobacter pylori colonization ameliorates glucose homeostasis in mice through a PPAR γ-dependent mechanism.

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    Josep Bassaganya-Riera

    Full Text Available BACKGROUND: There is an inverse secular trend between the incidence of obesity and gastric colonization with Helicobacter pylori, a bacterium that can affect the secretion of gastric hormones that relate to energy homeostasis. H. pylori strains that carry the cag pathogenicity island (PAI interact more intimately with gastric epithelial cells and trigger more extensive host responses than cag(- strains. We hypothesized that gastric colonization with H. pylori strains differing in cag PAI status exert distinct effects on metabolic and inflammatory phenotypes. METHODOLOGY/PRINCIPAL FINDINGS: To test this hypothesis, we examined metabolic and inflammatory markers in db/db mice and mice with diet-induced obesity experimentally infected with isogenic forms of H. pylori strain 26695: the cag PAI wild-type and its cag PAI mutant strain 99-305. H. pylori colonization decreased fasting blood glucose levels, increased levels of leptin, improved glucose tolerance, and suppressed weight gain. A response found in both wild-type and mutant H. pylori strain-infected mice included decreased white adipose tissue macrophages (ATM and increased adipose tissue regulatory T cells (Treg cells. Gene expression analyses demonstrated upregulation of gastric PPAR γ-responsive genes (i.e., CD36 and FABP4 in H. pylori-infected mice. The loss of PPAR γ in immune and epithelial cells in mice impaired the ability of H. pylori to favorably modulate glucose homeostasis and ATM infiltration during high fat feeding. CONCLUSIONS/SIGNIFICANCE: Gastric infection with some commensal strains of H. pylori ameliorates glucose homeostasis in mice through a PPAR γ-dependent mechanism and modulates macrophage and Treg cell infiltration into the abdominal white adipose tissue.

  18. p21-Activated protein kinases and their emerging roles in glucose homeostasis.

    Science.gov (United States)

    Chiang, Yu-ting Alex; Jin, Tianru

    2014-04-01

    p21-Activated protein kinases (PAKs) are centrally involved in a plethora of cellular processes and functions. Their function as effectors of small GTPases Rac1 and Cdc42 has been extensively studied during the past two decades, particularly in the realms of cell proliferation, apoptosis, and hence tumorigenesis, as well as cytoskeletal remodeling and related cellular events in health and disease. In recent years, a large number of studies have shed light onto the fundamental role of group I PAKs, most notably PAK1, in metabolic homeostasis. In skeletal muscle, PAK1 was shown to mediate the function of insulin on stimulating GLUT4 translocation and glucose uptake, while in pancreatic β-cells, PAK1 participates in insulin granule localization and vesicle release. Furthermore, we demonstrated that PAK1 mediates the cross talk between insulin and Wnt/β-catenin signaling pathways and hence regulates gut proglucagon gene expression and the production of the incretin hormone glucagon-like peptide-1 (GLP-1). The utilization of chemical inhibitors of PAK and the characterization of Pak1(-/-) mice enabled us to gain mechanistic insights as well as to assess the overall contribution of PAKs in metabolic homeostasis. This review summarizes our current understanding of PAKs, with an emphasis on the emerging roles of PAK1 in glucose homeostasis.

  19. Parameters of glucose metabolism and the aging brain

    DEFF Research Database (Denmark)

    Akintola, Abimbola A; van den Berg, Annette; Altmann-Schneider, Irmhild;

    2015-01-01

    Given the concurrent, escalating epidemic of diabetes mellitus and neurodegenerative diseases, two age-related disorders, we aimed to understand the relation between parameters of glucose metabolism and indices of pathology in the aging brain. From the Leiden Longevity Study, 132 participants (mean...... different parameters of glucose metabolism (impairment of which is characteristic of diabetes mellitus) and brain aging....... age 66 years) underwent a 2-h oral glucose tolerance test to assess glucose tolerance (fasted and area under the curve (AUC) glucose), insulin sensitivity (fasted and AUC insulin and homeostatic model assessment of insulin sensitivity (HOMA-IS)) and insulin secretion (insulinogenic index). 3-T brain...

  20. Altered glucose homeostasis and hepatic function in obese mice deficient for both kinin receptor genes.

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    Carlos C Barros

    Full Text Available The Kallikrein-Kinin System (KKS has been implicated in several aspects of metabolism, including the regulation of glucose homeostasis and adiposity. Kinins and des-Arg-kinins are the major effectors of this system and promote their effects by binding to two different receptors, the kinin B2 and B1 receptors, respectively. To understand the influence of the KKS on the pathophysiology of obesity and type 2 diabetes (T2DM, we generated an animal model deficient for both kinin receptor genes and leptin (obB1B2KO. Six-month-old obB1B2KO mice showed increased blood glucose levels. Isolated islets of the transgenic animals were more responsive to glucose stimulation releasing greater amounts of insulin, mainly in 3-month-old mice, which was corroborated by elevated serum C-peptide concentrations. Furthermore, they presented hepatomegaly, pronounced steatosis, and increased levels of circulating transaminases. This mouse also demonstrated exacerbated gluconeogenesis during the pyruvate challenge test. The hepatic abnormalities were accompanied by changes in the gene expression of factors linked to glucose and lipid metabolisms in the liver. Thus, we conclude that kinin receptors are important for modulation of insulin secretion and for the preservation of normal glucose levels and hepatic functions in obese mice, suggesting a protective role of the KKS regarding complications associated with obesity and T2DM.

  1. Perinatal bisphenol A exposure and adult glucose homeostasis: identifying critical windows of exposure.

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    Jingli Liu

    Full Text Available Bisphenol A (BPA is a widespread endocrine-disrupting chemical used as the building block for polycarbonate plastics. Epidemiological evidence has correlated BPA exposure with higher risk of heart disease and type 2 diabetes. However, it remains unknown whether there are critical windows of susceptibility to BPA exposure on the development of dysglycemia. This study was an attempt to investigate the critical windows and the long-term consequences of perinatal exposure to BPA on glucose homeostasis. Pregnant mice were given either vehicle or BPA (100 µg/kg/day at different time of perinatal stage: 1 on days 1-6 of pregnancy (P1-P6, preimplantation exposure; 2 from day 6 of pregnancy until postnatal day (PND 0 (P6-PND0, fetal exposure; 3 from lactation until weaning (PND0-PND21, neonatal exposure; and 4 from day 6 of gestation until weaning (P6-PND21, fetal and neonatal exposure. At 3, 6 and 8 months of age, offspring in each group were challenged with glucose and insulin tolerance tests. Then islet morphometry and β-cell function were measured. The glucose homeostasis was impaired in P6-PND0 mice from 3 to 6 months of age, and this continued to 8 months in males, but not females. While in PND0-PND21 and P6-PND21 BPA-treated groups, only the 3-month-old male offspring developed glucose intolerance. Moreover, at the age of 3 months, perinatal exposure to BPA resulted in the increase of β-cell mass mainly due to the coordinate changes in cell replication, neogenesis, and apoptosis. The alterations of insulin secretion and insulin sensitivity, rather than β-cell mass, were consistent with the development of glucose intolerance. Our findings suggest that BPA may contribute to metabolic disorders relevant to glucose homeostasis and the effects of BPA were dose, sex, and time-dependent. Fetal development stage may be the critical window of susceptibility to BPA exposure.

  2. Adipocyte-specific protein tyrosine phosphatase 1B deletion increases lipogenesis, adipocyte cell size and is a minor regulator of glucose homeostasis.

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    Carl Owen

    Full Text Available Protein tyrosine phosphatase 1B (PTP1B, a key negative regulator of leptin and insulin signaling, is positively correlated with adiposity and contributes to insulin resistance. Global PTP1B deletion improves diet-induced obesity and glucose homeostasis via enhanced leptin signaling in the brain and increased insulin signaling in liver and muscle. However, the role of PTP1B in adipocytes is unclear, with studies demonstrating beneficial, detrimental or no effect(s of adipose-PTP1B-deficiency on body mass and insulin resistance. To definitively establish the role of adipocyte-PTP1B in body mass regulation and glucose homeostasis, adipocyte-specific-PTP1B knockout mice (adip-crePTP1B(-/- were generated using the adiponectin-promoter to drive Cre-recombinase expression. Chow-fed adip-crePTP1B(-/- mice display enlarged adipocytes, despite having similar body weight/adiposity and glucose homeostasis compared to controls. High-fat diet (HFD-fed adip-crePTP1B(-/- mice display no differences in body weight/adiposity but exhibit larger adipocytes, increased circulating glucose and leptin levels, reduced leptin sensitivity and increased basal lipogenesis compared to controls. This is associated with decreased insulin receptor (IR and Akt/PKB phosphorylation, increased lipogenic gene expression and increased hypoxia-induced factor-1-alpha (Hif-1α expression. Adipocyte-specific PTP1B deletion does not beneficially manipulate signaling pathways regulating glucose homeostasis, lipid metabolism or adipokine secretion in adipocytes. Moreover, PTP1B does not appear to be the major negative regulator of the IR in adipocytes.

  3. Modulation of proinsulin messenger RNA after partial pancreatectomy in rats. Relationships to glucose homeostasis.

    OpenAIRE

    Orland, M. J.; Chyn, R; Permutt, M A

    1985-01-01

    These studies of partial pancreatectomy assess pancreatic proinsulin messenger RNA (mRNA) levels as an index of in vivo insulin biosynthesis, and show relationships to glucose homeostasis. Rats were subjected to sham operation, 50% pancreatectomy (Px), or 90% Px, and were examined after 1, 3, or 14 wk. Proinsulin mRNA was measured by dot hybridization to complementary DNA. After 50% Px there was a nearly complete adaptation of proinsulin mRNA. After 90% Px a marked increase of proinsulin mRNA...

  4. Homeostasis

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    Anna Negroni

    2015-01-01

    Full Text Available Intestinal epithelial cells (IECs form a physiochemical barrier that separates the intestinal lumen from the host’s internal milieu and is critical for electrolyte passage, nutrient absorption, and interaction with commensal microbiota. Moreover, IECs are strongly involved in the intestinal mucosal inflammatory response as well as in mucosal innate and adaptive immune responses. Cell death in the intestinal barrier is finely controlled, since alterations may lead to severe disorders, including inflammatory diseases. The emerging picture indicates that intestinal epithelial cell death is strictly related to the maintenance of tissue homeostasis. This review is focused on previous reports on different forms of cell death in intestinal epithelium.

  5. Lak of influence of glucagon on glucose homeostasis after prolonged exercise in rats

    DEFF Research Database (Denmark)

    Galbo, H; Richter, Erik; Holst, J J;

    1977-01-01

    in plasma throughout. Nevertheless, all other parameters measured showed similar changes in the two groups. Thus after exercise the grossly diminished hepatic glycogen concentrations remained constant, while the decreased blood glucose concentrations were partially restored. Simultaneously concentrations......The significance of glucagon for post-exercise glucose homeostasis has been studied in rats fasted overnight. Immediately after exhaustive swimming either rabbit-antiglucagon serum or normal rabbit serum was injected by cardiac puncture. Cardiac blood and samples of liver and muscle tissue were...... collected before exercise and repeatedly during a 120 min recovery period after exercise. During the post-exercise period plasma glucagon concentrations decreased but remained above pre-exercise values in rats treated with normal serum, while rats treated with antiglucagon serum has excess antibody...

  6. Involvement of IL-1 in the Maintenance of Masseter Muscle Activity and Glucose Homeostasis.

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    Ko Chiba

    Full Text Available Physical exercise reportedly stimulates IL-1 production within working skeletal muscles, but its physiological significance remains unknown due to the existence of two distinct IL-1 isoforms, IL-1α and IL-1β. The regulatory complexities of these two isoforms, in terms of which cells in muscles produce them and their distinct/redundant biological actions, have yet to be elucidated. Taking advantage of our masticatory behavior (Restrained/Gnawing model, we herein show that IL-1α/1β-double-knockout (IL-1-KO mice exhibit compromised masseter muscle (MM activity which is at least partially attributable to abnormalities of glucose handling (rapid glycogen depletion along with impaired glucose uptake and dysfunction of IL-6 upregulation in working MMs. In wild-type mice, masticatory behavior clearly increased IL-1β mRNA expression but no incremental protein abundance was detectable in whole MM homogenates, whereas immunohistochemical staining analysis revealed that both IL-1α- and IL-1β-immunopositive cells were recruited around blood vessels in the perimysium of MMs after masticatory behavior. In addition to the aforementioned phenotype of IL-1-KO mice, we found the IL-6 mRNA and protein levels in MMs after masticatory behavior to be significantly lower in IL-1-KO than in WT. Thus, our findings confirm that the locally-increased IL-1 elicited by masticatory behavior, although present small in amounts, contributes to supporting MM activity by maintaining normal glucose homeostasis in these muscles. Our data also underscore the importance of IL-1-mediated local interplay between autocrine myokines including IL-6 and paracrine cytokines in active skeletal muscles. This interplay is directly involved in MM performance and fatigability, perhaps mediated through maintaining muscular glucose homeostasis.

  7. Glucose homeostasis in Egyptian children and adolescents with β-Thalassemia major: Relationship to oxidative stress

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    Kotb Abbass Metwalley

    2014-01-01

    Full Text Available Background: Oxidative stress in children with β-thalassemia may contribute to shortened life span of erythrocytes and endocrinal abnormalities. Aim: This study was aimed to evaluate glucose homeostasis in Egyptian children and adolescents with β-thalassemia major and its relation to oxidative stress. Materials and Methods: Sixty children and adolescents with β-thalassemia major were studied in comparison to 30 healthy age and sex-matched subjects. Detailed medical history, thorough clinical examination, and laboratory assessment of oral glucose tolerance test (OGTT, serum ferritin, alanine transferase (ALT, fasting insulin levels, plasma malondialdehyde (MDA as oxidant marker and serum total antioxidants capacity (TAC were performed. Patients were divided into two groups according to the presence of abnormal OGTT. Results: The prevalence of diabetes was 5% (3 of 60 and impaired glucose tolerance test (IGT was 8% (5 of 60. Fasting blood glucose, 2-hour post-load plasma glucose, serum ferritin, ALT, fasting insulin level, homeostatic model assessment for insulin resistance index (HOMA-IR and MDA levels were significantly elevated while TAC level was significantly decreased in thalassemic patients compared with healthy controls (P < 0.001 for each. The difference was more evident in patients with abnormal OGTT than those with normal oral glucose tolerance (P < 0.001 for each. We also observed that thalassemic patients not receiving or on irregular chelation therapy had significantly higher fasting, 2-h post-load plasma glucose, serum ferritin, ALT, fasting insulin, HOMA-IR, oxidative stress markers OSI and MDA levels and significantly lower TAC compared with either those on regular chelation or controls. HOMA-IR was positively correlated with age, serum ferritin, ALT, MDA, and negatively correlated with TAC. Conclusions: The development of abnormal glucose tolerance in Egyptian children and adolescents with β--thalassemia is associated with

  8. Perfluorooctanoic acid exposure for 28 days affects glucose homeostasis and induces insulin hypersensitivity in mice

    Science.gov (United States)

    Yan, Shengmin; Zhang, Hongxia; Zheng, Fei; Sheng, Nan; Guo, Xuejiang; Dai, Jiayin

    2015-06-01

    Perfluoroalkyl acids (PFAAs) are widely used in many applications due to their unique physical and chemical characteristics. Because of the increasing prevalence of metabolic syndromes, including obesity, dyslipidemia and insulin resistance, concern has arisen about the roles of environmental pollutants in such diseases. Earlier epidemiologic studies showed a potential association between perfluorooctanoic acid (PFOA) and glucose metabolism, but how PFOA influences glucose homeostasis is still unknown. Here, we report on the modulation of the phosphatidylinositol 3-kinase-serine/threonine protein kinase (PI3K-AKT) signaling pathway in the livers of mice after 28 d of exposure to PFOA. Compared with normal mice, PFOA exposure significantly decreased the expression of the phosphatase and tensin homologue (PTEN) protein and affected the PI3K-AKT signaling pathway in the liver. Tolerance tests further indicated that PFOA exposure induced higher insulin sensitivity and glucose tolerance in mice. Biochemical analysis revealed that PFOA exposure reduced hepatic glycogen synthesis, which might be attributed to gluconeogenesis inhibition. The levels of several circulating proteins were altered after PFOA exposure, including proteins potentially related to diabetes and liver disease. Our results suggest that PFOA affected glucose metabolism and induced insulin hypersensitivity in mice.

  9. Cigarette smoking and brain regulation of energy homeostasis

    Directory of Open Access Journals (Sweden)

    Hui eChen

    2012-07-01

    Full Text Available Cigarette smoking is an addictive behaviour, and is the primary cause of cardiovascular and pulmonary disease, and cancer (among other diseases. Cigarette smoke contains thousands of components that may affect caloric intake and energy expenditure, although nicotine is the major addictive substance present, and has the best described actions. Nicotine exposure from cigarette smoke can change brain feeding regulation to reduce appetite via both energy homeostatic and reward mechanisms, causing a negative energy state which is characterized by reduced energy intake and increased energy expenditure that are linked to low body weight. These findings have led to the public perception that smoking is associated with weight loss. However, its effects at reducing abdominal fat mass (a predisposing factor for glucose intolerance and insulin resistance are marginal, and its promotion of lean body mass loss in animal studies suggests a limited potential for treatment in obesity. Smoking during pregnancy puts pressure on the mother’s metabolic system and is a significant contributor to adverse pregnancy outcomes. Smoking is a predictor of future risk for respiratory dysfunction, social behavioral problems, cardiovascular disease, obesity and type-2 diabetes. Catch-up growth is normally observed in children exposed to intrauterine smoke, which has been linked to subsequent childhood obesity. Nicotine can have a profound impact on the developing fetal brain, via its ability to rapidly and fully pass the placenta. In animal studies this has been linked with abnormal hypothalamic gene expression of appetite regulators such as downregulation of NPY and POMC in the arcuate nucleus of the hypothalamus. Maternal smoking or nicotine replacement leads to unhealthy eating habits (such as junk food addiction and other behavioral disorders in the offspring.

  10. Effects of sodium benzoate, a widely used food preservative, on glucose homeostasis and metabolic profiles in humans.

    Science.gov (United States)

    Lennerz, Belinda S; Vafai, Scott B; Delaney, Nigel F; Clish, Clary B; Deik, Amy A; Pierce, Kerry A; Ludwig, David S; Mootha, Vamsi K

    2015-01-01

    Sodium benzoate is a widely used preservative found in many foods and soft drinks. It is metabolized within mitochondria to produce hippurate, which is then cleared by the kidneys. We previously reported that ingestion of sodium benzoate at the generally regarded as safe (GRAS) dose leads to a robust excursion in the plasma hippurate level [1]. Since previous reports demonstrated adverse effects of benzoate and hippurate on glucose homeostasis in cells and in animal models, we hypothesized that benzoate might represent a widespread and underappreciated diabetogenic dietary exposure in humans. Here, we evaluated whether acute exposure to GRAS levels of sodium benzoate alters insulin and glucose homeostasis through a randomized, controlled, cross-over study of 14 overweight subjects. Serial blood samples were collected following an oral glucose challenge, in the presence or absence of sodium benzoate. Outcome measurements included glucose, insulin, glucagon, as well as temporal mass spectrometry-based metabolic profiles. We did not find a statistically significant effect of an acute oral exposure to sodium benzoate on glucose homeostasis. Of the 146 metabolites targeted, four changed significantly in response to benzoate, including the expected rise in benzoate and hippurate. In addition, anthranilic acid, a tryptophan metabolite, exhibited a robust rise, while acetylglycine dropped. Although our study shows that GRAS doses of benzoate do not have an acute, adverse effect on glucose homeostasis, future studies will be necessary to explore the metabolic impact of chronic benzoate exposure.

  11. Sex-Related Differences in the Effects of the Mediterranean Diet on Glucose and Insulin Homeostasis

    Directory of Open Access Journals (Sweden)

    Alexandra Bédard

    2014-01-01

    Full Text Available Objective. To document sex differences in the impact of the Mediterranean diet (MedDiet on glucose/insulin homeostasis and to verify whether these sex-related effects were associated with changes in nonesterified fatty acids (NEFA. Methods. All foods were provided to 38 men and 32 premenopausal women (24–53 y during 4 weeks. Variables were measured during a 180 min OGTT before and after the MedDiet. Results. A sex-by-time interaction for plasma insulin iAUC was found (men: −17.8%, P=0.02; women: +9.4%, P=0.63; P for sex-by-time interaction = 0.005. A sex-by-time interaction was also observed for insulin sensitivity (Cederholm index, P=0.03, for which only men experienced improvements (men: +8.1%, P=0.047; women: −5.9%, P=0.94. No sex difference was observed for glucose and C-peptide responses. Trends toward a decrease in NEFA AUC (P=0.06 and an increase in NEFA suppression rate (P=0.06 were noted, with no sex difference. Changes in NEFA were not associated with change in insulin sensitivity. Conclusions. Results suggest that the more favorable changes in glucose/insulin homeostasis observed in men compared to women in response to the MedDiet are not explained by sex differences in NEFA response. This clinical trial is registered with clinicaltrials.gov NCT01293344.

  12. TDP-43, an ALS linked protein, regulates fat deposition and glucose homeostasis.

    Directory of Open Access Journals (Sweden)

    Nancy R Stallings

    Full Text Available The identification of proteins which determine fat and lean body mass composition is critical to better understanding and treating human obesity. TDP-43 is a well-conserved RNA-binding protein known to regulate alternative splicing and recently implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS. While TDP-43 knockout mice show early embryonic lethality, post-natal conditional knockout mice show weight loss, fat depletion, and rapid death, suggesting an important role for TDP-43 in regulating energy metabolism. Here we report, that over-expression of TDP-43 in transgenic mice can result in a phenotype characterized by increased fat deposition and adipocyte hypertrophy. In addition, TDP-43 over-expression in skeletal muscle results in increased steady state levels of Tbc1d1, a RAB-GTPase activating protein involved in Glucose 4 transporter (Glut4 translocation. Skeletal muscle fibers isolated from TDP-43 transgenic mice show altered Glut4 translocation in response to insulin and impaired insulin mediated glucose uptake. These results indicate that levels of TDP-43 regulate body fat composition and glucose homeostasis in vivo.

  13. TDP-43, an ALS linked protein, regulates fat deposition and glucose homeostasis.

    Science.gov (United States)

    Stallings, Nancy R; Puttaparthi, Krishna; Dowling, Katherine J; Luther, Christina M; Burns, Dennis K; Davis, Kathryn; Elliott, Jeffrey L

    2013-01-01

    The identification of proteins which determine fat and lean body mass composition is critical to better understanding and treating human obesity. TDP-43 is a well-conserved RNA-binding protein known to regulate alternative splicing and recently implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). While TDP-43 knockout mice show early embryonic lethality, post-natal conditional knockout mice show weight loss, fat depletion, and rapid death, suggesting an important role for TDP-43 in regulating energy metabolism. Here we report, that over-expression of TDP-43 in transgenic mice can result in a phenotype characterized by increased fat deposition and adipocyte hypertrophy. In addition, TDP-43 over-expression in skeletal muscle results in increased steady state levels of Tbc1d1, a RAB-GTPase activating protein involved in Glucose 4 transporter (Glut4) translocation. Skeletal muscle fibers isolated from TDP-43 transgenic mice show altered Glut4 translocation in response to insulin and impaired insulin mediated glucose uptake. These results indicate that levels of TDP-43 regulate body fat composition and glucose homeostasis in vivo.

  14. TDP-43, an ALS Linked Protein, Regulates Fat Deposition and Glucose Homeostasis

    Science.gov (United States)

    Stallings, Nancy R.; Puttaparthi, Krishna; Dowling, Katherine J.; Luther, Christina M.; Burns, Dennis K.; Davis, Kathryn; Elliott, Jeffrey L.

    2013-01-01

    The identification of proteins which determine fat and lean body mass composition is critical to better understanding and treating human obesity. TDP-43 is a well-conserved RNA-binding protein known to regulate alternative splicing and recently implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). While TDP-43 knockout mice show early embryonic lethality, post-natal conditional knockout mice show weight loss, fat depletion, and rapid death, suggesting an important role for TDP-43 in regulating energy metabolism. Here we report, that over-expression of TDP-43 in transgenic mice can result in a phenotype characterized by increased fat deposition and adipocyte hypertrophy. In addition, TDP-43 over-expression in skeletal muscle results in increased steady state levels of Tbc1d1, a RAB-GTPase activating protein involved in Glucose 4 transporter (Glut4) translocation. Skeletal muscle fibers isolated from TDP-43 transgenic mice show altered Glut4 translocation in response to insulin and impaired insulin mediated glucose uptake. These results indicate that levels of TDP-43 regulate body fat composition and glucose homeostasis in vivo. PMID:23967244

  15. Adipocyte-Specific Protein Tyrosine Phosphatase 1B Deletion Increases Lipogenesis, Adipocyte Cell Size and is a Minor Regulator of Glucose Homeostasis

    OpenAIRE

    Carl Owen; Alicja Czopek; Abdelali Agouni; Louise Grant; Robert Judson; Lees, Emma K; George D Mcilroy; Olga Göransson; Andy Welch; Bence, Kendra K.; Kahn, Barbara B.; Neel, Benjamin G.; Nimesh Mody; Mirela Delibegović

    2012-01-01

    Protein tyrosine phosphatase 1B (PTP1B), a key negative regulator of leptin and insulin signaling, is positively correlated with adiposity and contributes to insulin resistance. Global PTP1B deletion improves diet-induced obesity and glucose homeostasis via enhanced leptin signaling in the brain and increased insulin signaling in liver and muscle. However, the role of PTP1B in adipocytes is unclear, with studies demonstrating beneficial, detrimental or no effect(s) of adipose-PTP1B-deficiency...

  16. Chronic Effect of Aspartame on Ionic Homeostasis and Monoamine Neurotransmitters in the Rat Brain.

    Science.gov (United States)

    Abhilash, M; Alex, Manju; Mathews, Varghese V; Nair, R Harikumaran

    2014-05-28

    Aspartame is one of the most widely used artificial sweeteners globally. Data concerning acute neurotoxicity of aspartame is controversial, and knowledge on its chronic effect is limited. In the current study, we investigated the chronic effects of aspartame on ionic homeostasis and regional monoamine neurotransmitter concentrations in the brain. Our results showed that aspartame at high dose caused a disturbance in ionic homeostasis and induced apoptosis in the brain. We also investigated the effects of aspartame on brain regional monoamine synthesis, and the results revealed that there was a significant decrease of dopamine in corpus striatum and cerebral cortex and of serotonin in corpus striatum. Moreover, aspartame treatment significantly alters the tyrosine hydroxylase activity and amino acids levels in the brain. Our data suggest that chronic use of aspartame may affect electrolyte homeostasis and monoamine neurotransmitter synthesis dose dependently, and this might have a possible effect on cognitive functions.

  17. Short and Long-Term Effects of Baccharis articulata on Glucose Homeostasis

    Directory of Open Access Journals (Sweden)

    Flávio H. Reginatto

    2012-06-01

    Full Text Available In this study, the in vivo effect of the crude extract and n-butanol and aqueous residual fractions of Baccharis articulata (Lam. Pers. on serum glucose levels, insulin secretion and liver and muscle glycogen content, as well as in vitro action on serum intestinal disaccharidase activity and albumin glycation were investigated. Oral administration of the extract and fractions reduced glycemia in hyperglycemic rats. Additionally, the n-butanol fraction, which has high flavonoids content, stimulated insulin secretion, exhibiting an insulinogenic index similar to that of glipizide. Also, the n-butanol fraction treatment significantly increased glycogen content in both liver and muscle tissue. In vitro incubation with the crude extract and n-butanol and aqueous residual fractions inhibited maltase activity and the formation of advanced glycation end-products (AGEs. Thus, the results demonstrated that B. articulata exhibits a significant antihyperglycemic and insulin-secretagogue role. These effects on the regulation of glucose homeostasis observed for B. articulata indicate potential anti-diabetic properties.

  18. A novel oral form of salmon calcitonin improves glucose homeostasis and reduces body weight in diet-induced obese rats

    DEFF Research Database (Denmark)

    Feigh, M; Henriksen, K; Andreassen, K V;

    2011-01-01

    To investigate the effects of acute and chronic administration of a novel oral formulation of salmon calcitonin (sCT) on glycaemic control, glucose homeostasis and body weight regulation in diet-induced obese (DIO) rats-an animal model of obesity-related insulin resistance and type 2 diabetes....

  19. A low-protein diet combined with low-dose endotoxin leads to changes in glucose homeostasis in weanling rats

    NARCIS (Netherlands)

    Bandsma, Robert H. J.; Ackerley, Cameron; Koulajian, Khajag; Zhang, Ling; van Zutphen, Tim; van Dijk, Theo H.; Xiao, Changting; Giacca, Adria; Lewis, Gary F.

    2015-01-01

    Severe malnutrition is a leading cause of global childhood mortality, and infection and hypoglycemia or hyperglycemia are commonly present. The etiology behind the changes in glucose homeostasis is poorly understood. Here, we generated an animal model of severe malnutrition with and without low-grad

  20. Glial Hsp70 Protects K+ Homeostasis in the Drosophila Brain during Repetitive Anoxic Depolarization

    Science.gov (United States)

    Armstrong, Gary A. B.; Xiao, Chengfeng; Krill, Jennifer L.; Seroude, Laurent; Dawson-Scully, Ken; Robertson, R. Meldrum

    2011-01-01

    Neural tissue is particularly vulnerable to metabolic stress and loss of ion homeostasis. Repetitive stress generally leads to more permanent dysfunction but the mechanisms underlying this progression are poorly understood. We investigated the effects of energetic compromise in Drosophila by targeting the Na+/K+-ATPase. Acute ouabain treatment of intact flies resulted in subsequent repetitive comas that led to death and were associated with transient loss of K+ homeostasis in the brain. Heat shock pre-conditioned flies were resistant to ouabain treatment. To control the timing of repeated loss of ion homeostasis we subjected flies to repetitive anoxia while recording extracellular [K+] in the brain. We show that targeted expression of the chaperone protein Hsp70 in glial cells delays a permanent loss of ion homeostasis associated with repetitive anoxic stress and suggest that this is a useful model for investigating molecular mechanisms of neuroprotection. PMID:22174942

  1. Glial Hsp70 protects K+ homeostasis in the Drosophila brain during repetitive anoxic depolarization.

    Directory of Open Access Journals (Sweden)

    Gary A B Armstrong

    Full Text Available Neural tissue is particularly vulnerable to metabolic stress and loss of ion homeostasis. Repetitive stress generally leads to more permanent dysfunction but the mechanisms underlying this progression are poorly understood. We investigated the effects of energetic compromise in Drosophila by targeting the Na(+/K(+-ATPase. Acute ouabain treatment of intact flies resulted in subsequent repetitive comas that led to death and were associated with transient loss of K(+ homeostasis in the brain. Heat shock pre-conditioned flies were resistant to ouabain treatment. To control the timing of repeated loss of ion homeostasis we subjected flies to repetitive anoxia while recording extracellular [K(+] in the brain. We show that targeted expression of the chaperone protein Hsp70 in glial cells delays a permanent loss of ion homeostasis associated with repetitive anoxic stress and suggest that this is a useful model for investigating molecular mechanisms of neuroprotection.

  2. Utero-placental transfer of alternate energy substrates and glucose homeostasis in the newborn pig

    Energy Technology Data Exchange (ETDEWEB)

    Thulin, A.J.

    1985-01-01

    In the first experiment, three sows in late gestation were infused with (/sup 14/C)..beta..-hydroxybutyrate to evaluate utero-placental transfer of ketones. ..beta..-Hydroxy-butyrate (BOHB) concentrations were low in both the mother and fetus throughout the experiments (0.0189, 0.0197, 0.0054, and 0.0063 mmole/liter blood for UV, UA, FV, and FA, respectively). Radioactive BOHB was detected in fetal blood within two minutes post-injection. Lipid extracts of liver and adipose tissue exhibited the greatest relative incorporation of (/sup 14/C)..beta..-hydroxybutyrate followed by lung and heart tissues (3540, 3674, 1214, and 528 dpm/g wet weight, respectively). In a second study, five gravid gilts during late gestation were used to determine utero-placental transfer of maternal free fatty acids (FFA). Using similar techniques as Exp. 1, injections were given containing (/sup 14/C) linoleic acid and (/sup 3/H) palmitic acid or (/sup 14/C) octanoic acid. In a third experiment, gravid gilts were fed supplemental energy as starch (C), soybean oil (SO) or medium-chain triglycerides (MCT) during late gestation to determine the influence on colostrum composition and neonatal pig glucose homeostasis. Energy content of colostrum was increased (P = 0.05 by feeding SO and MCT. After a 36 h fast, mean piglet glucose concentrations were higher (P < 0.05) for MCT pigs. Glucose and creatinine levels showed quadratic effects, while FFA and blood urea nitrogen (BUN) exhibited cubic patterns during the fasting period. Although creatine levels were similar, BUN concentrations were higher (P < 0.01) for MCT progeny.

  3. Regulation of brain copper homeostasis by the brain barrier systems: Effects of Fe-overload and Fe-deficiency

    Energy Technology Data Exchange (ETDEWEB)

    Monnot, Andrew D.; Behl, Mamta; Ho, Sanna; Zheng, Wei, E-mail: wzheng@purdue.edu

    2011-11-15

    Maintaining brain Cu homeostasis is vital for normal brain function. The role of systemic Fe deficiency (FeD) or overload (FeO) due to metabolic diseases or environmental insults in Cu homeostasis in the cerebrospinal fluid (CSF) and brain tissues remains unknown. This study was designed to investigate how blood-brain barrier (BBB) and blood-SCF barrier (BCB) regulated Cu transport and how FeO or FeD altered brain Cu homeostasis. Rats received an Fe-enriched or Fe-depleted diet for 4 weeks. FeD and FeO treatment resulted in a significant increase (+ 55%) and decrease (- 56%) in CSF Cu levels (p < 0.05), respectively; however, neither treatment had any effect on CSF Fe levels. The FeD, but not FeO, led to significant increases in Cu levels in brain parenchyma and the choroid plexus. In situ brain perfusion studies demonstrated that the rate of Cu transport into the brain parenchyma was significantly faster in FeD rats (+ 92%) and significantly slower (- 53%) in FeO rats than in controls. In vitro two chamber Transwell transepithelial transport studies using primary choroidal epithelial cells revealed a predominant efflux of Cu from the CSF to blood compartment by the BCB. Further ventriculo-cisternal perfusion studies showed that Cu clearance by the choroid plexus in FeD animals was significantly greater than control (p < 0.05). Taken together, our results demonstrate that both the BBB and BCB contribute to maintain a stable Cu homeostasis in the brain and CSF. Cu appears to enter the brain primarily via the BBB and is subsequently removed from the CSF by the BCB. FeD has a more profound effect on brain Cu levels than FeO. FeD increases Cu transport at the brain barriers and prompts Cu overload in the CNS. The BCB plays a key role in removing the excess Cu from the CSF.

  4. Dietary fructose aggravates the pathobiology of traumatic brain injury by influencing energy homeostasis and plasticity.

    Science.gov (United States)

    Agrawal, Rahul; Noble, Emily; Vergnes, Laurent; Ying, Zhe; Reue, Karen; Gomez-Pinilla, Fernando

    2016-05-01

    Fructose consumption has been on the rise for the last two decades and is starting to be recognized as being responsible for metabolic diseases. Metabolic disorders pose a particular threat for brain conditions characterized by energy dysfunction, such as traumatic brain injury. Traumatic brain injury patients experience sudden abnormalities in the control of brain metabolism and cognitive function, which may worsen the prospect of brain plasticity and function. The mechanisms involved are poorly understood. Here we report that fructose consumption disrupts hippocampal energy homeostasis as evidenced by a decline in functional mitochondria bioenergetics (oxygen consumption rate and cytochrome C oxidase activity) and an aggravation of the effects of traumatic brain injury on molecular systems engaged in cell energy homeostasis (sirtuin 1, peroxisome proliferator-activated receptor gamma coactivator-1alpha) and synaptic plasticity (brain-derived neurotrophic factor, tropomyosin receptor kinase B, cyclic adenosine monophosphate response element binding, synaptophysin signaling). Fructose also worsened the effects of traumatic brain injury on spatial memory, which disruption was associated with a decrease in hippocampal insulin receptor signaling. Additionally, fructose consumption and traumatic brain injury promoted plasma membrane lipid peroxidation, measured by elevated protein and phenotypic expression of 4-hydroxynonenal. These data imply that high fructose consumption exacerbates the pathology of brain trauma by further disrupting energy metabolism and brain plasticity, highlighting the impact of diet on the resilience to neurological disorders. PMID:26661172

  5. The short-chain fatty acid receptor, FFA2, contributes to gestational glucose homeostasis.

    Science.gov (United States)

    Fuller, Miles; Priyadarshini, Medha; Gibbons, Sean M; Angueira, Anthony R; Brodsky, Michael; Hayes, M Geoffrey; Kovatcheva-Datchary, Petia; Bäckhed, Fredrik; Gilbert, Jack A; Lowe, William L; Layden, Brian T

    2015-11-15

    The structure of the human gastrointestinal microbiota can change during pregnancy, which may influence gestational metabolism; however, a mechanism of action remains unclear. Here we observed that in wild-type (WT) mice the relative abundance of Actinobacteria and Bacteroidetes increased during pregnancy. Along with these changes, short-chain fatty acids (SCFAs), which are mainly produced through gut microbiota fermentation, significantly changed in both the cecum and peripheral blood throughout gestation in these mice. SCFAs are recognized by G protein-coupled receptors (GPCRs) such as free fatty acid receptor-2 (FFA2), and we have previously demonstrated that the fatty acid receptor-2 gene (Ffar2) expression is higher in pancreatic islets during pregnancy. Using female Ffar2-/- mice, we explored the physiological relevance of signaling through this GPCR and found that Ffar2-deficient female mice developed fasting hyperglycemia and impaired glucose tolerance in the setting of impaired insulin secretion compared with WT mice during, but not before, pregnancy. Insulin tolerance tests were similar in Ffar2-/- and WT mice before and during pregnancy. Next, we examined the role of FFA2 in gestational β-cell mass, observing that Ffar2-/- mice had diminished gestational expansion of β-cells during pregnancy. Interestingly, mouse genotype had no significant impact on the composition of the gut microbiome, but did affect the observed SCFA profiles, suggesting a functional difference in the microbiota. Together, these results suggest a potential link between increased Ffar2 expression in islets and the alteration of circulating SCFA levels, possibly explaining how changes in the gut microbiome contribute to gestational glucose homeostasis. PMID:26394664

  6. Impact of streptozotocin on altering normal glucose homeostasis during insulin testing in diabetic rats compared to normoglycemic rats

    Directory of Open Access Journals (Sweden)

    Qinna NA

    2015-05-01

    Full Text Available Nidal A Qinna,1 Adnan A Badwan2 1Department of Pharmacology and Biomedical Sciences, Faculty of Pharmacy and Medical Sciences, University of Petra, 2Research and Innovation Centre, The Jordanian Pharmaceutical Manufacturing Co. Plc. (JPM, Amman, Jordan Abstract: Streptozotocin (STZ is currently the most used diabetogenic agent in testing insulin and new antidiabetic drugs in animals. Due to the toxic and disruptive nature of STZ on organs, apart from pancreas, involved in preserving the body’s normal glucose homeostasis, this study aims to reassess the action of STZ in inducing different glucose response states in diabetic rats while testing insulin. Diabetic Sprague-Dawley rats induced with STZ were classified according to their initial blood glucose levels into stages. The effect of randomizing rats in such a manner was investigated for the severity of interrupting normal liver, pancreas, and kidney functions. Pharmacokinetic and pharmacodynamic actions of subcutaneously injected insulin in diabetic and nondiabetic rats were compared. Interruption of glucose homeostasis by STZ was challenged by single and repeated administrations of injected insulin and oral glucose to diabetic rats. In diabetic rats with high glucose (451–750 mg/dL, noticeable changes were seen in the liver and kidney functions compared to rats with lower basal glucose levels. Increased serum levels of recombinant human insulin were clearly indicated by a significant increase in the calculated maximum serum concentration and area under the concentration–time curve. Reversion of serum glucose levels to normal levels pre- and postinsulin and oral glucose administrations to STZ diabetic rats were found to be variable. In conclusion, diabetic animals were more responsive to insulin than nondiabetic animals. STZ was capable of inducing different levels of normal glucose homeostasis disruption in rats. Both pharmacokinetic and pharmacodynamic actions of insulin were

  7. Involvement of SIK3 in glucose and lipid homeostasis in mice.

    Directory of Open Access Journals (Sweden)

    Tatsuya Uebi

    Full Text Available Salt-inducible kinase 3 (SIK3, an AMP-activated protein kinase-related kinase, is induced in the murine liver after the consumption of a diet rich in fat, sucrose, and cholesterol. To examine whether SIK3 can modulate glucose and lipid metabolism in the liver, we analyzed phenotypes of SIK3-deficent mice. Sik3(-/- mice have a malnourished the phenotype (i.e., lipodystrophy, hypolipidemia, hypoglycemia, and hyper-insulin sensitivity accompanied by cholestasis and cholelithiasis. The hypoglycemic and hyper-insulin-sensitive phenotypes may be due to reduced energy storage, which is represented by the low expression levels of mRNA for components of the fatty acid synthesis pathways in the liver. The biliary disorders in Sik3(-/- mice are associated with the dysregulation of gene expression programs that respond to nutritional stresses and are probably regulated by nuclear receptors. Retinoic acid plays a role in cholesterol and bile acid homeostasis, wheras ALDH1a which produces retinoic acid, is expressed at low levels in Sik3(-/- mice. Lipid metabolism disorders in Sik3(-/- mice are ameliorated by the treatment with 9-cis-retinoic acid. In conclusion, SIK3 is a novel energy regulator that modulates cholesterol and bile acid metabolism by coupling with retinoid metabolism, and may alter the size of energy storage in mice.

  8. Microglia development follows a stepwise program to regulate brain homeostasis.

    Science.gov (United States)

    Matcovitch-Natan, Orit; Winter, Deborah R; Giladi, Amir; Vargas Aguilar, Stephanie; Spinrad, Amit; Sarrazin, Sandrine; Ben-Yehuda, Hila; David, Eyal; Zelada González, Fabiola; Perrin, Pierre; Keren-Shaul, Hadas; Gury, Meital; Lara-Astaiso, David; Thaiss, Christoph A; Cohen, Merav; Bahar Halpern, Keren; Baruch, Kuti; Deczkowska, Aleksandra; Lorenzo-Vivas, Erika; Itzkovitz, Shalev; Elinav, Eran; Sieweke, Michael H; Schwartz, Michal; Amit, Ido

    2016-08-19

    Microglia, the resident myeloid cells of the central nervous system, play important roles in life-long brain maintenance and in pathology. Despite their importance, their regulatory dynamics during brain development have not been fully elucidated. Using genome-wide chromatin and expression profiling coupled with single-cell transcriptomic analysis throughout development, we found that microglia undergo three temporal stages of development in synchrony with the brain--early, pre-, and adult microglia--which are under distinct regulatory circuits. Knockout of the gene encoding the adult microglia transcription factor MAFB and environmental perturbations, such as those affecting the microbiome or prenatal immune activation, led to disruption of developmental genes and immune response pathways. Together, our work identifies a stepwise microglia developmental program integrating immune response pathways that may be associated with several neurodevelopmental disorders.

  9. Microglia development follows a stepwise program to regulate brain homeostasis.

    Science.gov (United States)

    Matcovitch-Natan, Orit; Winter, Deborah R; Giladi, Amir; Vargas Aguilar, Stephanie; Spinrad, Amit; Sarrazin, Sandrine; Ben-Yehuda, Hila; David, Eyal; Zelada González, Fabiola; Perrin, Pierre; Keren-Shaul, Hadas; Gury, Meital; Lara-Astaiso, David; Thaiss, Christoph A; Cohen, Merav; Bahar Halpern, Keren; Baruch, Kuti; Deczkowska, Aleksandra; Lorenzo-Vivas, Erika; Itzkovitz, Shalev; Elinav, Eran; Sieweke, Michael H; Schwartz, Michal; Amit, Ido

    2016-08-19

    Microglia, the resident myeloid cells of the central nervous system, play important roles in life-long brain maintenance and in pathology. Despite their importance, their regulatory dynamics during brain development have not been fully elucidated. Using genome-wide chromatin and expression profiling coupled with single-cell transcriptomic analysis throughout development, we found that microglia undergo three temporal stages of development in synchrony with the brain--early, pre-, and adult microglia--which are under distinct regulatory circuits. Knockout of the gene encoding the adult microglia transcription factor MAFB and environmental perturbations, such as those affecting the microbiome or prenatal immune activation, led to disruption of developmental genes and immune response pathways. Together, our work identifies a stepwise microglia developmental program integrating immune response pathways that may be associated with several neurodevelopmental disorders. PMID:27338705

  10. Changes in Glucose Homeostasis after Roux-en-Y Gastric Bypass Surgery for Obesity at Day Three, Two Months, and One Year after Surgery

    DEFF Research Database (Denmark)

    Falkén, Y; Hellström, P M; Holst, Jens Juul;

    2011-01-01

    Context: Endocrine effects of gastric bypass (GBP) surgery for obesity on glucose homeostasis are not fully understood. Main Objective: The main objective of the study was to assess the changes in plasma glucose, insulin, glucagon-like peptide-1 (GLP-1), leptin, somatostatin, glucose...

  11. Impact of low dose prenatal ethanol exposure on glucose homeostasis in Sprague-Dawley rats aged up to eight months.

    Directory of Open Access Journals (Sweden)

    Megan E Probyn

    Full Text Available Excessive exposure to alcohol prenatally has a myriad of detrimental effects on the health and well-being of the offspring. It is unknown whether chronic low-moderate exposure of alcohol prenatally has similar and lasting effects on the adult offspring's health. Using our recently developed Sprague-Dawley rat model of 6% chronic prenatal ethanol exposure, this study aimed to determine if this modest level of exposure adversely affects glucose homeostasis in male and female offspring aged up to eight months. Plasma glucose concentrations were measured in late fetal and postnatal life. The pancreas of 30 day old offspring was analysed for β-cell mass. Glucose handling and insulin action was measured at four months using an intraperitoneal glucose tolerance test and insulin challenge, respectively. Body composition and metabolic gene expression were measured at eight months. Despite normoglycaemia in ethanol consuming dams, ethanol-exposed fetuses were hypoglycaemic at embryonic day 20. Ethanol-exposed offspring were normoglycaemic and normoinsulinaemic under basal fasting conditions and had normal pancreatic β-cell mass at postnatal day 30. However, during a glucose tolerance test, male ethanol-exposed offspring were hyperinsulinaemic with increased first phase insulin secretion. Female ethanol-exposed offspring displayed enhanced glucose clearance during an insulin challenge. Body composition and hepatic, muscle and adipose tissue metabolic gene expression levels at eight months were not altered by prenatal ethanol exposure. Low-moderate chronic prenatal ethanol exposure has subtle, sex specific effects on glucose homeostasis in the young adult rat. As aging is associated with glucose dysregulation, further studies will clarify the long lasting effects of prenatal ethanol exposure.

  12. Diabetes-Related Ankyrin Repeat Protein (DARP/Ankrd23 Modifies Glucose Homeostasis by Modulating AMPK Activity in Skeletal Muscle.

    Directory of Open Access Journals (Sweden)

    Yoshiaki Shimoda

    Full Text Available Skeletal muscle is the major site for glucose disposal, the impairment of which closely associates with the glucose intolerance in diabetic patients. Diabetes-related ankyrin repeat protein (DARP/Ankrd23 is a member of muscle ankyrin repeat proteins, whose expression is enhanced in the skeletal muscle under diabetic conditions; however, its role in energy metabolism remains poorly understood. Here we report a novel role of DARP in the regulation of glucose homeostasis through modulating AMP-activated protein kinase (AMPK activity. DARP is highly preferentially expressed in skeletal muscle, and its expression was substantially upregulated during myotube differentiation of C2C12 myoblasts. Interestingly, DARP-/- mice demonstrated better glucose tolerance despite similar body weight, while their insulin sensitivity did not differ from that in wildtype mice. We found that phosphorylation of AMPK, which mediates insulin-independent glucose uptake, in skeletal muscle was significantly enhanced in DARP-/- mice compared to that in wildtype mice. Gene silencing of DARP in C2C12 myotubes enhanced AMPK phosphorylation, whereas overexpression of DARP in C2C12 myoblasts reduced it. Moreover, DARP-silencing increased glucose uptake and oxidation in myotubes, which was abrogated by the treatment with AICAR, an AMPK activator. Of note, improved glucose tolerance in DARP-/- mice was abolished when mice were treated with AICAR. Mechanistically, gene silencing of DARP enhanced protein expression of LKB1 that is a major upstream kinase for AMPK in myotubes in vitro and the skeletal muscle in vivo. Together with the altered expression under diabetic conditions, our data strongly suggest that DARP plays an important role in the regulation of glucose homeostasis under physiological and pathological conditions, and thus DARP is a new therapeutic target for the treatment of diabetes mellitus.

  13. Berberine Improves Glucose Homeostasis in Streptozotocin-Induced Diabetic Rats in Association with Multiple Factors of Insulin Resistance

    OpenAIRE

    Junzeng Zhang; Changhao Sun; Alfonso Lopez; Yanwen Wang; Yanfeng Chen

    2011-01-01

    The present study was carried out to determine the effect of berberine on glucose homeostasis and several biomarkers associated with insulin sensitivity in male Wistar rats with intraperitoneal injection of streptozotocin (STZ)-induced diabetes. Rats with fasting blood glucose 16.7 mmol/L after 2 weeks of STZ injection were divided into two groups. One group was used as the diabetic control and another treated by gavage feeding with 100 mg/kg/d of berberine in water containing 0.5% carboxymet...

  14. Analysis of FTO Gene Variants with Measures of Obesity and Glucose Homeostasis in the IRAS Family Study

    OpenAIRE

    Wing, Maria R; Ziegler, Julie; Langefeld, Carl D.; Ng, Maggie CY; Haffner, Steven M.; Norris, Jill M.; Goodarzi, Mark O; Donald W Bowden

    2009-01-01

    Multiple studies have identified FTO gene variants associated with measures of adiposity in European-derived populations. The study objective was to determine whether FTO variants were associated with adiposity, including visceral and subcutaneous adipose tissue (VAT; SAT), and glucose homeostasis measures in the Insulin Resistance Atherosclerosis Family Study (IRASFS). A total of 27 SNPs in FTO intron 1, including SNPs prominent in the literature (rs9939609, rs8050136, rs1121980, rs17817449,...

  15. Physically active vs. inactive lifestyle, muscle properties, and glucose homeostasis in middle-aged and older twins

    OpenAIRE

    Leskinen, T.; Sipilä, S.; Kaprio, J.; Kainulainen, H.; Alen, M.; Kujala, U. M.

    2013-01-01

    Exercise-induced positive changes in skeletal muscle properties and metabolism decrease the risk for disability, cardiometabolic diseases and mortality. Here, we studied muscle properties and glucose homeostasis in a non-exercise stage in twin pairs with co-twins discordant for physical activity habits for at least 32 years of their adult lives. Isometric knee extension force, MR imaging of midthigh tissue composition and muscle volume, and fasting blood samples were acquired from 16 same-sex...

  16. Reviewing the Effects of l-Leucine Supplementation in the Regulation of Food Intake, Energy Balance, and Glucose Homeostasis

    OpenAIRE

    Pedroso, João A. B.; Thais T. Zampieri; Jose Donato

    2015-01-01

    Leucine is a well-known activator of the mammalian target of rapamycin (mTOR). Because mTOR signaling regulates several aspects of metabolism, the potential of leucine as a dietary supplement for treating obesity and diabetes mellitus has been investigated. The objective of the present review was to summarize and discuss the available evidence regarding the mechanisms and the effects of leucine supplementation on the regulation of food intake, energy balance, and glucose homeostasis. Based on...

  17. High Physiological Omega-3 Fatty Acid Supplementation Affects Muscle Fatty Acid Composition and Glucose and Insulin Homeostasis in Obese Adolescents

    OpenAIRE

    Frida Dangardt; Yun Chen; Eva Gronowitz; Jovanna Dahlgren; Peter Friberg; Birgitta Strandvik

    2012-01-01

    Obese adolescents have high concentrations of saturated fatty acids and low omega-3 long-chain polyunsaturated fatty acids (LCUFAs) in plasma phospholipids. We aimed to investigate effects of omega-3 LCPUFA supplementation to obese adolescents on skeletal muscle lipids and glucose and insulin homeostasis. Twenty-five obese adolescents (14–17 years old, 14 females) completed a randomized double-blind crossover study supplying capsules containing either 1.2 g omega-3 LCPUFAs or placebo, for 3 m...

  18. Effect of curcumin supplementation on blood glucose, plasma insulin, and glucose homeostasis related enzyme activities in diabetic db/db mice.

    Science.gov (United States)

    Seo, Kwon-Il; Choi, Myung-Sook; Jung, Un Ju; Kim, Hye-Jin; Yeo, Jiyoung; Jeon, Seon-Min; Lee, Mi-Kyung

    2008-09-01

    We investigated the effect of curcumin on insulin resistance and glucose homeostasis in male C57BL/KsJ-db/db mice and their age-matched lean non-diabetic db/+ mice. Both db/+ and db/db mice were fed with or without curcumin (0.02%, wt/wt) for 6 wks. Curcumin significantly lowered blood glucose and HbA 1c levels, and it suppressed body weight loss in db/db mice. Curcumin improved homeostasis model assessment of insulin resistance and glucose tolerance, and elevated the plasma insulin level in db/db mice. Hepatic glucokinase activity was significantly higher in the curcumin-supplemented db/db group than in the db/db group, whereas glucose-6-phosphatase and phosphoenolpyruvate carboxykinase activities were significantly lower. In db/db mice, curcumin significantly lowered the hepatic activities of fatty acid synthase, beta-oxidation, 3-hydroxy-3-methylglutaryl coenzyme reductase, and acyl-CoA: cholesterol acyltransferase. Curcumin significantly lowered plasma free fatty acid, cholesterol, and triglyceride concentrations and increased the hepatic glycogen and skeletal muscle lipoprotein lipase in db/db mice. Curcumin normalized erythrocyte and hepatic antioxidant enzyme activities (superoxide dismutase, catalase, gluthathione peroxidase) in db/db mice that resulted in a significant reduction in lipid peroxidation. However, curcumin showed no effect on the blood glucose, plasma insulin, and glucose regulating enzyme activities in db/+ mice. These results suggest that curcumin seemed to be a potential glucose-lowering agent and antioxidant in type 2 diabetic db/db mice, but had no affect in non-diabetic db/+ mice.

  19. Effects of MDMA on blood glucose levels and brain glucose metabolism

    Energy Technology Data Exchange (ETDEWEB)

    Soto-Montenegro, M.L.; Vaquero, J.J.; Garcia-Barreno, P.; Desco, M. [Hospital General Universitario Gregorio Maranon, Laboratorio de Imagen, Medicina Experimental, Madrid (Spain); Arango, C. [Hospital General Gregorio Maranon, Departamento de Psiquiatria, Madrid (Spain); Ricaurte, G. [Johns Hopkins University School of Medicine, Department of Neurology, Baltimore, MD (United States)

    2007-06-15

    This study was designed to assess changes in glucose metabolism in rats administered single or repeated doses of MDMA. Two different experiments were performed: (1) A single-dose study with four groups receiving 20 mg/kg, 40 mg/kg, saline or heat, and (2) a repeated-dose study with two groups receiving three doses, at intervals of 2 h, of 5 mg/kg or saline. Rats were imaged using a dedicated small-animal PET scanner 1 h after single-dose administration or 7 days after repeated doses. Glucose metabolism was measured in 12 cerebral regions of interest. Rectal temperature and blood glucose were monitored. Peak body temperature was reached 1 h after MDMA administration. Blood glucose levels decreased significantly after MDMA administration. In the single-dose experiment, brain glucose metabolism showed hyperactivation in cerebellum and hypo-activation in the hippocampus, amygdala and auditory cortex. In the repeated-dose experiment, brain glucose metabolism did not show any significant change at day 7. These results are the first to indicate that MDMA has the potential to produce significant hypoglycaemia. In addition, they show that MDMA alters glucose metabolism in components of the motor, limbic and somatosensory systems acutely but not on a long-term basis. (orig.)

  20. The Effects of Empagliflozin, an SGLT2 Inhibitor, on Pancreatic β-Cell Mass and Glucose Homeostasis in Type 1 Diabetes

    OpenAIRE

    Sam Tsz Wai Cheng; Lihua Chen; Stephen Yu Ting Li; Eric Mayoux; Po Sing Leung

    2016-01-01

    The novel sodium glucose co-transporter 2 (SGLT2) inhibitor empagliflozin has recently been reported to improve glycemic control in streptozotocin-induced type 1 diabetic rats in an insulin-independent manner, via an increase in urinary glucose output. We investigated the potential of empagliflozin to recover insulin pathways in type 1 diabetes by improving pancreatic β-cell mass. Blood glucose homeostasis was assessed by an intraperitoneal glucose tolerance test. Serum insulin levels and ins...

  1. Period2 gene mutant mice show compromised insulin-mediated endothelial nitric oxide release and altered glucose homeostasis

    Directory of Open Access Journals (Sweden)

    João Miguel Carvas

    2012-08-01

    Full Text Available Period2 (Per2 is an important component of the circadian clock. Mutation of this gene is associated with vascular endothelial dysfunction and altered glucose metabolism. The aim of this study is to further characterize whole body glucose homeostasis and endothelial NO production in response to insulin in the mPer2Brdm1 mice. We show that mPer2Brdm1 mice exhibit compromised insulin receptor activation and Akt signaling in various tissues including liver, fat, heart, and aortas with a tissue-specific heterogeneous diurnal pattern, and decreased insulin-stimulated endothelial NO release in the aortas in both active and inactive phases of the animals. As compared to wild type mice, the mPer2Brdm1 mice reveal hyperinsulinemia, hypoglycemia with lower fasting hepatic glycogen content and glycogen synthase level, no difference in glucose tolerance and insulin tolerance. The mPer2Brdm1 mice do not show increased predisposition to obesity either on normal chow or high fat diet compared to wild type controls. Thus, mice with Per2 gene mutation show altered glucose homeostasis and compromised insulin-stimulated endothelial NO release, independently of obesity.

  2. A low-protein diet combined with low-dose endotoxin leads to changes in glucose homeostasis in weanling rats.

    Science.gov (United States)

    Bandsma, Robert H J; Ackerley, Cameron; Koulajian, Khajag; Zhang, Ling; van Zutphen, Tim; van Dijk, Theo H; Xiao, Changting; Giacca, Adria; Lewis, Gary F

    2015-09-01

    Severe malnutrition is a leading cause of global childhood mortality, and infection and hypoglycemia or hyperglycemia are commonly present. The etiology behind the changes in glucose homeostasis is poorly understood. Here, we generated an animal model of severe malnutrition with and without low-grade inflammation to investigate the effects on glucose homeostasis. Immediately after weaning, rats were fed diets containing 5 [low-protein diet (LP)] or 20% protein [control diet (CTRL)], with or without repeated low-dose intraperitoneal lipopolysaccharide (LPS; 2 mg/kg), to mimic inflammation resulting from infections. After 4 wk on the diets, hyperglycemic clamps or euglycemic hyperinsulinemic clamps were performed with infusion of [U-(13)C6]glucose and [2-(13)C]glycerol to assess insulin secretion, action, and hepatic glucose metabolism. In separate studies, pancreatic islets were isolated for further analyses of insulin secretion and islet morphometry. Glucose clearance was reduced significantly by LP feeding alone (16%) and by LP feeding with LPS administration (43.8%) compared with control during the hyperglycemic clamps. This was associated with a strongly reduced insulin secretion in LP-fed rats in vivo as well as ex vivo in islets but signficantly enhanced whole body insulin sensitivity. Gluconeogenesis rates were unaffected by LP feeding, but glycogenolysis was higher after LP feeding. A protein-deficient diet in young rats leads to a susceptibility to low-dose endotoxin-induced impairment in glucose clearance with a decrease in the islet insulin secretory pathway. A protein-deficient diet is associated with enhanced peripheral insulin sensitivity but impaired insulin-mediated suppression of hepatic glycogenolysis. PMID:26152763

  3. Combined heart rate- and accelerometer-assessed physical activity energy expenditure and associations with glucose homeostasis markers in a population at high risk of developing diabetes

    DEFF Research Database (Denmark)

    Hansen, Anne-Louise Smidt; Carstensen, Bendix; Helge, Jørn Wulff;

    2013-01-01

    energy expenditure (PAEE) with detailed measures of glucose homeostasis. RESEARCH DESIGN AND METHODS: In 1,531 men and women, with low to high risk of developing type 2 diabetes, we measured 7 days of PAEE using a combined accelerometry and heart rate monitor (ActiHeart). Measures and indices of glucose...... homeostasis were derived from a 3-point oral glucose tolerance test in addition to measures of long-term glycemia (glycated hemoglobin A1c and advanced glycation end products). Associations of PAEE with glucose homeostasis markers were examined using linear regression models. RESULTS: Median age (IQR) was 66.......05). CONCLUSIONS: Even in an elderly population with low levels of PA, we found higher objectively measured PAEE levels to be associated with a more beneficial glucose metabolic profile. Although our findings are cross-sectional, they indicate that even without high-intensity exercise, increasing the overall level...

  4. Oxygen Glucose Deprivation in Rat Hippocampal Slice Cultures Results in Alterations in Carnitine Homeostasis and Mitochondrial Dysfunction

    OpenAIRE

    Thomas F. Rau; Qing Lu; Shruti Sharma; Xutong Sun; Gregory Leary; Beckman, Matthew L.; Yali Hou; Wainwright, Mark S; Michael Kavanaugh; Poulsen, David J.; Black, Stephen M.

    2012-01-01

    Mitochondrial dysfunction characterized by depolarization of mitochondrial membranes and the initiation of mitochondrial-mediated apoptosis are pathological responses to hypoxia-ischemia (HI) in the neonatal brain. Carnitine metabolism directly supports mitochondrial metabolism by shuttling long chain fatty acids across the inner mitochondrial membrane for beta-oxidation. Our previous studies have shown that HI disrupts carnitine homeostasis in neonatal rats and that L-carnitine can be neurop...

  5. Glucose-6-phosphate reduces calcium accumulation in rat brain endoplasmic reticulum

    Directory of Open Access Journals (Sweden)

    Jeffrey Thomas Cole

    2012-04-01

    Full Text Available Brain cells expend large amounts of energy sequestering calcium (Ca2+, while loss of Ca2+ compartmentalization leads to cell damage or death. Upon cell entry, glucose is converted to glucose-6-phosphate (G6P, a parent substrate to several metabolic major pathways, including glycolysis. In several tissues, G6P alters the ability of the endoplasmic reticulum to sequester Ca2+. This led to the hypothesis that G6P regulates Ca2+ accumulation by acting as an endogenous ligand for sarco-endoplasmic reticulum calcium ATPase (SERCA. Whole brain ER microsomes were pooled from adult male Sprague-Dawley rats. Using radio-isotopic assays, 45Ca2+ accumulation was quantified following incubation with increasing amounts of G6P, in the presence or absence of thapsigargin, a potent SERCA inhibitor. To qualitatively assess SERCA activity, the simultaneous release of inorganic phosphate (Pi coupled with Ca2+ accumulation was quantified. Addition of G6P significantly and decreased Ca2+ accumulation in a dose-dependent fashion (1-10 mM. The reduction in Ca2+ accumulation was not significantly different that seen with addition of thapsigargin. Addition of glucose-1-phosphate or fructose-6-phosphate, or other glucose metabolic pathway intermediates, had no effect on Ca2+ accumulation. Further, the release of Pi was markedly decreased, indicating G6P-mediated SERCA inhibition as the responsible mechanism for reduced Ca2+ uptake. Simultaneous addition of thapsigargin and G6P did decrease inorganic phosphate in comparison to either treatment alone, which suggests that the two treatments have different mechanisms of action. Therefore, G6P may be a novel, endogenous regulator of SERCA activity. Additionally, pathological conditions observed during disease states that disrupt glucose homeostasis, may be attributable to Ca2+ dystasis caused by altered G6P regulation of SERCA activity

  6. A glucose fuel cell for implantable brain-machine interfaces.

    Directory of Open Access Journals (Sweden)

    Benjamin I Rapoport

    Full Text Available We have developed an implantable fuel cell that generates power through glucose oxidation, producing 3.4 μW cm(-2 steady-state power and up to 180 μW cm(-2 peak power. The fuel cell is manufactured using a novel approach, employing semiconductor fabrication techniques, and is therefore well suited for manufacture together with integrated circuits on a single silicon wafer. Thus, it can help enable implantable microelectronic systems with long-lifetime power sources that harvest energy from their surrounds. The fuel reactions are mediated by robust, solid state catalysts. Glucose is oxidized at the nanostructured surface of an activated platinum anode. Oxygen is reduced to water at the surface of a self-assembled network of single-walled carbon nanotubes, embedded in a Nafion film that forms the cathode and is exposed to the biological environment. The catalytic electrodes are separated by a Nafion membrane. The availability of fuel cell reactants, oxygen and glucose, only as a mixture in the physiologic environment, has traditionally posed a design challenge: Net current production requires oxidation and reduction to occur separately and selectively at the anode and cathode, respectively, to prevent electrochemical short circuits. Our fuel cell is configured in a half-open geometry that shields the anode while exposing the cathode, resulting in an oxygen gradient that strongly favors oxygen reduction at the cathode. Glucose reaches the shielded anode by diffusing through the nanotube mesh, which does not catalyze glucose oxidation, and the Nafion layers, which are permeable to small neutral and cationic species. We demonstrate computationally that the natural recirculation of cerebrospinal fluid around the human brain theoretically permits glucose energy harvesting at a rate on the order of at least 1 mW with no adverse physiologic effects. Low-power brain-machine interfaces can thus potentially benefit from having their implanted units

  7. Human monoclonal antibodies against glucagon receptor improve glucose homeostasis by suppression of hepatic glucose output in diet-induced obese mice.

    Directory of Open Access Journals (Sweden)

    Wook-Dong Kim

    Full Text Available AIM: Glucagon is an essential regulator of hepatic glucose production (HGP, which provides an alternative therapeutic target for managing type 2 diabetes with glucagon antagonists. We studied the effect of a novel human monoclonal antibody against glucagon receptor (GCGR, NPB112, on glucose homeostasis in diet-induced obese (DIO mice. METHODS: The glucose-lowering efficacy and safety of NPB112 were investigated in DIO mice with human GCGR for 11 weeks, and a hyperinsulinemic-euglycemic clamp study was conducted to measure HGP. RESULTS: Single intraperitoneal injection of NPB112 with 5 mg/kg effectively decreased blood glucose levels in DIO mice for 5 days. A significant reduction in blood glucose was observed in DIO mice treated with NPB112 at a dose ≥5 mg/kg for 6 weeks, and its glucose-lowering effect was dose-dependent. Long-term administration of NPB112 also caused a mild 29% elevation in glucagon level, which was returned to the normal range after discontinuation of treatment. The clamp study showed that DIO mice injected with NPB112 at 5 mg/kg were more insulin sensitive than control mice, indicating amelioration of insulin resistance by treatment with NPB112. DIO mice treated with NPB112 showed a significant improvement in the ability of insulin to suppress HGP, showing a 33% suppression (from 8.3 mg/kg/min to 5.6 mg/kg/min compared to the 2% suppression (from 9.8 mg/kg/min to 9.6 mg/kg/min in control mice. In addition, no hypoglycemia or adverse effect was observed during the treatment. CONCLUSIONS: A novel human monoclonal GCGR antibody, NPB112, effectively lowered the glucose level in diabetic animal models with mild and reversible hyperglucagonemia. Suppression of excess HGP with NPB112 may be a promising therapeutic modality for the treatment of type 2 diabetes.

  8. The Action of Antidiabetic Plants of the Canadian James Bay Cree Traditional Pharmacopeia on Key Enzymes of Hepatic Glucose Homeostasis

    Directory of Open Access Journals (Sweden)

    Abir Nachar

    2013-01-01

    Full Text Available We determined the capacity of putative antidiabetic plants used by the Eastern James Bay Cree (Canada to modulate key enzymes of gluconeogenesis and glycogen synthesis and key regulating kinases. Glucose-6-phosphatase (G6Pase and glycogen synthase (GS activities were assessed in cultured hepatocytes treated with crude extracts of seventeen plant species. Phosphorylation of AMP-dependent protein kinase (AMPK, Akt, and Glycogen synthase kinase-3 (GSK-3 were probed by Western blot. Seven of the seventeen plant extracts significantly decreased G6Pase activity, Abies balsamea and Picea glauca, exerting an effect similar to insulin. This action involved both Akt and AMPK phosphorylation. On the other hand, several plant extracts activated GS, Larix laricina and A. balsamea, far exceeding the action of insulin. We also found a significant correlation between GS stimulation and GSK-3 phosphorylation induced by plant extract treatments. In summary, three Cree plants stand out for marked effects on hepatic glucose homeostasis. P. glauca affects glucose production whereas L. laricina rather acts on glucose storage. However, A. balsamea has the most promising profile, simultaneously and powerfully reducing G6Pase and stimulating GS. Our studies thus confirm that the reduction of hepatic glucose production likely contributes to the therapeutic potential of several antidiabetic Cree traditional medicines.

  9. Improved Glucose Homeostasis in Mice with Muscle-Specific Deletion of Protein-Tyrosine Phosphatase 1B▿

    OpenAIRE

    Delibegovic, Mirela; Bence, Kendra K.; Mody, Nimesh; Hong, Eun-Gyoung; Ko, Hwi Jin; Jason K Kim; Kahn, Barbara B.; Neel, Benjamin G

    2007-01-01

    Obesity and type 2 diabetes are characterized by insulin resistance. Mice lacking the protein-tyrosine phosphatase PTP1B in all tissues are hypersensitive to insulin but also have diminished fat stores. Because adiposity affects insulin sensitivity, the extent to which PTP1B directly regulates glucose homeostasis has been unclear. We report that mice lacking PTP1B only in muscle have body weight and adiposity comparable to those of controls on either chow or a high-fat diet (HFD). Muscle trig...

  10. Metformin improves postprandial glucose homeostasis in rainbow trout fed dietary carbohydrates : a link with the induction of hepatic lipogenic capacities ?

    OpenAIRE

    Panserat, Stephane; Skiba-Cassy, Sandrine; Seiliez, Iban; Lansard, Marine; Plagnes- Juan, Elisabeth; VACHOT, Christiane; Aguirre, Pierre; Larroquet, Laurence; Chavernac, G.; Médale, Françoise; Corraze, Geneviève; Kaushik, Sadasivam; Moon, T.W.

    2009-01-01

    Panserat S, Skiba-Cassy S, Seiliez I, Lansard M, Plagnes-Juan E, Vachot C, Aguirre P, Larroquet L, Chavernac G, Medale F, Corraze G, Kaushik S, Moon TW. Metformin improves postprandial glucose homeostasis in rainbow trout fed dietary carbohydrates: a link with the induction of hepatic lipogenic capacities? Am J Physiol Regul Integr Comp Physiol 297: R707-R715, 2009. First published June 24, 2009; doi: 10.1152/ajpregu.00120.2009.-Carnivorous fish are poor users of dietary carbohydrates and are...

  11. Co-administration of paroxetine and pravastatin causes deregulation of glucose homeostasis in diabetic rats via enhanced paroxetine exposure

    OpenAIRE

    Li, Feng; Zhang, Mian; Dan XU; Liu, Can; Zhong, Ze-yu; Jia, Ling-ling; Hu, Meng-yue; Yang, Yang; Liu, Li; Liu, Xiao-Dong

    2014-01-01

    Aim: Clinical evidence shows that co-administration of pravastatin and paroxetine deregulates glucose homeostasis in diabetic patients. The aim of this study was to verify this phenomenon in diabetic rats and to elucidate the underlying mechanisms. Methods: Diabetes mellitus was induced in male SD rats by a high-fat diet combined with a low-dose streptozotocin injection. The rats were orally administered paroxetine (10 mg/kg) and pravastatin (10 mg/d) or both the drugs daily for 28 d. The pha...

  12. The cAMP-HMGA1-RBP4 system: a novel biochemical pathway for modulating glucose homeostasis

    Directory of Open Access Journals (Sweden)

    Foti Daniela

    2009-05-01

    Full Text Available Abstract Background We previously showed that mice lacking the high mobility group A1 gene (Hmga1-knockout mice developed a type 2-like diabetic phenotype, in which cell-surface insulin receptors were dramatically reduced (below 10% of those in the controls in the major targets of insulin action, and glucose intolerance was associated with increased peripheral insulin sensitivity. This particular phenotype supports the existence of compensatory mechanisms of insulin resistance that promote glucose uptake and disposal in peripheral tissues by either insulin-dependent or insulin-independent mechanisms. We explored the role of these mechanisms in the regulation of glucose homeostasis by studying the Hmga1-knockout mouse model. Also, the hypothesis that increased insulin sensitivity in Hmga1-deficient mice could be related to the deficit of an insulin resistance factor is discussed. Results We first show that HMGA1 is needed for basal and cAMP-induced retinol-binding protein 4 (RBP4 gene and protein expression in living cells of both human and mouse origin. Then, by employing the Hmga1-knockout mouse model, we provide evidence for the identification of a novel biochemical pathway involving HMGA1 and the RBP4, whose activation by the cAMP-signaling pathway may play an essential role for maintaining glucose metabolism homeostasis in vivo, in certain adverse metabolic conditions in which insulin action is precluded. In comparative studies of normal and mutant mice, glucagon administration caused a considerable upregulation of HMGA1 and RBP4 expression both at the mRNA and protein level in wild-type animals. Conversely, in Hmga1-knockout mice, basal and glucagon-mediated expression of RBP4 was severely attenuated and correlated inversely with increased Glut4 mRNA and protein abundance in skeletal muscle and fat, in which the activation state of the protein kinase Akt, an important downstream mediator of the metabolic effects of insulin on Glut4

  13. New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk

    NARCIS (Netherlands)

    J. Dupuis (Josée); C. Langenberg (Claudia); I. Prokopenko (Inga); R. Saxena (Richa); N. Soranzo (Nicole); A.U. Jackson (Anne); E. Wheeler (Eleanor); N.L. Glazer (Nicole); N. Bouatia-Naji (Nabila); A.L. Gloyn (Anna); C.M. Lindgren (Cecilia); R. Mägi (Reedik); A.P. Morris (Andrew); J.C. Randall (Joshua); T. Johnson (Toby); P. Elliott (Paul); D. Rybin (Denis); G. Thorleifsson (Gudmar); V. Steinthorsdottir (Valgerdur); P. Henneman (Peter); H. Grallert (Harald); A. Dehghan (Abbas); J. JanHottenga (Jouke); C.S. Franklin (Christopher); P. Navarro (Pau); K. Song (Kijoung); A. Goel (Anuj); J.R.B. Perry (John); J.M. Egan (Josephine); T. Lajunen (Taina); N. Grarup (Niels); T. Sparsø (Thomas); A.S.F. Doney (Alex); B.F. Voight (Benjamin); H.M. Stringham (Heather); M. Li (Man); S. Kanoni (Stavroula); P. Shrader (Peter); C. Cavalcanti-Proença (Christine); M. Kumari (Meena); L. Qi (Lu); N. Timpson (Nicholas); C. Gieger (Christian); C. Zabena (Carina); G. Rocheleau (Ghislain); E. Ingelsson (Erik); P. An (Ping); J.R. O´Connell; J. Luan; S.A. McCarroll (Steven); F. Payne (Felicity); R.M. Roccasecca; F. Pattou (François); P. Sethupathy (Praveen); K.G. Ardlie (Kristin); Y. Ariyurek (Yavuz); B. Balkau (Beverley); P. Barter (Phil); J.P. Beilby (John); Y. Ben-Shlomo; R. Benediktsson (Rafn); A.J. Bennett (Amanda); S.M. Bergmann (Sven); M. Bochud (Murielle); E. Boerwinkle (Eric); A. Bonnefond (Amélie); L.L. Bonnycastle (Lori); K. Borch-Johnsen; Y. Böttcher (Yvonne); E. Brunner (Eric); S. Bumpstead (Suzannah); G. Charpentier (Guillaume); Y. der IdaChen (Yii); P.S. Chines (Peter); R. Clarke; L.J. McOin (Lachlan); M.N. Cooper (Matthew); M. Cornelis (Marilyn); G. Crawford (Gabe); L. Crisponi (Laura); I.N.M. Day (Ian); E.J.C. de Geus (Eco); J. Delplanque (Jerome); C. Dina (Christian); M.R. Erdos (Michael); A.C. Fedson (Annette); A. Fischer-Rosinsky (Antje); N.G. Forouhi (Nita); C.S. Fox (Caroline); R.R. Frants (Rune); M. GraziaFranzosi (Maria); P. Galan (Pilar); M. Goodarzi (Mark); J. Graessler (Jürgen); C.J. Groves (Christopher); S.M. Grundy (Scott); R. Gwilliam (Rhian); U. Gyllensten (Ulf); S. Hadjadj (Samy); G. Hallmans (Göran); N. Hammond (Naomi); X. Han (Xijing); A.-L. Hartikainen (Anna-Liisa); N. Hassanali (Neelam); C. Hayward (Caroline); S.C. Heath (Simon); S. Hercberg (Serge); C. Herder (Christian); A.A. Hicks (Andrew); D.R. Hillman (David); A. Hingorani (Aroon); A. Hofman (Albert); J. Hui (Jennie); J. Hung; B. Isomaa (Bo); T. Jørgensen (Torben); A. Jula (Antti); M. Kaakinen (Marika); J. Kaprio (Jaakko); Y. AnteroKesaniemi; M. Kivimaki (Mika); B. Knight (Beatrice); S. Koskinen (Seppo); P. Kovacs (Peter); K.O. Kyvik (Kirsten Ohm); G.M. Lathrop (Mark); D.A. Lawlor (Debbie); O.L. Bacquer (Olivier); C. Lecoeur (Cécile); V. Lyssenko (Valeriya); R. Mahley (Robert); M. Mangino (Massimo); A.K. Manning (Alisa); M. TeresaMartínez-Larrad (María); J.B. McAteer (Jarred); L.J. McCulloch (Laura); R. McPherson (Ruth); C. Meisinger (Christa); D. Melzer (David); D. Meyre (David); B.D. Mitchell (Braxton); M.A. Morken (Mario); S. Mukherjee (Sutapa); S. Naitza (Silvia); N. Narisu (Narisu); M.J. Neville (Matthew); B.A. Oostra (Ben); M. Orrù (Marco); R. Pakyz (Ruth); C.N.A. Palmer (Colin); G. Paolisso (Giuseppe); C. Pattaro (Cristian); D. Pearson (Daniel); J. Peden (John); N.L. Pedersen (Nancy); M. Perola (Markus); A.F.H. Pfeiffer (Andreas); I. Pichler (Irene); O. Polasek (Ozren); D. Posthuma (Danielle); S.C. Potter (Simon); A. Pouta (Anneli); M.A. Province (Mike); B.M. Psaty (Bruce); W. Rathmann (Wolfgang); N.W. Rayner (Nigel William); K. Rice (Kenneth); S. Ripatti (Samuli); F. Rivadeneira Ramirez (Fernando); M. Roden (Michael); O. Rolandsson (Olov); A. Sandbaek (Annelli); M.S. Sandhu (Manjinder); S. Sanna (Serena); A.A. Sayer; P. Scheet (Paul); L.J. Scott (Laura); U. Seedorf (Udo); S.J. Sharp (Stephen); B.M. Shields (Beverley); G. Sigursson (Gunnar); E.J.G. Sijbrands (Eric); A. Silveira (Angela); L. Simpson (Laila); A. Singleton (Andrew); N.L. Smith (Nicholas); U. Sovio (Ulla); A.J. Swift (Amy); H. Syddall (Holly); A.-C. Syvänen (Ann-Christine); T. Tanaka (Toshiko); B. Thorand (Barbara); J. Tichet (Jean); A. Tönjes (Anke); T. Tuomi (Tiinamaija); A.G. Uitterlinden (André); J.A.P. Willems van Dijk (Ko); M.V. Hoek; D. Varma (Dhiraj); S. Visvikis-Siest (Sophie); V. Vitart (Veronique); N. Vogelzangs (Nicole); G. Waeber (Gérard); P.J. Wagner (Peter); A. Walley (Andrew); G. BragiWalters; K.L. Ward (Kim); H. Watkins (Hugh); M.N. Weedon (Michael)

    2010-01-01

    textabstractLevels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA

  14. New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk

    DEFF Research Database (Denmark)

    Dupuis, Josée; Langenberg, Claudia; Prokopenko, Inga;

    2010-01-01

    Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in u...

  15. Zinc Status Affects Glucose Homeostasis and Insulin Secretion in Patients with Thalassemia

    Directory of Open Access Journals (Sweden)

    Ellen B. Fung

    2015-06-01

    Full Text Available Up to 20% of adult patients with Thalassemia major (Thal live with diabetes, while 30% may be zinc deficient. The objective of this study was to explore the relationship between zinc status, impaired glucose tolerance and insulin sensitivity in Thal patients. Charts from thirty subjects (16 male, 27.8 ± 9.1 years with Thal were reviewed. Patients with low serum zinc had significantly lower fasting insulin, insulinogenic and oral disposition indexes (all p < 0.05 and elevated glucose response curve, following a standard 75 g oral load of glucose compared to those with normal serum zinc after controlling for baseline (group × time interaction p = 0.048. Longitudinal data in five patients with a decline in serum zinc over a two year follow up period (−19.0 ± 9.6 μg/dL, showed consistent increases in fasting glucose (3.6 ± 3.2 mg/dL and insulin to glucose ratios at 120 min post glucose dose (p = 0.05. Taken together, these data suggest that the frequently present zinc deficiency in Thal patients is associated with decreased insulin secretion and reduced glucose disposal. Future zinc trials will require modeling of oral glucose tolerance test data and not simply measurement of static indices in order to understand the complexities of pancreatic function in the Thal patient.

  16. Effect of somatostatin on glucose homeostasis in conscious long-fasted dogs

    International Nuclear Information System (INIS)

    The effects of somatostatin plus intraportal insulin and glucagon replacement (pancreatic clamp) on carbohydrate metabolism were studied in conscious dogs fasted for 7 days so that gluconeogenesis was a major contributor to total glucose production. By use of [3-3H]glucose, glucose production (Ra) and utilization (Rd) and glucose clearance were assessed before and after implementation of the pancreatic clamp. After an initial control period, somatostatin (0.8 μg·kg-1·min-1) was infused with intraportal replacement amounts of glucagon and insulin. The insulin infusion rate was varied to maintain euglycemia and then kept constant for 250 min. Plasma glucagon was similar before and during somatostatin infusion, while plasma insulin was lower. Plasma glucose levels remained similar while Ra and Rd and the ratio of glucose clearance to plasma insulin were significantly increased. Net hepatic lactate uptake and [14C]alanine plus [14C]lactate conversion to [14C]glucose increased. In conclusion, somatostatin alters glucose clearance in 7-day fasted dogs, resulting in changes in several indices of carbohydrate metabolism

  17. Short-chain fructooligosaccharides do not alter glucose homeostasis but improve the lipid profile in obese rats

    Directory of Open Access Journals (Sweden)

    Fernanda Soares da Silva-Morita

    2015-07-01

    Full Text Available The present study investigated the effects of short-chain fructooligosaccharides (scFOS feeding on body weight, fat accumulation, glucose homeostasis and lipid profile in cafeteria (CAF obese rats. Male Wistar rats were divided randomly into two groups: control group (CTL, n = 10, which received a chow diet and water and CAF (n = 20, which received the cafeteria diet, standard chow and soda. After 30 weeks of diet, 10 animals of CAF group received scFOS in the diet (50 g kg-1 of diet over a period of 50 days, forming the CAF FOS group. Were evaluated the body weight, fat pad as well as, quantity of feces, glucose tolerance, insulin resistance (IR and serum lipids levels. Animals submitted to the CAF diet displayed obesity, hyperglycemia, glucose intolerance, hyperinsulinemia and IR. The scFOS feeding   not altered obesity, glucose intolerance, hyperinsulinemia and IR. CAF rats also presented hypertriglyceridemia and lower levels of HDL-cholesterol. The CAF FOS animals had reduced serum triglycerides (TG and increased HDL-cholesterol. Thus, the use of scFOS in the diet can be considered as a hypolipidemic agent in the obese state.

  18. Long-term disruption of maternal glucose homeostasis induced by prenatal glucocorticoid treatment correlates with miR-29 upregulation.

    Science.gov (United States)

    Gomes, Patrícia R; Graciano, Maria F; Pantaleão, Lucas C; Rennó, André L; Rodrigues, Sandra C; Velloso, Licio A; Latorraca, Márcia Q; Carpinelli, Angelo R; Anhê, Gabriel F; Bordin, Silvana

    2014-01-01

    Excess of glucocorticoids (GCs) during pregnancy is strongly associated with the programming of glucose intolerance in the offspring. However, the impact of high GC levels on maternal metabolism is not clearly documented. This study aimed to test the hypothesis that mothers exposed to elevated levels of GCs might also display long-term disturbances in glucose homeostasis. Dexamethasone (DEX) was administered noninvasively to the mothers via drinking water between the 14th and the 19th days of pregnancy. Mothers were subjected to glucose and insulin tolerance tests at 1, 2, 3, 6, and 12 mo postweaning. Pregnant rats not treated with DEX and age-matched virgin rats were used as controls. Pancreatic islets were isolated at the 20th day of pregnancy and 12 mo postweaning in order to evaluate glucose-stimulated insulin secretion. The expression of the miR-29 family was also studied due to its responsiveness to GCs and its well-documented role in the regulation of pancreatic β-cell function. Rats treated with DEX during pregnancy presented long-term glucose intolerance and impaired insulin secretion. These changes correlated with 1) increased expression of miR-29 and its regulator p53, 2) reduced expression of syntaxin-1a, a direct target of miR-29, and 3) altered expression of genes related to cellular senescence. Our data demonstrate that the use of DEX during pregnancy results in deleterious outcomes to the maternal metabolism, hallmarked by reduced insulin secretion and glucose intolerance. This maternal metabolic programming might be a consequence of time-sustained upregulation of miR-29s in maternal pancreatic islets. PMID:24253049

  19. A whole-body model for glycogen regulation reveals a critical role for substrate cycling in maintaining blood glucose homeostasis.

    Directory of Open Access Journals (Sweden)

    Ke Xu

    2011-12-01

    Full Text Available Timely, and sometimes rapid, metabolic adaptation to changes in food supply is critical for survival as an organism moves from the fasted to the fed state, and vice versa. These transitions necessitate major metabolic changes to maintain energy homeostasis as the source of blood glucose moves away from ingested carbohydrates, through hepatic glycogen stores, towards gluconeogenesis. The integration of hepatic glycogen regulation with extra-hepatic energetics is a key aspect of these adaptive mechanisms. Here we use computational modeling to explore hepatic glycogen regulation under fed and fasting conditions in the context of a whole-body model. The model was validated against previous experimental results concerning glycogen phosphorylase a (active and glycogen synthase a dynamics. The model qualitatively reproduced physiological changes that occur during transition from the fed to the fasted state. Analysis of the model reveals a critical role for the inhibition of glycogen synthase phosphatase by glycogen phosphorylase a. This negative regulation leads to high levels of glycogen synthase activity during fasting conditions, which in turn increases substrate (futile cycling, priming the system for a rapid response once an external source of glucose is restored. This work demonstrates that a mechanistic understanding of the design principles used by metabolic control circuits to maintain homeostasis can benefit from the incorporation of mathematical descriptions of these networks into "whole-body" contextual models that mimic in vivo conditions.

  20. A protein homeostasis signature in healthy brains recapitulates tissue vulnerability to Alzheimer's disease.

    Science.gov (United States)

    Freer, Rosie; Sormanni, Pietro; Vecchi, Giulia; Ciryam, Prajwal; Dobson, Christopher M; Vendruscolo, Michele

    2016-08-01

    In Alzheimer's disease, aggregates of Aβ and tau in amyloid plaques and neurofibrillary tangles spread progressively across brain tissues following a characteristic pattern, implying a tissue-specific vulnerability to the disease. We report a transcriptional analysis of healthy brains and identify an expression signature that predicts-at ages well before the typical onset-the tissue-specific progression of the disease. We obtain this result by finding a quantitative correlation between the histopathological staging of the disease and the expression patterns of the proteins that coaggregate in amyloid plaques and neurofibrillary tangles, together with those of the protein homeostasis components that regulate Aβ and tau. Because this expression signature is evident in healthy brains, our analysis provides an explanatory link between a tissue-specific environmental risk of protein aggregation and a corresponding vulnerability to Alzheimer's disease. PMID:27532054

  1. Restraint Stress Impairs Glucose Homeostasis Through Altered Insulin Signalling in Sprague-Dawley Rat.

    Science.gov (United States)

    Morakinyo, Ayodele O; Ajiboye, Kolawole I; Oludare, Gabriel O; Samuel, Titilola A

    2016-01-01

    The study investigated the potential alteration in the level of insulin and adiponectin, as well as the expression of insulin receptors (INSR) and glucose transporter 4 GLUT-4 in chronic restraint stress rats. Sprague-Dawley rats were randomly divided into two groups: the control group and stress group in which the rats were exposed to one of the four different restraint stressors; 1 h, twice daily for a period of 7 days (S7D), 14 days (S14D) and 28 days (S28D). Glucose tolerance and insulin sensitivity were evaluated following the final stress exposure. ELISA were performed to assess the level of insulin and adiponectin as well as expression of INSR and GLUT4 protein in skeletal muscle. Plasma corticosterone level was also determined as a marker of stress exposure. Restraint stress for 7 days caused transient glucose intolerance, while S14D rats demonstrated increased glucose intolerance and insulin insensitivity. However, restraint stress for 28 days had no effect on glucose tolerance, but did cause an increase in glucose response to insulin challenge. The serum level of adiponectin was significantly (pcontrol value while insulin remained unchanged except at in S28D rats that had a significant (pcontrol counterparts. Restraint stress caused glucose intolerance and insulin insensitivity in male Sprague-Dawley rats, which becomes accommodated with prolonged exposure and was likely related to the blunted insulin signalling in skeletal muscle. PMID:27574760

  2. Impairment of brain endothelial glucose transporter by methamphetamine causes blood-brain barrier dysfunction

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    Murrin L Charles

    2011-03-01

    Full Text Available Abstract Background Methamphetamine (METH, an addictive psycho-stimulant drug with euphoric effect is known to cause neurotoxicity due to oxidative stress, dopamine accumulation and glial cell activation. Here we hypothesized that METH-induced interference of glucose uptake and transport at the endothelium can disrupt the energy requirement of the blood-brain barrier (BBB function and integrity. We undertake this study because there is no report of METH effects on glucose uptake and transport across the blood-brain barrier (BBB to date. Results In this study, we demonstrate that METH-induced disruption of glucose uptake by endothelium lead to BBB dysfunction. Our data indicate that a low concentration of METH (20 μM increased the expression of glucose transporter protein-1 (GLUT1 in primary human brain endothelial cell (hBEC, main component of BBB without affecting the glucose uptake. A high concentration of 200 μM of METH decreased both the glucose uptake and GLUT1 protein levels in hBEC culture. Transcription process appeared to regulate the changes in METH-induced GLUT1 expression. METH-induced decrease in GLUT1 protein level was associated with reduction in BBB tight junction protein occludin and zonula occludens-1. Functional assessment of the trans-endothelial electrical resistance of the cell monolayers and permeability of dye tracers in animal model validated the pharmacokinetics and molecular findings that inhibition of glucose uptake by GLUT1 inhibitor cytochalasin B (CB aggravated the METH-induced disruption of the BBB integrity. Application of acetyl-L-carnitine suppressed the effects of METH on glucose uptake and BBB function. Conclusion Our findings suggest that impairment of GLUT1 at the brain endothelium by METH may contribute to energy-associated disruption of tight junction assembly and loss of BBB integrity.

  3. Effects of Noise Exposure on Systemic and Tissue-Level Markers of Glucose Homeostasis and Insulin Resistance in Male Mice

    Science.gov (United States)

    Liu, Lijie; Wang, Fanfan; Lu, Haiying; Cao, Shuangfeng; Du, Ziwei; Wang, Yongfang; Feng, Xian; Gao, Ye; Zha, Mingming; Guo, Min; Sun, Zilin; Wang, Jian

    2016-01-01

    Background: Epidemiological studies have indicated that noise exposure is associated with an increased risk of type 2 diabetes mellitus (T2DM). However, the nature of the connection between noise exposure and T2DM remains to be explored. Objectives: We explored whether and how noise exposure affects glucose homeostasis in mice as the initial step toward T2DM development. Methods: Male ICR mice were randomly assigned to one of four groups: the control group and three noise groups (N20D, N10D, and N1D), in which the animals were exposed to white noise at 95 decibel sound pressure level (dB SPL) for 4 hr per day for 20 successive days, 10 successive days, or 1 day, respectively. Glucose tolerance and insulin sensitivity were evaluated 1 day, 1 week, and 1 month after the final noise exposure (1DPN, 1WPN, and 1MPN). Standard immunoblots, immunohistochemical methods, and enzyme-linked immunosorbent assays (ELISA) were performed to assess insulin signaling in skeletal muscle, the morphology of β cells, and plasma corticosterone levels. Results: Noise exposure for 1 day caused transient glucose intolerance and insulin resistance, whereas noise exposure for 10 and 20 days had no effect on glucose tolerance but did cause prolonged insulin resistance and an increased insulin response to glucose challenge. Akt phosphorylation and GLUT4 translocation in response to exogenous insulin were decreased in the skeletal muscle of noise-exposed animals. Conclusions: Noise exposure at 95 dB SPL caused insulin resistance in male ICR mice, which was prolonged with longer noise exposure and was likely related to the observed blunted insulin signaling in skeletal muscle. Citation: Liu L, Wang F, Lu H, Cao S, Du Z, Wang Y, Feng X, Gao Y, Zha M, Guo M, Sun Z, Wang J. 2016. Effects of noise exposure on systemic and tissue-level markers of glucose homeostasis and insulin resistance in male mice. Environ Health Perspect 124:1390–1398; http://dx.doi.org/10.1289/EHP162 PMID:27128844

  4. VERSATILITY OF THE COMPLEMENT SYSTEM IN NEUROINFLAMMATION, NEURODEGENERATION AND BRAIN HOMEOSTASIS

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    Franca Orsini

    2014-11-01

    Full Text Available The immune response after brain injury is highly complex and involves both local and systemic events at the cellular and molecular level. It is associated to a dramatic over-activation of enzyme systems, the expression of proinflammatory genes and the activation/recruitment of immune cells. The complement system represents a powerful component of the innate immunity and is highly involved in the inflammatory response. Complement components are synthesized predominantly by the liver and circulate in the bloodstream primed for activation. Moreover, brain cells can produce complement proteins and receptors. After acute brain injury, the rapid and uncontrolled activation of the complement leads to massive release of inflammatory anaphylatoxins, recruitment of cells to the injury site, phagocytosis and induction of blood brain barrier damage. Brain endothelial cells are particularly susceptible to complement-mediated effects, since they are exposed to both circulating and locally synthesized complement proteins. Conversely, during neurodegenerative disorders, complement factors play distinct roles depending on the stage and degree of neuropathology. In addition to the deleterious role of the complement, increasing evidence suggest that it may also play a role in normal nervous system development (wiring the brain and adulthood (either maintaining brain homeostasis or supporting regeneration after brain injury. This article represents a compendium of the current knowledge on the complement role in the brain, prompting a novel view that complement activation can result in either protective or detrimental effects in brain conditions that depend exquisitely on the nature, the timing and the degree of the stimuli that induce its activation. A deeper understanding of the acute, subacute and chronic consequences of complement activation is needed and may lead to new therapeutic strategies, including the ability of targeting selective step in the complement

  5. Preventive effects of procyanidin A2 on glucose homeostasis, pancreatic and duodenal homebox 1, and glucose transporter 2 gene expression disturbance induced by bisphenol A in male mice.

    Science.gov (United States)

    Ahangarpour, A; Afshari, G; Mard, S A; Khodadadi, A; Hashemitabar, M

    2016-04-01

    Procyanidins (PCs) as oligomeric compounds with antidiabetic properties formed from catechin and epicatechin molecules. Bisphenol A(BPA) is a common chemical material use in food and beverage packaging. The aim of this study was to explore the protective effects of procyanidin A2 (PCA2) against glucose homeostasis disturbance and gene expression of pancreatic and duodenal homebox 1 (Pdx1) as well as glucose transporter 2 (Glut2) induced by BPA in male mice. First tested these five concentrations of PCA2 (3 - 300 μM) alone and in combination with BPA(100 μg/L), on insulin secretion from isolated islets at in vitro condition. Next, examined the influence of BPA and PCA2 on islet apoptosis using flowcytometry. At in vivo condition, the BPA (100 μg/kg) and PCA2 (10 μmol/kg) administered for 20 days then, blood glucose and insulin, Pdx1 and, Glut2 genes expression, and oxidative stress markers examined. The results indicated that PCA2 strongly prevents islet cells apoptosis induced by BPA and, co-administration of PCA2 and BPA modified hyperglycemia. BPA reduced Pdx1 and Glut2 mRNA expression and antioxidant level in pancreas tissue, whereas PCA2 prevented from these effects. The findings from these studies suggest that use of PCA2 rich plants have preventive effects on hyperglycemia, and type 2 diabetes. PMID:27226184

  6. Cocoa-rich diet ameliorates hepatic insulin resistance by modulating insulin signaling and glucose homeostasis in Zucker diabetic fatty rats.

    Science.gov (United States)

    Cordero-Herrera, Isabel; Martín, María Ángeles; Escrivá, Fernando; Álvarez, Carmen; Goya, Luis; Ramos, Sonia

    2015-07-01

    Insulin resistance is the primary characteristic of type 2 diabetes and results from insulin signaling defects. Cocoa has been shown to exert anti-diabetic effects by lowering glucose levels. However, the molecular mechanisms responsible for this preventive activity and whether cocoa exerts potential beneficial effects on the insulin signaling pathway in the liver remain largely unknown. Thus, in this study, the potential anti-diabetic properties of cocoa on glucose homeostasis and insulin signaling were evaluated in type 2 diabetic Zucker diabetic fatty (ZDF) rats. Male ZDF rats were fed a control or cocoa-rich diet (10%), and Zucker lean animals received the control diet. ZDF rats supplemented with cocoa (ZDF-Co) showed a significant decrease in body weight gain, glucose and insulin levels, as well as an improved glucose tolerance and insulin resistance. Cocoa-rich diet further ameliorated the hepatic insulin resistance by abolishing the increased serine-phosphorylated levels of the insulin receptor substrate 1 and preventing the inactivation of the glycogen synthase kinase 3/glycogen synthase pathway in the liver of cocoa-fed ZDF rats. The anti-hyperglycemic effect of cocoa appeared to be at least mediated through the decreased levels of hepatic phosphoenolpyruvate carboxykinase and increased values of glucokinase and glucose transporter 2 in the liver of ZDF-Co rats. Moreover, cocoa-rich diet suppressed c-Jun N-terminal kinase and p38 activation caused by insulin resistance. These findings suggest that cocoa has the potential to alleviate both hyperglycemia and hepatic insulin resistance in type 2 diabetic ZDF rats.

  7. The tumor suppressor gene lkb1 is essential for glucose homeostasis during zebrafish early development.

    Science.gov (United States)

    Kuang, Xia; Liu, Chao; Fang, Junshun; Ma, Weirui; Zhang, Jian; Cui, Sheng

    2016-07-01

    The liver kinase B1 (LKB1) is encoded by tumor suppressor gene STK11, which is mutated in Peutz-Jeghers syndrome patients. Lkb1 plays indispensable roles in energy homeostasis. However, how Lkb1 regulates energy homeostasis in vivo remains to be fully understood. We found that inactivation of zebrafish Lkb1 upregulates pyruvate dehydrogenase kinase 2 expression and inactivates pyruvate dehydrogenase complex by increasing phosphorylation of pyruvate dehydrogenase. As a result, glycolysis is significantly enhanced as indicated by increased lactate production, which resembles the Warburg effect in cancer cells. Inhibition of Pdk2 in lkb1 mutants with dichloroacetate, a promising anticancer drug, rescued the lactate production to wild-type level, suggesting the lkb1 mutant may be used to screen compounds targeting aerobic glycolysis in cancer therapy. PMID:27264935

  8. Helicobacter pylori Colonization Ameliorates Glucose Homeostasis in Mice through a PPAR γ-Dependent Mechanism

    OpenAIRE

    Josep Bassaganya-Riera; Maria Gloria Dominguez-Bello; Barbara Kronsteiner; Adria Carbo; Pinyi Lu; Monica Viladomiu; Mireia Pedragosa; Xiaoying Zhang; Sobral, Bruno W.; Mane, Shrinivasrao P.; Mohapatra, Saroj K.; Horne, William T.; Guri, Amir J.; Michael Groeschl; Gabriela Lopez-Velasco

    2012-01-01

    Background: There is an inverse secular trend between the incidence of obesity and gastric colonization with Helicobacter pylori, a bacterium that can affect the secretion of gastric hormones that relate to energy homeostasis. H. pylori strains that carry the cag pathogenicity island (PAI) interact more intimately with gastric epithelial cells and trigger more extensive host responses than cag− strains. We hypothesized that gastric colonization with H. pylori strains differing in cag PAI stat...

  9. Thioredoxin interacting protein is a potential regulator of glucose and energy homeostasis in endogenous Cushing's syndrome.

    Directory of Open Access Journals (Sweden)

    Tove Lekva

    Full Text Available Recent studies have described bone as an endocrine organ regulating glucose metabolism, with insulin signaling regulating osteocalcin secretion and osteocalcin regulating β cell function. We have previously demonstrated increased bone expression of TXNIP in patients with endogenous Cushing's syndrome (CS, and we hypothesized that TXNIP could contribute to the dysregulated glucose metabolism in CS. We studied 33 CS patients and 29 matched controls, with bone biopsies from nine patients, before and after surgical treatment. In vitro, the effect of silencing TXNIP (siTXNIP in osteoblasts, including its effect on human islet cells, was examined. Our major findings were: (i The high mRNA levels of TXNIP in bone from CS patients were significantly associated with high levels of glucose and insulin, increased insulin resistance, and decreased insulin sensitivity in these patients. (ii Silencing TXNIP in osteoblasts enhanced their OC response to insulin and glucose and down-regulated interleukin (IL-8 levels in these cells. (iii Conditional media from siTXNIP-treated osteoblasts promoted insulin content and anti-inflammatory responses in human islet cells. We recently demonstrated that the thioredoxin/TXNIP axis may mediate some detrimental effects of glucocorticoid excess on bone tissue in CS. Here we show that alterations in this axis also may affect glucose metabolism in these patients.

  10. Effect of somatostatin on nonesterified fatty acid levels modifies glucose homeostasis during fasting

    International Nuclear Information System (INIS)

    In the 7-days fasted conscious dog, unlike the postabsorptive conscious dog, somatostatin infusion results in decreased levels of nonesterified fatty acids (NEFA) and increased glucose utilization (Rd) even when insulin and glucagon levels are held constant. The aim of this study was to determine whether NEFA replacement in such animals would prevent the increase in Rd. In each of three protocols there was an 80-min tracer equilibration period, a 40-min basal period, and a 3-h test period. During the test period in the first protocol saline was infused, in the second protocol somatostatin was infused along with intraportal replacement amounts of insulin and glucagon (hormone replacement), while in the third protocol somatostatin plus the pancreatic hormones were infused with concurrent heparin plus Intralipid infusion. Glucose turnover was assessed using [3-3H]glucose. The peripheral levels of insulin, glucagon, and glucose were similar and constant in all three protocols; however, during somatostatin infusion, exogenous glucose infusion was necessary to maintain euglycemia. The NEFA level was constant during saline infusion and decreased in the hormone replacement protocol. In the hormone replacement plus NEFA protocol, the NEFA level did not change during the first 90-min period and then increased during the second 90-min period. After a prolonged fast in the dog, (1) somatostatin directly or indirectly inhibits adipose tissue NEFA release and causes a decrease in the plasma NEFA level, and (2) this decrease in the NEFA level causes an increase in Rd

  11. Rapid, transient drop in brain glucose after intravenous phloretin or 3-0-methyl-D-glucose.

    Science.gov (United States)

    Oldendorf, W H; Crane, P D; Lawner, P M; Braun, L D

    1983-01-01

    Rats were injected intravenously with either phloretin (100 mg/kg) or 3-0-methyl glucose (2 g/kg) to reduce the carrier-mediated flux of glucose into brain. Plasma glucose and brain free glucose (BFG), lactate, and glycogen were measured over a 16 min time course. Injection of these substances caused a rapid drop in BFG to 60% of control at one minute and a minimum (50% of control values) at 4 min., followed by a gradual rise to control levels at 16 min. While plasma glucose fell, and then increased after injection, brain lactate and glycogen content was unaffected. Repeated injections of phloretin eventually caused a drop in brain glycogen; but with either competitor, BFG never fell below 50% of normal values. The i.v. injection of the glucose analog, 3-0-methyl glucose (the less toxic of the two drugs) is proposed as a possible means of cutting off the potentially hazardous supply of blood glucose to the postischemic brain.

  12. Homocysteine homeostasis and betaine-homocysteine S-methyltransferase expression in the brain of hibernating bats.

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    Yijian Zhang

    Full Text Available Elevated homocysteine is an important risk factor that increases cerebrovascular and neurodegenerative disease morbidity. In mammals, B vitamin supplementation can reduce homocysteine levels. Whether, and how, hibernating mammals, that essentially stop ingesting B vitamins, maintain homocysteine metabolism and avoid cerebrovascular impacts and neurodegeneration remain unclear. Here, we compare homocysteine levels in the brains of torpid bats, active bats and rats to identify the molecules involved in homocysteine homeostasis. We found that homocysteine does not elevate in torpid brains, despite declining vitamin B levels. At low levels of vitamin B6 and B12, we found no change in total expression level of the two main enzymes involved in homocysteine metabolism (methionine synthase and cystathionine β-synthase, but a 1.85-fold increase in the expression of the coenzyme-independent betaine-homocysteine S-methyltransferase (BHMT. BHMT expression was observed in the amygdala of basal ganglia and the cerebral cortex where BHMT levels were clearly elevated during torpor. This is the first report of BHMT protein expression in the brain and suggests that BHMT modulates homocysteine in the brains of hibernating bats. BHMT may have a neuroprotective role in the brains of hibernating mammals and further research on this system could expand our biomedical understanding of certain cerebrovascular and neurodegenerative disease processes.

  13. Effect of simvastatin on the expression of farnesoid X receptor in diabetic animal models of altered glucose homeostasis

    Institute of Scientific and Technical Information of China (English)

    Wang Lulu; Huang Xianping; Hu Su; Ma Xiaoli; Wang Shaolian; Pang Shuguang

    2014-01-01

    Background Statin therapy has affected glucose homoeostasis of type 2 diabetes patients,which could be related with bile acids metabolism.Whether bile acid metabolism and the expression of farnesoid X receptor (FXR),liver X receptor-α (LXR-α) and sterol regulatory element-binding protein (Srebp)-1c is regulated by hyperglycemia,or whether simvastatin therapy led to higher glucose is related with down-regulated expression of FXR in diabetic rats remained unclear.Methods Forty male Wistar rats were randomly divided into four groups:normal control rats,insulin resistance rats,diabetic model rats,and the late simvastatin induced diabetic rats.Normal control rats were fed with standard diet,others were fed with high-fat diet.Diabetic model rats were induced by a single intraperitoneal injection of streptozotocin (STZ).The late simvastatin induced diabetic rats started simvastatin administration after STZ induced diabetic model rats.Characteristics of fasting blood glucose (FPG),lipid files and total bile acids (TBAs) were measured and the oral glucose tolerance test (OGTT) was performed after overnight fasting at the eighth weekend.RNA and protein levels of FXR,LXR-α and Srebp-1c were tested by Western blotting and reverse transcription polymerase chain reaction (RT-PCR).Results The insulin resistance rats showed higher glucose,lipid files and lower expression of FXR compared with normal control rats (P >0.05).The diabetic model rats showed significantly higher glucose,lipid files,TBA and lower expression of FXR compared with insulin resistance rats (P <0.05).The late simvastatin induced diabetic rats displayed higher glucose and TBA and lower expression of FXR compared with diabetic model rats (P <0.05).Conclusions Changes in bile acid homeostasis,including the alterations of bile acid levels and bile acid receptors,are either a cause or a consequence of the metabolic disturbances observed during diabetic models.Statin therapy induced hyperglycemia may be

  14. Brain functional magnetic resonance imaging response to glucose and fructose infusions in humans

    Science.gov (United States)

    Objective: In animals, intracerebroventricular glucose and fructose have opposing effects on appetite and weight regulation. In humans, functional brain magnetic resonance imaging (fMRI) studies during carbohydrate ingestion suggest that glucose may regulate HT signaling but are potentially confoun...

  15. Regulatory role of mucosal maltase-glucoamylase in starch digestion and glucose homeostasis

    Science.gov (United States)

    Slower rates of starch digestion by sucrase-isomaltase (Si) in Mgam null mice may fail to regulate gluconeogenesis (GNG). Mgam nulls have 40% reduction of glucose production from starch. The aim of this study was to measure glycemic index and rate of gluconeogenesis (fGNG) as fraction of total gluc...

  16. Mitochondrial ferritin in the regulation of brain iron homeostasis and neurodegenerative diseases

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    Guofen eGao

    2014-02-01

    Full Text Available Mitochondrial ferritin (FtMt is a novel iron-storage protein in mitochondria. Evidences have shown that FtMt is structurally and functionally similar to the cytosolic H-chain ferritin. It protects mitochondria from iron-induced oxidative damage presumably through sequestration of potentially harmful excess free iron. It also participates in the regulation of iron distribution between cytosol and mitochondrial contents. Unlike the ubiquitously expressed H-ferritin, FtMt is mainly expressed in testis and brain, which suggests its tissue-related roles. FtMt is involved in pathogenesis of neurodegenerative diseases, as its increased expression has been observed in Alzheimer’s disease, restless legs syndrome and Friedreich’s ataxia. Studies from our laboratory showed that in Alzheimer’s disease, FtMt overexpression attenuated the β-amyloid induced neurotoxicity, which on the other hand increased significantly when FtMt expression was knocked down. It is also found that, by maintaining mitochondrial iron homeostasis, FtMt could prevent 6-hydroxydopamine induced dopaminergic cell damage in Parkinson’s disease. These recent findings on FtMt regarding its functions in regulation of brain iron homeostasis and its protective role in pathogenesis of neurodegenerative diseases are summarized and reviewed.

  17. The Proton-Activated Receptor GPR4 Modulates Glucose Homeostasis by Increasing Insulin Sensitivity

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    Luca Giudici

    2013-11-01

    Full Text Available Background: The proton-activated G protein-coupled receptor GPR4 is expressed in many tissues including white adipose tissue. GPR4 is activated by extracellular protons in the physiological pH range (i.e. pH 7.7 - 6.8 and is coupled to the production of cAMP. Methods: We examined mice lacking GPR4 and examined glucose tolerance and insulin sensitivity in young and aged mice as well as in mice fed with a high fat diet. Expression profiles of pro- and anti-inflammatory cytokines in white adipose tissue, liver and skeletal muscle was assessed. Results: Here we show that mice lacking GPR4 have an improved intraperitoneal glucose tolerance test and increased insulin sensitivity. Insulin levels were comparable but leptin levels were increased in GPR4 KO mice. Gpr4-/- showed altered expression of PPARα, IL-6, IL-10, TNFα, and TGF-1β in skeletal muscle, white adipose tissue, and liver. High fat diet abolished the differences in glucose tolerance and insulin sensitivity between Gpr4+/+ and Gpr4-/- mice. In contrast, in aged mice (12 months old, the positive effect of GPR4 deficiency on glucose tolerance and insulin sensitivity was maintained. Liver and adipose tissue showed no major differences in the mRNA expression of pro- and anti-inflammatory factors between aged mice of both genotypes. Conclusion: Thus, GPR4 deficiency improves glucose tolerance and insulin sensitivity. The effect may involve an altered balance between pro- and anti-inflammatory factors in insulin target tissues.

  18. Exercise training is an effective alternative to estrogen supplementation for improving glucose homeostasis in ovariectomized rats.

    Science.gov (United States)

    MacDonald, Tara L; Ritchie, Kerry L; Davies, Sarah; Hamilton, Melissa J; Cervone, Daniel T; Dyck, David J

    2015-11-01

    The irreversible loss of estrogen (specifically 17-β-estradiol; E2) compromises whole-body glucose tolerance in women. Hormone replacement therapy (HRT) is frequently prescribed to treat estrogen deficiency, but has several deleterious side effects. Exercise has been proposed as an HRT substitute, however, their relative abilities to treat glucose intolerance are unknown. Thirty ovariectomized (OVX) and 20 SHAM (control) rats underwent glucose tolerance tests (GTT) 10 weeks post surgery. Area under the curve (AUC) for OVX rats was 60% greater than SHAM controls (P = 0.0005). Rats were then randomly assigned to the following treatment groups: SHAM sedentary (sed) or exercise (ex; 60 min, 5×/weeks), OVX sed, ex, or E2 (28 μg/kg bw/day) for 4 weeks. OVX ex rats experienced a ~45% improvement in AUC relative to OVX sed rats, whereas OVX E2 underwent a partial reduction (17%; P = 0.08). Maximal insulin-stimulated glucose uptake in soleus and EDL was not impaired in OVX rats, or augmented with exercise or E2. Akt phosphorylation did not differ in soleus, EDL, or liver of any group. However, OVX ex and OVX E2 experienced greater increases in p-Akt Ser473 in VAT and SQ tissues compared with SHAM and OVX sed groups. Mitochondrial markers CS, COXIV, and core1 were increased in soleus posttraining in OVX ex rats. The content of COXIV was reduced by 52% and 61% in SQ of OVX sed and E2 rats, compared to SHAM controls, but fully restored in OVX ex rats. In summary, exercise restores glucose tolerance in OVX rats more effectively than E2. This is not reflected by alterations in muscle maximal insulin response, but increased insulin signaling in adipose depots may underlie whole-body improvements. PMID:26603453

  19. Magnesium deficiency improves glucose homeostasis in the rat: studies in vivo and in isolated islets in vitro.

    Science.gov (United States)

    Reis, M A; Latorraca, M Q; Carneiro, E M; Boschero, A C; Saad, M J; Velloso, L A; Reyes, F G

    2001-05-01

    The serum mineral levels, glucose disappearance rate (kg), total area under the glucose (DeltaG) and insulin (DeltaI) curves, and static insulin secretion were compared among rats fed a Mg-deficient diet for 6 (DF-6) or 11 (DF-11) weeks, and rats fed a control diet for the same periods (CO-6 and CO-11 groups). No change in glucose homeostasis was observed among DF-6, CO-6 and CO-11 rats. DF-11 rats showed an elevated kg and a reduced DeltaG and DeltaI. For evaluating the effect of supplementation, rats fed a control or Mg-deficient diet for 6 weeks were then fed a Mg- supplemented diet for 5 weeks (SCO and SDF groups respectively). The serum Mg levels in SDF rats were similar to those in CO-11 and SCO rats, but higher than in the DF-11 group. SDF rats showed similar kg, DeltaG and DeltaI compared with the CO-11 and SCO groups. However, a significantly lower kg and higher DeltaG and DeltaI were observed in SDF compared with DF-11 rats. Basal and 8.3 mmol glucose/l-stimulated insulin secretion by islets from DF-11 rats were higher than by islets from CO-11 rats. These results indicate that moderate Mg depletion for a long period may increase the secretion and sensitivity to insulin, while Mg supplementation in formerly Mg-deficient rats may prevent the increase in sensitivity and secretion of insulin. PMID:11348569

  20. Thyroid hormone’s role in regulating brain glucose metabolism and potentially modulating hippocampal cognitive processes

    OpenAIRE

    Jahagirdar, V; McNay, EC

    2012-01-01

    Cognitive performance is dependent on adequate glucose supply to the brain. Insulin, which regulates systemic glucose metabolism, has been recently shown both to regulate hippocampal metabolism and to be a mandatory component of hippocampally-mediated cognitive performance. Thyroid hormones (TH) regulate systemic glucose metabolism and may also be involved in regulation of brain glucose metabolism. Here we review potential mechanisms for such regulation. Importantly, TH imbalance is often enc...

  1. Taurine supplementation ameliorates glucose homeostasis, prevents insulin and glucagon hypersecretion, and controls β, α, and δ-cell masses in genetic obese mice.

    Science.gov (United States)

    Santos-Silva, Junia C; Ribeiro, Rosane Aparecida; Vettorazzi, Jean F; Irles, Esperanza; Rickli, Sarah; Borck, Patrícia C; Porciuncula, Patricia M; Quesada, Ivan; Nadal, Angel; Boschero, Antonio C; Carneiro, Everardo M

    2015-08-01

    Taurine (Tau) regulates β-cell function and glucose homeostasis under normal and diabetic conditions. Here, we assessed the effects of Tau supplementation upon glucose homeostasis and the morphophysiology of endocrine pancreas, in leptin-deficient obese (ob) mice. From weaning until 90-day-old, C57Bl/6 and ob mice received, or not, 5% Tau in drinking water (C, CT, ob and obT). Obese mice were hyperglycemic, glucose intolerant, insulin resistant, and exhibited higher hepatic glucose output. Tau supplementation did not prevent obesity, but ameliorated glucose homeostasis in obT. Islets from ob mice presented a higher glucose-induced intracellular Ca(2+) influx, NAD(P)H production and insulin release. Furthermore, α-cells from ob islets displayed a higher oscillatory Ca(2+) profile at low glucose concentrations, in association with glucagon hypersecretion. In Tau-supplemented ob mice, insulin and glucagon secretion was attenuated, while Ca(2+) influx tended to be normalized in β-cells and Ca(2+) oscillations were increased in α-cells. Tau normalized the inhibitory action of somatostatin (SST) upon insulin release in the obT group. In these islets, expression of the glucagon, GLUT-2 and TRPM5 genes was also restored. Tau also enhanced MafA, Ngn3 and NeuroD mRNA levels in obT islets. Morphometric analysis demonstrated that the hypertrophy of ob islets tends to be normalized by Tau with reductions in islet and β-cell masses, but enhanced δ-cell mass in obT. Our results indicate that Tau improves glucose homeostasis, regulating β-, α-, and δ-cell morphophysiology in ob mice, indicating that Tau may be a potential therapeutic tool for the preservation of endocrine pancreatic function in obesity and diabetes. PMID:25940922

  2. Brain-derived neurotrophic factor inhibits glucose intolerance after cerebral ischemia

    OpenAIRE

    Shu, Xiaoliang; Zhang, Yongsheng; Xu, Han; Kang, Kai; Cai, Donglian

    2013-01-01

    Brain-derived neurotrophic factor is associated with the insulin signaling pathway and glucose tabolism. We hypothesized that expression of brain-derived neurotrophic factor and its receptor may be involved in glucose intolerance following ischemic stress. To verify this hypothesis, this study aimed to observe the changes in brain-derived neurotrophic factor and tyrosine kinase B receptor expression in glucose metabolism-associated regions following cerebral ischemic stress in mice. At day 1 ...

  3. Alteration of brain insulin and leptin signaling promotes energy homeostasis impairment and neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    Taouis Mohammed

    2011-09-01

    Full Text Available The central nervous system (CNS controls vital functions, by efficiently coordinating peripheral and central cascades of signals and networks in a coordinated manner. Historically, the brain was considered to be an insulin-insensitive tissue. But, new findings demonstrating that insulin is present in different regions of themammalian brain, in particular the hypothalamus and the hippocampus. Insulin acts through specific receptors and dialogues with numerous peptides, neurotransmitters and adipokines such as leptin. The cross-talk between leptin and insulin signaling pathways at the hypothalamic level is clearly involved in the control of energy homeostasis. Both hormones are anorexigenic through their action on hypothalamic arcuate nucleus by inducing the expression of anorexigenic neuropetides such as POMC (pro-opiomelanocortin, the precursor of aMSH and reducing the expression of orexigenic neuropeptide such as NPY (Neuropeptide Y. Central defect of insulin and leptin signaling predispose to obesity (leptin-resistant state and type-2 diabetes (insulin resistant state. Obesity and type-2 diabetes are associated to deep alterations in energy homeostasis control but also to other alterations of CNS functions as the predisposition to neurodegenerative diseases such as Alzheimer’s disease (AD. AD is a neurodegenerative disorder characterized by distinct hallmarks within the brain. Postmortem observation of AD brains showed the presence of parenchymal plaques due to the accumulation of the amyloid beta (AB peptide and neurofibrillary tangles. These accumulations result from the hyperphosphorylation of tau (a mictrotubule-interacting protein. Both insulin and leptin have been described to modulate tau phosphorylation and therefore in leptin and insulin resistant states may contribute to AD. The concentrations of leptin and insulin cerebrospinal fluid are decreased type2 diabetes and obese patients. In addition, the concentration of insulin in the

  4. Glucose homeostasis in the intensive care: the end of a cycle

    LENUS (Irish Health Repository)

    Murphy, JFA

    2012-10-01

    Over the last decade there has been extensive literature and debate about blood glucose control in adults and children undergoing intensive care. The concept of tight glycaemic management began in adults and subsequently trickled down to paediatric patients. Hyperglycaemia is known to correlate with the degree of organ failure and death. The central question is whether hyperglycaemia is simply a marker of illness severity or a contributory factor in the patient’s illness. This is of fundamental importance in that it determines whether one should intervene or defer insulin treatment. The other issue is whether treatment with insulin is beneficial or harmful in this ICU setting. Possible explanations for the adverse effects of high glucose include pro-inflammatory responses. It was postulated that lethal perfusion injury to vital organs could be reduced by the prevention of hyperglycaemia with insulin. It was clear that randomised trials were needed to determine the best course of action.

  5. Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system.

    Science.gov (United States)

    Arriola Apelo, Sebastian I; Neuman, Joshua C; Baar, Emma L; Syed, Faizan A; Cummings, Nicole E; Brar, Harpreet K; Pumper, Cassidy P; Kimple, Michelle E; Lamming, Dudley W

    2016-02-01

    Inhibition of the mechanistic target of rapamycin (mTOR) signaling pathway by the FDA-approved drug rapamycin has been shown to promote lifespan and delay age-related diseases in model organisms including mice. Unfortunately, rapamycin has potentially serious side effects in humans, including glucose intolerance and immunosuppression, which may preclude the long-term prophylactic use of rapamycin as a therapy for age-related diseases. While the beneficial effects of rapamycin are largely mediated by the inhibition of mTOR complex 1 (mTORC1), which is acutely sensitive to rapamycin, many of the negative side effects are mediated by the inhibition of a second mTOR-containing complex, mTORC2, which is much less sensitive to rapamycin. We hypothesized that different rapamycin dosing schedules or the use of FDA-approved rapamycin analogs with different pharmacokinetics might expand the therapeutic window of rapamycin by more specifically targeting mTORC1. Here, we identified an intermittent rapamycin dosing schedule with minimal effects on glucose tolerance, and we find that this schedule has a reduced impact on pyruvate tolerance, fasting glucose and insulin levels, beta cell function, and the immune system compared to daily rapamycin treatment. Further, we find that the FDA-approved rapamycin analogs everolimus and temsirolimus efficiently inhibit mTORC1 while having a reduced impact on glucose and pyruvate tolerance. Our results suggest that many of the negative side effects of rapamycin treatment can be mitigated through intermittent dosing or the use of rapamycin analogs. PMID:26463117

  6. Soluble CLEC2 Extracellular Domain Improves Glucose and Lipid Homeostasis by Regulating Liver Kupffer Cell Polarization

    Directory of Open Access Journals (Sweden)

    Xinle Wu

    2015-03-01

    Full Text Available The polarization of tissue resident macrophages toward the alternatively activated, anti-inflammatory M2 phenotype is believed to positively impact obesity and insulin resistance. Here we show that the soluble form of the extracellular domain (ECD of C-type lectin-like receptor 2, CLEC2, regulates Kupffer cell polarization in the liver and improves glucose and lipid parameters in diabetic animal models. Over-expression of Fc-CLEC2(ECD in mice via in vivo gene delivery, or injection of recombinant Fc-CLEC2(ECD protein, results in a reduction of blood glucose and liver triglyceride levels and improves glucose tolerance. Furthermore, Fc-CLEC2(ECD treatment improves cytokine profiles and increases both the M2 macrophage population and the genes involved in the oxidation of lipid metabolism in the liver. These data reveal a previously unidentified role for CLEC2 as a regulator of macrophage polarity, and establish CLEC2 as a promising therapeutic target for treatment of diabetes and liver disease.

  7. Astragalus polysaccharide reduces hepatic endoplasmic reticulum stress and restores glucose homeostasis in a diabetic KKAy mouse model

    Institute of Scientific and Technical Information of China (English)

    Xian-qing MAO; Yong WU; Ke WU; Ming LIU; Jing-fang ZHANG; Feng ZOU; Jing-ping OU-YANG

    2007-01-01

    Aim: To examine the potential effects of Astragalus polysaccharide (APS) on hepatic endoplasmic reticulum (ER) stress in vivo and in vitro and its link with hypoglycemia activity, thus establishing the mechanism underlying the hypogly- cemic action of APS. Methods: The obese and type 2 diabetic KKAy mouse model, which is the yellow offspring of the KK mice expressed Ay2 gene (700 mg·kg-12-d-12, 8 weeks) and a high glucose-induced HepG2 cell model (200 μg/mL, 24 h) were treated with APS. The oral glucose tolerance test was measured to reflex insulin sensitivity with the calculated homeostasis model assessment (HOMA- IR) index. XBP1 (Xho1 site-binding protein 1) transcription and splicing, an indica- tor of ER stress, was analyzed by RT-PCR and real-time PCR. The expression and activation of glycogen synthase kinase 3 beta (GSK3β), an insulin signaling protein, was measured by Western blotting. Results: APS can alleviate ER stress in cul- tured cells in vivo. The hyperglycemia status, systemic insulin sensitivity, fatty liver disease, and insulin action in the liver of diabetic mice were partly normalized or improved in response to APSadministration. Conclusion: Our results indicate that APS enables insulin-sensitizing and hypoglycemic activity at least in part by enhancing the adaptive capacity of the ER, which can further promote insulin signal transduction. Thus, APS has promising application in the treatment of type 2 diabetes.

  8. Hibiscus rosa sinensis Linn. Petals Modulates Glycogen Metabolism and Glucose Homeostasis Signalling Pathway in Streptozotocin-Induced Experimental Diabetes.

    Science.gov (United States)

    Pillai, Sneha S; Mini, S

    2016-03-01

    The prevalence of diabetes mellitus is becoming more and more serious and reaches epidemic proportions worldwide. Scientific research is constantly looking for new agents that could be used as dietary functional ingredients in the fight against diabetes. The objective of the present study was to evaluate the effect of ethyl acetate fraction of Hibiscus rosa sinensis Linn. petals on experimental diabetes at a dose of 25 mg/kg body weight and it was compared with standard anti-diabetic drug metformin. The elevated levels of serum glucose (398.56 ± 35.78) and glycated haemoglobin (12.89 ± 1.89) in diabetic rats were significantly decreased (156.89 ± 14.45 and 6.12 ± 0.49, respectively) by Hibiscus rosa sinensis petals (EHRS) administration. Hepatotoxicity marker enzyme levels in serum were normalized. The fraction supplementation restored the glycogen content by regulating the activities of glycogen metabolizing enzymes. It significantly modulated the expressions of marker genes involved in glucose homeostasis signalling pathway. Histopathological analysis of liver and pancreas supported our findings. The overall effect was comparable with metformin. Hence, our study reveals the role of hibiscus petals for alleviation of diabetes complications, thus it can be propagated as a nutraceutical agent. PMID:26590603

  9. Cognitive Performance: A Cross-Sectional Study on Serum Vitamin D and Its Interplay With Glucose Homeostasis in Dutch Older Adults

    NARCIS (Netherlands)

    Brouwer-Brolsma, E.M.; Dhonukshe-Rutten, R.A.; Wijngaarden, J.P. van; Zwaluw, N.L. van der; Veld, P.H. In 't; Wins, S.; Swart, K.M.; Enneman, A.W.; Ham, A.C. van der; Dijk, S.C. van; Schoor, N.M. van; Velde, N. van der; Uitterlinden, A.G.; Lips, P.; Kessels, R.P.C.; Steegenga, W.T.; Feskens, E.J.M.; Groot, L.C. de

    2015-01-01

    OBJECTIVES: First, the association between serum 25-hydroxyvitamin D (25[OH]D) and cognitive performance was examined. Second, we assessed whether there was evidence for an interplay between 25(OH)D and glucose homeostasis in the association with cognitive performance. DESIGN, SETTING, AND PARTICIPA

  10. Cognitive performance: A cross-sectional study on serum vitamin D and its interplay with glucose homeostasis in Dutch older adults

    NARCIS (Netherlands)

    Brouwer-Brolsma, E.M.; Dhonukshe-Rutten, R.A.M.; Wijngaarden, J.P. van; Zwaluw, N.L. van der; Veld, P.H. in 't; Wins, S.; Swart, K.M.A.; Enneman, A.W.; Ham, A.C.; Dijk, S.C. van; Schoor, N.M. van; Velde, N. van der; Uitterlinden, A.G.; Lips, P.J.; Kessels, R.P.C.; Steegenga, W.T.; Feskens, E.J.M.; Groot, L.C.P.G.M. de

    2015-01-01

    Objectives First, the association between serum 25-hydroxyvitamin D (25[OH]D) and cognitive performance was examined. Second, we assessed whether there was evidence for an interplay between 25(OH)D and glucose homeostasis in the association with cognitive performance. Design, Setting, and Participan

  11. Ribosomal S6K1 in POMC and AgRP Neurons Regulates Glucose Homeostasis but Not Feeding Behavior in Mice

    Directory of Open Access Journals (Sweden)

    Mark A. Smith

    2015-04-01

    Full Text Available Hypothalamic ribosomal S6K1 has been suggested as a point of convergence for hormonal and nutrient signals in the regulation of feeding behavior, bodyweight, and glucose metabolism. However, the long-term effects of manipulating hypothalamic S6K1 signaling on energy homeostasis and the cellular mechanisms underlying these roles are unclear. We therefore inactivated S6K1 in pro-opiomelanocortin (POMC and agouti-related protein (AgRP neurons, key regulators of energy homeostasis, but in contrast to the current view, we found no evidence that S6K1 regulates food intake and bodyweight. In contrast, S6K1 signaling in POMC neurons regulated hepatic glucose production and peripheral lipid metabolism and modulated neuronal excitability. S6K1 signaling in AgRP neurons regulated skeletal muscle insulin sensitivity and was required for glucose sensing by these neurons. Our findings suggest that S6K1 signaling is not a general integrator of energy homeostasis in the mediobasal hypothalamus but has distinct roles in the regulation of glucose homeostasis by POMC and AgRP neurons.

  12. The cannabinoid CB1 receptor and mTORC1 signalling pathways interact to modulate glucose homeostasis in mice.

    Science.gov (United States)

    Bermudez-Silva, Francisco J; Romero-Zerbo, Silvana Y; Haissaguerre, Magalie; Ruz-Maldonado, Inmaculada; Lhamyani, Said; El Bekay, Rajaa; Tabarin, Antoine; Marsicano, Giovanni; Cota, Daniela

    2016-01-01

    The endocannabinoid system (ECS) is an intercellular signalling mechanism that is present in the islets of Langerhans and plays a role in the modulation of insulin secretion and expansion of the β-cell mass. The downstream signalling pathways mediating these effects are poorly understood. Mammalian target of rapamycin complex 1 (mTORC1) signalling is a key intracellular pathway involved in energy homeostasis and is known to importantly affect the physiology of pancreatic islets. We investigated the possible relationship between cannabinoid type 1 (CB1) receptor signalling and the mTORC1 pathway in the endocrine pancreas of mice by using pharmacological analysis as well as mice genetically lacking the CB1 receptor or the downstream target of mTORC1, the kinase p70S6K1. In vitro static secretion experiments on islets, western blotting, and in vivo glucose and insulin tolerance tests were performed. The CB1 receptor antagonist rimonabant decreased glucose-stimulated insulin secretion (GSIS) at 0.1 µM while increasing phosphorylation of p70S6K1 and ribosomal protein S6 (rpS6) within the islets. Specific pharmacological blockade of mTORC1 by 3 nM rapamycin, as well as genetic deletion of p70S6K1, impaired the CB1-antagonist-mediated decrease in GSIS. In vivo experiments showed that 3 mg/kg body weight rimonabant decreased insulin levels and induced glucose intolerance in lean mice without altering peripheral insulin sensitivity; this effect was prevented by peripheral administration of low doses of rapamycin (0.1 mg/kg body weight), which increased insulin sensitivity. These findings suggest a functional interaction between the ECS and the mTORC1 pathway within the endocrine pancreas and at the whole-organism level, which could have implications for the development of new therapeutic approaches for pancreatic β-cell diseases.

  13. Momordica charantia and its novel polypeptide regulate glucose homeostasis in mice via binding to insulin receptor.

    Science.gov (United States)

    Lo, Hsin-Yi; Ho, Tin-Yun; Lin, Chingju; Li, Chia-Cheng; Hsiang, Chien-Yun

    2013-03-13

    Momordica charantia (MC) has been used as an alternative therapy for diabetes mellitus. This study analyzed and elucidated therapeutic targets contributing to the hypoglycemic effect of aqueous extract of MC seeds (MCSE) by transcriptomic analysis. Protein ingredients aimed at the hypoglycemic target were further identified by proteomic, docking, and receptor-binding assays. The data showed that MSCE (1 g/kg) significantly lowered the blood glucose level in normal and diabetic mice. Moreover, MCSE primarily regulated the insulin signaling pathway in muscles and adipose tissues, suggesting that MCSE might target insulin receptor (IR), stimulate the IR-downstream pathway, and subsequently display hypoglycemic activity in mice. It was further revealed that inhibitor against trypsin (TI) of MC directly docked into IR and activated the kinase activity of IR in a dose-dependent manner. In conclusion, the findings suggested that MCSE regulated glucose metabolism mainly via the insulin signaling pathway. Moreover, TI was newly identified as a novel IR-binding protein of MC that triggered the insulin signaling pathway via binding to IR. PMID:23414136

  14. Role of myotonic dystrophy protein kinase (DMPK) in glucose homeostasis and muscle insulin action.

    Science.gov (United States)

    Llagostera, Esther; Catalucci, Daniele; Marti, Luc; Liesa, Marc; Camps, Marta; Ciaraldi, Theodore P; Kondo, Richard; Reddy, Sita; Dillmann, Wolfgang H; Palacin, Manuel; Zorzano, Antonio; Ruiz-Lozano, Pilar; Gomis, Ramon; Kaliman, Perla

    2007-01-01

    Myotonic dystrophy 1 (DM1) is caused by a CTG expansion in the 3'-unstranslated region of the DMPK gene, which encodes a serine/threonine protein kinase. One of the common clinical features of DM1 patients is insulin resistance, which has been associated with a pathogenic effect of the repeat expansions. Here we show that DMPK itself is a positive modulator of insulin action. DMPK-deficient (dmpk-/-) mice exhibit impaired insulin signaling in muscle tissues but not in adipocytes and liver, tissues in which DMPK is not expressed. Dmpk-/- mice display metabolic derangements such as abnormal glucose tolerance, reduced glucose uptake and impaired insulin-dependent GLUT4 trafficking in muscle. Using DMPK mutants, we show that DMPK is required for a correct intracellular trafficking of insulin and IGF-1 receptors, providing a mechanism to explain the molecular and metabolic phenotype of dmpk-/- mice. Taken together, these findings indicate that reduced DMPK expression may directly influence the onset of insulin-resistance in DM1 patients and point to dmpk as a new candidate gene for susceptibility to type 2-diabetes. PMID:17987120

  15. Role of myotonic dystrophy protein kinase (DMPK in glucose homeostasis and muscle insulin action.

    Directory of Open Access Journals (Sweden)

    Esther Llagostera

    Full Text Available Myotonic dystrophy 1 (DM1 is caused by a CTG expansion in the 3'-unstranslated region of the DMPK gene, which encodes a serine/threonine protein kinase. One of the common clinical features of DM1 patients is insulin resistance, which has been associated with a pathogenic effect of the repeat expansions. Here we show that DMPK itself is a positive modulator of insulin action. DMPK-deficient (dmpk-/- mice exhibit impaired insulin signaling in muscle tissues but not in adipocytes and liver, tissues in which DMPK is not expressed. Dmpk-/- mice display metabolic derangements such as abnormal glucose tolerance, reduced glucose uptake and impaired insulin-dependent GLUT4 trafficking in muscle. Using DMPK mutants, we show that DMPK is required for a correct intracellular trafficking of insulin and IGF-1 receptors, providing a mechanism to explain the molecular and metabolic phenotype of dmpk-/- mice. Taken together, these findings indicate that reduced DMPK expression may directly influence the onset of insulin-resistance in DM1 patients and point to dmpk as a new candidate gene for susceptibility to type 2-diabetes.

  16. Regulation of calpain activity in rat brain with altered Ca2+ homeostasis.

    Science.gov (United States)

    Averna, Monica; Stifanese, Roberto; De Tullio, Roberta; Passalacqua, Mario; Defranchi, Enrico; Salamino, Franca; Melloni, Edon; Pontremoli, Sandro

    2007-01-26

    Activation of calpain occurs as an early event in correlation with an increase in [Ca2+]i induced in rat brain upon treatment with a high salt diet for a prolonged period of time. The resulting sequential events have been monitored in the brain of normal and hypertensive rats of the Milan strain, diverging for a constitutive alteration in the level of [Ca2+]i found to be present in nerve cells of hypertensive animals. After 2 weeks of treatment, the levels of the plasma membrane Ca2+-ATPase and of native calpastatin are profoundly decreased. These degradative processes, more pronounced in the brain of hypertensive rats, are progressively and efficiently compensated in the brain of both rat strains by different incoming mechanisms. Along with calpastatin degradation, 15-kDa still-active inhibitory fragments are accumulated, capable of efficiently replacing the loss of native inhibitor molecules. A partial return to a more efficient control of Ca2+ homeostasis occurs in parallel, assured by an early increase in the expression of Ca2+-ATPase and of calpastatin, both producing, after 12 weeks of a high salt (sodium) diet, the restoration of almost original levels of the Ca2+ pump and of significant amounts of native inhibitor molecules. Thus, conservative calpastatin fragmentation, associated with an increased expression of Ca2+-ATPase and of the calpain natural inhibitor, has been demonstrated to occur in vivo in rat brain. This represents a sequential adaptive response capable of overcoming the effects of calpain activation induced by a moderate long term elevation of [Ca2+]i.

  17. Planar Cell Polarity Controls Pancreatic Beta Cell Differentiation and Glucose Homeostasis

    DEFF Research Database (Denmark)

    Cortijo, Cedric; Gouzi, Mathieu; Tissir, Fadel;

    2012-01-01

    Planar cell polarity (PCP) refers to the collective orientation of cells within the epithelial plane. We show that progenitor cells forming the ducts of the embryonic pancreas express PCP proteins and exhibit an active PCP pathway. Planar polarity proteins are acquired at embryonic day 11.......5 synchronously to apicobasal polarization of pancreas progenitors. Loss of function of the two PCP core components Celsr2 and Celsr3 shows that they control the differentiation of endocrine cells from polarized progenitors, with a prevalent effect on insulin-producing beta cells. This results in a decreased...... glucose clearance. Loss of Celsr2 and 3 leads to a reduction of Jun phosphorylation in progenitors, which, in turn, reduces beta cell differentiation from endocrine progenitors. These results highlight the importance of the PCP pathway in cell differentiation in vertebrates. In addition, they reveal...

  18. Altered Brain Response to Drinking Glucose and Fructose in Obese Adolescents.

    Science.gov (United States)

    Jastreboff, Ania M; Sinha, Rajita; Arora, Jagriti; Giannini, Cosimo; Kubat, Jessica; Malik, Saima; Van Name, Michelle A; Santoro, Nicola; Savoye, Mary; Duran, Elvira J; Pierpont, Bridget; Cline, Gary; Constable, R Todd; Sherwin, Robert S; Caprio, Sonia

    2016-07-01

    Increased sugar-sweetened beverage consumption has been linked to higher rates of obesity. Using functional MRI, we assessed brain perfusion responses to drinking two commonly consumed monosaccharides, glucose and fructose, in obese and lean adolescents. Marked differences were observed. In response to drinking glucose, obese adolescents exhibited decreased brain perfusion in brain regions involved in executive function (prefrontal cortex [PFC]) and increased perfusion in homeostatic appetite regions of the brain (hypothalamus). Conversely, in response to drinking glucose, lean adolescents demonstrated increased PFC brain perfusion and no change in perfusion in the hypothalamus. In addition, obese adolescents demonstrated attenuated suppression of serum acyl-ghrelin and increased circulating insulin level after glucose ingestion; furthermore, the change in acyl-ghrelin and insulin levels after both glucose and fructose ingestion was associated with increased hypothalamic, thalamic, and hippocampal blood flow in obese relative to lean adolescents. Additionally, in all subjects there was greater perfusion in the ventral striatum with fructose relative to glucose ingestion. Finally, reduced connectivity between executive, homeostatic, and hedonic brain regions was observed in obese adolescents. These data demonstrate that obese adolescents have impaired prefrontal executive control responses to drinking glucose and fructose, while their homeostatic and hedonic responses appear to be heightened. Thus, obesity-related brain adaptations to glucose and fructose consumption in obese adolescents may contribute to excessive consumption of glucose and fructose, thereby promoting further weight gain. PMID:27207544

  19. Continuous and simultaneous electrochemical measurements of glucose, lactate, and ascorbate in rat brain following brain ischemia.

    Science.gov (United States)

    Lin, Yuqing; Yu, Ping; Hao, Jie; Wang, Yuexiang; Ohsaka, Takeo; Mao, Lanqun

    2014-04-15

    Developing new tools and technologies to enable recording the dynamic changes of multiple neurochemicals is the essence of better understanding of the molecular basis of brain functions. This study demonstrates a microfluidic chip-based online electrochemical system (OECS) for in vivo continuous and simultaneous monitoring of glucose, lactate, and ascorbate in rat brain. To fabricate the microfluidic chip-based detecting system, a microfluidic chip with patterned channel is developed into an electrochemical flow cell by incorporating the chip with three surface-modified indium-tin oxide (ITO) electrodes as working electrodes, a Ag/AgCl wire as reference electrode, and a stainless steel tube as counter electrode. Selective detection of ascorbate is achieved by the use of single-walled carbon nanotubes (SWNTs) to largely facilitate the electrochemical oxidation of ascorbate, while a dehydrogenase-based biosensing mechanism with methylene green (MG) adsorbed onto SWNTs as an electrocatalyst for the oxidation of dihydronicotiamide adenine dinucleotide (NADH) is employed for biosensing of glucose and lactate. To avoid the crosstalk among three sensors, the sensor alignment is carefully designed with the SWNT-modified electrode in the upstream channel and paralleled glucose and lactate biosensors in the downstream channels. With the microfluidic chip-based electrochemical flow cell as the detector, an OECS is successfully established by directly integrating the microfluidic chip-based electrochemical flow cell with in vivo microdialysis. The OECS exhibits a good linear response toward glucose, lactate, and ascorbate with less crosstalk. This property, along with the high stability and selectivity, enables the OECS for continuously monitoring three species in rat brain following brain ischemia. PMID:24621127

  20. Plasma metabolomic profiles reflective of glucose homeostasis in non-diabetic and type 2 diabetic obese African-American women.

    Directory of Open Access Journals (Sweden)

    Oliver Fiehn

    Full Text Available Insulin resistance progressing to type 2 diabetes mellitus (T2DM is marked by a broad perturbation of macronutrient intermediary metabolism. Understanding the biochemical networks that underlie metabolic homeostasis and how they associate with insulin action will help unravel diabetes etiology and should foster discovery of new biomarkers of disease risk and severity. We examined differences in plasma concentrations of >350 metabolites in fasted obese T2DM vs. obese non-diabetic African-American women, and utilized principal components analysis to identify 158 metabolite components that strongly correlated with fasting HbA1c over a broad range of the latter (r = -0.631; p<0.0001. In addition to many unidentified small molecules, specific metabolites that were increased significantly in T2DM subjects included certain amino acids and their derivatives (i.e., leucine, 2-ketoisocaproate, valine, cystine, histidine, 2-hydroxybutanoate, long-chain fatty acids, and carbohydrate derivatives. Leucine and valine concentrations rose with increasing HbA1c, and significantly correlated with plasma acetylcarnitine concentrations. It is hypothesized that this reflects a close link between abnormalities in glucose homeostasis, amino acid catabolism, and efficiency of fuel combustion in the tricarboxylic acid (TCA cycle. It is speculated that a mechanism for potential TCA cycle inefficiency concurrent with insulin resistance is "anaplerotic stress" emanating from reduced amino acid-derived carbon flux to TCA cycle intermediates, which if coupled to perturbation in cataplerosis would lead to net reduction in TCA cycle capacity relative to fuel delivery.

  1. Neuronal SH2B1 is essential for controlling energy and glucose homeostasis

    OpenAIRE

    Ren, Decheng; Zhou, Yingjiang; Morris, David; Li, Minghua; Li, Zhiqin; Rui, Liangyou

    2007-01-01

    SH2B1 (previously named SH2-B), a cytoplasmic adaptor protein, binds via its Src homology 2 (SH2) domain to a variety of protein tyrosine kinases, including JAK2 and the insulin receptor. SH2B1-deficient mice are obese and diabetic. Here we demonstrated that multiple isoforms of SH2B1 (α, β, γ, and/or δ) were expressed in numerous tissues, including the brain, hypothalamus, liver, muscle, adipose tissue, heart, and pancreas. Rat SH2B1β was specifically expressed in neural tissue in SH2B1-tran...

  2. Quantitative Susceptibility Mapping Indicates a Disturbed Brain Iron Homeostasis in Neuromyelitis Optica – A Pilot Study

    Science.gov (United States)

    Granado, Vanessa; Rueda, Fernanda; Deistung, Andreas; Reichenbach, Juergen R.; Tukamoto, Gustavo; Gasparetto, Emerson Leandro; Schweser, Ferdinand

    2016-01-01

    Dysregulation of brain iron homeostasis is a hallmark of many neurodegenerative diseases and can be associated with oxidative stress. The objective of this study was to investigate brain iron in patients with Neuromyelitis Optica (NMO) using quantitative susceptibility mapping (QSM), a quantitative iron-sensitive MRI technique. 12 clinically confirmed NMO patients (6 female and 6 male; age 35.4y±14.2y) and 12 age- and sex-matched healthy controls (7 female and 5 male; age 33.9±11.3y) underwent MRI of the brain at 3 Tesla. Quantitative maps of the effective transverse relaxation rate (R2*) and magnetic susceptibility were calculated and a blinded ROI-based group comparison analysis was performed. Normality of the data and differences between patients and controls were tested by Kolmogorov-Smirnov and t-test, respectively. Correlation with age was studied using Spearman’s rank correlation and an ANCOVA-like analysis. Magnetic susceptibility values were decreased in the red nucleus (p0.95; between -15 and -22 ppb depending on reference region) with a trend toward increasing differences with age. R2* revealed significantly decreased relaxation in the optic radiations of five of the 12 patients (p<0.0001; -3.136±0.567 s-1). Decreased relaxation in the optic radiation is indicative for demyelination, which is in line with previous findings. Decreased magnetic susceptibility in the red nucleus is indicative for a lower brain iron concentration, a chemical redistribution of iron into less magnetic forms, or both. Further investigations are necessary to elucidate the pathological cause or consequence of this finding. PMID:27171423

  3. Calbindin-D9k Ablation Disrupt Glucose/Pancreatic Insulin Homeostasis

    Science.gov (United States)

    Ahn, Changhwan; Lee, Dongoh; Lee, Jae-Hwan; Yang, Hyun; An, Beum-Soo

    2016-01-01

    It has been proposed that cellular Ca2+ signals activate hormone secretion. In pancreatic β cells, which produce insulin, Ca2+ signals have been known to contribute to insulin secretion. Prior to this study, we confirmed that insulin-secreting β cells express CaBP-9k, and assumed that CaBP-9k play a role in β cell insulin synthesis or secretion. Using CaBP-9k knock out (KO) mice, we demonstrated that ablation of CaBP-9k causes reducing insulin secretion and increasing serum glucose. To compare the role of CaBP-9k with pathophysiological conditions, we exposed wild-type and CaBP-9k KO mice to hypoxic conditions for 10 days. Hypoxia induced endoplasmic reticulum (ER) stress, increasing both insulin signaling and insulin resistance. By exposing hypoxia, CaBP-9k KO mice showed an increased level of ER stress marker protein relative to wild type mice. Without hypoxic conditions, CaBP-9K ablation regulates calcium channels and causes ER stress in a CaBP-9K specific manner. Ablation of CaBP-9k also showed decreased levels of sulfonylurea receptor1 (SUR1) and inward-rectifier potassium ion channel 6.2 (Kir6.2), which are insulin secretion marker genes. Overall, the results of the present study demonstrated that CaBP-9k regulates synthesis of insulin and is part of the insulin-secreting calcium signaling. PMID:27736926

  4. Neuronal Rap1 Regulates Energy Balance, Glucose Homeostasis, and Leptin Actions

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    Kentaro Kaneko

    2016-09-01

    Full Text Available The CNS contributes to obesity and metabolic disease; however, the underlying neurobiological pathways remain to be fully established. Here, we show that the small GTPase Rap1 is expressed in multiple hypothalamic nuclei that control whole-body metabolism and is activated in high-fat diet (HFD-induced obesity. Genetic ablation of CNS Rap1 protects mice from dietary obesity, glucose imbalance, and insulin resistance in the periphery and from HFD-induced neuropathological changes in the hypothalamus, including diminished cellular leptin sensitivity and increased endoplasmic reticulum (ER stress and inflammation. Furthermore, pharmacological inhibition of CNS Rap1 signaling normalizes hypothalamic ER stress and inflammation, improves cellular leptin sensitivity, and reduces body weight in mice with dietary obesity. We also demonstrate that Rap1 mediates leptin resistance via interplay with ER stress. Thus, neuronal Rap1 critically regulates leptin sensitivity and mediates HFD-induced obesity and hypothalamic pathology and may represent a potential therapeutic target for obesity treatment.

  5. Effects of 2 Months Aerobic Exercis on Glucose Homeostasis Index and Cardiovascular Risk Factors

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    A Rashidlamir

    2011-06-01

    Full Text Available Introduction: The cause of many metabolic diseases is a progressive increase in fasting insulin levels that is generally associated with inflammatory status. In such conditions, circulating resistin hormonal levels and CRP levels also increase. The aim of the present study was to determine the effect of 2 months aerobic training on insulin resistance and inflammatory markers. Methods: In the study, 30 middle aged healthy men volunteered (Age=38.56±4.77, BMI=25.14±2.16 to participate and based on their body fat percentage were assigned in two equal groups. Experimental group was asked to perform 2 months of aerobic exercise, 4 sessions a week with 60-80% maximum heart rate, while the control group was sedentary during the same period. Blood samples were collected 48 hours before the first session and 48 hours after the last session under similar conditions. Results: Plasma insulin (p≤0.001 and glucose (p≤0.001 levels decreased and consequently insulin resistance index also decreased (p≤0.001 in the experimental group as compared to controls. Also, resistin concentrations increased (p≤0.001, while CRP concentrations decreased (p≤0.001, respectively in the experimental group. Conclusion: In general, it can be concluded that regular aerobic exercise due to improved insulin resistance and plasma levels of two inflammatory markers (CRP and the resistin reduces risk factors of metabolic disease and atherosclerosis and can be used as an effective strategy to prevent such diseases.

  6. Plasma 25-Hydroxyvitamin D Is Related to Protein Signaling Involved in Glucose Homeostasis in a Tissue-Specific Manner

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    Lewan Parker

    2016-10-01

    Full Text Available Vitamin D has been suggested to play a role in glucose metabolism. However, previous findings are contradictory and mechanistic pathways remain unclear. We examined the relationship between plasma 25-hydroxyvitamin D (25(OHD, insulin sensitivity, and insulin signaling in skeletal muscle and adipose tissue. Seventeen healthy adults (Body mass index: 26 ± 4; Age: 30 ± 12 years underwent a hyperinsulinemic-euglycemic clamp, and resting skeletal muscle and adipose tissue biopsies. In this cohort, the plasma 25(OHD concentration was not associated with insulin sensitivity (r = 0.19, p = 0.56. However, higher plasma 25(OHD concentrations correlated with lower phosphorylation of glycogen synthase kinase-3 (GSK-3 αSer21 and βSer9 in skeletal muscle (r = −0.66, p = 0.015 and r = −0.53, p = 0.06, respectively and higher GSK-3 αSer21 and βSer9 phosphorylation in adipose tissue (r = 0.82, p < 0.01 and r = 0.62, p = 0.042, respectively. Furthermore, higher plasma 25(OHD concentrations were associated with greater phosphorylation of both protein kinase-B (AktSer473 (r = 0.78, p < 0.001 and insulin receptor substrate-1 (IRS-1Ser312 (r = 0.71, p = 0.01 in adipose tissue. No associations were found between plasma 25(OHD concentration and IRS-1Tyr612 phosphorylation in skeletal muscle and adipose tissue. The divergent findings between muscle and adipose tissue with regard to the association between 25(OHD and insulin signaling proteins may suggest a tissue-specific interaction with varying effects on glucose homeostasis. Further research is required to elucidate the physiological relevance of 25(OHD in each tissue.

  7. Coffee Consumption, Newly Diagnosed Diabetes, and Other Alterations in Glucose Homeostasis: A Cross-Sectional Analysis of the Longitudinal Study of Adult Health (ELSA-Brasil)

    Science.gov (United States)

    Yarmolinsky, James; Mueller, Noel T.; Duncan, Bruce B.; Bisi Molina, Maria del Carmen; Goulart, Alessandra C.; Schmidt, Maria Inês

    2015-01-01

    Introduction Observational studies have reported fairly consistent inverse associations between coffee consumption and risk of type 2 diabetes, but this association has been little investigated with regard to lesser degrees of hyperglycemia and other alterations in glucose homeostasis. Additionally, the association between coffee consumption and diabetes has been rarely investigated in South American populations. We examined the cross-sectional relationships of coffee intake with newly diagnosed diabetes and measures of glucose homeostasis, insulin sensitivity, and insulin secretion, in a large Brazilian cohort of middle-aged and elderly individuals. Methods We used baseline data from 12,586 participants of the Longitudinal Study of Adult Health (ELSA-Brasil). Logistic regression analyses were performed to examine associations between coffee consumption and newly diagnosed diabetes. Analysis of covariance was used to assess coffee intake in relation to two-hour glucose from an oral glucose tolerance test, fasting glucose, glycated hemoglobin, fasting and –2-hour postload insulin and measures of insulin sensitivity. Results We found an inverse association between coffee consumption and newly diagnosed diabetes, after adjusting for multiple covariates [23% and 26% lower odds of diabetes for those consuming coffee 2–3 and >3 times per day, respectively, compared to those reporting never or almost never consuming coffee, (p = .02)]. An inverse association was also found for 2-hour postload glucose [Never/almost never: 7.57 mmol/L, ≤1 time/day: 7.48 mmol/L, 2-3 times/day: 7.22 mmol/L, >3 times/day: 7.12 mol/L, p3 times/day: 262.2 pmol/L, p = 0.0005) but not with fasting insulin concentrations (p = .58). Conclusion Our present study provides further evidence of a protective effect of coffee on risk of adult-onset diabetes. This effect appears to act primarily, if not exclusively, through postprandial, as opposed to fasting, glucose homeostasis. PMID:25978631

  8. Deterioration of plasticity and metabolic homeostasis in the brain of the UCD-T2DM rat model of naturally occurring type-2 diabetes

    Science.gov (United States)

    Agrawal, Rahul; Zhuang, Yumei; Cummings, Bethany P.; Stanhope, Kimber L.; Graham, James L.; Havel, Peter J.; Gomez-Pinilla, Fernando

    2014-01-01

    The rising prevalence of type-2 diabetes (T2DM) is becoming a pressing issue based on emerging reports that T2DM can also adversely impact mental health. We have utilized the UCD-T2DM rat model in which the onset of T2DM develops spontaneously across time and can serve to understand the pathophysiology of diabetes in humans. An increased insulin resistance index and plasma glucose levels manifested the onset of T2DM. There was a decrease in hippocampal insulin receptor (InR) signaling in the hippocampus, which correlated with peripheral insulin resistance index along the course of diabetes onset (r=−0.56, p< 0.01). T2DM increased the hippocampal levels of 4-hydroxynonenal (4-HNE; a marker of lipid peroxidation) in inverse proportion to the changes in the mitochondrial regulator PGC-1α. Disrupted energy homeostasis was further manifested by a concurrent reduction in energy metabolic markers, including TFAM, SIRT1, and AMPK phosphorylation. In addition, T2DM influenced brain plasticity as evidenced by a significant reduction of BDNF-TrkB signaling. These results suggest that the pathology of T2DM in the brain involves a progressive and coordinated disruption of insulin signaling, and energy homeostasis, with profound consequences for brain function and plasticity. All the described consequences of T2DM were attenuated by treatment with the glucagon-like peptide-1 receptor agonist, liraglutide. Similar results to those of liraglutide were obtained by exposing T2DM rats to a food energy restricted diet, which suggest that normalization of brain energy metabolism is a crucial factor to counteract central insulin sensitivity and synaptic plasticity associated with T2DM. PMID:24840661

  9. The Hijacking of Cellular Signaling and the Diabetes Epidemic: Mechanisms of Environmental Disruption of Insulin Action and Glucose Homeostasis

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    Robert M. Sargis

    2014-02-01

    Full Text Available The burgeoning epidemic of metabolic disease causes significant societal and individual morbidity and threatens the stability of health care systems around the globe. Efforts to understand the factors that contribute to metabolic derangements are critical for reversing these troubling trends. While excess caloric consumption and physical inactivity superimposed on a susceptible genetic background are central drivers of this crisis, these factors alone fail to fully account for the magnitude and rapidity with which metabolic diseases have increased in prevalence worldwide. Recent epidemiological evidence implicates endocrine disrupting chemicals in the pathogenesis of metabolic diseases. These compounds represent a diverse array of chemicals to which humans are exposed via multiple routes in adulthood and during development. Furthermore, a growing ensemble of animal- and cell-based studies provides preclinical evidence supporting the hypothesis that environmental contaminants contribute to the development of metabolic diseases, including diabetes. Herein are reviewed studies linking specific endocrine disruptors to impairments in glucose homeostasis as well as tying these compounds to disturbances in insulin secretion and impairments in insulin signal transduction. While the data remains somewhat incomplete, the current body of evidence supports the hypothesis that our chemically polluted environment may play a contributing role in the current metabolic crisis.

  10. Weight Loss After Bariatric Surgery Reverses Insulin-Induced Increases in Brain Glucose Metabolism of the Morbidly Obese

    OpenAIRE

    Tuulari, Jetro J.; Henry K Karlsson; Hirvonen, Jussi; Hannukainen, Jarna C.; Bucci, Marco; Helmiö, Mika; Ovaska, Jari; Soinio, Minna; Salminen, Paulina; Savisto, Nina; Nummenmaa, Lauri; Nuutila, Pirjo

    2013-01-01

    Obesity and insulin resistance are associated with altered brain glucose metabolism. Here, we studied brain glucose metabolism in 22 morbidly obese patients before and 6 months after bariatric surgery. Seven healthy subjects served as control subjects. Brain glucose metabolism was measured twice per imaging session: with and without insulin stimulation (hyperinsulinemic-euglycemic clamp) using [18F]fluorodeoxyglucose scanning. We found that during fasting, brain glucose metabolism was not dif...

  11. Brain-derived neurotrophic factor inhibits glucose intolerance after cerebral ischemia

    Science.gov (United States)

    Shu, Xiaoliang; Zhang, Yongsheng; Xu, Han; Kang, Kai; Cai, Donglian

    2013-01-01

    Brain-derived neurotrophic factor is associated with the insulin signaling pathway and glucose tabolism. We hypothesized that expression of brain-derived neurotrophic factor and its receptor may be involved in glucose intolerance following ischemic stress. To verify this hypothesis, this study aimed to observe the changes in brain-derived neurotrophic factor and tyrosine kinase B receptor expression in glucose metabolism-associated regions following cerebral ischemic stress in mice. At day 1 after middle cerebral artery occlusion, the expression levels of brain-derived neurotrophic factor were significantly decreased in the ischemic cortex, hypothalamus, liver, skeletal muscle, and pancreas. The expression levels of tyrosine kinase B receptor were decreased in the hypothalamus and liver, and increased in the skeletal muscle and pancreas, but remained unchanged in the cortex. Intrahypothalamic administration of brain-derived neurotrophic factor (40 ng) suppressed the decrease in insulin receptor and tyrosine-phosphorylated insulin receptor expression in the liver and skeletal muscle, and inhibited the overexpression of gluconeogenesis-associated phosphoenolpyruvate carboxykinase and glucose-6-phosphatase in the liver of cerebral ischemic mice. However, serum insulin levels remained unchanged. Our experimental findings indicate that brain-derived neurotrophic factor can promote glucose metabolism, reduce gluconeogenesis, and decrease blood glucose levels after cerebral ischemic stress. The low expression of brain-derived neurotrophic factor following cerebral ischemia may be involved in the development of glucose intolerance. PMID:25206547

  12. Brain-derived neurotrophic factor inhibits glucose intolerance after cerebral ischemia***

    Institute of Scientific and Technical Information of China (English)

    Xiaoliang Shu; Yongsheng Zhang; Han Xu; Kai Kang; Donglian Cai

    2013-01-01

    Brain-derived neurotrophic factor is associated with the insulin signaling pathway and glucose tabolism. We hypothesized that expression of brain-derived neurotrophic factor and its receptor may be involved in glucose intolerance fol owing ischemic stress. To verify this hypothesis, this study aimed to observe the changes in brain-derived neurotrophic factor and tyrosine kinase B receptor expression in glucose metabolism-associated regions fol owing cerebral ischemic stress in mice. At day 1 after middle cerebral artery occlusion, the expression levels of brain-derived neurotrophic factor were significantly decreased in the ischemic cortex, hypothalamus, liver, skeletal muscle, and pancreas. The expression levels of tyrosine kinase B receptor were decreased in the hypothalamus and liver, and increased in the skeletal muscle and pancreas, but remained unchanged in the cortex. Intrahypothalamic administration of brain-derived neurotrophic factor (40 ng) suppressed the de-crease in insulin receptor and tyrosine-phosphorylated insulin receptor expression in the liver and skeletal muscle, and inhibited the overexpression of gluconeogenesis-associated phosphoenolpy-ruvate carboxykinase and glucose-6-phosphatase in the liver of cerebral ischemic mice. However, serum insulin levels remained unchanged. Our experimental findings indicate that brain-derived neurotrophic factor can promote glucose metabolism, reduce gluconeogenesis, and decrease blood glucose levels after cerebral ischemic stress. The low expression of brain-derived neurotrophic factor fol owing cerebral ischemia may be involved in the development of glucose intolerance.

  13. Glucose homeostasis and metabolic adaptation in the pregnant and lactating sheep are affected by the level of nutrition previously provided during her late fetal life

    DEFF Research Database (Denmark)

    Husted, Sanne Munch; Nielsen, Mette Benedicte Olaf; Blache, D.;

    2008-01-01

    This study investigated whether undernutrition (UN) during late fetal life can programme the subsequent adult life adaptation of glucose homeostasis and metabolism during pregnancy and lactation. Twenty-four primiparous experimental ewes were used. Twelve had been exposed to a prenatal NORM level...... of nutrition (maternal diet approximately 15 MJME/d) and 12 to a LOW level of nutrition (maternal diet approximately 7 MJME/d) during the last 6 weeks pre-partum. The experimental ewes were subjected to two intravenous glucose tolerance tests (IGTT) in late gestation (one prior to (G-IGTT) and one by the end...

  14. Hemispherical dominance of glucose metabolic rate in the brain of the 'normal' ageing population

    NARCIS (Netherlands)

    Cutts, DA; Maguire, RP; Leenders, KL; Spyrou, NM

    2004-01-01

    In the 'normal' ageing brain a decrease in the cerebral metabolic rate has been determined across many brain regions. This study determines whether age differences would affect metabolic rates in regions and different hemispheres of the brain. The regional metabolic rate of glucose (rCMRGlu) was exa

  15. Dose and Latency Effects of Leucine Supplementation in Modulating Glucose Homeostasis: Opposite Effects in Healthy and Glucocorticoid-Induced Insulin-Resistance States

    OpenAIRE

    Nelo Eidy Zanchi; Lucas Guimarães-Ferreira; Mário Alves de Siqueira-Filho; Vitor Felitti; Humberto Nicastro; Carlos Bueno; Fábio Santos Lira; Marshall Alan Naimo; Patrícia Campos-Ferraz; Maria Tereza Nunes; Marília Seelaender; Carla Roberta de Oliveira Carvalho; François Blachier; Antonio Herbert Lancha

    2012-01-01

    Dexamethasone (DEXA) is a potent immunosupressant and anti-inflammatory agent whose main side effects are muscle atrophy and insulin resistance in skeletal muscles. In this context, leucine supplementation may represent a way to limit the DEXA side effects. In this study, we have investigated the effects of a low and a high dose of leucine supplementation (via a bolus) on glucose homeostasis, muscle mass and muscle strength in energy-restricted and DEXA-treated rats. Since the leucine respons...

  16. Zinc transporter ZIP14 functions in hepatic zinc, iron and glucose homeostasis during the innate immune response (endotoxemia.

    Directory of Open Access Journals (Sweden)

    Tolunay Beker Aydemir

    altered in the Zip14(-/- mice and their phenotype shows defects in glucose homeostasis.

  17. A role for adipose tissue de novo lipogenesis in glucose homeostasis during catch-up growth: a Randle cycle favoring fat storage.

    Science.gov (United States)

    Marcelino, Helena; Veyrat-Durebex, Christelle; Summermatter, Serge; Sarafian, Delphine; Miles-Chan, Jennifer; Arsenijevic, Denis; Zani, Fabio; Montani, Jean-Pierre; Seydoux, Josiane; Solinas, Giovanni; Rohner-Jeanrenaud, Françoise; Dulloo, Abdul G

    2013-02-01

    Catch-up growth, a risk factor for type 2 diabetes, is characterized by hyperinsulinemia and accelerated body fat recovery. Using a rat model of semistarvation-refeeding that exhibits catch-up fat, we previously reported that during refeeding on a low-fat diet, glucose tolerance is normal but insulin-dependent glucose utilization is decreased in skeletal muscle and increased in adipose tissue, where de novo lipogenic capacity is concomitantly enhanced. Here we report that isocaloric refeeding on a high-fat (HF) diet blunts the enhanced in vivo insulin-dependent glucose utilization for de novo lipogenesis (DNL) in adipose tissue. These are shown to be early events of catch-up growth that are independent of hyperphagia and precede the development of overt adipocyte hypertrophy, adipose tissue inflammation, or defective insulin signaling. These results suggest a role for enhanced DNL as a glucose sink in regulating glycemia during catch-up growth, which is blunted by exposure to an HF diet, thereby contributing, together with skeletal muscle insulin resistance, to the development of glucose intolerance. Our findings are presented as an extension of the Randle cycle hypothesis, whereby the suppression of DNL constitutes a mechanism by which dietary lipids antagonize glucose utilization for storage as triglycerides in adipose tissue, thereby impairing glucose homeostasis during catch-up growth.

  18. Unexpected severe consequences of Pikfyve deletion by aP2- or Aq-promoter-driven Cre expression for glucose homeostasis and mammary gland development.

    Science.gov (United States)

    Ikonomov, Ognian C; Sbrissa, Diego; Delvecchio, Khortnal; Rillema, James A; Shisheva, Assia

    2016-06-01

    Systemic deficiency of PIKfyve, the evolutionarily conserved phosphoinositide kinase synthesizing cellular PtdIns5P and PtdIns(3,5)P2 and implicated in insulin signaling, causes early embryonic death in mice. In contrast, mice with muscle-specific Pikfyve disruption have normal lifespan but exhibit early-age whole-body glucose intolerance and muscle insulin resistance, thus establishing the key role of muscle PIKfyve in glucose homeostasis. Fat and muscle tissues control postprandial glucose clearance through different mechanisms, raising questions as to whether adipose Pikfyve disruption will also trigger whole-body metabolic abnormalities, and if so, what the mechanism might be. To clarify these issues, here we have characterized two new mouse models with adipose tissue disruption of Pikfyve through Cre recombinase expression driven by adipose-specific aP2- or adiponectin (Aq) promoters. Whereas both mouse lines were ostensibly normal until adulthood, their glucose homeostasis and systemic insulin sensitivity were severely dysregulated. These abnormalities stemmed in part from accelerated fat-cell lipolysis and elevated serum FFA Intriguingly, aP2-Cre-PIKfyve(fl/fl) but not Aq-Cre-PIKfyve(fl/fl) females had severely impaired pregnancy-induced mammary gland differentiation and lactogenesis, consistent with aP2-Cre-mediated Pikfyve excision in nonadipogenic tissues underlying this defect. Intriguingly, whereas mammary glands from postpartum control and Aq-Cre-PIKfyve(fl/fl) mice or ex vivo mammary gland explants showed profound upregulation of PIKfyve protein levels subsequent to prolactin receptor activation, such increases were not apparent in aP2-Cre-PIKfyve(fl/fl) females. Collectively, our data identify for the first time that adipose tissue Pikfyve plays a key role in the mechanisms regulating glucose homeostasis and that the PIKfyve pathway is critical in mammary epithelial differentiation during pregnancy and lactogenesis downstream of prolactin receptor

  19. Pancreatic alpha-cell dysfunction contributes to the disruption of glucose homeostasis and compensatory insulin hypersecretion in glucocorticoid-treated rats.

    Directory of Open Access Journals (Sweden)

    Alex Rafacho

    Full Text Available Glucocorticoid (GC-based therapies can cause insulin resistance (IR, glucose intolerance, hyperglycemia and, occasionally, overt diabetes. Understanding the mechanisms behind these metabolic disorders could improve the management of glucose homeostasis in patients undergoing GC treatment. For this purpose, adult rats were treated with a daily injection of dexamethasone (1 mg/kg b.w., i.p. (DEX or saline as a control for 5 consecutive days. The DEX rats developed IR, augmented glycemia, hyperinsulinemia and hyperglucagonemia. Treatment of the DEX rats with a glucagon receptor antagonist normalized their blood glucose level. The characteristic inhibitory effect of glucose on glucagon secretion was impaired in the islets of the DEX rats, while no direct effects were found on α-cells in islets that were incubated with DEX in vitro. A higher proportion of docked secretory granules was found in the DEX α-cells as well as a trend towards increased α-cell mass. Additionally, insulin secretion in the presence of glucagon was augmented in the islets of the DEX rats, which was most likely due to their higher glucagon receptor content. We also found that the enzyme 11βHSD-1, which participates in GC metabolism, contributed to the insulin hypersecretion in the DEX rats under basal glucose conditions. Altogether, we showed that GC treatment induces hyperglucagonemia, which contributes to an imbalance in glucose homeostasis and compensatory β-cell hypersecretion. This hyperglucagonemia may result from altered α-cell function and, likely, α-cell mass. Additionally, blockage of the glucagon receptor seems to be effective in preventing the elevation in blood glucose levels induced by GC administration.

  20. Effects of taurine supplementation and swimming, associated or not, on obesity and glucose homeostasis in mice - 10.4025/actascihealthsci.v34ispec.10433

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    Sandra Lucinei Balbo

    2012-12-01

    Full Text Available Studies show that physical exercise (PE is associated with a reduced fat accumulation and increased insulin sensitivity, and taurine (TAU improves glucose homeostasis in lean rodents. The aim  in this work was evaluate the effects of supplementing TAU and practice of PE, associated or not, on obesity and glucose homeostasis on obese MSG-mice. Neonate male Swiss mice received injections of monosodium glutamate (MSG group or saline (CON group. From the 30th to the 90th day of life, one group of animals received TAU in drinking water (MSG TAU group, another was subjected to PE (MSG PE group and a third group underwent both procedures (MSG PE TAU group. Mice treated with MSG become obese, hypertriglyceridemic, glucose intolerant and insulin resistant. The supplementation with TAU and the PE, isolated or associated, reduced the triglycerides (38%, glucose intolerance (around 30% and KITT (79% in MSG-obese animals, but did not influence the accumulation of fat. Interestingly, the combination of both strategies significantly reduced the insulin resistance, compared to animals subjected to isolated strategies. In conclusion, the supplementation with TAU and PE, isolated or associated, did not influence the accumulation of fat in MSG-obese mice, however, reduce the triglycerides and insulin resistance.  

  1. Relationship of impaired brain glucose metabolism to learning deficit in the senescence-accelerated mouse.

    Science.gov (United States)

    Ohta, H; Nishikawa, H; Hirai, K; Kato, K; Miyamoto, M

    1996-10-11

    The relationship between brain glucose metabolism and learning deficit was examined in the senescence-accelerated-prone mouse (SAMP) 8, which has been proven to be a useful murine model of age-related behavioral disorders. SAMP8, 7 months old, exhibited marked learning impairment in the passive avoidance task, as compared with the control strain, senescence-accelerated-resistant mice (SAMR) 1. SAMP8 also exhibited a reduction in brain glucose metabolism, as indicated by a reduction in [14C]2-deoxyglucose accumulation in the brain following the intravenous injection impaired glucose metabolism correlated significantly with the learning impairment in all brain regions in SAMR1 and SAMP8. In the SAMP8, a significant correlation was observed in the posterior half of the cerebral cortex. These results suggest that the SAMP8 strain is a useful model of not only age-related behavioral disorders, but also glucose hypometabolism observed in aging and dementias. PMID:8905734

  2. The Effects of Empagliflozin, an SGLT2 Inhibitor, on Pancreatic β-Cell Mass and Glucose Homeostasis in Type 1 Diabetes.

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    Sam Tsz Wai Cheng

    Full Text Available The novel sodium glucose co-transporter 2 (SGLT2 inhibitor empagliflozin has recently been reported to improve glycemic control in streptozotocin-induced type 1 diabetic rats in an insulin-independent manner, via an increase in urinary glucose output. We investigated the potential of empagliflozin to recover insulin pathways in type 1 diabetes by improving pancreatic β-cell mass. Blood glucose homeostasis was assessed by an intraperitoneal glucose tolerance test. Serum insulin levels and insulin mRNA expression were determined using commercial insulin ELISA kits and real-time quantitative polymerase chain reaction, respectively. Immunohistochemistry was used to investigate β-cell areas, β-cell proliferation, apoptosis of pancreatic β-cells, and reactive oxygen species production in the pancreatic β-cells. Results showed that glucose tolerance was significantly improved in streptozotocin-induced type 1 diabetic mice treated with empagliflozin. Empagliflozin-treated mice also showed an increase in insulin mRNA expression. Higher serum insulin levels were detected in mice treated with empagliflozin compared with the vehicle group. Immunohistochemistry indicated that β-cell area/total pancreatic area and the expression of cell proliferation marker Ki-67 (co-stained with insulin were significantly enhanced by empagliflozin treatment. These effects were due, probably, to a reduction in apoptosis and reactive oxygen species in the pancreatic β-cells. Taken together, the results of this study indicate that empagliflozin may have a beneficial effect on preserving β-cell regeneration, thus improving blood glucose homeostasis in type 1 diabetes mellitus, probably via the protection of pancreatic β-cell from glucotoxicity-induced oxidative stress.

  3. Exposure to low level of arsenic and lead in drinking water from Antofagasta city induces gender differences in glucose homeostasis in rats.

    Science.gov (United States)

    Palacios, Javier; Roman, Domingo; Cifuentes, Fredi

    2012-08-01

    Populations chronically exposed to arsenic in drinking water often have increased prevalence of diabetes mellitus. The purpose of this study was to compare the glucose homeostasis of male and female rats exposed to low levels of heavy metals in drinking water. Treated groups were Sprague-Dawley male and female rats exposed to drinking water from Antofagasta city, with total arsenic of 30 ppb and lead of 53 ppb for 3 months; control groups were exposed to purified water by reverse osmosis. The two treated groups in both males and females showed arsenic and lead in the hair of rats. The δ-aminolevulinic acid dehydratase was used as a sensitive biomarker of arsenic toxicity and lead. The activity of δ-aminolevulinic acid dehydratase was reduced only in treated male rats, compared to the control group. Treated males showed a significantly sustained increase in blood glucose and plasma insulin levels during oral glucose tolerance test compared to control group. The oral glucose tolerance test and the homeostasis model assessment of insulin resistance demonstrated that male rats were insulin resistant, and females remained sensitive to insulin after treatment. The total cholesterol and LDL cholesterol increased in treated male rats vs. the control, and triglyceride increased in treated female rats vs. the control. The activity of intestinal Na+/glucose cotransporter in male rats increased compared to female rats, suggesting a significant increase in intestinal glucose absorption. The findings indicate that exposure to low levels of arsenic and lead in drinking water could cause gender differences in insulin resistance.

  4. The Effects of Empagliflozin, an SGLT2 Inhibitor, on Pancreatic β-Cell Mass and Glucose Homeostasis in Type 1 Diabetes

    Science.gov (United States)

    Cheng, Sam Tsz Wai; Chen, Lihua; Li, Stephen Yu Ting; Mayoux, Eric; Leung, Po Sing

    2016-01-01

    The novel sodium glucose co-transporter 2 (SGLT2) inhibitor empagliflozin has recently been reported to improve glycemic control in streptozotocin-induced type 1 diabetic rats in an insulin-independent manner, via an increase in urinary glucose output. We investigated the potential of empagliflozin to recover insulin pathways in type 1 diabetes by improving pancreatic β-cell mass. Blood glucose homeostasis was assessed by an intraperitoneal glucose tolerance test. Serum insulin levels and insulin mRNA expression were determined using commercial insulin ELISA kits and real-time quantitative polymerase chain reaction, respectively. Immunohistochemistry was used to investigate β-cell areas, β-cell proliferation, apoptosis of pancreatic β-cells, and reactive oxygen species production in the pancreatic β-cells. Results showed that glucose tolerance was significantly improved in streptozotocin-induced type 1 diabetic mice treated with empagliflozin. Empagliflozin-treated mice also showed an increase in insulin mRNA expression. Higher serum insulin levels were detected in mice treated with empagliflozin compared with the vehicle group. Immunohistochemistry indicated that β-cell area/total pancreatic area and the expression of cell proliferation marker Ki-67 (co-stained with insulin) were significantly enhanced by empagliflozin treatment. These effects were due, probably, to a reduction in apoptosis and reactive oxygen species in the pancreatic β-cells. Taken together, the results of this study indicate that empagliflozin may have a beneficial effect on preserving β-cell regeneration, thus improving blood glucose homeostasis in type 1 diabetes mellitus, probably via the protection of pancreatic β-cell from glucotoxicity-induced oxidative stress. PMID:26807719

  5. Role of exercise-induced brain-derived neurotrophic factor production in the regulation of energy homeostasis in mammals

    DEFF Research Database (Denmark)

    Pedersen, Bente K; Pedersen, Maria; Krabbe, Karen S;

    2009-01-01

    Brain-derived neurotrophic factor (BDNF) has been shown to regulate neuronal development and plasticity and plays a role in learning and memory. Moreover, it is well established that BDNF plays a role in the hypothalamic pathway that controls body weight and energy homeostasis. Recent evidence...... identifies BDNF as a player not only in central metabolism, but also in regulating energy metabolism in peripheral organs. Low levels of BDNF are found in patients with neurodegenerative diseases, including Alzheimer's disease and major depression. In addition, BDNF levels are low in obesity...... and independently so in patients with type 2 diabetes. Brain-derived neurotrophic factor is expressed in non-neurogenic tissues, including skeletal muscle, and exercise increases BDNF levels not only in the brain and in plasma, but in skeletal muscle as well. Brain-derived neurotrophic factor mRNA and protein...

  6. Influence of blood glucose on the expression of glucose transporter proteins 1 and 3 in the brain of diabetic rats

    Institute of Scientific and Technical Information of China (English)

    HOU Wei-kai; FU Chun-li; ZHANG Wen-wen; CHEN Li; XIAN Yu-xin; ZHANG Li; LAI Hong; HOU Xin-guo; XU Yu-xin; YU Ting; XU Fu-yu; SONG Jun

    2007-01-01

    Background The delivery of glucose from the blood to the brain involves its passage across the endothelial cells of the blood-brain barrier (BBB), which is mediated by the facilitative glucose transporter protein 1 (GLUT1), and then across the neural cell membranes, which is mediated by GLUT3. This study aimed to evaluate the dynamic influence of hyperglycemia on the expression of these GLUTs by measuring their expression in the brain at different blood glucose levels in a rat model of diabetes. This might help to determine the proper blood glucose threshold level in the treatment of diabetic apoplexy.Methods Diabetes mellitus was induced with streptozotocin (STZ) in 30 rats. The rats were randomly divided into 3 groups: diabetic group without blood glucose control (group DM1), diabetic rats treated with low dose insulin (group DM2),and diabetic rats treated with high dose insulin (group DM3). The mRNA and protein levels of GLUT1 and GLUT3 were assayed by reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry, respectively.Results Compared with normal control rats, the GLUT1 mRNA was reduced by 46.08%, 29.80%, 19.22% (P<0.01) in DM1, DM2, and DM3 group, respectively; and the GLUT3 mRNA was reduced by 75.00%, 46.75%, and 17.89% (P<0.01)in DM1, DM2, and DM3 group, respectively. The abundance of GLUT1 and GLUT3 proteins had negative correlation with the blood glucose level (P<0.01). The density of microvessels in the brain of diabetic rats did not change significantly compared with normal rats.Conclusions Chronic hyperglycemia downregulates GLUT1 and GLUT3 expression at both mRNA and protein levels in the rat brain, which is not due to the decrease of the density of microvessels. The downregulation of GLUT1 and GLUT3 expression might be the adaptive reaction of the body to prevent excessive glucose entering the cell that may lead to cell damage.

  7. Effect of mild hypothermia on glucose metabolism and glycerol of brain tissue in patients with severe traumatic brain injury

    Institute of Scientific and Technical Information of China (English)

    WANG Qiong; LI Ai-lin; ZHI Da-shi; HUANG Hui-ling

    2007-01-01

    Objective:To study the effect of mild hypothermia on glucose metabolism and glycerol of brain tissue in patients with severe traumatic brain injury (STBI) using clinical microdialysis.Methods: Thirty-one patients with STBI ( GCS ≤8) were randomly divided into hypothermic group (Group A) and control group (Group B). Microdialysis catheters were inserted into the cerebral cortex of perilesional and normal brain tissue. All samples were analyzed using CMA microdialysis analyzer.Results: In comparison with the control group, lactate/glucose ratio ( L/G) , lactate/pyruvate ratio ( L/P) and glycerol (Gly) in perilensional tissue were significantly decreased; L/P in normal brain tissue was significantly decreased. In control group, L/G, L/P and Gly in perilensional tissue were higher than that in normal brain tissue. In the hypothermic group, L/P in perilensional tissue was higher than that in relative normal brain.Conclusions: Mild hypothermia protects brain tissues by decreasing L/G, L/P and Gly in perilensional tissue and L/P in "normal brain" tissues. The energy crisis and membrane phospholipid degradation in perilensional tissue are easier to happen after traumatic brain injury, and mild hypothermia protects brain better in perilensional tissue than in normal brain tissue.

  8. A Thyroid Hormone Challenge in Hypothyroid Rats Identifies T3 Regulated Genes in the Hypothalamus and in Models with Altered Energy Balance and Glucose Homeostasis

    OpenAIRE

    Herwig, Annika; Campbell, Gill; Mayer, Claus-Dieter; Boelen, Anita; Richard A. Anderson; Alexander W Ross; Mercer, Julian G.; Barrett, Perry

    2014-01-01

    Background: The thyroid hormone triiodothyronine (T3) is known to affect energy balance. Recent evidence points to an action of T3 in the hypothalamus, a key area of the brain involved in energy homeostasis, but the components and mechanisms are far from understood. The aim of this study was to identify components in the hypothalamus that may be involved in the action of T3 on energy balance regulatory mechanisms.

  9. Myeloid-Cell-Derived VEGF Maintains Brain Glucose Uptake and Limits Cognitive Impairment in Obesity.

    Science.gov (United States)

    Jais, Alexander; Solas, Maite; Backes, Heiko; Chaurasia, Bhagirath; Kleinridders, André; Theurich, Sebastian; Mauer, Jan; Steculorum, Sophie M; Hampel, Brigitte; Goldau, Julia; Alber, Jens; Förster, Carola Y; Eming, Sabine A; Schwaninger, Markus; Ferrara, Napoleone; Karsenty, Gerard; Brüning, Jens C

    2016-05-01

    High-fat diet (HFD) feeding induces rapid reprogramming of systemic metabolism. Here, we demonstrate that HFD feeding of mice downregulates glucose transporter (GLUT)-1 expression in blood-brain barrier (BBB) vascular endothelial cells (BECs) and reduces brain glucose uptake. Upon prolonged HFD feeding, GLUT1 expression is restored, which is paralleled by increased expression of vascular endothelial growth factor (VEGF) in macrophages at the BBB. In turn, inducible reduction of GLUT1 expression specifically in BECs reduces brain glucose uptake and increases VEGF serum concentrations in lean mice. Conversely, myeloid-cell-specific deletion of VEGF in VEGF(Δmyel) mice impairs BBB-GLUT1 expression, brain glucose uptake, and memory formation in obese, but not in lean mice. Moreover, obese VEGF(Δmyel) mice exhibit exaggerated progression of cognitive decline and neuroinflammation on an Alzheimer's disease background. These experiments reveal that transient, HFD-elicited reduction of brain glucose uptake initiates a compensatory increase of VEGF production and assign obesity-associated macrophage activation a homeostatic role to restore cerebral glucose metabolism, preserve cognitive function, and limit neurodegeneration in obesity. PMID:27133169

  10. p53-upregulated-modulator-of-apoptosis (PUMA) deficiency affects food intake but does not impact on body weight or glucose homeostasis in diet-induced obesity.

    Science.gov (United States)

    Litwak, Sara A; Loh, Kim; Stanley, William J; Pappas, Evan G; Wali, Jibran A; Selck, Claudia; Strasser, Andreas; Thomas, Helen E; Gurzov, Esteban N

    2016-01-01

    BCL-2 proteins have been implicated in the control of glucose homeostasis and metabolism in different cell types. Thus, the aim of this study was to determine the role of the pro-apoptotic BH3-only protein, p53-upregulated-modulator-of-apoptosis (PUMA), in metabolic changes mediated by diet-induced obesity, using PUMA deficient mice. At 10 weeks of age, knockout and wild type mice either continued consuming a low fat chow diet (6% fat), or were fed with a high fat diet (23% fat) for 14-17 weeks. We measured body composition, glucose and insulin tolerance, insulin response in peripheral tissues, energy expenditure, oxygen consumption, and respiratory exchange ratio in vivo. All these parameters were indistinguishable between wild type and knockout mice on chow diet and were modified equally by diet-induced obesity. Interestingly, we observed decreased food intake and ambulatory capacity of PUMA knockout mice on high fat diet. This was associated with increased adipocyte size and fasted leptin concentration in the blood. Our findings suggest that although PUMA is dispensable for glucose homeostasis in lean and obese mice, it can affect leptin levels and food intake during obesity. PMID:27033313

  11. Restricted expression of the erythroid/brain glucose transporter isoform to perivenous hepatocytes in rats. Modulation by glucose.

    OpenAIRE

    Tal, M.; Schneider, D L; Thorens, B.; Lodish, H F

    1990-01-01

    The "erythroid/brain" glucose transporter (GT) isoform is expressed only in a subset of hepatocytes, those forming the first row around the terminal hepatic venules, while the "liver" GT is expressed in all hepatocytes. After 3 d of starvation, a three- to fourfold elevation of expression of the erythroid/brain GT mRNA and protein is detected in the liver as a whole; this correlates with the expression of this GT in more hepatocytes, those forming the first three to four rows around the hepat...

  12. An aqueous extract of Curcuma longa (turmeric) rhizomes stimulates insulin release and mimics insulin action on tissues involved in glucose homeostasis in vitro.

    Science.gov (United States)

    Mohankumar, Sureshkumar; McFarlane, James R

    2011-03-01

    Curcuma longa (turmeric) has been used widely as a spice, particularly in Asian countries. It is also used in the Ayurvedic system of medicine as an antiinflammatory and antimicrobial agent and for numerous other curative properties. The aim of this study was to investigate the effects of an aqueous extract of Curcuma longa (AEC) on tissues involved in glucose homeostasis. The extract was prepared by soaking 100 g of ground turmeric in 1 L of water, which was filtered and stored at -20°C prior to use. Pancreas and muscle tissues of adult mice were cultured in DMEM with 5 or 12 mmol/L glucose and varying doses of extract. The AEC stimulated insulin secretion from mouse pancreatic tissues under both basal and hyperglycaemic conditions, although the maximum effect was only 68% of that of tolbutamide. The AEC induced stepwise stimulation of glucose uptake from abdominal muscle tissues in the presence and absence of insulin, and the combination of AEC and insulin significantly potentiated the glucose uptake into abdominal muscle tissue. However, this effect was attenuated by wortmannin, suggesting that AEC possibly acts via the insulin-mediated glucose uptake pathway. In summary, water soluble compounds of turmeric exhibit insulin releasing and mimicking actions within in vitro tissue culture conditions.

  13. Brain metabolism in autism. Resting cerebral glucose utilization rates as measured with positron emission tomography

    International Nuclear Information System (INIS)

    The cerebral metabolic rate for glucose was studied in ten men (mean age = 26 years) with well-documented histories of infantile autism and in 15 age-matched normal male controls using positron emission tomography and (F-18) 2-fluoro-2-deoxy-D-glucose. Positron emission tomography was completed during rest, with reduced visual and auditory stimulation. While the autistic group as a whole showed significantly elevated glucose utilization in widespread regions of the brain, there was considerable overlap between the two groups. No brain region showed a reduced metabolic rate in the autistic group. Significantly more autistic, as compared with control, subjects showed extreme relative metabolic rates (ratios of regional metabolic rates to whole brain rates and asymmetries) in one or more brain regions

  14. Consumption of added sugars from liquid but not solid sources predicts impaired glucose homeostasis and insulin resistance among youth at risk of obesity.

    Science.gov (United States)

    Wang, Jiawei; Light, Kelly; Henderson, Mélanie; O'Loughlin, Jennifer; Mathieu, Marie-Eve; Paradis, Gilles; Gray-Donald, Katherine

    2014-01-01

    Little is known about longitudinal associations between added sugar consumption (solid and liquid sources) and glucose-insulin homeostasis among youth. Caucasian children (8-10 y) with at least one obese biological parent were recruited in the QUébec Adipose and Lifestyle InvesTigation in Youth (QUALITY) cohort (n = 630) and followed-up 2 y later (n = 564). Added sugars were assessed by 3 24-h dietary recalls at baseline. Two-year changes were examined in multivariate linear regression models, adjusting for baseline level, age, sex, Tanner stage, energy intake, fat mass (dual-energy X-ray absorptiometry), and physical activity (7 d accelerometer). Added sugar intake in either liquid or solid sources was not related to changes in adiposity measures (fat mass, body mass index, or waist circumference). However, a higher consumption (10 g/d) of added sugars from liquid sources was associated with 0.04 mmol/L higher fasting glucose, 2.3 pmol/L higher fasting insulin, 0.1 unit higher homeostasis model assessment of insulin resistance (HOMA-IR), and 0.4 unit lower Matsuda-insulin sensitivity index (Matsuda-ISI) in all participants (P sugars from solid sources. Overweight/obese children at baseline had greater increases in adiposity indicators, fasting insulin, and HOMA-IR and decreases in Matsuda-ISI during those 2 y than normal-weight children. Consumption of added sugars from liquid or solid sources was not associated with changes in adiposity, but liquid added sugars were a risk factor for the development of impaired glucose homeostasis and insulin resistance over 2 y among youth at risk of obesity.

  15. Exposure to Bisphenol-A during Pregnancy Partially Mimics the Effects of a High-Fat Diet Altering Glucose Homeostasis and Gene Expression in Adult Male Mice

    OpenAIRE

    Marta García-Arevalo; Paloma Alonso-Magdalena; Junia Rebelo Dos Santos; Ivan Quesada; Carneiro, Everardo M.; Angel Nadal

    2014-01-01

    Bisphenol-A (BPA) is one of the most widespread EDCs used as a base compound in the manufacture of polycarbonate plastics. The aim of our research has been to study how the exposure to BPA during pregnancy affects weight, glucose homeostasis, pancreatic β-cell function and gene expression in the major peripheral organs that control energy flux: white adipose tissue (WAT), the liver and skeletal muscle, in male offspring 17 and 28 weeks old. Pregnant mice were treated with a subcutaneous injec...

  16. Relationship between regional brain glucose metabolism and temperament factor of personality

    Energy Technology Data Exchange (ETDEWEB)

    Cho, Sang Soo; Lee, Eun Ju; Yoon, Eun Jin; Kim, Yu Kyeong; Lee, Won Woo; Kim, Sang Eun [Seoul National University College of Medicine, Seoul (Korea, Republic of)

    2005-07-01

    Temperament factor of personality has been considered to have correlation with activity in a specific central monoaminergic system. In an attempt to explore neuronal substrate of biogenetic personality traits, we examined the relationship between regional brain glucose metabolism and temperament factor of personality. Twenty right-handed healthy subjects (age, 24{+-}4 yr: 10 females and 10 males) were studied with FDG PET. Their temperaments were assessed using the Temperament and Character Inventory (TCI), which consisted of four temperament factors (harm avoidance (HA), novelty seeking (NS), reward dependence (RD), persistency) and three personality factors. The relationship between regional glucose metabolism and each temperament score was tested using SPM99 (P < 0.005, uncorrected). NS score was negatively correlated with glucose metabolism in the frontal areas, insula, and superior temporal gyrus mainly in the right hemisphere. Positive correlation between NS score and glucose metabolism was observed in the left superior temporal gyrus. HA score showed negative correlation with glucose metabolism in the middle and orbitofrontal gyri as well as in the parahippocampal gyrus. RD score was positively correlated with glucose metabolism in the left middle frontal gyrus and negative correlated in the posterior cingulate gyrus and caudate nucleus. We identified the relationship between regional brain glucose metabolism and temperamental personality trait. Each temperament factor had a relation with functions of specific brain areas. These results help understand biological background of personality and specific feedback circuits associated with each temperament factor.

  17. Acute Alcohol Intoxication Decreases Glucose Metabolism but Increases Acetate Uptake in the Human Brain

    Science.gov (United States)

    Volkow, Nora D.; Kim, Sung Won; Wang, Gene-Jack; Alexoff, David; Logan, Jean; Muench, Lisa; Shea, Colleen; Telang, Frank; Fowler, Joanna S.; Wong, Christopher; Benveniste, Helene; Tomasi, Dardo

    2012-01-01

    Alcohol intoxication results in marked reductions in brain glucose metabolism, which we hypothesized reflect not just its GABAergic enhancing effects but also metabolism of acetate as an alternative brain energy source. To test this hypothesis we separately assessed the effects of alcohol intoxication on brain glucose and acetate metabolism using Positron Emission Tomography (PET). We found that alcohol intoxication significantly decreased whole brain glucose metabolism (measured with FDG) with the largest decrements in cerebellum and occipital cortex and the smallest in thalamus. In contrast, alcohol intoxication caused a significant increase in [1-11C]acetate brain uptake (measured as standard uptake value, SUV), with the largest increases occurring in cerebellum and the smallest in thalamus. In heavy alcohol drinkers [1-11C]acetate brain uptake during alcohol challenge trended to be higher than in occasional drinkers (p <0.06) and the increases in [1-11C]acetate uptake in cerebellum with alcohol were positively associated with the reported amount of alcohol consumed (r=0.66, p<0.01). Our findings corroborate a reduction of brain glucose metabolism during intoxication and document an increase in brain acetate uptake. The opposite changes observed between regional brain metabolic decrements and regional increases in [1-11C]acetate uptake support the hypothesis that during alcohol intoxication the brain may rely on acetate as an alternative brain energy source and provides preliminary evidence that heavy alcohol exposures may facilitate the use of acetate as an energy substrate. These findings raise the question of the potential therapeutic benefits that increasing plasma acetate concentration (ie ketogenic diets) may have in alcoholics undergoing alcohol detoxification. PMID:22947541

  18. Glucose and amino acid metabolism in rat brain during sustained hypoglycemia

    International Nuclear Information System (INIS)

    The metabolism of glucose in brains during sustained hypoglycemia was studied. [U-14C]Glucose (20 microCi) was injected into control rats, and into rats at 2.5 hr after a bolus injection of 2 units of insulin followed by a continuous infusion of 0.2 units/100 g rat/hr. This regimen of insulin injection was found to result in steady-state plasma glucose levels between 2.5 and 3.5 mumol per ml. In the brains of control rats carbon was transferred rapidly from glucose to glutamate, glutamine, gamma-aminobutyric acid and aspartate and this carbon was retained in the amino acids for at least 60 min. In the brains of hypoglycemic rats, the conversion of carbon from glucose to amino acids was increased in the first 15 min after injection. After 15 min, the specific activity of the amino acids decreased in insulin-treated rats but not in the controls. The concentrations of alanine, glutamate, and gamma-amino-butyric acid decreased, and the concentration of aspartate increased, in the brains of the hypoglycemic rats. The concentration of pyridoxal-5'-phosphate, a cofactor in many of the reactions whereby these amino acids are formed from tricarboxylic acid cycle intermediates, was less in the insulin-treated rats than in the controls. These data provide evidence that glutamate, glutamine, aspartate, and GABA can serve as energy sources in brain during insulin-induced hypoglycemia

  19. Changes in Plasma Levels of N-Arachidonoyl Ethanolamine and N-Palmitoylethanolamine following Bariatric Surgery in Morbidly Obese Females with Impaired Glucose Homeostasis

    Directory of Open Access Journals (Sweden)

    Akhila Mallipedhi

    2015-01-01

    Full Text Available Aim. We examined endocannabinoids (ECs in relation to bariatric surgery and the association between plasma ECs and markers of insulin resistance. Methods. A study of 20 participants undergoing bariatric surgery. Fasting and 2-hour plasma glucose, lipids, insulin, and C-peptide were recorded preoperatively and 6 months postoperatively with plasma ECs (AEA, 2-AG and endocannabinoid-related lipids (PEA, OEA. Results. Gender-specific analysis showed differences in AEA, OEA, and PEA preoperatively with reductions in AEA and PEA in females postoperatively. Preoperatively, AEA was correlated with 2-hour glucose (r=0.55, P=0.01, HOMA-IR (r=0.61, P=0.009, and HOMA %S (r=-0.71, P=0.002. OEA was correlated with weight (r=0.49, P=0.03, waist circumference (r=0.52, P=0.02, fasting insulin (r=0.49, P=0.04, and HOMA-IR (r=0.48, P=0.05. PEA was correlated with fasting insulin (r=0.49, P=0.04. 2-AG had a negative correlation with fasting glucose (r=-0.59, P=0.04. Conclusion. Gender differences exist in circulating ECs in obese subjects. Females show changes in AEA and PEA after bariatric surgery. Specific correlations exist between different ECs and markers of obesity and insulin and glucose homeostasis.

  20. Effects of Saturated Fat, Polyunsaturated Fat, Monounsaturated Fat, and Carbohydrate on Glucose-Insulin Homeostasis: A Systematic Review and Meta-analysis of Randomised Controlled Feeding Trials.

    Directory of Open Access Journals (Sweden)

    Fumiaki Imamura

    2016-07-01

    Full Text Available Effects of major dietary macronutrients on glucose-insulin homeostasis remain controversial and may vary by the clinical measures examined. We aimed to assess how saturated fat (SFA, monounsaturated fat (MUFA, polyunsaturated fat (PUFA, and carbohydrate affect key metrics of glucose-insulin homeostasis.We systematically searched multiple databases (PubMed, EMBASE, OVID, BIOSIS, Web-of-Knowledge, CAB, CINAHL, Cochrane Library, SIGLE, Faculty1000 for randomised controlled feeding trials published by 26 Nov 2015 that tested effects of macronutrient intake on blood glucose, insulin, HbA1c, insulin sensitivity, and insulin secretion in adults aged ≥18 years. We excluded trials with non-isocaloric comparisons and trials providing dietary advice or supplements rather than meals. Studies were reviewed and data extracted independently in duplicate. Among 6,124 abstracts, 102 trials, including 239 diet arms and 4,220 adults, met eligibility requirements. Using multiple-treatment meta-regression, we estimated dose-response effects of isocaloric replacements between SFA, MUFA, PUFA, and carbohydrate, adjusted for protein, trans fat, and dietary fibre. Replacing 5% energy from carbohydrate with SFA had no significant effect on fasting glucose (+0.02 mmol/L, 95% CI = -0.01, +0.04; n trials = 99, but lowered fasting insulin (-1.1 pmol/L; -1.7, -0.5; n = 90. Replacing carbohydrate with MUFA lowered HbA1c (-0.09%; -0.12, -0.05; n = 23, 2 h post-challenge insulin (-20.3 pmol/L; -32.2, -8.4; n = 11, and homeostasis model assessment for insulin resistance (HOMA-IR (-2.4%; -4.6, -0.3; n = 30. Replacing carbohydrate with PUFA significantly lowered HbA1c (-0.11%; -0.17, -0.05 and fasting insulin (-1.6 pmol/L; -2.8, -0.4. Replacing SFA with PUFA significantly lowered glucose, HbA1c, C-peptide, and HOMA. Based on gold-standard acute insulin response in ten trials, PUFA significantly improved insulin secretion capacity (+0.5 pmol/L/min; 0.2, 0.8 whether replacing

  1. Glucose administration after traumatic brain injury improves cerebral metabolism and reduces secondary neuronal injury

    OpenAIRE

    Moro, Nobuhiro; Ghavim, Sima; Harris, Neil G.; Hovda, David A.; Sutton, Richard L.

    2013-01-01

    Clinical studies have indicated an association between acute hyperglycemia and poor outcomes in patients with traumatic brain injury (TBI), although optimal blood glucose levels needed to maximize outcomes for these patients’ remains under investigation. Previous results from experimental animal models suggest that post-TBI hyperglycemia may be harmful, neutral, or beneficial. The current studies determined the effects of single or multiple episodes of acute hyperglycemia on cerebral glucose ...

  2. Mice deficient in GEM GTPase show abnormal glucose homeostasis due to defects in beta-cell calcium handling.

    Directory of Open Access Journals (Sweden)

    Jenny E Gunton

    Full Text Available AIMS AND HYPOTHESIS: Glucose-stimulated insulin secretion from beta-cells is a tightly regulated process that requires calcium flux to trigger exocytosis of insulin-containing vesicles. Regulation of calcium handling in beta-cells remains incompletely understood. Gem, a member of the RGK (Rad/Gem/Kir family regulates calcium channel handling in other cell types, and Gem over-expression inhibits insulin release in insulin-secreting Min6 cells. The aim of this study was to explore the role of Gem in insulin secretion. We hypothesised that Gem may regulate insulin secretion and thus affect glucose tolerance in vivo. METHODS: Gem-deficient mice were generated and their metabolic phenotype characterised by in vivo testing of glucose tolerance, insulin tolerance and insulin secretion. Calcium flux was measured in isolated islets. RESULTS: Gem-deficient mice were glucose intolerant and had impaired glucose stimulated insulin secretion. Furthermore, the islets of Gem-deficient mice exhibited decreased free calcium responses to glucose and the calcium oscillations seen upon glucose stimulation were smaller in amplitude and had a reduced frequency. CONCLUSIONS: These results suggest that Gem plays an important role in normal beta-cell function by regulation of calcium signalling.

  3. Magnesium enhances exercise performance via increasing glucose availability in the blood, muscle, and brain during exercise.

    Directory of Open Access Journals (Sweden)

    Hsuan-Ying Chen

    Full Text Available Glucose mobilization and utilization in the periphery and central nervous system are important during exercise and are responsible for exercise efficacy. Magnesium (Mg is involved in energy production and plays a role in exercise performance. This study aimed to explore the effects of Mg on the dynamic changes in glucose and lactate levels in the muscle, blood and brain of exercising rats using a combination of auto-blood sampling and microdialysis. Sprague-Dawley rats were pretreated with saline or magnesium sulfate (MgSO4, 90 mg/kg, i.p. 30 min before treadmill exercise (20 m/min for 60 min. Our results indicated that the muscle, blood, and brain glucose levels immediately increased during exercise, and then gradually decreased to near basal levels in the recovery periods of both groups. These glucose levels were significantly enhanced to approximately two-fold (P<0.05 in the Mg group. Lactate levels in the muscle, blood, and brain rapidly and significantly increased in both groups during exercise, and brain lactate levels in the Mg group further elevated (P<0.05 than those in the control group during exercise. Lactate levels significantly decreased after exercise in both groups. In conclusion, Mg enhanced glucose availability in the peripheral and central systems, and increased lactate clearance in the muscle during exercise.

  4. Cellular pathways of energy metabolism in the brain: is glucose used by neurons or astrocytes?

    Science.gov (United States)

    Nehlig, Astrid; Coles, Jonathan A

    2007-09-01

    Most techniques presently available to measure cerebral activity in humans and animals, i.e. positron emission tomography (PET), autoradiography, and functional magnetic resonance imaging, do not record the activity of neurons directly. Furthermore, they do not allow the investigator to discriminate which cell type is using glucose, the predominant fuel provided to the brain by the blood. Here, we review the experimental approaches aimed at determining the percentage of glucose that is taken up by neurons and by astrocytes. This review is integrated in an overview of the current concepts on compartmentation and substrate trafficking between astrocytes and neurons. In the brain in vivo, about half of the glucose leaving the capillaries crosses the extracellular space and directly enters neurons. The other half is taken up by astrocytes. Calculations suggest that neurons consume more energy than do astrocytes, implying that astrocytes transfer an intermediate substrate to neurons. Experimental approaches in vitro on the honeybee drone retina and on the isolated vagus nerve also point to a continuous transfer of intermediate metabolites from glial cells to neurons in these tissues. Solid direct evidence of such transfer in the mammalian brain in vivo is still lacking. PET using [(18)F]fluorodeoxyglucose reflects in part glucose uptake by astrocytes but does not indicate to which step the glucose taken up is metabolized within this cell type. Finally, the sequence of metabolic changes occurring during a transient increase of electrical activity in specific regions of the brain remains to be clarified. PMID:17659529

  5. The impact of glucose disorders on cognition and brain volumes in the elderly: the Sydney Memory and Ageing Study

    OpenAIRE

    Samaras, Katherine; Lutgers, Helen L.; Kochan, Nicole A.; Crawford, John D.; Campbell, Lesley V; Wen, Wei; Slavin, Melissa J.; Baune, Bernard T.; Lipnicki, Darren M; Brodaty, Henry; Julian N Trollor; Perminder S Sachdev

    2014-01-01

    Type 2 diabetes predicts accelerated cognitive decline and brain atrophy. We hypothesized that impaired fasting glucose (IFG) and incident glucose disorders have detrimental effects on global cognition and brain volume. We further hypothesized that metabolic and inflammatory derangements accompanying hyperglycaemia contribute to change in brain structure and function. This was a longitudinal study of a community-dwelling elderly cohort with neuropsychological testing (n = 880) and brain volum...

  6. Hepatocyte nuclear factor 4 alpha is a key factor related to depression and physiological homeostasis in the mouse brain.

    Directory of Open Access Journals (Sweden)

    Kyosuke Yamanishi

    Full Text Available Major depressive disorder (MDD is a common psychiatric disorder that involves marked disabilities in global functioning, anorexia, and severe medical comorbidities. MDD is associated with not only psychological and sociocultural problems, but also pervasive physical dysfunctions such as metabolic, neurobiological and immunological abnormalities. Nevertheless, the mechanisms underlying the interactions between these factors have yet to be determined in detail. The aim of the present study was to identify the molecular mechanisms responsible for the interactions between MDD and dysregulation of physiological homeostasis, including immunological function as well as lipid metabolism, coagulation, and hormonal activity in the brain. We generated depression-like behavior in mice using chronic mild stress (CMS as a model of depression. We compared the gene expression profiles in the prefrontal cortex (PFC of CMS and control mice using microarrays. We subsequently categorized genes using two web-based bioinformatics applications: Ingenuity Pathway Analysis and The Database for Annotation, Visualization, and Integrated Discovery. We then confirmed significant group-differences by analyzing mRNA and protein expression levels not only in the PFC, but also in the thalamus and hippocampus. These web tools revealed that hepatocyte nuclear factor 4 alpha (Hnf4a may exert direct effects on various genes specifically associated with amine synthesis, such as genes involved in serotonin metabolism and related immunological functions. Moreover, these genes may influence lipid metabolism, coagulation, and hormonal activity. We also confirmed the significant effects of Hnf4a on both mRNA and protein expression levels in the brain. These results suggest that Hnf4a may have a critical influence on physiological homeostasis under depressive states, and may be associated with the mechanisms responsible for the interactions between MDD and the dysregulation of

  7. The resist diabetes trial: Rationale, design, and methods of a hybrid efficacy/effectiveness intervention trial for resistance training maintenance to improve glucose homeostasis in older prediabetic adults.

    Science.gov (United States)

    Marinik, Elaina L; Kelleher, Sarah; Savla, Jyoti; Winett, Richard A; Davy, Brenda M

    2014-01-01

    Advancing age is associated with reduced levels of physical activity, increased body weight and fat, decreased lean body mass, and a high prevalence of type 2 diabetes (T2D). Resistance training (RT) increases muscle strength and lean body mass, and reduces risk of T2D among older adults. The Resist Diabetes trial will determine if a social cognitive theory (SCT)-based intervention improves RT maintenance in older, prediabetic adults, using a hybrid efficacy/effectiveness approach. Sedentary, overweight/obese (BMI: 25-39.9 kg/m(2)) adults aged 50-69 (N = 170) with prediabetes (impaired fasting glucose and/or impaired glucose tolerance) completed a supervised 3-month RT (2×/wk) initiation phase and were then randomly assigned (N = 159; 94% retention) to one of two 6-month maintenance conditions: SCT or standard care. The SCT intervention consisted of faded contacts compared to standard care. Participants continue RT at an approved, self-selected community facility during maintenance. A subsequent 6-month period involves no contact for both conditions. Assessments occur at baseline and months 3 (post-initiation), 9 (post-intervention), and 15 (six months after no contact). Primary outcomes are prediabetes indices (i.e., impaired fasting and 2-hour glucose concentration) and strength. Secondary measures include insulin sensitivity, beta-cell responsiveness, and disposition index (oral glucose and C-peptide minimal model); adherence; body composition; and SCT measures. Resist Diabetes is the first trial to examine the effectiveness of a high fidelity SCT-based intervention for maintaining RT in older adults with prediabetes to improve glucose homeostasis. Successful application of SCT constructs for RT maintenance may support translation of our RT program for diabetes prevention into community settings. PMID:24252311

  8. A palatable hyperlipidic diet causes obesity and affects brain glucose metabolism in rats

    Directory of Open Access Journals (Sweden)

    Motoyama Caio SM

    2011-09-01

    Full Text Available Abstract Background We have previously shown that either the continuous intake of a palatable hyperlipidic diet (H or the alternation of chow (C and an H diet (CH regimen induced obesity in rats. Here, we investigated whether the time of the start and duration of these feeding regimens are relevant and whether they affect brain glucose metabolism. Methods Male Wistar rats received C, H, or CH diets during various periods of their life spans: days 30-60, days 30-90, or days 60-90. Experiments were performed the 60th or the 90th day of life. Rats were killed by decapitation. The glucose, insulin, leptin plasma concentration, and lipid content of the carcasses were determined. The brain was sliced and incubated with or without insulin for the analysis of glucose uptake, oxidation, and the conversion of [1-14C]-glucose to lipids. Results The relative carcass lipid content increased in all of the H and CH groups, and the H30-60 and H30-90 groups had the highest levels. Groups H30-60, H30-90, CH30-60, and CH30-90 exhibited a higher serum glucose level. Serum leptin increased in all H groups and in the CH60-90 and CH30-90 groups. Serum insulin was elevated in the H30-60, H60-90, CH60-90, CH30-90 groups. Basal brain glucose consumption and hypothalamic insulin receptor density were lower only in the CH30-60 group. The rate of brain lipogenesis was increased in the H30-90 and CH30-90 groups. Conclusion These findings indicate that both H and CH diet regimens increased body adiposity independent treatment and the age at which treatment was started, whereas these diets caused hyperglycemia and affected brain metabolism when started at an early age.

  9. Glucose Administration Enhances fMRI Brain Activation and Connectivity Related to Episodic Memory Encoding for Neutral and Emotional Stimuli

    Science.gov (United States)

    Parent, Marise B.; Krebs-Kraft, Desiree L.; Ryan, John P.; Wilson, Jennifer S.; Harenski, Carla; Hamann, Stephan

    2011-01-01

    Glucose enhances memory in a variety of species. In humans, glucose administration enhances episodic memory encoding, although little is known regarding the neural mechanisms underlying these effects. Here we examined whether elevating blood glucose would enhance functional MRI (fMRI) activation and connectivity in brain regions associated with…

  10. Age-and diet-dependent requirement of DJ-1 for glucose homeostasis in mice with implications for human type 2 diabetes

    Institute of Scientific and Technical Information of China (English)

    Deepak Jain; Ruchi Jain; Daniel Eberhard; Jan Eglinger; Marco Bugliani; Lorenzo Piemonti; Piero Marchetti; Eckhard Lammert

    2012-01-01

    Elderly patients often suffer from multiple age-related diseases.Here we show that the expression of DJ-1,an antioxidant protein with reduced expression in the central nervous system of patients with Parkinson's disease,is reduced in pancreatic islets of patients with type 2 diabetes mellitus (T2DM).In contrast,under non-diabetic conditions,DJ-1 expression increases in mouse and human islets during aging.In mouse islets,we show that DJ-1 prevents an increase in reactive oxygen species levels as the mice age.This antioxidant function preserves mitochondrial integrity and physiology,prerequisites for glucose-stimulated insulin secretion.Accordingly,DJ-1-deficient mice develop glucose intolerance and reduced β cell area as they age or gain weight.Our data suggest that DJ-1 is more generally involved in age-and lifestyle-related human diseases and show for the first time that DJ-1 plays a key role in glucose homeostasis and might serve as a novel drug target for T2DM.

  11. Maternal and post-weaning high-fat, high-sucrose diet modulates glucose homeostasis and hypothalamic POMC promoter methylation in mouse offspring.

    Science.gov (United States)

    Zheng, Jia; Xiao, Xinhua; Zhang, Qian; Yu, Miao; Xu, Jianping; Wang, Zhixin; Qi, Cuijuan; Wang, Tong

    2015-10-01

    Substantial evidence demonstrated that maternal dietary nutrients can significantly determine the susceptibility to developing metabolic disorders in the offspring. Therefore, we aimed to investigate the later-life effects of maternal and postweaning diets interaction on epigenetic modification of the central nervous system in the offspring. We examined the effects of dams fed a high-fat, high-sucrose (FS) diet during pregnancy and lactation and weaned to FS diet continuously until 32 weeks of age. Then, DNA methylation and gene expressions of hypothalamic proopiomelanocortin (POMC) and melanocortin receptor 4 (MC4R) were determined in the offspring. Offspring of FS diet had heavier body weight, impaired glucose tolerance, decreased insulin sensitivity and higher serum leptin level at 32-week age (p age (p Maternal and post-weaning high-fat diet predisposes the offspring for obesity, glucose intolerance and insulin resistance in later life. Our findings can advance our thinking around the DNA methylation status of the promoter of the POMC and MC4R genes between long-term high-fat, high-sucrose diet and glucose homeostasis in mouse. PMID:25936720

  12. The effect of long-term taurine supplementation and fructose feeding on glucose and lipid homeostasis in Wistar rats.

    Science.gov (United States)

    Larsen, Lea Hüche; Orstrup, Laura Kofoed Hvidsten; Hansen, Svend Høime; Grunnet, Niels; Quistorff, Bjørn; Mortensen, Ole Hartvig

    2013-01-01

    The nonprotein amino acid taurine has been shown to counteract the negative effects of a high-fructose diet in rats with regard to insulin resistance and dyslipidemia. Here we examined the long-term (26 weeks) effects of oral taurine supplementation (2% in the drinking water) in fructose-fed Wistar rats.The combination of fructose and taurine caused a significant increase in fasting glucose compared to the control diet without changing hepatic phosphoenol pyruvate carboxykinase mRNA levels. The combination of fructose and taurine also improved glucose tolerance compared to control. Neither a high-fructose diet nor taurine supplementation induced significant changes in body weight, body fat or total calorie intake, fasting insulin levels, HOMA-IR, or insulin-induced Akt phosphorylation in skeletal muscle.Fructose alone caused a decrease in liver triglyceride content, with taurine supplementation preventing this. There was no effect of long-term fructose diet and/or taurine supplementation on plasma triglycerides, plasma nonesterified fatty acids, as well as plasma HDL, LDL, and total cholesterol.In conclusion, the study suggests that long-term taurine supplementation improves glucose tolerance and normalize hepatic triglyceride content following long-term fructose feeding. However, as the combination of taurine and fructose also increased fasting glucose levels, the beneficial effect of taurine supplementation towards amelioration of glucose intolerance and insulin resistance may be questionable.

  13. Meta-analysis investigating associations between healthy diet and fasting glucose and insulin levels and modification by loci associated with glucose homeostasis in data from 15 cohorts

    Science.gov (United States)

    Whether loci that influence fasting glucose (FG) and fasting insulin (FI) levels, as identified by genome-wide association studies, modify associations of diet with FG or FI is unknown. We utilized data from 15 US and European cohort studies comprising 51,289 persons without diabetes to test whether...

  14. Deletion of glutamate dehydrogenase in beta-cells abolishes part of the insulin secretory response not required for glucose homeostasis

    DEFF Research Database (Denmark)

    Carobbio, Stefania; Frigerio, Francesca; Rubi, Blanca;

    2009-01-01

    Insulin exocytosis is regulated in pancreatic ss-cells by a cascade of intracellular signals translating glucose levels into corresponding secretory responses. The mitochondrial enzyme glutamate dehydrogenase (GDH) is regarded as a major player in this process, although its abrogation has not been...... tested yet in animal models. Here, we generated transgenic mice, named betaGlud1(-/-), with ss-cell-specific GDH deletion. Our results show that GDH plays an essential role in the full development of the insulin secretory response. In situ pancreatic perfusion revealed that glucose-stimulated insulin...

  15. Parameters of glucose metabolism and the aging brain: a magnetization transfer imaging study of brain macro- and micro-structure in older adults without diabetes

    OpenAIRE

    Akintola, Abimbola A.; VAN DEN BERG, Annette; Altmann-Schneider, Irmhild; Jansen, Steffy W.; van Buchem, Mark A.; Slagboom, P. Eline; Westendorp, Rudi G.; van Heemst, Diana; van der Grond, Jeroen

    2015-01-01

    Given the concurrent, escalating epidemic of diabetes mellitus and neurodegenerative diseases, two age-related disorders, we aimed to understand the relation between parameters of glucose metabolism and indices of pathology in the aging brain. From the Leiden Longevity Study, 132 participants (mean age 66 years) underwent a 2-h oral glucose tolerance test to assess glucose tolerance (fasted and area under the curve (AUC) glucose), insulin sensitivity (fasted and AUC insulin and homeostatic mo...

  16. Control of insulin secretion and glucose homeostasis in exercising diabetic rats with intrasplenic or kidney subcapsular islet grafts

    NARCIS (Netherlands)

    Houwing, H; Hilbrands, LG; VanSuylichem, PTR; Bruggink, JE; Steffens, AB; Strubbe, JH; Hilbrands, Luchiena G.

    1997-01-01

    This study was designed 1) to investigate mechanisms of insulin secretion during exercise after transplantation of islets in the spleen and under the kidney capsule, and 2) to compare these organs as transplantation site regarding an adequate portal or systemic delivery of insulin and glucose homeos

  17. Effect of intracarotid injection of iopamidol on local cerebral glucose utilization in rat brain.

    Science.gov (United States)

    d'Avella, D; Cicciarello, R; Albiero, F; Piscitelli, G; Fiori, M G; Mesiti, M; Princi, P; d'Aquino, S

    1989-01-01

    We assessed, by means of the [14C]-2-deoxy-D-glucose autoradiography method, the effect of intracarotid injection of a nonionic, low-osmolar contrast medium (iopamidol) on local cerebral glucose utilization in the rat brain. Contrast medium was injected at 20 degrees C and at 37 degrees C, and the relative changes in local cerebral glucose utilization were measured. At 20 degrees C the viscosity of the contrast agent was about twice that of the same solution at 37 degrees C, and resulted in a statistically significant increase in local cerebral glucose utilization in the hemisphere ipsilateral to the side of intracarotid infusion. Saline control studies showed that the metabolic change was not related to either the solution temperature or the osmolality. These findings suggest that increased viscosity of a contrast medium may contribute to its neurotoxic effects during cerebral angiography, hence emphasizing the importance of preheating contrast material to avoid adverse reactions.

  18. Assessment of regional glucose metabolism in aging brain and dementia with positron-emission tomography

    Energy Technology Data Exchange (ETDEWEB)

    Reivich, M.; Alavi, A.; Ferris, S.; Christman, D.; Fowler, J.; MacGregor, R.; Farkas, T.; Greenberg, J.; Dann, R.; Wolf, A.

    1981-01-01

    This paper explores the alterations in regional glucose metabolism that occur in elderly subjects and those with senile dementia compared to normal young volunteers. Results showed a tendency for the frontal regions to have a lower metabolic rate in patients with dementia although this did not reach the level of significance when compared to the elderly control subjects. The changes in glucose metabolism were symmetrical in both the left and right hemispheres. There was a lack of correlation between the mean cortical metabolic rates for glucose and the global mental function in the patients with senile dementia. This is at variance with most of the regional cerebral blood flow data that has been collected. This may be partly related to the use of substrates other than glucose by the brain in elderly and demented subjects. (PSB)

  19. Comparison of clinical types of Wilson's disease and glucose metabolism in extrapyramidal motor brain regions.

    Science.gov (United States)

    Hermann, W; Barthel, H; Hesse, S; Grahmann, F; Kühn, H-J; Wagner, A; Villmann, T

    2002-07-01

    In Wilson's disease a disturbed glucose metabolism especially in striatal and cerebellar areas has been reported. This is correlated with the severity of extrapyramidal motor symptoms (EPS). These findings are only based on a small number of patients. Up to now it is unknown whether EPS are caused by various patterns of disturbed basal ganglia glucose metabolism. We investigated 37 patients and 9 normal volunteers to characterize the disturbed glucose metabolism in Wilson's disease more precisely. The glucose metabolism was determined in 5 cerebellar and cerebral areas (putamen, caput nuclei caudati, cerebellum, midbrain and thalamic area) by using (18)F-Fluorodesoxyglucose-Positron-Emission-Tomography ( [(18)F]FDG-PET). The database was evaluated by a cluster analysis. Additionally, the severity extrapyramidal motor symptoms were judged by a clinical score system. Three characteristic patterns of glucose metabolism in basal ganglia were obtained. Two of them may be assigned to patients with neurological symptoms whereas the third cluster corresponds to most patients without EPS or normal volunteers. The clusters can be identified by characteristic consumption rates in this 5 brain areas. The severity of EPS can not clearly be assigned to one of the clusters with disturbed glucose metabolism. However, the most severe cases are characterized by the lowest consumption in the striatal area. When there is marked improvement of EPS impaired glucose consumption reveals a persistent brain lesion. Finally, the neurological symptoms in Wilson's disease are caused by (at least) two different patterns of disturbed glucose metabolism in basal ganglia and cerebellum. The severity of EPS seems to be determined by a disturbed consumption in the striatal area. PMID:12140675

  20. Glucose-coated gold nanoparticles transfer across human brain endothelium and enter astrocytes in vitro.

    Directory of Open Access Journals (Sweden)

    Radka Gromnicova

    Full Text Available The blood-brain barrier prevents the entry of many therapeutic agents into the brain. Various nanocarriers have been developed to help agents to cross this barrier, but they all have limitations, with regard to tissue-selectivity and their ability to cross the endothelium. This study investigated the potential for 4 nm coated gold nanoparticles to act as selective carriers across human brain endothelium and subsequently to enter astrocytes. The transfer rate of glucose-coated gold nanoparticles across primary human brain endothelium was at least three times faster than across non-brain endothelia. Movement of these nanoparticles occurred across the apical and basal plasma membranes via the cytosol with relatively little vesicular or paracellular migration; antibiotics that interfere with vesicular transport did not block migration. The transfer rate was also dependent on the surface coating of the nanoparticle and incubation temperature. Using a novel 3-dimensional co-culture system, which includes primary human astrocytes and a brain endothelial cell line hCMEC/D3, we demonstrated that the glucose-coated nanoparticles traverse the endothelium, move through the extracellular matrix and localize in astrocytes. The movement of the nanoparticles through the matrix was >10 µm/hour and they appeared in the nuclei of the astrocytes in considerable numbers. These nanoparticles have the correct properties for efficient and selective carriers of therapeutic agents across the blood-brain barrier.

  1. Homeostasis of Microglia in the Adult Brain: Review of Novel Microglia Depletion Systems.

    Science.gov (United States)

    Waisman, Ari; Ginhoux, Florent; Greter, Melanie; Bruttger, Julia

    2015-10-01

    Microglia are brain macrophages that emerge from early erythro-myeloid precursors in the embryonic yolk sac and migrate to the brain mesenchyme before the blood brain barrier is formed. They seed the brain, and proliferate until they have formed a grid-like distribution in the central nervous system that is maintained throughout lifespan. The mechanisms through which these embryonic-derived cells contribute to microglia homoeostasis at steady state and upon inflammation are still not entirely clear. Here we review recent studies that provided insight into the contribution of embryonically-derived microglia and of adult 'microglia-like' cells derived from monocytes during inflammation. We examine different microglia depletion models, and discuss the origin of their rapid repopulation after depletion and outline important areas of future research.

  2. Methylphenidate decreased the amount of glucose needed by the brain to perform a cognitive task.

    Directory of Open Access Journals (Sweden)

    Nora D Volkow

    Full Text Available The use of stimulants (methylphenidate and amphetamine as cognitive enhancers by the general public is increasing and is controversial. It is still unclear how they work or why they improve performance in some individuals but impair it in others. To test the hypothesis that stimulants enhance signal to noise ratio of neuronal activity and thereby reduce cerebral activity by increasing efficiency, we measured the effects of methylphenidate on brain glucose utilization in healthy adults. We measured brain glucose metabolism (using Positron Emission Tomography and 2-deoxy-2[18F]fluoro-D-glucose in 23 healthy adults who were tested at baseline and while performing an accuracy-controlled cognitive task (numerical calculations given with and without methylphenidate (20 mg, oral. Sixteen subjects underwent a fourth scan with methylphenidate but without cognitive stimulation. Compared to placebo methylphenidate significantly reduced the amount of glucose utilized by the brain when performing the cognitive task but methylphenidate did not affect brain metabolism when given without cognitive stimulation. Whole brain metabolism when the cognitive task was given with placebo increased 21% whereas with methylphenidate it increased 11% (50% less. This reflected both a decrease in magnitude of activation and in the regions activated by the task. Methylphenidate's reduction of the metabolic increases in regions from the default network (implicated in mind-wandering was associated with improvement in performance only in subjects who activated these regions when the cognitive task was given with placebo. These results corroborate prior findings that stimulant medications reduced the magnitude of regional activation to a task and in addition document a "focusing" of the activation. This effect may be beneficial when neuronal resources are diverted (i.e., mind-wandering or impaired (i.e., attention deficit hyperactivity disorder, but it could be detrimental when

  3. The Action of Antidiabetic Plants of the Canadian James Bay Cree Traditional Pharmacopeia on Key Enzymes of Hepatic Glucose Homeostasis

    OpenAIRE

    Abir Nachar; Diane Vallerand; Lina Musallam; Louis Lavoie; Alaa Badawi; John Arnason; Haddad, Pierre S.

    2013-01-01

    We determined the capacity of putative antidiabetic plants used by the Eastern James Bay Cree (Canada) to modulate key enzymes of gluconeogenesis and glycogen synthesis and key regulating kinases. Glucose-6-phosphatase (G6Pase) and glycogen synthase (GS) activities were assessed in cultured hepatocytes treated with crude extracts of seventeen plant species. Phosphorylation of AMP-dependent protein kinase (AMPK), Akt, and Glycogen synthase kinase-3 (GSK-3) were probed by Western blot. Seven of...

  4. Brain Phosphorus Magnetic Resonance Spectroscopy Imaging of Sleep Homeostasis and Restoration in Drug Dependence

    Directory of Open Access Journals (Sweden)

    George H. Trksak

    2007-01-01

    Full Text Available Numerous reports have documented a high occurrence of sleep difficulties in drug-dependent populations, prompting researchers to characterize sleep profiles and physiology in drug abusing populations. This mini-review examines studies indicating that drug-dependent populations exhibit alterations in sleep homeostatic and restoration processes in response to sleep deprivation. Sleep deprivation is a principal sleep research tool that results in marked physiological challenge, which provides a means to examine sleep homeostatic processes in response to extended wakefulness. A report from our laboratory demonstrated that following recovery sleep from sleep deprivation, brain high-energy phosphates particularly beta–nucleoside triphosphate (beta-NTP are markedly increased as measured with phosphorus magnetic resonance spectroscopy (MRS. A more recent study examined the effects of sleep deprivation in opiate-dependent methadone-maintained (MM subjects. The study demonstrated increases in brain beta-NTP following recovery sleep. Interestingly, these increases were of a markedly greater magnitude in MM subjects compared to control subjects. A similar study examined sleep deprivation in cocaine-dependent subjects demonstrating that cocaine-dependent subjects exhibit greater increases in brain beta-NTP following recovery sleep when compared to control subjects. The studies suggest that sleep deprivation in both MM subjects and cocaine-dependent subjects is characterized by greater changes in brain ATP levels than control subjects. Greater enhancements in brain ATP following recovery sleep may reflect a greater disruption to or impact of sleep deprivation in drug dependent subjects, whereby sleep restoration processes may be unable to properly regulate brain ATP and maintain brain high-energy equilibrium. These studies support the notion of a greater susceptibility to sleep loss in drug dependent populations. Additional sleep studies in drug abusing

  5. The role of DNA base excision repair in brain homeostasis and disease

    DEFF Research Database (Denmark)

    Akbari, Mansour; Morevati, Marya; Croteau, Deborah;

    2015-01-01

    Chemical modification and spontaneous loss of nucleotide bases from DNA are estimated to occur at the rate of thousands per human cell per day. DNA base excision repair (BER) is a critical mechanism for repairing such lesions in nuclear and mitochondrial DNA. Defective expression or function of p...... energy homeostasis, mitochondrial function and cellular bioenergetics, with especially strong influence on neurological function. Further studies in this area could lead to novel approaches to prevent and treat human neurodegenerative disease....... of proteins required for BER or proteins that regulate BER have been consistently associated with neurological dysfunction and disease in humans. Recent studies suggest that DNA lesions in the nuclear and mitochondrial compartments and the cellular response to those lesions have a profound effect on cellular...

  6. Plasma antioxidants and brain glucose metabolism in elderly subjects with cognitive complaints

    Energy Technology Data Exchange (ETDEWEB)

    Picco, Agnese; Ferrara, Michela; Arnaldi, Dario; Brugnolo, Andrea; Nobili, Flavio [University of Genoa and IRCCS San Martino-IST, Clinical Neurology, Department of Neuroscience (DINOGMI), Largo P. Daneo, 3, 16132, Genoa (Italy); Polidori, M.C. [University of Cologne, Institute of Geriatrics, Cologne (Germany); Cecchetti, Roberta; Baglioni, Mauro; Bastiani, Patrizia; Mecocci, Patrizia [University of Perugia, Institute of Gerontology and Geriatrics, Department of Clinical and Experimental Medicine, Perugia (Italy); Morbelli, Silvia; Bossert, Irene [University of Genoa and IRCCS San Martino-IST, Nuclear Medicine, Department of Health Science (DISSAL), Genoa (Italy); Fiorucci, Giuliana; Dottorini, Massimo Eugenio [Nuclear Medicine, S. M. della Misericordia Hospital, Perugia (Italy)

    2014-04-15

    The role of oxidative stress is increasingly recognized in cognitive disorders of the elderly, notably Alzheimer's disease (AD). In these subjects brain{sup 18}F-FDG PET is regarded as a reliable biomarker of neurodegeneration. We hypothesized that oxidative stress could play a role in impairing brain glucose utilization in elderly subjects with increasing severity of cognitive disturbance. The study group comprised 85 subjects with cognitive disturbance of increasing degrees of severity including 23 subjects with subjective cognitive impairment (SCI), 28 patients with mild cognitive impairment and 34 patients with mild AD. In all subjects brain FDG PET was performed and plasma activities of extracellular superoxide dismutase (eSOD), catalase and glutathione peroxidase were measured. Voxel-based analysis (SPM8) was used to compare FDG PET between groups and to evaluate correlations between plasma antioxidants and glucose metabolism in the whole group of subjects, correcting for age and Mini-Mental State Examination score. Brain glucose metabolism progressively decreased in the bilateral posterior temporoparietal and cingulate cortices across the three groups, from SCI to mild AD. eSOD activity was positively correlated with glucose metabolism in a large area of the left temporal lobe including the superior, middle and inferior temporal gyri and the fusiform gyrus. These results suggest a role of oxidative stress in the impairment of glucose utilization in the left temporal lobe structures in elderly patients with cognitive abnormalities, including AD and conditions predisposing to AD. Further studies exploring the oxidative stress-energy metabolism axis are considered worthwhile in larger groups of these patients in order to identify pivotal pathophysiological mechanisms and innovative therapeutic opportunities. (orig.)

  7. The role of GluN2A and GluN2B NMDA receptor subunits in AgRP and POMC neurons on body weight and glucose homeostasis

    Directory of Open Access Journals (Sweden)

    Aykut Üner

    2015-10-01

    Conclusions: GluN2B-containing NMDA receptors in AgRP neurons play a critical role in central control of body weight homeostasis and blood glucose balance via mechanisms that likely involve regulation of AgRP neuronal survival and structure, and modulation of hypothalamic leptin action.

  8. Central serotonergic neurons activate and recruit thermogenic brown and beige fat and regulate glucose and lipid homeostasis

    DEFF Research Database (Denmark)

    McGlashon, Jacob M; Gorecki, Michelle C; Kozlowski, Amanda E;

    2015-01-01

    adipose tissue (WAT). In parallel, blood glucose increased 3.5-fold, free fatty acids 13.4-fold, and triglycerides 6.5-fold. Similar BAT and beige fat defects occurred in Lmx1b(f/f)ePet1(Cre) mice in which 5-HT neurons fail to develop in utero. We conclude 5-HT neurons play a major role in regulating...... diphtheria toxin receptor (DTR) was selectively expressed in central 5-HT neurons. Treatment with diphtheria toxin (DT) eliminated 5-HT neurons and caused loss of thermoregulation, brown adipose tissue (BAT) steatosis, and a >50% decrease in uncoupling protein 1 (Ucp1) expression in BAT and inguinal white...

  9. Exposure to bisphenol-A during pregnancy partially mimics the effects of a high-fat diet altering glucose homeostasis and gene expression in adult male mice.

    Directory of Open Access Journals (Sweden)

    Marta García-Arevalo

    Full Text Available Bisphenol-A (BPA is one of the most widespread EDCs used as a base compound in the manufacture of polycarbonate plastics. The aim of our research has been to study how the exposure to BPA during pregnancy affects weight, glucose homeostasis, pancreatic β-cell function and gene expression in the major peripheral organs that control energy flux: white adipose tissue (WAT, the liver and skeletal muscle, in male offspring 17 and 28 weeks old. Pregnant mice were treated with a subcutaneous injection of 10 µg/kg/day of BPA or a vehicle from day 9 to 16 of pregnancy. One month old offspring were divided into four different groups: vehicle treated mice that ate a normal chow diet (Control group; BPA treated mice that also ate a normal chow diet (BPA; vehicle treated animals that had a high fat diet (HFD and BPA treated animals that were fed HFD (HFD-BPA. The BPA group started to gain weight at 18 weeks old and caught up to the HFD group before week 28. The BPA group as well as the HFD and HFD-BPA ones presented fasting hyperglycemia, glucose intolerance and high levels of non-esterified fatty acids (NEFA in plasma compared with the Control one. Glucose stimulated insulin release was disrupted, particularly in the HFD-BPA group. In WAT, the mRNA expression of the genes involved in fatty acid metabolism, Srebpc1, Pparα and Cpt1β was decreased by BPA to the same extent as with the HFD treatment. BPA treatment upregulated Pparγ and Prkaa1 genes in the liver; yet it diminished the expression of Cd36. Hepatic triglyceride levels were increased in all groups compared to control. In conclusion, male offspring from BPA-treated mothers presented symptoms of diabesity. This term refers to a form of diabetes which typically develops in later life and is associated with obesity.

  10. EFFECTS OF ADDROGRAPHIS PANICULATA (NEES. ON ARSENIC- INDUCED ALTERED GLUCOSE HOMEOSTASIS AND OXIDATIVE IMPAIRMENT IN PANCREAS OF SWISS MICE

    Directory of Open Access Journals (Sweden)

    MANDAVA V. RAO

    2007-01-01

    Full Text Available The effect of Andrographis paniculata (Nees. on arsenic-induced changes in biochemical and cellular antioxident sytem was studies in adult female mice. Daily oral administration of arsenic trioxide (0.5 and 1.0mg/kg b.w for 30days induced a significant increase in blood glucose level which was associated with impaired glucose tolrence. Arsenic treatment also resulted in elevated level panreatic tissue specific makers such as activities of amylase and lipase in serum indicating pancreatic dysfunction. Interestingly, this biochemical dysfuntion was accompanied by a marked dose related enchancement of lipid peroxidation indicating significant induction of oxidative damage. Additional evidence such as deletion in reduced gluatathione levels and alterations in enzymic antioxidant defences like superoxide dismutase, catalase and glutathione peroxidase in pancreas suggested induction of oxidative stress. Concomitant administration of Adrographis paniculata (50 mg/kg b.w. with arsenic significant restored all these parameters. These results suggest that Adrographis paniculata is capable to reducing arsenic-induce cellular oxidative and inflammatory changes in pancreas.

  11. Reduced cerebral glucose metabolism and increased brain capillary permeability following high-dose methotrexate chemotherapy: a positron emission tomographic study

    International Nuclear Information System (INIS)

    Regional glucose metabolic rate constants and blood-to-brain transport of rubidium were estimated using positron emission tomography in an adolescent patient with a brain tumor, before and after chemotherapy with intravenous high-dose methotrexate. Widespread depression of cerebral glucose metabolism was apparent 24 hours after drug administration, which may reflect reduced glucose phosphorylation, and the influx rate constant for 82Rb was increased, indicating a drug-induced alteration in blood-brain barrier function. Associated changes in neuropsychological performance, electroencephalogram, and plasma amino acid concentration were identified in the absence of evidence of systemic methotrexate toxicity, suggesting primary methotrexate neurotoxicity

  12. Glucose metabolism of fetal rat brain in utero, measured with labeled deoxyglucose

    International Nuclear Information System (INIS)

    Mammals have low cerebral metabolic rates immediately after birth and, by inference, also before birth. In this study, we extended the deoxyglucose method to the fetal rat brain in utero. Rate constants for deoxyglucose transfer across the maternal placental and fetal blood-brain barriers, and lumped constant, have not been reported. Therefore, we applied a new method of determining the lumped constant regionally to the fetal rat brain in utero. The lumped constant averaged 0.55 ± 0.15 relative to the maternal circulation. On this basis, we determined the glucose metabolic rate of the fetal rat brain to be one third of the corresponding maternal value, or 19 ± 2 μmol hg-1 min-1. (author)

  13. Depleted uranium induces disruption of energy homeostasis and oxidative stress in isolated rat brain mitochondria.

    Science.gov (United States)

    Shaki, Fatemeh; Hosseini, Mir-Jamal; Ghazi-Khansari, Mahmoud; Pourahmad, Jalal

    2013-06-01

    Depleted uranium (DU) is emerging as an environmental pollutant primarily due to its military applications. Gulf War veterans with embedded DU showed cognitive disorders that suggest that the central nervous system is a target of DU. Recent evidence has suggested that DU could induce oxidative stress and mitochondrial dysfunction in brain tissue. However, the underlying mechanisms of DU toxicity in brain mitochondria are not yet well understood. Brain mitochondria were obtained using differential centrifugation and were incubated with different concentrations (50, 100 and 200 μM) of uranyl acetate (UA) as a soluble salt of U(238) for 1 h. In this research, mitochondrial ROS production, collapse of mitochondrial membrane potential and mitochondrial swelling were examined by flow cytometry following the addition of UA. Meanwhile, mitochondrial sources of ROS formation were determined using specific substrates and inhibitors. Complex II and IV activity and also the extent of lipid peroxidation and glutathione (GSH) oxidation were detected via spectroscopy. Furthermore, we investigated the concentration of ATP and ATP/ADP ratio using luciferase enzyme and cytochrome c release from mitochondria which was detected by ELISA kit. UA caused concentration-dependent elevation of succinate-linked mitochondrial ROS production, lipid peroxidation, GSH oxidation and inhibition of mitochondrial complex II. UA also induced mitochondrial permeability transition, ATP production decrease and increase in cytochrome c release. Pre-treatment with antioxidants significantly inhibited all the above mentioned toxic effects of UA. This study suggests that mitochondrial oxidative stress and impairment of oxidative phosphorylation in brain mitochondria may play a key role in DU neurotoxicity as reported in Gulf War Syndrome. PMID:23629690

  14. Classic and novel stem cell niches in brain homeostasis and repair.

    Science.gov (United States)

    Lin, Ruihe; Iacovitti, Lorraine

    2015-12-01

    Neural stem cells (NSCs) critical for the continued production of new neurons and glia are sequestered in distinct areas of the brain called stem cell niches. Until recently, only two forebrain sites, the subventricular zone (SVZ) of the anterolateral ventricle and the subgranular zone (SGZ) of the hippocampus, have been recognized adult stem cell niches (Alvarez-Buylla and Lim, 2004; Doetsch et al., 1999a, 1999b; Doetsch, 2003a, 2003b; Lie et al., 2004; Ming and Song, 2005). Nonetheless, the last decade has been witness to a growing literature suggesting that in fact the adult brain contains stem cell niches along the entire extent of the ventricular system. These niches are capable of widespread neurogenesis and gliogenesis, particularly after injury (Barnabé-Heider et al., 2010; Carlén et al., 2009; Decimo et al., 2012; Lin et al., 2015; Lindvall and Kokaia, 2008; Robins et al., 2013) or other inductive stimuli (Bennett et al., 2009; Cunningham et al., 2012; Decimo et al., 2011; Kokoeva et al., 2007, 2005; Lee et al., 2012a, 2012b; Migaud et al., 2010; Pencea et al., 2001b; Sanin et al., 2013; Suh et al., 2007; Sundholm-Peters et al., 2004; Xu et al., 2005; Zhang et al., 2007). This review focuses on the role of these novel and classic brain niches in maintaining adult neurogenesis and gliogenesis in response to normal physiological and injury-related pathological cues. This article is part of a Special Issue entitled SI: Neuroprotection. PMID:25931262

  15. Study of cerebral metabolism of glucose in normal human brain correlated with age

    International Nuclear Information System (INIS)

    Full text: The objective was to determine whether cerebral metabolism in various regions of the brain differs with advancing age by using 18F-FDG PET instrument and SPM software. Materials and Methods We reviewed clinical information of 295 healthy normal samples who were examined by a whole body GE Discovery LS PET-CT instrument in our center from Aug. 2004 to Dec. 2005.They (with the age ranging from 21 to 88; mean age+/-SD: 49.77+/-13.51) were selected with: (i)absence of clear focal brain lesions (epilepsy.cerebrovascular diseases etc);(ii) absence of metabolic diseases, such as hyperthyroidism, hypothyroidism and diabetes;(iii) absence of psychiatric disorders and abuse of drugs and alcohol. They were sub grouped into six groups with the interval of 10 years old starting from 21, and the gender, educational background and serum glucose were matched. All subgroups were compared to the control group of 31-40 years old (84 samples; mean age+/-SD: 37.15+/-2.63). All samples were injected with 18F-FDG (5.55MBq/kg), 45-60 minutes later, their brains were scanned for 10min. Pixel-by-pixel t-statistic analysis was applied to all brain images using the Statistical parametric mapping (SPM2) .The hypometabolic areas (p < 0. 01 or p<0.001, uncorrected) were identified in the Stereotaxic coordinate human brain atlas and three-dimensional localized by MNI Space utility (MSU) software. Results:Relative hypometabolic brain areas detected are mainly in the cortical structures such as bilateral prefrontal cortex, superior temporal gyrus(BA22), parietal cortex (inferior parietal lobule and precuneus(BA40, insula(BA13)), parahippocampal gyrus and amygdala (p<0.01).It is especially apparent in the prefrontal cortex (BA9)and sensory-motor cortex(BA5, 7) (p<0.001), while basal ganglia and cerebellum remained metabolically unchanged with advancing age. Conclusions Regional cerebral metabolism of glucose shows a descent tendency with aging, especially in the prefrontal cortex (BA9)and

  16. Effects of macronutrient composition and cyclooxygenase-inhibition on diet-induced obesity, low grade inflammation and glucose homeostasis

    DEFF Research Database (Denmark)

    Fjære, Even

    is escalating, and in view of the increased consumption of obesogenic diets with high levels of dietary carbohydrates and fat, the metabolic consequences of cyclooxygenase-inhibition warrants investigation. Results: High fat/high sucrose diets increased obesity development and expression of macrophage...... was combined with a low fat diet. This further highlights the importance of the background diet and macronutrient composition of experimental diets. Conclusions: In summary, our results demonstrate that the composition of background diet modulates the obesogenic effect of the high fat diet. The obesogenic......Background: Obesity and its related metabolic complications are an increasing problem worldwide. A high fat diet in combination with sucrose has been shown to induce obesity and development of glucose intolerance and insulin resistance in rodents. C57BL/6J mice were fed high fat diets with sucrose...

  17. TAS2R38 and its influence on smoking behavior and glucose homeostasis in the German Sorbs.

    Directory of Open Access Journals (Sweden)

    Maria Keller

    Full Text Available BACKGROUND: Genetic variants within the bitter taste receptor gene TAS2R38 are associated with sensitivity to bitter taste and are related to eating behavior in the Amish population. Sensitivity to bitter taste is further related to anthropometric traits in an genetically isolated Italian population. We tested whether the TAS2R38 variants (rs713598; rs1726866 and rs10246939 may be related to eating behavior, anthropometric parameters, metabolic traits and consumer goods intake in the German Sorbs. MATERIALS AND METHODS: The three SNPs were genotyped in a total cohort of 1007 individuals (male/female: 405/602. The German version of the three-factor eating questionnaire was completed by 548 individuals. Genetic association analyses for smoking behavior, alcohol and coffee intake, eating behavior factors (restraint, disinhibition and hunger and other metabolic traits were analyzed. Further, by combining the three SNPs we applied comparative haplotype analyses categorizing PAV (proline-alanine-valine carriers (tasters vs. homozygous AVI (alanin-valine-isoleucine carriers (non-tasters. RESULTS: Significant associations of genetic variants within TAS2R38 were identified with percentage of body fat, which were driven by associations in women. In men, we observed significant associations with 30 min plasma glucose, and area under the curve for plasma glucose (0-120 min (all adjusted P≤0.05. Further, we found that carriers of at least one PAV allele show significantly lower cigarette smoking per day (P = 0.002 as well as, albeit non-significant, lower alcohol intake. We did not confirm previously reported associations between genetic variants of TAS2R38 and eating behavior. CONCLUSION: Our data suggest that genetic variation in TAS2R38 is related to individual body composition measures and may further influence consumer goods intake in the Sorbs possibly via individual sensitivity to bitter taste.

  18. Elevation of brain glucose and polyol-pathway intermediates with accompanying brain-copper deficiency in patients with Alzheimer’s disease: metabolic basis for dementia

    OpenAIRE

    Jingshu Xu; Paul Begley; Stephanie J. Church; Stefano Patassini; Selina McHarg; Nina Kureishy; Hollywood, Katherine A; Waldvogel, Henry J; Hong Liu; Shaoping Zhang; Wanchang Lin; Karl Herholz; Clinton Turner; Synek, Beth J.; Curtis, Maurice A.

    2016-01-01

    Impairment of brain-glucose uptake and brain-copper regulation occurs in Alzheimer’s disease (AD). Here we sought to further elucidate the processes that cause neurodegeneration in AD by measuring levels of metabolites and metals in brain regions that undergo different degrees of damage. We employed mass spectrometry (MS) to measure metabolites and metals in seven post-mortem brain regions of nine AD patients and nine controls, and plasma-glucose and plasma-copper levels in an ante-mortem cas...

  19. Correlation of glucose metabolism in brain cells and brain morphological changes with clinical typing in children with cerebral palsy

    Institute of Scientific and Technical Information of China (English)

    Qiongxiang Zhai; Huixian Qiao; Jiqing Liu

    2006-01-01

    BACKGROUND:It is widely known that fluorino-18-fluorodeoxyglucose positron emission tomography(18F-FDG PET)is commonly used to evaluate and diagnose epilepsy;however,whether it is beneficial to understand functional metabolism of bra in cells so as to reflect injured site and degree of brain cells or not should be studied further.OBJECTIVE:To evaluate the correlation between glucose metabolism and clinical typling as well as the conelation between active function of brain cells and degree of brain injury among children with cerbral palsy with 18F-FDG PET and MRI and compare the results of them.DESIGN:Case analysis.SETTING:Department of Pediatrics,People's Hospital of Guangdong Province.PARTICIPANTS:A total of 31 children with cerebral palsy were selected from Out-patient Clinic and In-patient Department of People's Hospital of Guangdong Province from July 2001 to August 2004.Based on clinical criteria of cerebral palsy,patients were classified into spasm(n=10),gradual movement(n=4),mixed type(n =13)and ataxia(n=4).There were 18 boys and 13 girls aged from 10 months to 4 years.All of them were met the diagnostic criteria of cerebral palsy and all parents of them were told the facts.Exclusion cdteria:Patients who had cerebral palsy caused by genetic metabolism disease were excluded.METHODS:①All children accepted MRI examination after hospitalization with Philips Acs NT 15T superconductling magnetic resonance scanner.②All children were fasted for 4 hours.And then,PET image of brain was collected based on T+EID type.If obvious hypermetabolism or hypometabolism region successively occurred on two layers, the image was regarded as abnormality. ③Different correlations of various abnormal greups of MRI and vadous types of cerebral palsy with PET image were compared and analyzed with Erusal-Willas rank sum test.MAIN OUTCOME MEASURES:①Results of 18F-FDG PET;②Results of MRI examination;③Correlation of variously abnormal groups of MRI and various types of cerebral

  20. Dietary Protein Source and Cyclooxygenase-Inhibition Influence Development of Diet-Induced Obesity, Glucose Homeostasis and Brown Adipose Tissue

    DEFF Research Database (Denmark)

    Aune, Ulrike Liisberg

    The prevalence of obesity and associated diseases, such as Type 2 diabetes, cardiovascular disease and non-alcoholic fatty liver disease, are accelerating worldwide and require urgent attention. Many of the obesity-related morbidities are likely to originate from a state of chronic low-grade infl......The prevalence of obesity and associated diseases, such as Type 2 diabetes, cardiovascular disease and non-alcoholic fatty liver disease, are accelerating worldwide and require urgent attention. Many of the obesity-related morbidities are likely to originate from a state of chronic low......-grade inflammation accompanying the increasing adipose mass. In order to investigate the relationship between obesity, inflammation and insulin resistance, we ran an experiment feeding mice a high fat/high sucrose diet supplemented with the antiinflammatory cyclooxygenase-inhibitor, indomethacin. We saw......, at least in part, due to the maintenance of a classical interscapular brown depot with high expression of UCP1 in these mice. Conversely, proteins from terrestrial animals promoted gain of adipose mass, hyperinsulinemia and impaired glucose tolerance. In addition, when combined in a typical Western diet...

  1. GPR39, a receptor of the ghrelin receptor family, plays a role in the regulation of glucose homeostasis in a mouse model of early onset diet-induced obesity.

    Science.gov (United States)

    Verhulst, P J; Lintermans, A; Janssen, S; Loeckx, D; Himmelreich, U; Buyse, J; Tack, J; Depoortere, I

    2011-06-01

    GPR39, which may function as a Zn(2+) sensor, is a member of the G protein-coupled receptor family that also includes the receptor for the hunger hormone ghrelin. The down-regulation of GPR39 mRNA in adipose tissue of obese type 2 diabetic patients suggests that GPR39 may contribute to the pathogenesis of the disease. The present study aimed to investigate the role of GPR39 in the regulation of energy balance and glucose homeostasis in wild-type (GPR39(+/+) ) and GPR39 knockout mice (GPR39(-/-) ) with obesity-related type 2 diabetes. GPR39 mRNA levels in adipose tissue of fasted GPR39(+/+) mice fed a high-fat diet (HFD) for 30 weeks were reduced and correlated positively with blood glucose levels. Body weight, fat percentage and energy intake were increased in the HFD group but did not differ between both genotypes. Within the HFD group, blood glucose levels were lower in GPR39(-/-) than in GPR39(+/+) mice, despite significant reductions in prandial plasma insulin levels. The latter may not be a result of changes in β-cell hyperplasia because immunohistochemical staining of pancreata of mice on a HFD showed no differences between genotypes. The lower blood glucose levels may involve alterations in insulin sensitivity as revealed by glucose tolerance tests and respiratory quotient measurements that showed a preference of obese GPR39(-/-) mice for the use of carbohydrates as metabolic fuel. The increase in plasma ghrelin levels in GPR39(-/-) mice fed a HFD may contribute to the alterations in glucose homeostasis, whereas changes in gastric emptying or intestinal Zn(2+) absorption are not involved. The results obtained in the present study suggest that GPR39 plays a role in the pathogenesis of obesity-related type 2 diabetes by affecting the regulation of glucose homeostasis. PMID:21470317

  2. Steady-state brain glucose transport kinetics re-evaluated with a four-state conformational model

    Directory of Open Access Journals (Sweden)

    João M N Duarte

    2009-10-01

    Full Text Available Glucose supply from blood to brain occurs through facilitative transporter proteins. A near linear relation between brain and plasma glucose has been experimentally determined and described by a reversible model of enzyme kinetics. A conformational four-state exchange model accounting for trans-acceleration and asymmetry of the carrier was included in a recently developed multi-compartmental model of glucose transport. Based on this model, we demonstrate that brain glucose (Gbrain as function of plasma glucose (Gplasma can be described by a single analytical equation namely comprising three kinetic compartments: blood, endothelial cells and brain. Transport was described by four parameters: apparent half saturation constant Kt, apparent maximum rate constant Tmax, glucose consumption rate CMRglc, and the iso-inhibition constant Kii that suggests Gbrain as inhibitor of the isomerisation of the unloaded carrier. Previous published data, where Gbrain was quantified as a function of plasma glucose by either biochemical methods or NMR spectroscopy, were used to determine the aforementioned kinetic parameters. Glucose transport was characterized by Kt ranging from 1.5 to 3.5 mM, Tmax/CMRglc from 4.6 to 5.6, and Kii from 51 to 149 mM. It was noteworthy that Kt was on the order of a few mM, as previously determined from the reversible model. The conformational four-state exchange model of glucose transport into the brain includes both efflux and transport inhibition by Gbrain, predicting that Gbrain eventually approaches a maximum concentration. However, since Kii largely exceeds Gplasma, iso-inhibition is unlikely to be of substantial importance for plasma glucose below 25 mM. As a consequence, the reversible model can account for most experimental observations under euglycaemia and moderate cases of hypo- and hyperglycaemia.

  3. Fatigue is a brain-derived emotion that regulates the exercise behavior to ensure the protection of whole body homeostasis

    Directory of Open Access Journals (Sweden)

    Timothy David Noakes

    2012-04-01

    Full Text Available An influential book written by A. Mosso in the late 19th century proposed that fatigue that at first sight might appear an imperfection of our body, is on the contrary one of its most marvellous perfections. The fatigue increasing more rapidly than the amount of work done saves us from the injury which lesser sensibility would involve for the organism so that muscular fatigue also is at bottom an exhaustion of the nervous system.It has taken more than a century to confirm Mosso’s idea that both the brain and the muscles alter their function during exercise and that fatigue is predominantly an emotion, part of a complex regulation, the goal of which is to protect the body from harm. Mosso’s ideas were supplanted in the English literature by those of A.V. Hill who believed that fatigue was the result of biochemical changes in the exercising limb muscles - peripheral fatigue - to which the central nervous system makes no contribution. The past decade has witnessed the growing realization that this brainless model cannot explain exercise performance. This article traces the evolution of our modern understanding of how the CNS regulates exercise specifically to insure that each exercise bout terminates whilst homeostasis is retained in all bodily systems. The brain uses the symptoms of fatigue as key regulators to insure that the exercise is completed before harm develops. These sensations of fatigue are unique to each individual and are illusionary since their generation is largely independent of the real biological state of the athlete at the time they develop. The model predicts that attempts to understand fatigue and to explain superior human athletic performance purely on the basis of the body’s known physiological and metabolic responses to exercise must fail since subconscious and conscious mental decisions made by winners and losers, in both training and competition, are the ultimate determinants of both fatigue and athletic performance.

  4. Maternal flaxseed oil intake during lactation changes body fat, inflammatory markers and glucose homeostasis in the adult progeny: role of gender dimorphism.

    Science.gov (United States)

    Guarda, Deysla Sabino; de Moura, Egberto Gaspar; Carvalho, Janaíne Cavalcanti; Reis, Adelina Martha Dos; Soares, Patricia Novaes; Lisboa, Patricia Cristina; Figueiredo, Mariana Sarto

    2016-09-01

    We evaluated maternal flaxseed oil intake during lactation on body composition, lipid profile, glucose homeostasis and adipose tissue inflammation in male and female progeny at adulthood. Lactating rats were divided into the following: control 7% soybean oil (C), hyper 19% soybean oil (HS) and hyper 17% flaxseed oil+2% soybean oil (HF). Weaned pups received a standard diet. Offspring were killed in PN180. Male HF presented higher visceral adipose tissue (VAT) and triacylglycerol, and female HF showed insulin resistance. Both male and female HF had hyperleptinemia, and only male HF had hyperprolactinemia. In VAT, male HF presented lower PPAR-γ expressions and higher TNF-α, IL-6, IL-1β and IL-10 expressions; in subcutaneous adipose tissue (SAT), they presented lower PPAR-γ and TNF-α expressions. Female HF presented higher leptin, as well as lower adiponectin, TNF-α, IL-6 and IL-1β expressions in VAT and lower TNF-α in SAT. Flaxseed oil during lactation leads to gender-specific effects with more adiposity and dyslipidemia in male and insulin resistance in female. Higher prolactin and inflammatory cytokines in male could play a role in these gender differences. We suggest that the use of flaxseed oil during lactation increases metabolic syndrome risk in the adult progeny. PMID:27469994

  5. Maternal flaxseed oil intake during lactation changes body fat, inflammatory markers and glucose homeostasis in the adult progeny: role of gender dimorphism.

    Science.gov (United States)

    Guarda, Deysla Sabino; de Moura, Egberto Gaspar; Carvalho, Janaíne Cavalcanti; Reis, Adelina Martha Dos; Soares, Patricia Novaes; Lisboa, Patricia Cristina; Figueiredo, Mariana Sarto

    2016-09-01

    We evaluated maternal flaxseed oil intake during lactation on body composition, lipid profile, glucose homeostasis and adipose tissue inflammation in male and female progeny at adulthood. Lactating rats were divided into the following: control 7% soybean oil (C), hyper 19% soybean oil (HS) and hyper 17% flaxseed oil+2% soybean oil (HF). Weaned pups received a standard diet. Offspring were killed in PN180. Male HF presented higher visceral adipose tissue (VAT) and triacylglycerol, and female HF showed insulin resistance. Both male and female HF had hyperleptinemia, and only male HF had hyperprolactinemia. In VAT, male HF presented lower PPAR-γ expressions and higher TNF-α, IL-6, IL-1β and IL-10 expressions; in subcutaneous adipose tissue (SAT), they presented lower PPAR-γ and TNF-α expressions. Female HF presented higher leptin, as well as lower adiponectin, TNF-α, IL-6 and IL-1β expressions in VAT and lower TNF-α in SAT. Flaxseed oil during lactation leads to gender-specific effects with more adiposity and dyslipidemia in male and insulin resistance in female. Higher prolactin and inflammatory cytokines in male could play a role in these gender differences. We suggest that the use of flaxseed oil during lactation increases metabolic syndrome risk in the adult progeny.

  6. Regrowing the adult brain: NF-κB controls functional circuit formation and tissue homeostasis in the dentate gyrus.

    Directory of Open Access Journals (Sweden)

    Yvonne Imielski

    Full Text Available Cognitive decline during aging is correlated with a continuous loss of cells within the brain and especially within the hippocampus, which could be regenerated by adult neurogenesis. Here we show that genetic ablation of NF-κB resulted in severe defects in the neurogenic region (dentate gyrus of the hippocampus. Despite increased stem cell proliferation, axogenesis, synaptogenesis and neuroprotection were hampered, leading to disruption of the mossy fiber pathway and to atrophy of the dentate gyrus during aging. Here, NF-κB controls the transcription of FOXO1 and PKA, regulating axogenesis. Structural defects culminated in behavioral impairments in pattern separation. Re-activation of NF-κB resulted in integration of newborn neurons, finally to regeneration of the dentate gyrus, accompanied by a complete recovery of structural and behavioral defects. These data identify NF-κB as a crucial regulator of dentate gyrus tissue homeostasis suggesting NF-κB to be a therapeutic target for treating cognitive and mood disorders.

  7. Walking speed and brain glucose uptake are uncoupled in patients with multiple sclerosis

    Directory of Open Access Journals (Sweden)

    John H. Kindred

    2015-02-01

    Full Text Available Motor impairments of the upper and lower extremities are common symptoms of multiple sclerosis (MS. While some peripheral effects like muscle weakness and loss of balance have been shown to influence these symptoms, central nervous system activity has not been fully elucidated. The purpose of this study was to determine if alterations in glucose uptake were associated with motor impairments in patients with multiple sclerosis. Eight patients with multiple sclerosis (4 men and 8 sex matched healthy controls performed 15 minutes of treadmill walking at a self-selected pace, during which ≈ 322 MBq of the positron emission tomography glucose analogue [18F]-Fluorodeoxyglucose was injected. Immediately after the cessation of walking, participants underwent positron emission tomography imaging. Patients with MS had lower FDG uptake in ≈ 40% of the brain compared to the healthy controls (pFWE-corr -0.75, P < 0.032. Within patients with MS only 3 of the 15 regions showed significant correlations: insula (r = -0.74, P = 0.036, hippocampus (r = -0.72, P = 0.045, and calcarine sulcus (r = -0.77, P = 0.026. This data suggests that walking impairments in patients with MS may be due to network wide alterations in glucose metabolism. Understanding how brain activity and metabolism are altered in patients with MS may allow for better measures of disability and disease status within this clinical population.

  8. Enzyme-Immobilized 3D-Printed Reactors for Online Monitoring of Rat Brain Extracellular Glucose and Lactate.

    Science.gov (United States)

    Su, Cheng-Kuan; Yen, Shuo-Chih; Li, Tzu-Wen; Sun, Yuh-Chang

    2016-06-21

    In this study we constructed a highly sensitive system for in vivo monitoring of the concentrations of rat brain extracellular glucose and lactate. This system involved microdialysis (MD) sampling and fluorescence determination in conjunction with a novel sample derivatization scheme in which glucose oxidase and lactate oxidase were immobilized in ABS flow bioreactors (manufactured through low-cost three-dimensional printing (3DP)), via fused deposition modeling, for online oxidization of sampled glucose and lactate, respectively, in rat brain microdialysate. After optimizing the experimental conditions for MD sampling, the manufacture of the designed flow reactors, the enzyme immobilization procedure, and the online derivatization scheme, the available sampling frequency was 15 h(-1) and the system's detection limits reached as low as 0.060 mM for glucose and 0.059 mM for lactate, based on a 20-μL conditioned microdialysate; these characteristics were sufficient to reliably determine the concentrations of extracellular glucose and lactate in the brains of living rats. To demonstrate the system's applicability, we performed (i) spike analyses of offline-collected rat brain microdialysate and (ii) in vivo dynamic monitoring of the extracellular glucose and lactate in living rat brains, in addition to triggering neuronal depolarization by perfusing a high-K(+) medium from the implanted MD probe. Our analytical results and demonstrations confirm that postprinting functionalization of analytical devices manufactured using 3DP technology can be a powerful strategy for extending the diversity and adaptability of currently existing analytical configurations. PMID:27232384

  9. Simultaneous telemetric monitoring of brain glucose and lactate and motion in freely moving rats.

    Science.gov (United States)

    Rocchitta, Gaia; Secchi, Ottavio; Alvau, Maria Domenica; Farina, Donatella; Bazzu, Gianfranco; Calia, Giammario; Migheli, Rossana; Desole, Maria Speranza; O'Neill, Robert D; Serra, Pier A

    2013-11-01

    A new telemetry system for simultaneous detection of extracellular brain glucose and lactate and motion is presented. The device consists of dual-channel, single-supply miniature potentiostat-I/V converter, a microcontroller unit, a signal transmitter, and a miniaturized microvibration sensor. Although based on simple and inexpensive components, the biotelemetry device has been used for accurate transduction of the anodic oxidation currents generated on the surface of implanted glucose and lactate biosensors and animal microvibrations. The device was characterized and validated in vitro before in vivo experiments. The biosensors were implanted in the striatum of freely moving animals and the biotelemetric device was fixed to the animal's head. Physiological and pharmacological stimulations were given in order to induce striatal neural activation and to modify the motor behavior in awake, untethered animals. PMID:24102201

  10. Subchronic effects of inhaled ambient particulate matter on glucose homeostasis and target organ damage in a type 1 diabetic rat model

    Energy Technology Data Exchange (ETDEWEB)

    Yan, Yuan-Horng [Institute of Occupational Medicine and Industrial Hygiene, College of Public Health, National Taiwan University, Taipei, Taiwan (China); Department of Medical Research, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan (China); Charles, Chou C.-K. [Research Center for Environmental Changes, Academia Sinica, Taipei, Taiwan (China); Wang, Jyh-Seng [Department of Pathology and Laboratory Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan (China); Tung, Chun-Liang [Department of Pathology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan (China); Li, Ya-Ru; Lo, Kai [Institute of Occupational Medicine and Industrial Hygiene, College of Public Health, National Taiwan University, Taipei, Taiwan (China); Cheng, Tsun-Jen, E-mail: tcheng@ntu.edu.tw [Institute of Occupational Medicine and Industrial Hygiene, College of Public Health, National Taiwan University, Taipei, Taiwan (China); Department of Public Health, College of Public Health, National Taiwan University, Taipei, Taiwan (China)

    2014-12-01

    Epidemiological studies have reported associations between particulate matter (PM) and cardiovascular effects, and diabetes mellitus (DM) patients might be susceptible to these effects. The chief chronic injuries resulting from DM are small vascular injuries (micro-vascular complications) or large blood vessel injuries (macro-vascular complications). However, toxicological data regarding the effects of PM on DM-related cardiovascular complications is limited. Our objective was to investigate whether subchronic PM exposure alters glucose homeostasis and causes cardiovascular complications in a type 1 DM rat model. We constructed a real world PM{sub 2.5} exposure system, the Taipei Air Pollution Exposure System for Health Effects (TAPES), to continuously deliver non-concentrated PM for subchronic exposure. A type 1 DM rat model was induced using streptozotocin. Between December 22, 2009 and April 9, 2010, DM rats were exposed to PM or to filtered air (FA) using TAPES in Taipei, Taiwan, 24 h/day, 7 days/week, for a total of 16 weeks. The average concentrations (mean [SD]) of PM{sub 2.5} in the exposure and control chambers of the TAPES were 13.30 [8.65] and 0.13 [0.05] μg/m{sup 3}, respectively. Glycated hemoglobin A1c (HbA1c) was significantly elevated after exposure to PM compared with exposure to FA (mean [SD], 7.7% [3.1%] vs. 4.7% [1.0%], P < 0.05). Interleukin 6 and fibrinogen levels were significantly increased after PM exposure. PM caused focal myocarditis, aortic medial thickness, advanced glomerulosclerosis, and accentuation of tubular damage of the kidney (tubular damage index: 1.76 [0.77] vs. 1.15 [0.36], P < 0.001). PM exposure might induce the macro- and micro-vascular complications in DM through chronic hyperglycemia and systemic inflammation. - Highlights: • The study demonstrated cardiovascular and renal effects of PM in a rat model of DM. • TAPES is a continuous, real world, long-term PM exposure system. • HbA1c, a marker of glycemic

  11. Parameters of glucose metabolism and the aging brain: a magnetization transfer imaging study of brain macro- and micro-structure in older adults without diabetes.

    Science.gov (United States)

    Akintola, Abimbola A; van den Berg, Annette; Altmann-Schneider, Irmhild; Jansen, Steffy W; van Buchem, Mark A; Slagboom, P Eline; Westendorp, Rudi G; van Heemst, Diana; van der Grond, Jeroen

    2015-08-01

    Given the concurrent, escalating epidemic of diabetes mellitus and neurodegenerative diseases, two age-related disorders, we aimed to understand the relation between parameters of glucose metabolism and indices of pathology in the aging brain. From the Leiden Longevity Study, 132 participants (mean age 66 years) underwent a 2-h oral glucose tolerance test to assess glucose tolerance (fasted and area under the curve (AUC) glucose), insulin sensitivity (fasted and AUC insulin and homeostatic model assessment of insulin sensitivity (HOMA-IS)) and insulin secretion (insulinogenic index). 3-T brain MRI was used to detect macro-structural damage (atrophy, white matter hyper-intensities, infarcts and/or micro-bleeds) and magnetization transfer imaging (MTI) to detect loss of micro-structural homogeneity that remains otherwise invisible on conventional MRI. Macro-structurally, higher fasted glucose was significantly associated with white matter atrophy (P = 0.028). Micro-structurally, decreased magnetization transfer ratio (MTR) peak height in gray matter was associated with higher fasted insulin (P = 0.010), AUCinsulin (P = 0.001), insulinogenic index (P = 0.008) and lower HOMA-IS index (P macro-structural damage, impaired insulin action was associated more strongly with reduced micro-structural brain parenchymal homogeneity. These findings offer some insight into the association between different parameters of glucose metabolism (impairment of which is characteristic of diabetes mellitus) and brain aging.

  12. Involvement of ABA- and H2O2-dependent cytosolic glucose-6-phosphate dehydrogenase in maintaining redox homeostasis in soybean roots under drought stress.

    Science.gov (United States)

    Wang, Huahua; Yang, Lidan; Li, Yan; Hou, Junjie; Huang, Junjun; Liang, Weihong

    2016-10-01

    The roles of abscisic acid (ABA) and hydrogen peroxide (H2O2) in inducing glucose-6-phosphate dehydrogenase (G6PDH, EC 1.1.1.49) activity and the possible roles of G6PDH in regulating ascorbate-glutathione (AsA-GSH) cycle were investigated in soybean (Glycine max L.) roots under drought stress. Drought caused a marked increase of the total and cytosolic G6PDH activities and triggered a rapid ABA and H2O2 accumulation in soybean roots. Exogenous ABA or H2O2 treatment elevated the total and cytosolic G6PDH activities, whereas suppressing ABA or H2O2 production inhibited the drought-induced increase in total and cytosolic G6PDH activities, suggesting that ABA and H2O2 are required for drought-induced increase of total G6PDH activity, namely cytosolic G6PDH activity. Furthermore, ABA induced H2O2 production by stimulating NADPH oxidase activity under drought stress. Moreover, drought significantly increased the contents of AsA and GSH and the activities of key enzymes in AsA-GSH cycle, while application of G6PDH inhibitor to seedlings significantly reduced the above effect induced by drought. Taken together, these results indicate that H2O2 acting as a downstream signaling molecule of ABA mediates drought-induced increase in cytosolic G6PDH activity, and that enhanced cytosolic G6PDH activity maintains cellular redox homeostasis by regulating AsA-GSH cycle in soybean roots. PMID:27285781

  13. D-[U-11C]glucose uptake and metabolism in the brain of insulin-dependent diabetic subjects

    International Nuclear Information System (INIS)

    We used D-[U-11C]glucose to evaluate transport and metabolism of glucose in the brain in eight nondiabetic and six insulin-dependent diabetes mellitus (IDDM) subjects. IDDM subjects were treated by continuous subcutaneous insulin infusion. Blood glucose was regulated by a Biostator-controlled glucose infusion during a constant insulin infusion. D-[U-11C]-glucose was injected for positron emission tomography studies during normoglycemia as well as during moderate hypoglycemia [arterial plasma glucose 2.74 +/- 0.14 in nondiabetic and 2.80 +/- 0.26 mmol/l (means +/- SE) in IDDM subjects]. Levels of free insulin were constant and similar in both groups. The tracer data were analyzed using a three-compartment model with a fixed correction for 11CO2 egression. During normoglycemia the influx rate constant (k1) and blood-brain glucose flux did not differ between the two groups. During hypoglycemia k1 increased significantly and similarly in both groups (from 0.061 +/- 0.007 to 0.090 +/- 0.006 in nondiabetic and from 0.061 +/- 0.006 to 0.093 +/- 0.013 ml.g-1.min-1 in IDDM subjects). During normoglycemia the tracer-calculated metabolism of glucose was higher in the whole brain in the nondiabetic than in the diabetic subjects (22.0 +/- 1.9 vs. 15.6 +/- 1.1 mumol.100 g-1.min-1, P less than 0.01). During hypoglycemia tracer-calculated metabolism was decreased by 40% in nondiabetic subjects and by 28% in diabetic subjects. The results indicate that uptake of glucose is normal, but some aspect of glucose metabolism is abnormal in a group of well-controlled IDDM subjects

  14. D-(U-11C)glucose uptake and metabolism in the brain of insulin-dependent diabetic subjects

    Energy Technology Data Exchange (ETDEWEB)

    Gutniak, M.; Blomqvist, G.; Widen, L.; Stone-Elander, S.; Hamberger, B.; Grill, V. (Karolinska Hospital and Institute, Stockholm (Sweden))

    1990-05-01

    We used D-(U-11C)glucose to evaluate transport and metabolism of glucose in the brain in eight nondiabetic and six insulin-dependent diabetes mellitus (IDDM) subjects. IDDM subjects were treated by continuous subcutaneous insulin infusion. Blood glucose was regulated by a Biostator-controlled glucose infusion during a constant insulin infusion. D-(U-11C)-glucose was injected for positron emission tomography studies during normoglycemia as well as during moderate hypoglycemia (arterial plasma glucose 2.74 +/- 0.14 in nondiabetic and 2.80 +/- 0.26 mmol/l (means +/- SE) in IDDM subjects). Levels of free insulin were constant and similar in both groups. The tracer data were analyzed using a three-compartment model with a fixed correction for 11CO2 egression. During normoglycemia the influx rate constant (k1) and blood-brain glucose flux did not differ between the two groups. During hypoglycemia k1 increased significantly and similarly in both groups (from 0.061 +/- 0.007 to 0.090 +/- 0.006 in nondiabetic and from 0.061 +/- 0.006 to 0.093 +/- 0.013 ml.g-1.min-1 in IDDM subjects). During normoglycemia the tracer-calculated metabolism of glucose was higher in the whole brain in the nondiabetic than in the diabetic subjects (22.0 +/- 1.9 vs. 15.6 +/- 1.1 mumol.100 g-1.min-1, P less than 0.01). During hypoglycemia tracer-calculated metabolism was decreased by 40% in nondiabetic subjects and by 28% in diabetic subjects. The results indicate that uptake of glucose is normal, but some aspect of glucose metabolism is abnormal in a group of well-controlled IDDM subjects.

  15. Sleep Disturbances and Glucose Homeostasis

    NARCIS (Netherlands)

    Barf, R. Paulien; Scheurink, Anton J.W.

    2011-01-01

    Sleep disturbances, induced by either lifestyle, shift work or sleeping disorders, have become more prevalent in our 24/7 Western society. Sleep disturbances are associated with impaired health including metabolic diseases such as obesity and type 2 diabetes. The question remains whether there is a

  16. Homeostasis in anorexia nervosa

    OpenAIRE

    Södersten, Per; Bergh, Cecilia; Zandian, Modjtaba; Ioakimidis, Ioannis

    2014-01-01

    Brainstem and hypothalamic “orexigenic/anorexigenic” networks are thought to maintain body weight homeostasis in response to hormonal and metabolic feedback from peripheral sites. This approach has not been successful in managing over- and underweight patients. It is suggested that concept of homeostasis has been misinterpreted; rather than exerting control, the brain permits eating in proportion to the amount of physical activity necessary to obtain food. In support, animal experiments have ...

  17. Homeostasis in anorexia nervosa

    OpenAIRE

    Per eSodersten; Cecilia eBergh; Modjtaba eZandian; Ioannis eIoakimidis

    2014-01-01

    Brainstem and hypothalamic orexigenic/anorexigenic networks are thought to maintain body weight homeostasis in response to hormonal and metabolic feedback from peripheral sites. This approach has not been successful in managing over- and underweight patients. It is suggested that concept of homeostasis has been misinterpreted; rather than exerting control, the brain permits eating in proportion to the amount of physical activity necessary to obtain food. In support, animal experiments have sh...

  18. Short-term consumption of sucralose, a nonnutritive sweetener, is similar to water with regard to select markers of hunger signaling and short-term glucose homeostasis in women.

    Science.gov (United States)

    Brown, Andrew W; Bohan Brown, Michelle M; Onken, Kristine L; Beitz, Donald C

    2011-12-01

    Nonnutritive sweeteners have been used to lower the energy density of foods with the intention of affecting weight loss or weight maintenance. However, some epidemiological and animal evidence indicates an association between weight gain or insulin resistance and artificial sweetener consumption. In the present study, we hypothesized that the nonnutritive sweetener sucralose, a trichlorinated sucrose molecule, would elicit responses similar to water but different from sucrose and sucrose combined with sucralose on subjective and hormonal indications of hunger and short-term glucose homeostasis. Eight female volunteers (body mass index, 22.16 ± 1.71 kg/m(2); age, 21.75 ± 2.25 years) consumed sucrose and/or sucralose in water in a factorial design. Blood samples were taken at fasting and 30 and 60 minutes after treatment followed by a standardized breakfast across treatments, and blood samples were taken 30, 60, 90, and 120 minutes after breakfast. Plasma was analyzed for glucose, insulin, glucagon, triacylglycerols (TAG), and acylated ghrelin. Perceptions of hunger and other subjective measurements were assessed before each blood sample. No differences were detected in subjective responses, circulating triacylglycerol, or glucagon concentrations among treatments over time. Significant differences were observed in insulin, glucose, and acylated ghrelin concentrations over time only between sucrose-containing treatments and non-sucrose-containing treatments regardless of sucralose consumption. Therefore, sucralose may be a relatively inert nonnutritive sweetener with regard to hunger signaling and short-term glucose homeostasis. PMID:22153513

  19. UCP2 Regulates Mitochondrial Fission and Ventromedial Nucleus Control of Glucose Responsiveness.

    Science.gov (United States)

    Toda, Chitoku; Kim, Jung Dae; Impellizzeri, Daniela; Cuzzocrea, Salvatore; Liu, Zhong-Wu; Diano, Sabrina

    2016-02-25

    The ventromedial nucleus of the hypothalamus (VMH) plays a critical role in regulating systemic glucose homeostasis. How neurons in this brain area adapt to the changing metabolic environment to regulate circulating glucose levels is ill defined. Here, we show that glucose load results in mitochondrial fission and reduced reactive oxygen species in VMH neurons mediated by dynamin-related peptide 1 (DRP1) under the control of uncoupling protein 2 (UCP2). Probed by genetic manipulations and chemical-genetic control of VMH neuronal circuitry, we unmasked that this mitochondrial adaptation determines the size of the pool of glucose-excited neurons in the VMH and that this process regulates systemic glucose homeostasis. Thus, our data unmasked a critical cellular biological process controlled by mitochondrial dynamics in VMH regulation of systemic glucose homeostasis. PMID:26919426

  20. Novel MRI methodology to detect human whole-brain connectivity changes after ingestion of fructose or glucose

    Science.gov (United States)

    Tsao, Sinchai; Wilkins, Bryce; Page, Kathleen A.; Singh, Manbir

    2012-03-01

    A novel MRI protocol has been developed to investigate the differential effects of glucose or fructose consumption on whole-brain functional brain connectivity. A previous study has reported a decrease in the fMRI blood oxygen level dependent (BOLD) signal of the hypothalamus following glucose ingestion, but due to technical limitations, was restricted to a single slice covering the hypothalamus, and thus unable to detect whole-brain connectivity. In another previous study, a protocol was devised to acquire whole-brain fMRI data following food intake, but only after restricting image acquisition to an MR sampling or repetition time (TR) of 20s, making the protocol unsuitable to detect functional connectivity above 0.025Hz. We have successfully implemented a continuous 36-min, 40 contiguous slices, whole-brain BOLD acquisition protocol on a 3T scanner with TR=4.5s to ensure detection of up to 0.1Hz frequencies for whole-brain functional connectivity analysis. Human data were acquired first with ingestion of water only, followed by a glucose or fructose drink within the scanner, without interrupting the scanning. Whole-brain connectivity was analyzed using standard correlation methodology in the 0.01-0.1 Hz range. The correlation coefficient differences between fructose and glucose ingestion among targeted regions were converted to t-scores using the water-only correlation coefficients as a null condition. Results show a dramatic increase in the hypothalamic connectivity to the hippocampus, amygdala, insula, caudate and the nucleus accumben for fructose over glucose. As these regions are known to be key components of the feeding and reward brain circuits, these results suggest a preference for fructose ingestion.

  1. Voxel-based statistical analysis of cerebral glucose metabolism in patients with permanent vegetative state after acquired brain injury

    Institute of Scientific and Technical Information of China (English)

    Yong Wook Kim; Hyoung Seop Kim; Young-Sil An; Sang Hee Im

    2010-01-01

    Background Permanent vegetative state is defined as the impaired level of consciousness longer than 12 months after traumatic causes and 3 months after non-traumatic causes of brain injury. Although many studies assessed the cerebral metabolism in patients with acute and persistent vegetative state after brain injury, few studies investigated the cerebral metabolism in patients with permanent vegetative state. In this study, we performed the voxel-based analysis of cerebral glucose metabolism and investigated the relationship between regional cerebral glucose metabolism and the severity of impaired consciousness in patients with permanent vegetative state after acquired brain injury.Methods We compared the regional cerebral glucose metabolism as demonstrated by F-18 fluorodeoxyglucose positron emission tomography from 12 patients with permanent vegetative state after acquired brain injury with those from 12 control subjects. Additionally, covariance analysis was performed to identify regions where decreased changes in regional cerebral glucose metabolism significantly correlated with a decrease of level of consciousness measured by JFK-coma recovery scare. Statistical analysis was performed using statistical parametric mapping.Results Compared with controls, patients with permanent vegetative state demonstrated decreased cerebral glucose metabolism in the left precuneus, both posterior cingulate cortices, the left superior parietal lobule (Pcorrected <0.001), and increased cerebral glucose metabolism in the both cerebellum and the right supramarginal cortices (Pcorrected <0.001). In the covariance analysis, a decrease in the level of consciousness was significantly correlated with decreased cerebral glucose metabolism in the both posterior cingulate cortices (Puncorrected <0.005).Conclusion Our findings suggest that the posteromedial parietal cortex, which are part of neural network for consciousness, may be relevant structure for pathophysiological mechanism

  2. Maternal inflammation leads to impaired glutamate homeostasis and up-regulation of glutamate carboxypeptidase II in activated microglia in the fetal/newborn rabbit brain.

    Science.gov (United States)

    Zhang, Zhi; Bassam, Bassam; Thomas, Ajit G; Williams, Monica; Liu, Jinhuan; Nance, Elizabeth; Rojas, Camilo; Slusher, Barbara S; Kannan, Sujatha

    2016-10-01

    Astrocyte dysfunction and excessive activation of glutamatergic systems have been implicated in a number of neurologic disorders, including periventricular leukomalacia (PVL) and cerebral palsy (CP). However, the role of chorioamnionitis on glutamate homeostasis in the fetal and neonatal brains is not clearly understood. We have previously shown that intrauterine endotoxin administration results in intense microglial 'activation' and increased pro-inflammatory cytokines in the periventricular region (PVR) of the neonatal rabbit brain. In this study, we assessed the effect of maternal inflammation on key components of the glutamate pathway and its relationship to astrocyte and microglial activation in the fetal and neonatal New Zealand white rabbit brain. We found that intrauterine endotoxin exposure at gestational day 28 (G28) induced acute and prolonged glutamate elevation in the PVR of fetal (G29, 1day post-injury) and postnatal day 1 (PND1, 3days post-injury) brains along with prominent morphological changes in the astrocytes (soma hypertrophy and retracted processes) in the white matter tracts. There was a significant increase in glutaminase and N-Methyl-d-Aspartate receptor (NMDAR) NR2 subunit expression along with decreased glial L-glutamate transporter 1 (GLT-1) in the PVR at G29, that would promote acute dysregulation of glutamate homeostasis. This was accompanied with significantly decreased TGF-β1 at PND1 in CP kits indicating ongoing neuroinflammation. We also show for the first time that glutamate carboxypeptidase II (GCPII) was significantly increased in the activated microglia at the periventricular white matter area in both G29 and PND1 CP kits. This was confirmed by in vitro studies demonstrating that LPS activated primary microglia markedly upregulate GCPII enzymatic activity. These results suggest that maternal intrauterine endotoxin exposure results in early onset and long-lasting dysregulation of glutamate homeostasis, which may be mediated by

  3. Can ketones compensate for deteriorating brain glucose uptake during aging? Implications for the risk and treatment of Alzheimer's disease.

    Science.gov (United States)

    Cunnane, Stephen C; Courchesne-Loyer, Alexandre; St-Pierre, Valérie; Vandenberghe, Camille; Pierotti, Tyler; Fortier, Mélanie; Croteau, Etienne; Castellano, Christian-Alexandre

    2016-03-01

    Brain glucose uptake is impaired in Alzheimer's disease (AD). A key question is whether cognitive decline can be delayed if this brain energy defect is at least partly corrected or bypassed early in the disease. The principal ketones (also called ketone bodies), β-hydroxybutyrate and acetoacetate, are the brain's main physiological alternative fuel to glucose. Three studies in mild-to-moderate AD have shown that, unlike with glucose, brain ketone uptake is not different from that in healthy age-matched controls. Published clinical trials demonstrate that increasing ketone availability to the brain via moderate nutritional ketosis has a modest beneficial effect on cognitive outcomes in mild-to-moderate AD and in mild cognitive impairment. Nutritional ketosis can be safely achieved by a high-fat ketogenic diet, by supplements providing 20-70 g/day of medium-chain triglycerides containing the eight- and ten-carbon fatty acids octanoate and decanoate, or by ketone esters. Given the acute dependence of the brain on its energy supply, it seems reasonable that the development of therapeutic strategies aimed at AD mandates consideration of how the underlying problem of deteriorating brain fuel supply can be corrected or delayed. PMID:26766547

  4. Over-estimation of glucose-6-phosphatase activity in brain in vivo. Apparent difference in rates of [2-3H]glucose and [U-14C]glucose utilization is due to contamination of precursor pool with 14C-labeled products and incomplete recovery of 14C-labeled metabolites

    International Nuclear Information System (INIS)

    Significant dephosphorylation of glucose 6-phosphate due to glucose-6-phosphatase activity in rat brain in vivo was recently reported. The evidence was an apparent more rapid 3H than 14C loss from the glucose pool and faster [2-3H]glucose than [U-14C]glucose utilization following pulse labeling of the brain with [2-3H,U-14C]glucose. Radiochemical purity of the glucose and quantitative recovery of the labeled products of glucose metabolism isolated from the brain were obviously essential requirements of their study, but no evidence for purity and recovery was provided. When we repeated these experiments with the described isolation procedures, we replicated the results, but found that: 1) the precursor glucose pool contained detritiated, 14C-labeled contaminants arising from glucose metabolism, particularly 2-pyrrolidone-5-carboxylic acid derived from [14C]glutamine; 2) [14C]glucose metabolite were not quantitatively recovered; 3) the procedure used to isolate the glucose itself produced detritiated, 14C-labeled derivatives of [2-3H,U-14C]glucose. These deficiencies in the isolation procedures could fully account for the observations that were interpreted as evidence of significant glucose 6-phosphate dephosphorylation by glucose-6-phosphatase activity. When glucose was isolated by more rigorous procedures and its purity verified in the present studies, no evidence for such activity in rat brain was found

  5. A comparison between the impact of two types of dietary protein on brain glucose concentrations and oxidative stress in high fructose-induced metabolic syndrome rats

    OpenAIRE

    MADANI, ZOHRA; Malaisse, Willy J.; AIT-YAHIA, DALILA

    2015-01-01

    The present study explored the potential of fish proteins to counteract high glucose levels and oxidative stress induced by fructose in the brain. A total of 24 male Wistar rats consumed sardine protein or casein with or without high fructose (64%). After 2 months, brain tissue was used for analyses. The fructose rats exhibited an increase in body mass index (BMI), body weight, absolute and relative brain weights and brain glucose; however, there was a decrease in food and water intake. Fruct...

  6. Differential effects of fructose versus glucose on brain and appetitive responses to food cues and decisions for food rewards.

    Science.gov (United States)

    Luo, Shan; Monterosso, John R; Sarpelleh, Kayan; Page, Kathleen A

    2015-05-19

    Prior studies suggest that fructose compared with glucose may be a weaker suppressor of appetite, and neuroimaging research shows that food cues trigger greater brain reward responses in a fasted relative to a fed state. We sought to determine the effects of ingesting fructose versus glucose on brain, hormone, and appetitive responses to food cues and food-approach behavior. Twenty-four healthy volunteers underwent two functional magnetic resonance imaging (fMRI) sessions with ingestion of either fructose or glucose in a double-blinded, random-order cross-over design. fMRI was performed while participants viewed images of high-calorie foods and nonfood items using a block design. After each block, participants rated hunger and desire for food. Participants also performed a decision task in which they chose between immediate food rewards and delayed monetary bonuses. Hormones were measured at baseline and 30 and 60 min after drink ingestion. Ingestion of fructose relative to glucose resulted in smaller increases in plasma insulin levels and greater brain reactivity to food cues in the visual cortex (in whole-brain analysis) and left orbital frontal cortex (in region-of-interest analysis). Parallel to the neuroimaging findings, fructose versus glucose led to greater hunger and desire for food and a greater willingness to give up long-term monetary rewards to obtain immediate high-calorie foods. These findings suggest that ingestion of fructose relative to glucose results in greater activation of brain regions involved in attention and reward processing and may promote feeding behavior. PMID:25941364

  7. Rapid fluctuations in extracellular brain glucose levels induced by natural arousing stimuli and intravenous cocaine: fueling the brain during neural activation

    Science.gov (United States)

    Lenoir, Magalie

    2012-01-01

    Glucose, a primary energetic substrate for neural activity, is continuously influenced by two opposing forces that tend to either decrease its extracellular levels due to enhanced utilization in neural cells or increase its levels due to entry from peripheral circulation via enhanced cerebral blood flow. How this balance is maintained under physiological conditions and changed during neural activation remains unclear. To clarify this issue, enzyme-based glucose sensors coupled with high-speed amperometry were used in freely moving rats to evaluate fluctuations in extracellular glucose levels induced by brief audio stimulus, tail pinch (TP), social interaction with another rat (SI), and intravenous cocaine (1 mg/kg). Measurements were performed in nucleus accumbens (NAcc) and substantia nigra pars reticulata (SNr), which drastically differ in neuronal activity. In NAcc, where most cells are powerfully excited after salient stimulation, glucose levels rapidly (latency 2–6 s) increased (30–70 μM or 6–14% over baseline) by all stimuli; the increase differed in magnitude and duration for each stimulus. In SNr, where most cells are transiently inhibited by salient stimuli, TP, SI, and cocaine induced a biphasic glucose response, with the initial decrease (−20–40 μM or 5–10% below baseline) followed by a reboundlike increase. The critical role of neuronal activity in mediating the initial glucose response was confirmed by monitoring glucose currents after local microinjections of glutamate (GLU) or procaine (PRO). While intra-NAcc injection of GLU transiently increased glucose levels in this structure, intra-SNr PRO injection resulted in rapid, transient decreases in SNr glucose. Therefore, extracellular glucose levels in the brain change very rapidly after physiological and pharmacological stimulation, the response is structure specific, and the pattern of neuronal activity appears to be a critical factor determining direction and magnitude of physiological

  8. Influence of diabetes surgery on a gut-brain-liver axis regulating food intake and internal glucose production

    Directory of Open Access Journals (Sweden)

    G. Mithieux

    2013-01-01

    Full Text Available It has long been known that the brain, especially the hypothalamus, can modulate both insulin secretion and hepatic glucose fluxes, via the modulation of the sympathetic system (promoting glycogen breakdown and the parasympathetic system (stimulating glycogen deposition. Central insulin signalling or hypothalamic long-chain fatty acid oxidation can also control insulin's suppression of endogenous glucose production. Interestingly, intestinal gluconeogenesis can initiate a portal glucose signal, transmitted to the hypothalamus via the gastrointestinal nervous system. This signal may modulate the sensation of hunger and satiety and insulin sensitivity of hepatic glucose fluxes as well. The rapid improvements of glucose control taking place after gastric bypass surgery in obese diabetics has long been mysterious. Actually, the specificity of gastric bypass in obese diabetic mice relates to major changes in the sensations of hunger and to rapid improvement in insulin sensitivity of endogenous glucose production. We have shown that an induction of intestinal gluconeogenesis plays a major role in these phenomena. In addition, the restoration of the secretion of glucagon like peptide 1 and consequently of insulin plays a key additional role to improve postprandial glucose tolerance. Therefore, a synergy between incretin effects and intestinal gluconeogenesis might be a key feature explaining the rapid improvement of glucose control in obese diabetics after bypass surgery.

  9. Aqueous extract of tamarind seeds selectively increases glucose transporter-2, glucose transporter-4, and islets' intracellular calcium levels and stimulates β-cell proliferation resulting in improved glucose homeostasis in rats with streptozotocin-induced diabetes mellitus.

    Science.gov (United States)

    Sole, Sushant Shivdas; Srinivasan, B P

    2012-08-01

    Tamarindus indica Linn. has been in use for a long time in Asian food and traditional medicine for different diseases including diabetes and obesity. However, the molecular mechanisms of these effects have not been fully understood. In view of the multidimensional activity of tamarind seeds due to their having high levels of polyphenols and flavonoids, we hypothesized that the insulin mimetic effect of aqueous tamarind seed extract (TSE) might increase glucose uptake through improvement in the expression of genes of the glucose transporter (GLUT) family and sterol regulatory element-binding proteins (SREBP) 1c messenger RNA (mRNA) in the liver. Daily oral administration of TSE to streptozotocin (STZ)-induced (90 mg/kg intraperitoneally) type 2 diabetic male Wistar rats at different doses (120 and 240 mg/kg body weight) for 4 weeks showed positive correlation with intracellular calcium and insulin release in isolated islets of Langerhans. Tamarind seed extract supplementation significantly improved the GLUT-2 protein and SREBP-1c mRNA expression in the liver and GLUT-4 protein and mRNA expression in the skeletal muscles of diabetic rats. The elevated levels of serum nitric oxide (NO), glycosylated hemoglobin level (hemoglobin (A1c)) and tumor necrosis factor α (TNF-α) decreased after TSE administration. Immunohistochemical findings revealed that TSE abrogated STZ-induced apoptosis and increased β-cell neogenesis, indicating its effect on islets and β-cell mass. In conclusion, it was found that the antidiabetic effect of TSE on STZ-induced diabetes resulted from complex mechanisms of β-cell neogenesis, calcium handling, GLUT-2, GLUT-4, and SREBP-1c. These findings show the scope for formulating a new herbal drug for diabetes therapy.

  10. Monitoring arterio-venous differences of glucose and lactate in the anesthetized rat with or without brain damage with ultrafiltration and biosensor technology

    NARCIS (Netherlands)

    Leegsma-Vogt, G; Venema, K; Postema, F; Korf, J

    2001-01-01

    Continuous monitoring of arterio-venous glucose and lactate differences may serve as a diagnostic tool to assess normal brain function and brain pathology. We describe a method and some results obtained with arterio-venous measurements of glucose and lactate in the blood of the halothane-anesthetize

  11. Evidence that brain glucose availability influences exercise-enhanced extracellular 5-HT level in hippocampus: a microdialysis study in exercising rats.

    Science.gov (United States)

    Béquet, F; Gomez-Merino, D; Berthelot, M; Guezennec, C Y

    2002-09-01

    The relationship between brain glucose and serotonin is still unclear and no direct evidence of an action of brain glucose on serotonergic metabolism in central fatigue phenomena has been shown yet. In order to determine whether or not brain glucose could influence the brain 5-hydroxytryptamine (5-HT) system, we have monitored in microdialysis the effects of a direct injection of glucose in rat brain hippocampus on serotonergic metabolism [i.e. 5-HT, 5-hydroxyindoleacetic acid (5-HIAA) and tryptophan (TRP)], during high intensive treadmill running. The injection was performed just before and after exercise. We have shown that glucose induced a decrease of brain 5-HT levels to a minimum of 73.0 +/- 3.5% of baseline after the first injection (P exercise-induced 5-HT enhanced levels. We have observed the same phenomenon concerning the 5-HIAA, but brain TRP levels were not decreased by the injections. In conclusion, this study demonstrates that brain glucose can act on serotonergic metabolism and thus can prevent exercise-induced increase of 5-HT levels. The results also suggest that extracellular brain glucose does not act on the synthesis way of 5-HT, but probably on the release/reuptake system. PMID:12193220

  12. Effects of diabetes on brain metabolism - is brain glycogen a significant player?

    DEFF Research Database (Denmark)

    Sickmann, Helle M; Waagepetersen, Helle S.

    2015-01-01

    Brain glycogen, being an intracellular glucose reservoir, contributes to maintain energy and neurotransmitter homeostasis under physiological as well as pathological conditions. Under conditions with a disturbance in systemic glucose metabolism such as in diabetes, the supply of glucose to the br......Brain glycogen, being an intracellular glucose reservoir, contributes to maintain energy and neurotransmitter homeostasis under physiological as well as pathological conditions. Under conditions with a disturbance in systemic glucose metabolism such as in diabetes, the supply of glucose...... to the brain may be affected and have important impacts on brain metabolism and neurotransmission. This also implies that brain glycogen may serve an essential role in the diabetic state to sustain appropriate brain function. There are two main types of diabetes; type 1 and type 2 diabetes and both types may...... be associated with brain impairments e.g. cognitive decline and dementia. It is however, not clear how these impairments on brain function are linked to alterations in brain energy and neurotransmitter metabolism. In this review, we will illuminate how rodent diabetes models have contributed to a better...

  13. The expression of dominant negative TCF7L2 in pancreatic beta cells during the embryonic stage causes impaired glucose homeostasis

    Directory of Open Access Journals (Sweden)

    Weijuan Shao

    2015-04-01

    Conclusions: Our observations support a cell autonomous role for TCF7L2 in pancreatic β-cells suggested by most, though not all, investigations. βTCFDN is a novel model for further exploring the role of TCF7L2 in β-cell genesis and metabolic homeostasis.

  14. Brain glucose metabolism and neuropsychological test in patients with mild cognitive impairment

    Institute of Scientific and Technical Information of China (English)

    曹秋云; 江开达; 张明园; 刘永昌; 肖世富; 左传涛; 黄红芳

    2003-01-01

    Objective To investigate the features of regional cerebral metabolic rate of glucose (rCMRglc) in patients with mild cognitive impairment(MCI) by positron emission-tomography and its relationship with neuropsychological test.Methods Positron emission tomography, mini-mental state examination and Wechsler memory scale were applied in 10 patients with MCI and 10 healthy volunteers as the control group.Results Scores of mini-mental state examination and Wechsler memory scale in MCI patients were lower than those in the control group (P<0.01). rCMRglc of the left orbital gyrus, right middle temporal gyrus and right putamen was lower in the MCI group than in the control group (P<0.05). Correlation analysis in the MCI group indicated that rCMRglc of many brain regions such as the orbital gyrus, putamen, left hippocampus and parahippocampal gyrus, cingulate gyrus, left amygdaloid body, precentral gyrus, postcentral gyrus, and medial occipitotemporal gyrus in MCI patients, were correlated negatively with age; while the rCMRglc of many parts of the brain such as the left putamen, temporal lobe, anterior cingulate gyrus, left insular lobe, amygdaloid body, precentral gyrus, postcentral gyrus and medial occipitotemporal gyrus were correlated positively with mini-mental state examination; and rCMRglc of the left putamen, temporal lobe, left insular lobe, precentral gyrus and postcentral gyrus were correlated positively with Wechsler memory scale. The right putamen, the right inferior temporal gyrus, precentral gyrus, and left postcentral gyrus were correlated positively with the length of education. However, only rCMRglc of the left amygdaloid body were correlated positively with gender. Conclusion The rCMRglc was lower in the orbital gyrus and putamen of MCI patients. Their rCMRglc were correlated with their cognitive impairment severity, age, length of education and sex.

  15. Brain glucose utilization in systemic lupus erythematosus with neuropsychiatric symptoms: a controlled positron emission tomography study

    Energy Technology Data Exchange (ETDEWEB)

    Otte, A. [Institute of Nuclear Medicine, University Hospital, Basel (Switzerland)]|[Department of Nuclear Medicine, University Hospital Freiburg (Germany); Weiner, S.M. [Department of Rheumatology and Immunology, University Hospital Freiburg (Germany); Peter, H.H. [Department of Rheumatology and Immunology, University Hospital Freiburg (Germany); Mueller-Brand, J. [Institute of Nuclear Medicine, University Hospital, Basel (Switzerland); Goetze, M. [Institute of Nuclear Medicine, University Hospital, Basel (Switzerland); Moser, E. [Department of Nuclear Medicine, University Hospital Freiburg (Germany); Gutfleisch, J. [Department of Rheumatology and Immunology, University Hospital Freiburg (Germany); Hoegerle, S. [Department of Nuclear Medicine, University Hospital Freiburg (Germany); Juengling, F.D. [Department of Nuclear Medicine, University Hospital Freiburg (Germany); Nitzsche, E.U. [Department of Nuclear Medicine, University Hospital Freiburg (Germany)

    1997-07-01

    In contrast to morphological imaging [such as magnetic resonance imaging (MRI) or computed tomography], functional imaging may be of advantage in the detection of brain abnormalities in cases of neuropsychiatric systemic lupus erythematosus (SLE). Therefore, we studied 13 patients (aged 40{+-}14 years, 11 female, 2 male) with neuropsychiatric SLE who met four of the American Rheumatism Association criteria for the classification of SLE. Ten clinically and neurologically healthy volunteers served as controls (aged 40{+-}12 years, 5 female, 5 male). Both groups were investigated using fluorine-18-labelled fluorodeoxyglucose brain positron emission tomography (PET) and cranial MRI. The normal controls and 11 of the 13 patients showed normal MRI scans. However, PET scan was abnormal in all 13 SLE patients. Significant group-to-group differences in the glucose metabolic index (GMI=region of interest uptake/global uptake at the level of the basal ganglia and thalamus) were found in the parieto-occipital region on both sides: the GMI of the parieto-occipital region on the right side was 0.922{+-}0.045 in patients and 1.066{+-}0.081 in controls (P<0.0001, Mann Whitney U test), while on the left side it was 0.892{+-}0.060 in patients and 1.034{+-}0.051 in controls (P=0.0002). Parieto-occipital hypometabolism is a conspicuous finding in mainly MRI-negative neuropsychiatric SLE. As the parieto-occipital region is located at the boundary of blood supply of all three major arteries, it could be the most vulnerable zone of the cerebrum and may be affected at an early stage of the cerebrovascular disease. (orig.). With 1 fig., 1 tab.

  16. Evaluation of the Genetic and Nutritional Control of Obesity and Type 2 Diabetes in a Novel Mouse Model on Chromosome 7: An Insight into Insulin Signaling and Glucose Homeostasis

    Energy Technology Data Exchange (ETDEWEB)

    Nelson, S.; Dhar, M.

    2003-01-01

    Obesity is the main cause of type 2 diabetes, accounting for 90-95% of all diabetes cases in the US. Human obesity is a complex trait and can be studied using appropriate mouse models. A novel polygenic mouse model for studying the genetic and environmental contributions to and the physiological ramifications of obesity and related phenotypes is found in specific lines of mice bred and maintained at Oak Ridge National Laboratory. Heterozygous mice with a maternally inherited copy of two radiation-induced deletions in the p region of mouse chromosome 7, p23DFioD and p30PUb, have significantly greater body fat and show hyperinsulinemia compared to the wild-type. A single gene, Atp10c, maps to this critical region and codes for a putative aminophospholipid translocase. Biochemical and molecular studies were initiated to gain insight into obesity and glucose homeostasis in these animals and to study the biological role of Atp10c in creating these phenotypes. Glucose and insulin tolerance tests were standardized for the heterozygous p23DFioD and control mice on a custom-made diet containing 20% protein, 70% carbohydrate, and 10% fat (kcal). Atp10c expression profiles were also generated using Reverse-Transcriptase Polymerase Chain Reaction (RT-PCR). Heterozygous p23DFioD animals showed insulin resistance after receiving a dose of either 0.375 or 0.75 U/kg Illetin R insulin. RT-PCR data also shows differences in Atp10c expression in the mutants versus control mice. Using these standardized biochemical assays, future studies will further the understanding of genetic and nutritional controls of glucose homeostasis and obesity in animal models and subsequently in human populations.

  17. Selective vulnerability in brain hypoxia

    DEFF Research Database (Denmark)

    Cervos-Navarro, J.; Diemer, Nils Henrik

    1991-01-01

    Neuropathology, selective vulnerability, brain hypoxia, vascular factors, excitotoxicity, ion homeostasis......Neuropathology, selective vulnerability, brain hypoxia, vascular factors, excitotoxicity, ion homeostasis...

  18. Design, synthesis and preliminary bio-evaluation of glucose-cholesterol derivatives as ligands for brain targeting liposomes

    Institute of Scientific and Technical Information of China (English)

    Fan Lei; Wei Fan; Xian Kun Li; Shan Wang; Li Hai; Yong Wu

    2011-01-01

    A series of glucose-cholesterol derivatives 8a-8e as ligands for brain targeting liposomes were synthesized. The preparation of compound 6 involved temporary protection of glucose with chlorotrimethylsilicane and hexamethyldisilazane followed by selectively hydrolyzed. The known cholesteryl tosylate 1 were coupled to ethylene glycols to afford alcohol 2a-2e. Substitution and deprotection of alcohol 2a-2e furnished the acids 4a-4e, which was condensed with compound 6 to get compounds 7a-7e, and then was deprotected in tetrahydrofuran with TEA to obtain the title compounds. As a model drug, tegafur was entrapped by liposomes coupled with 8b, and preliminary in vivo evaluation shown 8b could enhance the ability of liposomes delivering tegafur across the blood brain barrier.

  19. Cytosolic NADPH homeostasis in glucose-starved procyclic Trypanosoma brucei relies on malic enzyme and the pentose phosphate pathway fed by gluconeogenic flux.

    Science.gov (United States)

    Allmann, Stefan; Morand, Pauline; Ebikeme, Charles; Gales, Lara; Biran, Marc; Hubert, Jane; Brennand, Ana; Mazet, Muriel; Franconi, Jean-Michel; Michels, Paul A M; Portais, Jean-Charles; Boshart, Michael; Bringaud, Frédéric

    2013-06-21

    All living organisms depend on NADPH production to feed essential biosyntheses and for oxidative stress defense. Protozoan parasites such as the sleeping sickness pathogen Trypanosoma brucei adapt to different host environments, carbon sources, and oxidative stresses during their infectious life cycle. The procyclic stage develops in the midgut of the tsetse insect vector, where they rely on proline as carbon source, although they prefer glucose when grown in rich media. Here, we investigate the flexible and carbon source-dependent use of NADPH synthesis pathways in the cytosol of the procyclic stage. The T. brucei genome encodes two cytosolic NADPH-producing pathways, the pentose phosphate pathway (PPP) and the NADP-dependent malic enzyme (MEc). Reverse genetic blocking of those pathways and a specific inhibitor (dehydroepiandrosterone) of glucose-6-phosphate dehydrogenase together established redundancy with respect to H2O2 stress management and parasite growth. Blocking both pathways resulted in ∼10-fold increase of susceptibility to H2O2 stress and cell death. Unexpectedly, the same pathway redundancy was observed in glucose-rich and glucose-depleted conditions, suggesting that gluconeogenesis can feed the PPP to provide NADPH. This was confirmed by (i) a lethal phenotype of RNAi-mediated depletion of glucose-6-phosphate isomerase (PGI) in the glucose-depleted Δmec/Δmec null background, (ii) an ∼10-fold increase of susceptibility to H2O2 stress observed for the Δmec/Δmec/(RNAi)PGI double mutant when compared with the single mutants, and (iii) the (13)C enrichment of glycolytic and PPP intermediates from cells incubated with [U-(13)C]proline, in the absence of glucose. Gluconeogenesis-supported NADPH supply may also be important for nucleotide and glycoconjugate syntheses in the insect host.

  20. Oral administration of SR-110, a peroxynitrite decomposing catalyst, enhances glucose homeostasis, insulin signaling, and islet architecture in B6D2F1 mice fed a high fat diet.

    Science.gov (United States)

    Johns, Michael; Esmaeili Mohsen Abadi, Sakineh; Malik, Nehal; Lee, Joshua; Neumann, William L; Rausaria, Smita; Imani-Nejad, Maryam; McPherson, Timothy; Schober, Joseph; Kwon, Guim

    2016-04-15

    Peroxynitrite has been implicated in type 2 diabetes and diabetic complications. As a follow-up study to our previous work on SR-135 (Arch Biochem Biophys 577-578: 49-59, 2015), we provide evidence that this series of compounds are effective when administered orally, and their mechanisms of actions extend to the peripheral tissues. A more soluble analogue of SR-135, SR-110 (from a new class of Mn(III) bis(hydroxyphenyl)-dipyrromethene complexes) was orally administered for 2 weeks to B6D2F1 mice fed a high fat-diet (HFD). Mice fed a HFD for 4 months gained significantly higher body weights compared to lean diet-fed mice (52 ± 1.5 g vs 34 ± 1.3 g). SR-110 (10 mg/kg daily) treatment significantly reduced fasting blood glucose and insulin levels, and enhanced glucose tolerance as compared to HFD control or vehicle (peanut butter) group. SR-110 treatment enhanced insulin signaling in the peripheral organs, liver, heart, and skeletal muscle, and reduced lipid accumulation in the liver. Furthermore, SR-110 increased insulin content, restored islet architecture, decreased islet size, and reduced tyrosine nitration. These results suggest that a peroxynitrite decomposing catalyst is effective in improving glucose homeostasis and restoring islet morphology and β-cell insulin content under nutrient overload. PMID:26970045

  1. 脂肪酸在中枢能量平衡调节中的作用%Role of fatty acids in tile energy homeostasis regulation of brain

    Institute of Scientific and Technical Information of China (English)

    王邦琼; 李启富; 程庆丰

    2009-01-01

    The hypothalamus,which has nutrient sensitive neurons perceiving the nutritional status of body,plays a key role in the maintenance of energy homeostasis. As energy signal,fatty acids (FAs) can affect the activity of hypothalamic FA-sensitive neurons, and modulate food intake, insulin secretion and hepatic glucose output, by changing the membrane potential, regulating the ion channels, and affecting the secretion of neurotransmitters. Moreover FAs metabolites in the neurons also paticipate in the lipid sensing of hypothalamus. Overload and dysfunction of their metabolism impair nervous control of energy homeostasis, and contribute to development of obesity and type 2 diabetes.%下丘脑足维持机体能量平衡的中枢,含有营养素敏感性神经元,可感知机体的营养状态.脂肪酸可作为能量信号,作用于下丘脑脂质敏感性神经元,改变膜电位,调节离子通道的开闭,影响神经递质的释放,从而参与摄食行为、胰岛素分泌、肝葡萄糖输出等代谢活动.另外,脂肪酸在神经元中的代谢产物也参与了下丘脑的脂质感知.因此,脂肪酸异常增加和其代谢紊乱,可导致神经系统对能量平衡控制的失调,从而诱发肥胖和2型糖尿病.

  2. Comparison of the effect of multiple short-duration with single long-duration exercise sessions on glucose homeostasis in type 2 diabetes mellitus

    DEFF Research Database (Denmark)

    Eriksen, L; Dahl-Petersen, I; Haugaard, Steen B;

    2007-01-01

    AIMS/HYPOTHESIS: We evaluated and compared the effects on glycaemic control of two different exercise protocols in elderly men with type 2 diabetes mellitus. METHODS: Eighteen patients with type 2 diabetes mellitus carried out home-based bicycle training for 5 weeks. Patients were randomly assigned...... glucose OGTT (p = 0.04) and plasma glucose concentration areas under the curve at 120 min (p exercise groups...... increased similarly in both exercise groups. A possible explanation is that the energy expenditure associated with multiple short daily sessions may be greater than that in a single daily session. Udgivelsesdato: 2007-Nov...

  3. Age-related changes of glutathione content, glucose transport and metabolism, and mitochondrial electron transfer function in mouse brain

    International Nuclear Information System (INIS)

    To evaluate the oxidative stress-related parameters and to determine their order of appearance in the brain aging process, radionuclide experiments were carried out on male DBF1 mice at 3, 12, 24 and 30 months of age. The content of nonprotein sulfhydryl compounds, mainly glutathione, was estimated with technetium-99m meso-hexamethyl propyleneamine oxime ([99mTc]meso-HMPAO) tissue sampling. Glucose transport and metabolism was examined with [1-14C]2-deoxy-D-glucose (2-DG) tissue sampling. Mitochondrial electron transport function was estimated with [15O]O2 gas-tissue ARG. [99mTc]Meso-HMPAO uptake in brain expressed as standardized uptake value (SUV), (radioactivity in brain tissue/tissue weight)/(total administered radioactivity/body weight), reached maximum at 12 months of age and decreased at 24 and 30 months of age in every region examined. The pattern of 2-DG, expressed as SUV, showed a tendency to increase rather than decrease with aging. [15O]O2 fixation in brain slices remained constant until 24 months, while it decreased significantly at 30 months of age. The results suggested the possibility of using imaging techniques in vivo for longitudinal evaluation of the aging process and indicated reduction of nonprotein sulfhydryl compounds including GSH at the early stages of aging may also accelerate the dysfunction of mitochondrial electron transport and neurodegeneration

  4. Persistent resetting of the cerebral oxygen/glucose uptake ratio by brain activation

    DEFF Research Database (Denmark)

    Madsen, P L; Hasselbalch, S G; Hagemann, L P;

    1995-01-01

    Global cerebral blood flow (CBF), global cerebral metabolic rates for oxygen (CMRO2), and for glucose (CMRglc), and lactate efflux were measured during rest and during cerebral activation induced by the Wisconsin card sorting test. Measurements were performed in healthy volunteers using the Kety...... stress indicators returned to baseline values. Activation-induced resetting of the cerebral oxygen/glucose uptake ratio is not necessarily accounted for by increased lactate production from nonoxidative glucose metabolism....

  5. The role of insulin-like growth factor-I and its binding proteins in glucose homeostasis and type 2 diabetes.

    Science.gov (United States)

    Rajpathak, Swapnil N; Gunter, Marc J; Wylie-Rosett, Judith; Ho, Gloria Y F; Kaplan, Robert C; Muzumdar, Radhika; Rohan, Thomas E; Strickler, Howard D

    2009-01-01

    This review addresses the possible role of the insulin-like growth factor (IGF)-axis in normal glucose homoeostasis and in the etiopathogenesis of type 2 diabetes. IGF-I, a peptide hormone, shares amino acid sequence homology with insulin and has insulin-like activity; most notably, the promotion of glucose uptake by peripheral tissues. Type 2 diabetes as well as pre-diabetic states, including impaired fasting glucose and impaired glucose tolerance, are associated cross-sectionally with altered circulating levels of IGF-I and its binding proteins (IGFBPs). Administration of recombinant human IGF-I has been reported to improve insulin sensitivity in healthy individuals as well as in patients with insulin resistance and type 2 diabetes. Further, IGF-I may have beneficial effects on systemic inflammation, a risk factor for type 2 diabetes, and on pancreatic beta-cell mass and function. There is considerable inter-individual heterogeneity in endogenous levels of IGF-I and its binding proteins; however, the relationship between these variations and the risk of developing type 2 diabetes has not been extensively investigated. Large prospective studies are required to evaluate this association.

  6. Antidiabetic and Antilipidemic Effect of Musa balbisiana Root Extract: A Potent Agent for Glucose Homeostasis in Streptozotocin-Induced Diabetic Rat

    Science.gov (United States)

    Kalita, Himadri; Boruah, Dulal C.; Deori, Meetali; Hazarika, Ankita; Sarma, Rahul; Kumari, Sima; Kandimalla, Raghuram; Kotoky, Jibon; Devi, Rajlakshmi

    2016-01-01

    Folklore studies have revealed that Musa balbisiana Colla (MB; Family: Musaceae) has high medicinal properties. The purpose of the present study is to evaluate antihyperglycemic, and antioxidant activity of MB extracts in streptozotocin (STZ) induced diabetic rats. In vitro antioxidant and antidiabetic activity of MB extracts, i.e., root extract (RE), shoot extract and inflorescence extract were determined by using various methods viz 1,-1-diphenyl-2-picrylhydrazyl (DPPH) and a method to assess their possible effect on glucose diffusion across gastrointestinal tract and identify bioactive compound of potent extract. In vivo antilipidemic and antidiabetic activity was evaluated by administrating oral dose of RE for 15 days on STZ- induced diabetic rat. RE showed highest antioxidant activity by scavenging DPPH radical (IC50 32.96 μg/ml) and inhibit 30% glucose movement in vitro. The methanol extract of root showed the presence of calyx [4] arene category of the compound. Furthermore, RE treated rat revealed a reduction in fasting blood glucose (62.5%), serum total cholesterol (36.2%), triglyceride (54.5%), and low-density lipoprotein (50.94%) after 15 days as compared to STZ treated animal. There was an initiation of regenerative structures of the affected organs after 15 days of RE treatment. Histopathological observations clearly differentiate the structural changes in pancreas, liver, and kidney of STZ and RE treated group. The presence of calyx [4] arene class of compound may be responsible for its antioxidant and antidiabetic properties by absorbing glucose in vivo. PMID:27199747

  7. Glucose metabolism via the pentose phosphate pathway, glycolysis and Krebs cycle in an orthotopic mouse model of human brain tumors.

    Science.gov (United States)

    Marin-Valencia, Isaac; Cho, Steve K; Rakheja, Dinesh; Hatanpaa, Kimmo J; Kapur, Payal; Mashimo, Tomoyuki; Jindal, Ashish; Vemireddy, Vamsidhara; Good, Levi B; Raisanen, Jack; Sun, Xiankai; Mickey, Bruce; Choi, Changho; Takahashi, Masaya; Togao, Osamu; Pascual, Juan M; Deberardinis, Ralph J; Maher, Elizabeth A; Malloy, Craig R; Bachoo, Robert M

    2012-10-01

    It has been hypothesized that increased flux through the pentose phosphate pathway (PPP) is required to support the metabolic demands of rapid malignant cell growth. Using orthotopic mouse models of human glioblastoma (GBM) and renal cell carcinoma metastatic to brain, we estimated the activity of the PPP relative to glycolysis by infusing [1,2-(13) C(2) ]glucose. The [3-(13) C]lactate/[2,3-(13) C(2) ]lactate ratio was similar for both the GBM and brain metastasis and their respective surrounding brains (GBM, 0.197 ± 0.011 and 0.195 ± 0.033, respectively (p = 1); metastasis: 0.126 and 0.119 ± 0.033, respectively). This suggests that the rate of glycolysis is significantly greater than the PPP flux in these tumors, and that the PPP flux into the lactate pool is similar in both tumors. Remarkably, (13) C-(13) C coupling was observed in molecules derived from Krebs cycle intermediates in both tumor types, denoting glucose oxidation. In the renal cell carcinoma, in contrast with GBM, (13) C multiplets of γ-aminobutyric acid (GABA) differed from its precursor glutamate, suggesting that GABA did not derive from a common glutamate precursor pool. In addition, the orthotopic renal tumor, the patient's primary renal mass and brain metastasis were all strongly immunopositive for the 67-kDa isoform of glutamate decarboxylase, as were 84% of tumors on a renal cell carcinoma tissue microarray of the same histology, suggesting that GABA synthesis is cell autonomous in at least a subset of renal cell carcinomas. Taken together, these data demonstrate that (13) C-labeled glucose can be used in orthotopic mouse models to study tumor metabolism in vivo and to ascertain new metabolic targets for cancer diagnosis and therapy.

  8. ONLINE MONITORING OF EXTRACELLULAR BRAIN GLUCOSE USING MICRODIALYSIS AND A NADPH-LINKED ENZYMATIC ASSAY

    NARCIS (Netherlands)

    VANDERKUIL, JHF; KORF, J

    1991-01-01

    A method to monitor extracellular glucose in freely moving rats, based on intracerebral microdialysis coupled to an enzyme reactor is described. The dialysate is continuously mixed with a solution containing the enzymes hexokinase and glucose-6-phosphate dehydrogenase, and the fluorescence of NADPH

  9. Glucose metabolism during fasting is altered in experimental porphobilinogen deaminase deficiency.

    Science.gov (United States)

    Collantes, María; Serrano-Mendioroz, Irantzu; Benito, Marina; Molinet-Dronda, Francisco; Delgado, Mercedes; Vinaixa, María; Sampedro, Ana; Enríquez de Salamanca, Rafael; Prieto, Elena; Pozo, Miguel A; Peñuelas, Iván; Corrales, Fernando J; Barajas, Miguel; Fontanellas, Antonio

    2016-04-01

    Porphobilinogen deaminase (PBGD) haploinsufficiency (acute intermittent porphyria, AIP) is characterized by neurovisceral attacks when hepatic heme synthesis is activated by endogenous or environmental factors including fasting. While the molecular mechanisms underlying the nutritional regulation of hepatic heme synthesis have been described, glucose homeostasis during fasting is poorly understood in porphyria. Our study aimed to analyse glucose homeostasis and hepatic carbohydrate metabolism during fasting in PBGD-deficient mice. To determine the contribution of hepatic PBGD deficiency to carbohydrate metabolism, AIP mice injected with a PBGD-liver gene delivery vector were included. After a 14 h fasting period, serum and liver metabolomics analyses showed that wild-type mice stimulated hepatic glycogen degradation to maintain glucose homeostasis while AIP livers activated gluconeogenesis and ketogenesis due to their inability to use stored glycogen. The serum of fasted AIP mice showed increased concentrations of insulin and reduced glucagon levels. Specific over-expression of the PBGD protein in the liver tended to normalize circulating insulin and glucagon levels, stimulated hepatic glycogen catabolism and blocked ketone body production. Reduced glucose uptake was observed in the primary somatosensorial brain cortex of fasted AIP mice, which could be reversed by PBGD-liver gene delivery. In conclusion, AIP mice showed a different response to fasting as measured by altered carbohydrate metabolism in the liver and modified glucose consumption in the brain cortex. Glucose homeostasis in fasted AIP mice was efficiently normalized after restoration of PBGD gene expression in the liver. PMID:26908609

  10. The renin-angiotensin system: a target of and contributor to dyslipidemias, altered glucose homeostasis, and hypertension of the metabolic syndrome.

    Science.gov (United States)

    Putnam, Kelly; Shoemaker, Robin; Yiannikouris, Frederique; Cassis, Lisa A

    2012-03-15

    The renin-angiotensin system (RAS) is an important therapeutic target in the treatment of hypertension. Obesity has emerged as a primary contributor to essential hypertension in the United States and clusters with other metabolic disorders (hyperglycemia, hypertension, high triglycerides, low HDL cholesterol) defined within the metabolic syndrome. In addition to hypertension, RAS blockade may also serve as an effective treatment strategy to control impaired glucose and insulin tolerance and dyslipidemias in patients with the metabolic syndrome. Hyperglycemia, insulin resistance, and/or specific cholesterol metabolites have been demonstrated to activate components required for the synthesis [angiotensinogen, renin, angiotensin-converting enzyme (ACE)], degradation (ACE2), or responsiveness (angiotensin II type 1 receptors, Mas receptors) to angiotensin peptides in cell types (e.g., pancreatic islet cells, adipocytes, macrophages) that mediate specific disorders of the metabolic syndrome. An activated local RAS in these cell types may contribute to dysregulated function by promoting oxidative stress, apoptosis, and inflammation. This review will discuss data demonstrating the regulation of components of the RAS by cholesterol and its metabolites, glucose, and/or insulin in cell types implicated in disorders of the metabolic syndrome. In addition, we discuss data supporting a role for an activated local RAS in dyslipidemias and glucose intolerance/insulin resistance and the development of hypertension in the metabolic syndrome. Identification of an activated RAS as a common thread contributing to several disorders of the metabolic syndrome makes the use of angiotensin receptor blockers and ACE inhibitors an intriguing and novel option for multisymptom treatment.

  11. Visualizing Sweetness: Increasingly Diverse Applications for Fluorescent-Tagged Glucose Bioprobes and Their Recent Structural Modifications

    Directory of Open Access Journals (Sweden)

    Darren R. Williams

    2012-04-01

    Full Text Available Glucose homeostasis is a fundamental aspect of life and its dysregulation is associated with important diseases, such as cancer and diabetes. Traditionally, glucose radioisotopes have been used to monitor glucose utilization in biological systems. Fluorescent-tagged glucose analogues were initially developed in the 1980s, but it is only in the past decade that their use as a glucose sensor has increased significantly. These analogues were developed for monitoring glucose uptake in blood cells, but their recent applications include tracking glucose uptake by tumor cells and imaging brain cell metabolism. This review outlines the development of fluorescent-tagged glucose analogues, describes their recent structural modifications and discusses their increasingly diverse biological applications.

  12. PCP-induced alterations in cerebral glucose utilization in rat brain: blockade by metaphit, a PCP-receptor-acylating agent

    Energy Technology Data Exchange (ETDEWEB)

    Tamminga, C.A.; Tanimoto, K.; Kuo, S.; Chase, T.N.; Contreras, P.C.; Rice, K.C.; Jackson, A.E.; O' Donohue, T.L.

    1987-01-01

    The effects of phencyclidine (PCP) on regional cerebral glucose utilization was determined by using quantitative autoradiography with (/sup 14/C)-2-deoxyglucose. PCP increased brain metabolism in selected areas of cortex, particularly limbic, and in the basal ganglia and thalamus, whereas the drug decreased metabolism in areas related to audition. These results are consistent with the known physiology of central PCP neurons and may help to suggest brain areas involved in PCP-mediated actions. Moreover, based on the behavioral similarities between PCP psychosis and an acute schizophrenic episode, these data may be relevant to the understanding of schizophrenia. The PCP-receptor-acylating agent, metaphit, blocked most of these PCP actions. In addition, metaphit by itself was found to diminish glucose utilization rather uniformly throughout brain. These results indicate an antagonist effect of metaphit on the PCP system and suggest a widespread action of metaphit, putatively at a PCP-related site, possibly in connection with the N-methyl-D-aspartate (NMDA) receptor.

  13. Cerebral glucose metabolism in long-term survivors of childhood primary brain tumors treated with surgery and radiotherapy

    DEFF Research Database (Denmark)

    Andersen, Preben B.; Krabbe, Katja; Leffers, Anne M.;

    2003-01-01

    Delayed structural cerebral sequelae has been reported following cranial radiation therapy (CRT) to children with primary brain tumors, but little is known about potential functional changes. Twenty-four patients were included, diagnosed and treated at a median age of 11 years, and examined after...... that there is a general reduction in rCMRglc in long-term recurrence free survivors of childhood primary brain tumors treated with CRT in high doses (44-56 Gy)......Delayed structural cerebral sequelae has been reported following cranial radiation therapy (CRT) to children with primary brain tumors, but little is known about potential functional changes. Twenty-four patients were included, diagnosed and treated at a median age of 11 years, and examined after...... a median recurrence free survival of 16 years by MRI and Positron Emission Tomography using the glucose analog 2-18F-fluoro-2-deoxy-D-glucose (18FDG). Three patients were not analyzed further due to diffuse cerebral atrophy, which might be related to previous hydrocephalus. Twenty-one patients were...

  14. A CREB-Sirt1-Hes1 Circuitry Mediates Neural Stem Cell Response to Glucose Availability

    OpenAIRE

    Salvatore Fusco; Lucia Leone; Saviana Antonella Barbati; Daniela Samengo; Roberto Piacentini; Giuseppe Maulucci; Gabriele Toietta; Matteo Spinelli; Michael McBurney; Giovambattista Pani; Claudio Grassi

    2016-01-01

    Adult neurogenesis plays increasingly recognized roles in brain homeostasis and repair and is profoundly affected by energy balance and nutrients. We found that the expression of Hes-1 (hairy and enhancer of split 1) is modulated in neural stem and progenitor cells (NSCs) by extracellular glucose through the coordinated action of CREB (cyclic AMP responsive element binding protein) and Sirt-1 (Sirtuin 1), two cellular nutrient sensors. Excess glucose reduced CREB-activated Hes-1 expression an...

  15. A Methyl-Deficient Diet Fed to Rat Dams during the Peri-Conception Period Programs Glucose Homeostasis in Adult Male but Not Female Offspring123

    Science.gov (United States)

    Maloney, Christopher A.; Hay, Susan M.; Young, Loraine E.; Sinclair, Kevin D.; Rees, William D.

    2011-01-01

    Methyl deficiencies have been implicated in metabolic programming during the periods of oocyte and embryo development. Semisynthetic methyl-deficient diets (MD) with no folic acid, 0.05% choline, and approximately one-half the recommended content of methionine were fed to female rats for 3 wk prior to mating and for the first 5 d of gestation. During the period of MD feeding, plasma homocysteine concentrations were approximately twice those of rats fed the complete (CON) diet. From d 5, both groups received a complete semipurified AIN diet until birth. On d 8, plasma homocysteine concentrations did not differ between the 2 groups. Thereafter, dams and offspring were fed a nonpurified diet for the remainder of the experiment. At 6 mo of age, the homeostatic model assessment (HOMA) index of the male MD offspring tended to be 32% higher (P = 0.053) and peak insulin during an oral glucose tolerance test (oGTT) was 39% higher (P < 0.05) compared with the male CON offspring. There was no difference in the response to an oGTT in the female offspring at 6 mo of age. The increased HOMA index of male MD offspring persisted to 12 mo of age. The peak glucose concentration during oGTT was 23% higher (P < 0.05) in MD compared with the CON males despite 39% greater (P < 0.05) peak insulin concentrations. This study shows that in rats, a physiologically relevant methyl-deficient diet fed during the period of oocyte maturation and preimplantation development programs gender-specific changes in glucose handling by the offspring. PMID:21106931

  16. Effects of adrenergic agents on intracellular ca(2+) homeostasis and metabolism of glucose in astrocytes with an emphasis on pyruvate carboxylation, oxidative decarboxylation and recycling

    DEFF Research Database (Denmark)

    Obel, Linea Lykke Frimodt; Andersen, Karen M H; Bak, Lasse Kristoffer;

    2012-01-01

    . Employing mass spectrometry, labeling in intracellular metabolites was determined. Moreover, the involvement of Ca(2+) in the noradrenergic response was studied. In unstimulated astrocytes, the labeling pattern of glutamate, aspartate, malate and citrate confirmed important roles for pyruvate carboxylation...... and oxidative decarboxylation in astrocytic glucose metabolism. Importantly, pyruvate carboxylation was best visualized at 10 min of incubation. The abundance and pattern of labeling in lactate and alanine indicated not only an extensive activity of malic enzyme (initial step for pyruvate recycling) but also...

  17. Neuronal LRP1 Regulates Glucose Metabolism and Insulin Signaling in the Brain

    OpenAIRE

    Liu, Chia-Chen; Hu, Jin; Tsai, Chih-Wei; Yue, Mei; Melrose, Heather L.; Kanekiyo, Takahisa; Bu, Guojun

    2015-01-01

    Alzheimer's disease (AD) is a neurological disorder characterized by profound memory loss and progressive dementia. Accumulating evidence suggests that Type 2 diabetes mellitus, a metabolic disorder characterized by insulin resistance and glucose intolerance, significantly increases the risk for developing AD. Whereas amyloid-β (Aβ) deposition and neurofibrillary tangles are major histological hallmarks of AD, impairment of cerebral glucose metabolism precedes these pathological changes durin...

  18. Combination of the sodium-glucose cotransporter-2 inhibitor empagliflozin with orlistat or sibutramine further improves the body-weight reduction and glucose homeostasis of obese rats fed a cafeteria diet.

    Science.gov (United States)

    Vickers, Steven P; Cheetham, Sharon C; Headland, Katie R; Dickinson, Keith; Grempler, Rolf; Mayoux, Eric; Mark, Michael; Klein, Thomas

    2014-01-01

    The present study assessed the potential of the sodium glucose-linked transporter (SGLT)-2 inhibitor empagliflozin to decrease body weight when administered alone or in combination with the clinically effective weight-loss agents orlistat and sibutramine in obese rats fed a cafeteria diet. Female Wistar rats were exposed to a cafeteria diet to induce obesity. Empagliflozin was dosed once daily (10, 30, and 60 mg/kg) for 28 days. Combination studies were subsequently performed using a submaximal empagliflozin dose (10 mg/kg) with either sibutramine or orlistat. Body weight, food, and water intake were recorded daily. The effect of drug treatment on glucose tolerance, relevant plasma parameters, and carcass composition was determined. Empagliflozin dose-dependently reduced body weight, plasma leptin, and body fat though increased urinary glucose excretion. The combination of empagliflozin and orlistat significantly reduced body weight compared to animals treated with either drug alone, and significantly improved glucose tolerance, plasma insulin, and leptin compared to vehicle-treated controls. The effect of sibutramine to improve glycemic control in an oral glucose-tolerance test was also significantly increased, with empagliflozin and combination treatment leading to a reduction in carcass fat greater than that observed with either drug alone. These data demonstrate that empagliflozin reduces body weight in cafeteria-fed obese rats. In combination studies, empagliflozin further improved the body-weight or body-fat loss of animals in comparison to orlistat or sibutramine alone. Such studies may indicate improved strategies for the treatment of obese patients with prediabetes or type 2 diabetes. PMID:25061325

  19. Combination of the sodium-glucose cotransporter-2 inhibitor empagliflozin with orlistat or sibutramine further improves the body-weight reduction and glucose homeostasis of obese rats fed a cafeteria diet

    Directory of Open Access Journals (Sweden)

    Vickers SP

    2014-07-01

    Full Text Available Steven P Vickers,1 Sharon C Cheetham,1 Katie R Headland,1 Keith Dickinson,1 Rolf Grempler,2 Eric Mayoux,2 Michael Mark,2 Thomas Klein2 1RenaSci, BioCity Nottingham, Nottingham, UK; 2Boehringer Ingelheim Pharma, Biberach an der Riss, Germany Abstract: The present study assessed the potential of the sodium glucose-linked transporter (SGLT-2 inhibitor empagliflozin to decrease body weight when administered alone or in combination with the clinically effective weight-loss agents orlistat and sibutramine in obese rats fed a cafeteria diet. Female Wistar rats were exposed to a cafeteria diet to induce obesity. Empagliflozin was dosed once daily (10, 30, and 60 mg/kg for 28 days. Combination studies were subsequently performed using a submaximal empagliflozin dose (10 mg/kg with either sibutramine or orlistat. Body weight, food, and water intake were recorded daily. The effect of drug treatment on glucose tolerance, relevant plasma parameters, and carcass composition was determined. Empagliflozin dose-dependently reduced body weight, plasma leptin, and body fat though increased urinary glucose excretion. The combination of empagliflozin and orlistat significantly reduced body weight compared to animals treated with either drug alone, and significantly improved glucose tolerance, plasma insulin, and leptin compared to vehicle-treated controls. The effect of sibutramine to improve glycemic control in an oral glucose-tolerance test was also significantly increased, with empagliflozin and combination treatment leading to a reduction in carcass fat greater than that observed with either drug alone. These data demonstrate that empagliflozin reduces body weight in cafeteria-fed obese rats. In combination studies, empagliflozin further improved the body-weight or body-fat loss of animals in comparison to orlistat or sibutramine alone. Such studies may indicate improved strategies for the treatment of obese patients with prediabetes or type 2 diabetes. Keywords

  20. Quantitative autoradiography of 14C-D-glucose metabolism of normal and traumatized rat brain using micro-absorption photometry

    International Nuclear Information System (INIS)

    It could be shown using 14C-glucose as energy-providing substrate for brain tissue metabolism that for bolus type application a retarded and even channelling of the substrate into the metabolic process takes place. The presence of tracer in the tissue was established using autoradiography. A linear correlation between the amount of tissue-incorporated 14C section thickness and exposure time could be established by means of densitometric measurement of brain sections of various thicknesses, by applying various 14C-activities and by different exposure times. From these correlations direct conclusions may be made regarding the specific activity of the tissue provided that exposure time and section thickness of the sample are known. Comparative studies between cortex and narrow and between traumatized and non-traumatized brain tissue show that the rate of metabolism in brain cortex is markedly higher than in the marrow and that 14C-incorporation is higher in traumatized tissue than in non-traumatized tissue. Whilst the difference in rate of metabolism between brain cortex and marrow can be clearly related to the differing cell count/unit surface area for cortex and marrow, the different energy conversion rates for functionally damaged and normal brain tissue is a specific characteristic of injury. Apart from the fact that an increased 14C-deposition is in no way indicative of an increased metabolic activity, the possibility of quantifying 14C-tissue content provides a basis for estimating therapeutic effects e.g. in the treatment of trauma-caused brain edema. (orig.)

  1. Tetrahydro iso-alpha acids from hops improve glucose homeostasis and reduce body weight gain and metabolic endotoxemia in high-fat diet-fed mice.

    Directory of Open Access Journals (Sweden)

    Amandine Everard

    Full Text Available Obesity and related metabolic disorders such as insulin resistance and type 2 diabetes are associated with a low-grade inflammatory state possibly through changes in gut microbiota composition and the development of higher plasma lipopolysaccharide (LPS levels, i.e. metabolic endotoxemia. Various phytochemical compounds have been investigated as potential tools to regulate these metabolic features. Humulus lupulus L. (hops contains several classes of compounds with anti-inflammatory potential. Recent evidence suggests that hops-derived compounds positively impact adipocyte metabolism and glucose tolerance in obese and diabetic rodents via undefined mechanisms. In this study, we found that administration of tetrahydro iso-alpha acids (termed META060 to high-fat diet (HFD-fed obese and diabetic mice for 8 weeks reduced body weight gain, the development of fat mass, glucose intolerance, and fasted hyperinsulinemia, and normalized insulin sensitivity markers. This was associated with reduced portal plasma LPS levels, gut permeability, and higher intestinal tight junction proteins Zonula occludens-1 and occludin. Moreover, META060 treatment increased the plasma level of the anti-inflammatory cytokine interleukin-10 and decreased the plasma level of the pro-inflammatory cytokine granulocyte colony-stimulating factor. In conclusion, this research allows us to decipher a novel mechanism contributing to the positive effects of META060 treatment, and supports the need to investigate such compounds in obese and type 2 diabetic patients.

  2. Heterozygous Hfe gene deletion leads to impaired glucose homeostasis, but not liver injury in mice fed a high-calorie diet.

    Science.gov (United States)

    Britton, Laurence; Jaskowski, Lesley; Bridle, Kim; Santrampurwala, Nishreen; Reiling, Janske; Musgrave, Nick; Subramaniam, V Nathan; Crawford, Darrell

    2016-06-01

    Heterozygous mutations of the Hfe gene have been proposed as cofactors in the development and progression of nonalcoholic fatty liver disease (NAFLD). Homozygous Hfe deletion previously has been shown to lead to dysregulated hepatic lipid metabolism and accentuated liver injury in a dietary mouse model of NAFLD We sought to establish whether heterozygous deletion of Hfe is sufficient to promote liver injury when mice are exposed to a high-calorie diet (HCD). Eight-week-old wild-type and Hfe(+/-) mice received 8 weeks of a control diet or HCD Liver histology and pathways of lipid and iron metabolism were analyzed. Liver histology demonstrated that mice fed a HCD had increased NAFLD activity score (NAS), steatosis, and hepatocyte ballooning. However, liver injury was unaffected by Hfe genotype. Hepatic iron concentration (HIC) was increased in Hfe(+/-) mice of both dietary groups. HCD resulted in a hepcidin-independent reduction in HIC Hfe(+/-) mice demonstrated raised fasting serum glucose concentrations and HOMA-IR score, despite unaltered serum adiponectin concentrations. Downstream regulators of hepatic de novo lipogenesis (pAKT, SREBP-1, Fas, Scd1) and fatty acid oxidation (AdipoR2, Pparα, Cpt1) were largely unaffected by genotype. In summary, heterozygous Hfe gene deletion is associated with impaired iron and glucose metabolism. However, unlike homozygous Hfe deletion, heterozygous gene deletion did not affect lipid metabolism pathways or liver injury in this model. PMID:27354540

  3. The Effects of Cocaine on Regional Brain Glucose Metabolism Is Attenuated in Dopamine Transporter Knockout Mice

    OpenAIRE

    Thanos, Panayotis K.; MICHAELIDES, MICHAEL; Benveniste, Helene; WANG, GENE JACK; Volkow, Nora D.

    2008-01-01

    Cocaine’s ability to block the dopamine transporter (DAT) is crucial for its reinforcing effects. However the brain functional consequences of DAT blockade by cocaine are less clear since they are confounded by its concomitant blockade of norepinephrine and serotonin transporters. To separate the dopaminergic from the non-dopaminergic effects of cocaine on brain function we compared the regional brain metabolic responses to cocaine between dopamine transporter deficient (DAT−/−) mice with tha...

  4. Alcohol decreases baseline brain glucose metabolism more in heavy drinkers than controls but has no effect on stimulation-induced metabolic increases

    International Nuclear Information System (INIS)

    During alcohol intoxication the human brain increases metabolism of acetate and decreases metabolism of glucose as energy substrate. Here we hypothesized that chronic heavy drinking facilitates this energy substrate shift both for baseline and stimulation conditions. To test this hypothesis we compared the effects of alcohol intoxication (0.75g/kg alcohol versus placebo) on brain glucose metabolism during video-stimulation (VS) versus when given with no-stimulation (NS), in 25 heavy drinkers (HD) and 23 healthy controls each of whom underwent four PET-18FDG scans. We showed that resting whole-brain glucose metabolism (placebo-NS) was lower in HD than controls (13%, p=0.04); that alcohol (compared to placebo) decreased metabolism more in HD (20±13%) than controls (9±11%, p=0.005) and in proportion to daily alcohol consumption (r=0.36, p=0.01) but found that alcohol did not reduce the metabolic increases in visual cortex from VS in either group. Instead, VS reduced alcohol-induced decreases in whole-brain glucose metabolism (10±12%) compared to NS in both groups (15±13%, p=0.04), consistent with stimulation-related glucose metabolism enhancement. These findings corroborate our hypothesis that heavy alcohol consumption facilitates use of alternative energy substrates (i.e. acetate) for resting activity during intoxication, which might persist through early sobriety, but indicate that glucose is still favored as energy substrate during brain stimulation. Our findings are consistent with reduced reliance on glucose as the main energy substrate for resting brain metabolism during intoxication (presumably shifting to acetate or other ketones) and a priming of this shift in heavy drinkers, which might make them vulnerable to energy deficits during withdrawal

  5. Alcohol Decreases Baseline Brain Glucose Metabolism More in Heavy Drinkers Than Controls But Has No Effect on Stimulation-Induced Metabolic Increases

    Science.gov (United States)

    Wang, Gene-Jack; Shokri Kojori, Ehsan; Fowler, Joanna S.; Benveniste, Helene; Tomasi, Dardo

    2015-01-01

    During alcohol intoxication, the human brain increases metabolism of acetate and decreases metabolism of glucose as energy substrate. Here we hypothesized that chronic heavy drinking facilitates this energy substrate shift both for baseline and stimulation conditions. To test this hypothesis, we compared the effects of alcohol intoxication (0.75 g/kg alcohol vs placebo) on brain glucose metabolism during video stimulation (VS) versus when given with no stimulation (NS), in 25 heavy drinkers (HDs) and 23 healthy controls, each of whom underwent four PET-18FDG scans. We showed that resting whole-brain glucose metabolism (placebo-NS) was lower in HD than controls (13%, p = 0.04); that alcohol (compared with placebo) decreased metabolism more in HD (20 ± 13%) than controls (9 ± 11%, p = 0.005) and in proportion to daily alcohol consumption (r = 0.36, p = 0.01) but found that alcohol did not reduce the metabolic increases in visual cortex from VS in either group. Instead, VS reduced alcohol-induced decreases in whole-brain glucose metabolism (10 ± 12%) compared with NS in both groups (15 ± 13%, p = 0.04), consistent with stimulation-related glucose metabolism enhancement. These findings corroborate our hypothesis that heavy alcohol consumption facilitates use of alternative energy substrates (i.e., acetate) for resting activity during intoxication, which might persist through early sobriety, but indicate that glucose is still favored as energy substrate during brain stimulation. Our findings are consistent with reduced reliance on glucose as the main energy substrate for resting brain metabolism during intoxication (presumably shifting to acetate or other ketones) and a priming of this shift in HDs, which might make them vulnerable to energy deficits during withdrawal. PMID:25698759

  6. 2-Deoxyglucose incorporation into rat brain glycogen during measurement of local cerebral glucose utilization by the 2-deoxyglucose method

    Energy Technology Data Exchange (ETDEWEB)

    Nelson, T.; Kaufman, E.E.; Sokoloff, L.

    1984-10-01

    The incorporation of 14C into glycogen in rat brain has been measured under the same conditions that exist during the measurement of local cerebral glucose utilization by the autoradiographic 2-(14C)deoxyglucose method. The results demonstrate that approximately 2% of the total 14C in brain 45 min after the pulse of 2-(14C)deoxyglucose is contained in the glycogen portion, and, in fact, incorporated into alpha-1-4 and alpha-1-6 deoxyglucosyl linkages. When the brain is removed by dissection, as is routinely done in the course of the procedure of the 2-(14C)deoxyglucose method to preserve the structure of the brain for autoradiography, the portion of total brain 14C contained in glycogen falls to less than 1%, presumably because of postmortem glycogenolysis which restores much of the label to deoxyglucose-phosphates. In any case, the incorporation of the 14C into glycogen is of no consequence to the validity of the autoradiographic deoxyglucose method, not because of its small magnitude, but because 2-(14C)deoxyglucose is incorporated into glycogen via (14C)deoxyglucose-6-phosphate, and the label in glycogen represents, therefore, an additional ''trapped'' product of deoxyglucose phosphorylation by hexokinase. With the autoradiographic 2-(14C)deoxyglucose method, in which only total 14C concentration in the brain tissue is measured by quantitative autoradiography, it is essential that all the labeled products derived directly or indirectly from (14C)deoxyglucose phosphorylation by hexokinase be retained in the tissue; their chemical identity is of no significance.

  7. Alzheimer's disease therapeutics targeted to the control of amyloid precursor protein translation: maintenance of brain iron homeostasis.

    Science.gov (United States)

    Bandyopadhyay, Sanghamitra; Rogers, Jack T

    2014-04-15

    The neurotoxicity of amyloid beta (Aβ), a major cleavage product of the amyloid precursor protein (APP), is enhanced by iron, as found in the amyloid plaques of Alzheimer's disease (AD) patients. By contrast, the long-known neuroprotective activity of APP is evident after α-secretase cleavage of the precursor to release sAPPα, and depends on the iron export actions of APP itself. The latter underlie its neurotrophic and protective effects in facilitating the homeostatic actions of ferroportin mediated-iron export. Thus APP-dependent iron export may alleviate oxidative stress by minimizing labile iron thus protecting neurons from iron overload during stroke and hemorrhage. Consistent with this, altered phosphorylation of iron-regulatory protein-1 (IRP1) and its signaling processes play a critical role in modulating APP translation via the 5' untranslated region (5'UTR) of its transcript. The APP 5'UTR region encodes a functional iron-responsive element (IRE) RNA stem loop that represents a potential target for modulating APP production. Targeted regulation of APP gene expression via the modulation of 5'UTR sequence function represents a novel approach for the potential treatment of AD since altering APP translation can be used to improve both the protective brain iron balance and provide anti-amyloid efficacy. Approved drugs including paroxetine and desferrioxamine and several novel compounds have been identified that suppress abnormal metal-promoted Aβ accumulation with a subset of these acting via APP 5'UTR-dependent mechanisms to modulate APP translation and cleavage to generate the non-toxic sAPPα.

  8. Combination of the sodium-glucose cotransporter-2 inhibitor empagliflozin with orlistat or sibutramine further improves the body-weight reduction and glucose homeostasis of obese rats fed a cafeteria diet

    OpenAIRE

    Vickers SP; Cheetham SC; Headl; Dell, KR; Dickinson K; Grempler R; Mayoux E; Mark M; Klein T.

    2014-01-01

    Steven P Vickers,1 Sharon C Cheetham,1 Katie R Headland,1 Keith Dickinson,1 Rolf Grempler,2 Eric Mayoux,2 Michael Mark,2 Thomas Klein2 1RenaSci, BioCity Nottingham, Nottingham, UK; 2Boehringer Ingelheim Pharma, Biberach an der Riss, Germany Abstract: The present study assessed the potential of the sodium glucose-linked transporter (SGLT)-2 inhibitor empagliflozin to decrease body weight when administered alone or in combination with the clinically effective weight-loss agents orlistat and si...

  9. Type 2 Diabetes-Associated K+ Channel TALK-1 Modulates β-Cell Electrical Excitability, Second-Phase Insulin Secretion, and Glucose Homeostasis.

    Science.gov (United States)

    Vierra, Nicholas C; Dadi, Prasanna K; Jeong, Imju; Dickerson, Matthew; Powell, David R; Jacobson, David A

    2015-11-01

    Two-pore domain K+ (K2P) channels play an important role in tuning β-cell glucose-stimulated insulin secretion (GSIS). The K2P channel TWIK-related alkaline pH-activated K2P (TALK)-1 is linked to type 2 diabetes risk through a coding sequence polymorphism (rs1535500); however, its physiological function has remained elusive. Here, we show that TALK-1 channels are expressed in mouse and human β-cells, where they serve as key regulators of electrical excitability and GSIS. We find that the rs1535500 polymorphism, which results in an alanine-to-glutamate substitution in the C-terminus of human TALK-1, increases channel activity. Genetic ablation of TALK-1 results in β-cell membrane potential depolarization, increased islet Ca2+ influx, and enhanced second-phase GSIS. Moreover, mice lacking TALK-1 channels are resistant to high-fat diet-induced elevations in fasting glycemia. These findings reveal TALK-1 channels as important modulators of second-phase insulin secretion and suggest a clinically relevant mechanism for rs1535500, which may increase type 2 diabetes risk by limiting GSIS. PMID:26239056

  10. Dichloroacetate effects on glucose and lactate oxidation by neurons and astroglia in vitro and on glucose utilization by brain in vivo

    OpenAIRE

    Itoh, Yoshiaki; Esaki, Takanori; Shimoji, Kazuaki; Cook, Michelle; Law, Mona J.; Kaufman, Elaine; Sokoloff, Louis

    2003-01-01

    Neuronal cultures in vitro readily oxidized both D-[14C]glucose and l-[14C]lactate to 14CO2, whereas astroglial cultures oxidized both substrates sparingly and metabolized glucose predominantly to lactate and released it into the medium. [14C]Glucose oxidation to 14CO2 varied inversely with unlabeled lactate concentration in the medium, particularly in neurons, and increased progressively with decreasing lactate concentration. Adding unlabeled glucose to the medium inhibited [14C]lactate oxid...

  11. Uniform distributions of glucose oxidation and oxygen extraction in gray matter of normal human brain: No evidence of regional differences of aerobic glycolysis.

    Science.gov (United States)

    Hyder, Fahmeed; Herman, Peter; Bailey, Christopher J; Møller, Arne; Globinsky, Ronen; Fulbright, Robert K; Rothman, Douglas L; Gjedde, Albert

    2016-05-01

    Regionally variable rates of aerobic glycolysis in brain networks identified by resting-state functional magnetic resonance imaging (R-fMRI) imply regionally variable adenosine triphosphate (ATP) regeneration. When regional glucose utilization is not matched to oxygen delivery, affected regions have correspondingly variable rates of ATP and lactate production. We tested the extent to which aerobic glycolysis and oxidative phosphorylation power R-fMRI networks by measuring quantitative differences between the oxygen to glucose index (OGI) and the oxygen extraction fraction (OEF) as measured by positron emission tomography (PET) in normal human brain (resting awake, eyes closed). Regionally uniform and correlated OEF and OGI estimates prevailed, with network values that matched the gray matter means, regardless of size, location, and origin. The spatial agreement between oxygen delivery (OEF≈0.4) and glucose oxidation (OGI ≈ 5.3) suggests that no specific regions have preferentially high aerobic glycolysis and low oxidative phosphorylation rates, with globally optimal maximum ATP turnover rates (VATP ≈ 9.4 µmol/g/min), in good agreement with (31)P and (13)C magnetic resonance spectroscopy measurements. These results imply that the intrinsic network activity in healthy human brain powers the entire gray matter with ubiquitously high rates of glucose oxidation. Reports of departures from normal brain-wide homogeny of oxygen extraction fraction and oxygen to glucose index may be due to normalization artefacts from relative PET measurements. PMID:26755443

  12. Hypoxia inducible factor-1alpha mediates protection of DL-3-n-butylphthalide in brain microvascular endothelial cells against oxygen glucose deprivation-induced injury

    Institute of Scientific and Technical Information of China (English)

    Weihong Yang; Ling Li; Ruxun Huang; Zhong Pei; Songjie Liao; Jinsheng Zeng

    2012-01-01

    Studies have demonstrated that DL-3-n-butylphthalide can significantly alleviate oxygen glucose deprivation-induced injury of human umbilical vein endothelial cells at least partly associated with its enhancement on oxygen glucose deprivation -induced hypoxia inducible factor-1α expression. In this study, we hypothesized that DL-3-n-butylphthalide can protect against oxygen glucose deprivation-induced injury of newborn rat brain microvascular endothelial cells by means of upregulating hypoxia inducible factor-1α expression. MTT assay and Hoechst staining results showed that DL-3-n-butylphthalide protected brain microvascular endothelial cells against oxygen glucose deprivation-induced injury in a dose-dependent manner. Western blot and immunofluorescent staining results further confirmed that the protective effect was related to upregulation of hypoxia inducible factor-1α. Real-time RT-PCR reaction results showed that DL-3-n-butylphthalide reduced apoptosis by inhibiting downregulation of pro-apoptotic gene caspase-3 mRNA expression and upregulation of apoptosis-executive protease bcl-2 mRNA expression; however, DL-3-n-butylphthalide had no protective effects on brain microvascular endothelial cells after knockdown of hypoxia inducible factor-1α by small interfering RNA. These findings suggest that DL-3-n-butylphthalide can protect brain microvascular endothelial cells against oxygen glucose deprivation-induced injury by upregulating bcl-2 expression and downregulating caspase-3 expression though hypoxia inducible factor-1α pathway.

  13. Pregnancy Hyperglycemia in Prolactin Receptor Mutant, but Not Prolactin Mutant, Mice and Feeding-Responsive Regulation of Placental Lactogen Genes Implies Placental Control of Maternal Glucose Homeostasis.

    Science.gov (United States)

    Rawn, Saara M; Huang, Carol; Hughes, Martha; Shaykhutdinov, Rustem; Vogel, Hans J; Cross, James C

    2015-09-01

    Pregnancy is often viewed as a conflict between the fetus and mother over metabolic resources. Insulin resistance occurs in mothers during pregnancy but does not normally lead to diabetes because of an increase in the number of the mother's pancreatic beta cells. In mice, this increase is dependent on prolactin (Prl) receptor signaling but the source of the ligand has been unclear. Pituitary-derived Prl is produced during the first half of pregnancy in mice but the placenta produces Prl-like hormones from implantation to term. Twenty-two separate mouse genes encode the placenta Prl-related hormones, making it challenging to assess their roles in knockout models. However, because at least four of them are thought to signal through the Prl receptor, we analyzed Prlr mutant mice and compared their phenotypes with those of Prl mutants. We found that whereas Prlr mutants develop hyperglycemia during gestation, Prl mutants do not. Serum metabolome analysis showed that Prlr mutants showed other changes consistent with diabetes. Despite the metabolic changes, fetal growth was normal in Prlr mutants. Of the four placenta-specific, Prl-related hormones that have been shown to interact with the Prlr, their gene expression localizes to different endocrine cell types. The Prl3d1 gene is expressed by trophoblast giant cells both in the labyrinth layer, sitting on the arterial side where maternal blood is highest in oxygen and nutrients, and in the junctional zone as maternal blood leaves the placenta. Expression increases during the night, though the increase in the labyrinth is circadian whereas it occurs only after feeding in the junctional zone. These data suggest that the placenta has a sophisticated endocrine system that regulates maternal glucose metabolism during pregnancy.

  14. Design of a sup 13 C (1H) RF probe for monitoring the in vivo metabolism of (1- sup 13 C)glucose in primate brain

    Energy Technology Data Exchange (ETDEWEB)

    Hammer, B.E.; Sacks, W.; Bigler, R.E.; Hennessy, M.J.; Sacks, S.; Fleischer, A.; Zanzonico, P.B. (Intermagnetics General Corporation, Guilderland, NY (USA))

    1990-01-01

    The design of an RF probe suitable for obtaining proton-decoupled {sup 13}C spectra from a subhuman primate brain is described. Two orthogonal saddle coils, one tuned to the resonant frequency of {sup 13}C and the other to the resonant frequency of 1H, were used to monitor the in vivo metabolism of (1-{sup 13}C)glucose in rhesus monkey brain at 2.1 T. Difference spectra showed the appearance of {sup 13}C-enriched glutamate and glutamine 30 to 40 min after a bolus injection of (1-{sup 13}C)glucose.

  15. Depressed glucose consumption at reperfusion following brain ischemia does not correlate with mitochondrial dysfunction and development of infarction: an in vivo positron emission tomography study.

    Science.gov (United States)

    Martín, Abraham; Rojas, Santiago; Pareto, Deborah; Santalucia, Tomàs; Millán, Olga; Abasolo, Ibane; Gómez, Vanessa; Llop, Jordi; Gispert, Joan D; Falcon, Carles; Bargalló, Núria; Planas, Anna M

    2009-05-01

    Glucose consumption is severely depressed in the ischemic core, whereas it is maintained or even increased in penumbral regions during ischemia. Conversely, glucose utilization is severely reduced early after reperfusion in spite that glucose and oxygen are available. Experimental studies suggest that glucose hypometabolism might be an early predictor of brain infarction. However, the relationship between early glucose hypometabolism with later development of infarction remains to be further studied in the same subjects. Here, glucose consumption was assessed in vivo by positron emission tomography (PET) with (18)F-fluorodeoxyglucose ((18)F-FDG) in a rat model of ischemia/reperfusion. Perfusion was evaluated by PET with (13)NH(3) during and after 2-hour (h) middle cerebral artery occlusion, and (18)F-FDG was given after 2h of reperfusion. Brain infarction was evaluated at 24h. Mitochondrial oxygen consumption was examined ex vivo using a biochemical method. Cortical (18)F-FDG uptake was reduced by 45% and 25% in the ischemic core and periphery, respectively. However, substantial alteration of mitochondrial respiration was not apparent until 24h, suggesting that mitochondria retained the ability to consume oxygen early after reperfusion. These results show reduced glucose use at early reperfusion in regions that will later develop infarction and, to a lesser extent, in adjacent regions. Depressed glucose metabolism in the ischemic core might be attributable to reduced metabolic requirement due to irreversible cellular injury. However, reduced glucose metabolism in peripheral regions suggests either an impairment of glycolysis or reduced glucose demand. Thus, our study supports that glycolytic depression early after reperfusion is not always related to subsequent development of infarction.

  16. INCREASED GLUCOSE AVAILABILITY DOES NOT RESTORE PROLONGED SPREADING DEPRESSION DURATIONS IN HYPOTENSIVE RATS WITHOUT BRAIN INJURY

    OpenAIRE

    Hoffmann, Ulrike; Sukhotinsky, Inna; ATALAY, YAHYA BURAK; Eikermann-Haerter, Katharina; Ayata, Cenk

    2012-01-01

    Maintenance of transmembrane ionic gradients and their restoration after cortical spreading depression (CSD) are energy dependent. We recently showed an inverse relationship between blood pressure and CSD duration that is independent of tissue oxygenation. Here, we tested the alternative hypothesis that glucose availability becomes rate-limiting for CSD recovery upon reduced blood pressure in anesthetized rats under full systemic physiological monitoring. Hypotension induced by controlled exs...

  17. Correlation of brain cell glucose metabolism and patient's condition in children with epileptic encephalopathy An assessment using fluorine-18-fluoro-2-deoxy-D-glucose positron emission computed tomography

    Institute of Scientific and Technical Information of China (English)

    Qiongxiang Zhai; Yuxiong Guo; Yuxin Zhang; Zhihong Chen; Jian Ding; Juan Gui; Ying Hao

    2011-01-01

    We examined a total of 16 children with epileptic encephalopathy using fluorine-18-fluoro-2-deoxy-D-glucose (18F-FDG) positron emission computed tomography (PET), magnetic resonance imaging (MRI) and electroencephalography.Children with infantile spasms showed significant mental retardation, severely abnormal electroencephalogram recordings, and bilateral diffuse cerebral cortex hypometabolism with 18F-FDG PET imaging.MRI in these cases showed brain atrophy, multi-micropolygyria, macrogyria, and porencephalia.In cases with Lennox-Gastaut syndrome, 18F-FDG PET showed bilateral diffuse glucose hypometabolism, while MRI showed cortical atrophy, heterotopic gray matter and tuberous sclerosis.MRI in cases with myoclonic encephalopathy demonstrated bilateral frontal and temporal cortical and white matter atrophy and 18F-FDG PET imaging showed bilateral frontal lobe atrophy with reduced bilateral frontal cortex, occipital cortex, temporal cortex and cerebellar glucose uptake.In children who could not be clearly classified, MRI demonstrated cerebral cortical atrophy and 18F-FDG PET exhibited multifocal glucose hypometabolism.Overall, this study demonstrated that the degree of brain metabolic abnormality was consistent with clinical seizure severity.In addition, 18F-FDG PET imaging after treatment was consistent with clinical outcomes.These findings indicate that 18F-FDG PET can be used to assess the severity of brain injury and prognosis in children with epileptic encephalopathy.

  18. Riluzole protects Huntington disease patients from brain glucose hypometabolism and grey matter volume loss and increases production of neurotrophins

    Energy Technology Data Exchange (ETDEWEB)

    Squitieri, Ferdinando; Orobello, Sara; Cannella, Milena; Martino, Tiziana [IRCCS Neuromed, Neurogenetics Unit and Centre for Rare Disease, Pozzilli (Italy); Romanelli, Pantaleo [IRCCS Neuromed, Department of Neurosurgery, Pozzilli (Italy); Giovacchini, Giampiero; Ciarmiello, Andrea [S. Andrea Hospital, Unit of Nuclear Medicine, La Spezia (Italy); Frati, Luigi [University ' ' Sapienza' ' , Department of Experimental Medicine, Rome (Italy); Mansi, Luigi [Second University of Naples, Department of Nuclear Medicine, Naples (Italy)

    2009-07-15

    Huntington disease (HD) mutation increases gain-of-toxic functions contributing to glutamate-mediated excitotoxicity. Riluzole interferes with glutamatergic neurotransmission, thereby reducing excitotoxicity, enhancing neurite formation in damaged motoneurons and increasing serum concentrations of BDNF, a brain cortex neurotrophin protecting striatal neurons from degeneration. We investigated metabolic and volumetric differences in distinct brain areas between 11 riluzole-treated and 12 placebo-treated patients by MRI and {sup 18}F-fluoro-2-deoxy-d-glucose (FDG) PET scanning, according to fully automated protocols. We also investigated the influence of riluzole on peripheral growth factor blood levels. Placebo-treated patients showed significantly greater proportional volume loss of grey matter and decrease in metabolic FDG uptake than patients treated with riluzole in all cortical areas (p<0.05). The decreased rate of metabolic FDG uptake correlated with worsening clinical scores in placebo-treated patients, compared to those who were treated with riluzole. The progressive decrease in metabolic FDG uptake observed in the frontal, parietal and occipital cortex correlated linearly with the severity of motor scores calculated by Unified Huntington Disease Rating Scale (UHDRS-I) in placebo-treated patients. Similarly, the rate of metabolic changes in the frontal and temporal areas of the brain cortex correlated linearly with worsening behavioural scores calculated by UHDRS-III in the placebo-treated patients. Finally, BDNF and transforming growth factor beta-1 serum levels were significantly higher in patients treated with riluzole. The linear correlation between decreased metabolic FDG uptake and worsening clinical scores in the placebo-treated patients suggests that FDG-PET may be a valuable procedure to assess brain markers of HD. (orig.)

  19. In vivo evaluation of amyloid deposition and brain glucose metabolism of 5XFAD mice using positron emission tomography.

    Science.gov (United States)

    Rojas, Santiago; Herance, José Raúl; Gispert, Juan Domingo; Abad, Sergio; Torrent, Elia; Jiménez, Xavier; Pareto, Deborah; Perpiña, Unai; Sarroca, Sara; Rodríguez, Elisenda; Ortega-Aznar, Arantxa; Sanfeliu, Coral

    2013-07-01

    Positron emission tomography (PET) has been used extensively to evaluate the neuropathology of Alzheimer's disease (AD) in vivo. Radiotracers directed toward the amyloid deposition such as [(18)F]-FDDNP (2-(1-{6-[(2-[F]Fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile) and [(11)C]-PIB (Pittsburg compound B) have shown exceptional value in animal models and AD patients. Previously, the glucose analogue [(18)F]-FDG (2-[(18)F]fluorodeoxyglucose) allowed researchers and clinicians to evaluate the brain glucose consumption and proved its utility for the early diagnosis and the monitoring of the progression of AD. Animal models of AD are based on the transgenic expression of different human mutant genes linked to familial AD. The novel transgenic 5XFAD mouse containing 5 mutated genes in its genome has been proposed as an AD model with rapid and massive cerebral amyloid deposition. PET studies performed with animal-dedicated scanners indicate that PET with amyloid-targeted radiotracers can detect the pathological amyloid deposition in transgenic mice and rats. However, in other studies no differences were found between transgenic mice and their wild type littermates. We sought to investigate in 5XFAD mice if the radiotracers [(11)C]-PIB, and [(18)F]-Florbetapir could quantify the amyloid deposition in vivo and if [(18)F]-FDG could do so with regard to glucose consumption. We found that 5XFAD animals presented higher cerebral binding of [(18)F]-Florbetapir, [(11)C]-PIB, and [(18)F]-FDG. These results support the use of amyloid PET radiotracers for the evaluation of AD animal models. Probably, the increased uptake observed with [(18)F]-FDG is a consequence of glial activation that occurs in 5XFAD mice.

  20. A proposed method for the determination of cerebral regional intermediary glucose metabolism in humans in vivo using specifically labeled 11C-glucose and positron emission transverse tomography (PETT). I. An animal model with 14C-glucose and rat brain autoradiography

    International Nuclear Information System (INIS)

    Based upon data obtained with our arterio-venous technique for the determination of cerebral metabolism in humans in vivo we have proposed a method for the determination of cerebral regional intermediary glucose metabolism in humans in vivo using specifically labeled 11C-glucose and positron emission transverse tomography (PETT). In it we would give the subject successive intravenous injections of [3,4-11C] glucose, [2,5-11C] glucose and [1-11C] glucose. There would be a 30 min period of continuous PETT measurements following each injection and a 2 hr interval after the first and second injections. The data would be used with suitable equations and algorithms to estimate for each specific region of the subject's brain the dynamics of the Embden-Meyerhof-Parnas (EMP) and the tricarboxylic acid cycle (TCA) metabolic pathways and the incorporation of glucose carbons into lactate, and the extent of dilution of glucose carbons into lactate, and the extent of dilution of glucose carbons in traversing the TCA with their subsequent incorporation into other carbon pools of the brain (ie, glutamate, glutamine, GABA, alanine). Using 14C as a model for 11C and autoradiographs made with rat brain slices, we have produced an animal model to demonstrate the feasibility of our proposed method. The resulting autoradiographs have provided evidence of the validity of the predictions made from our arterio-venous data. The model was employed to show the selective reductions in the rates of incorporation of specific carbon atoms of glucose into regions of the rat brain and evidence of altered metabolic pathways following a single electroconvulsive shock (ECS) and after a series of nine ECS

  1. Quantitative Rates of Brain Glucose Metabolism Distinguish Minimally Conscious from Vegetative State Patients

    DEFF Research Database (Denmark)

    Stender, Johan; Kupers, Ron; Rodell, Anders;

    2015-01-01

    The differentiation of the vegetative or unresponsive wakefulness syndrome (VS/UWS) from the minimally conscious state (MCS) is an important clinical issue. The cerebral metabolic rate of glucose (CMRglc) declines when consciousness is lost, and may reveal the residual cognitive function of these...... indistinguishable from those of MCS. Ordinal logistic regression predicted that patients are likely to emerge into MCS at CMRglc above 45% of normal. Receiver-operating characteristics showed that patients in MCS and VS/UWS can be differentiated with 82% accuracy, based on cortical metabolism. Together these...

  2. Blood-brain barrier transport of drugs for the treatment of brain diseases.

    Science.gov (United States)

    Gabathuler, Reinhard

    2009-06-01

    The central nervous system is a sanctuary protected by barriers that regulate brain homeostasis and control the transport of endogenous compounds into the brain. The blood-brain barrier, formed by endothelial cells of the brain capillaries, restricts access to brain cells allowing entry only to amino acids, glucose and hormones needed for normal brain cell function and metabolism. This very tight regulation of brain cell access is essential for the survival of neurons which do not have a significant capacity to regenerate, but also prevents therapeutic compounds, small and large, from reaching the brain. As a result, various strategies are being developed to enhance access of drugs to the brain parenchyma at therapeutically meaningful concentrations to effectively manage disease.

  3. Formaldehyde Metabolism and Formaldehyde-induced Alterations in Glucose and Glutathione Metabolism of Cultured Brain Cells

    OpenAIRE

    Tulpule, Ketki

    2013-01-01

    Formaldehyde is an environmental pollutant that is also generated in the body during normal metabolic processes. Interestingly, several pathological conditions are associated with an increase in formaldehyde-generating enzymes in the body. The level of formaldehyde in the brain is elevated with increasing age and in neurodegenerative conditions which may contribute to lowered cognitive functions. Although the neurotoxic potential of formaldehyde is well established, the molecular mechanisms i...

  4. Brain-Derived Neurotrophic Factor Val66Met and Blood Glucose: A Synergistic Effect on Memory

    OpenAIRE

    Naftali Raz; Dahle, Cheryl L.; Rodrigue, Karen M.; Kennedy, Kristen M.; Land, Susan J.; Jacobs, Bradley S.

    2008-01-01

    Age-related declines in episodic memory performance are frequently reported, but their mechanisms remain poorly understood. Although several genetic variants and vascular risk factors have been linked to mnemonic performance in general and age differences therein, it is unknown whether and how they modify age-related memory declines. To address that question, we investigated the effect of Brain-Derived Neurotrophic Factor (BDNF) Val66Met polymorphism that affects secretion of BDNF, and fastin...

  5. Lactography as an approach to monitor glucose metabolism on-line in brain and muscle.

    Science.gov (United States)

    Korf, J; de Boer, J

    1990-01-01

    1. Thus far metabolic processes in the intact animal (or man) have been studied either by the analysis of body fluids, of biopsies, of tissue obtained post mortem or by techniques, requiring dedicated and expensive equipment (such as positron emission tomography or magnetic resonance spectroscopy). 2. Here we describe a relatively simple and inexpensive technique, that can be applied in vivo to study metabolism in brain regions and muscle in the freely moving rat and in human peripheral tissue. 3. The method is based on microdialysis allowing continuous sampling from the extracellular space, the enzymatic conversion of lactate and the on-line detection of fluorescent NADH. 4. Examples of the application of our technique include the monitoring of lactate efflux from various brain regions of behaving animals under a variety of stress exposures, during ischemia or hypoxia and drug treatments. 5. The results indicate that in brain lactate is not exclusively formed under hypoxia and that neuronal activation leads also to lactate formation, possibly due to the compartmentation of both the involved enzymes and the energy metabolism. 6. The increase of lactate formation in contracting or ischemic muscle or during exercise could also be followed on-line in the rat, suggesting that our approach allows the continuous monitoring of anaerobic metabolism in man e.g. during traumatic or arteriosclerotic limb ischemia or lactic acidosis in shock states. 7. The principle of our approach can easily be adapted to other metabolites, thus enabling to monitor other metabolic pathways in vivo as well. PMID:2276411

  6. Stability of regional cerebral glucose metabolism in the normal brain measured by positron emission tomography

    International Nuclear Information System (INIS)

    Cerebral glucose utilization (LCMRGI) was measured using the [18F]fluorodeoxyglucose method with PET in two groups of ten healthy young volunteers, each scanned in a resting state under different methodological conditions. In addition, five subjects had a second scan within 48 hr. Mean hemispheric values averaged 45.8 +/- 3.3 mumol/100 g/min in the right cerebral hemisphere and 47.0 +/- 3.7 mumol/100 g/min in the left hemisphere. A four-way analysis of variance (group, sex, region, hemisphere) was carried out on the results using three different methods of data manipulation: (a) the raw values of glucose utilization, (b) LCMRGI values normalized by the mean hemispheric gray matter LCMRGI value, and (c) log transformed LCMRGI values. For all analysis techniques, significantly higher LCMRGI values were consistently seen in the left mid and posterior temporal area and caudate nucleus relative to the right, and in the right occipital region relative to the left. The coefficient of variation of intrasubject regional differences (9.9%) was significantly smaller than the coefficient of variation for regions between subjects (16.5%). No differences were noted between the sexes and no effect of repeat procedures was seen in subjects having multiple scans. In addition, inter-regional LCMRGI correlations were examined both in values from the 20 normal subjects, as well as in a set of hypothetical abnormal values. Results were compared with those reported from other PET centers; despite certain methodological differences, the intersubject and inter-regional variation of LCMRGI is fairly constant

  7. A CREB-Sirt1-Hes1 Circuitry Mediates Neural Stem Cell Response to Glucose Availability

    Directory of Open Access Journals (Sweden)

    Salvatore Fusco

    2016-02-01

    Full Text Available Adult neurogenesis plays increasingly recognized roles in brain homeostasis and repair and is profoundly affected by energy balance and nutrients. We found that the expression of Hes-1 (hairy and enhancer of split 1 is modulated in neural stem and progenitor cells (NSCs by extracellular glucose through the coordinated action of CREB (cyclic AMP responsive element binding protein and Sirt-1 (Sirtuin 1, two cellular nutrient sensors. Excess glucose reduced CREB-activated Hes-1 expression and results in impaired cell proliferation. CREB-deficient NSCs expanded poorly in vitro and did not respond to glucose availability. Elevated glucose also promoted Sirt-1-dependent repression of the Hes-1 promoter. Conversely, in low glucose, CREB replaced Sirt-1 on the chromatin associated with the Hes-1 promoter enhancing Hes-1 expression and cell proliferation. Thus, the glucose-regulated antagonism between CREB and Sirt-1 for Hes-1 transcription participates in the metabolic regulation of neurogenesis.

  8. A CREB-Sirt1-Hes1 Circuitry Mediates Neural Stem Cell Response to Glucose Availability.

    Science.gov (United States)

    Fusco, Salvatore; Leone, Lucia; Barbati, Saviana Antonella; Samengo, Daniela; Piacentini, Roberto; Maulucci, Giuseppe; Toietta, Gabriele; Spinelli, Matteo; McBurney, Michael; Pani, Giovambattista; Grassi, Claudio

    2016-02-01

    Adult neurogenesis plays increasingly recognized roles in brain homeostasis and repair and is profoundly affected by energy balance and nutrients. We found that the expression of Hes-1 (hairy and enhancer of split 1) is modulated in neural stem and progenitor cells (NSCs) by extracellular glucose through the coordinated action of CREB (cyclic AMP responsive element binding protein) and Sirt-1 (Sirtuin 1), two cellular nutrient sensors. Excess glucose reduced CREB-activated Hes-1 expression and results in impaired cell proliferation. CREB-deficient NSCs expanded poorly in vitro and did not respond to glucose availability. Elevated glucose also promoted Sirt-1-dependent repression of the Hes-1 promoter. Conversely, in low glucose, CREB replaced Sirt-1 on the chromatin associated with the Hes-1 promoter enhancing Hes-1 expression and cell proliferation. Thus, the glucose-regulated antagonism between CREB and Sirt-1 for Hes-1 transcription participates in the metabolic regulation of neurogenesis. PMID:26804914

  9. Glycolysis and the pentose phosphate pathway after human traumatic brain injury: microdialysis studies using 1,2-(13)C2 glucose.

    Science.gov (United States)

    Jalloh, Ibrahim; Carpenter, Keri L H; Grice, Peter; Howe, Duncan J; Mason, Andrew; Gallagher, Clare N; Helmy, Adel; Murphy, Michael P; Menon, David K; Carpenter, T Adrian; Pickard, John D; Hutchinson, Peter J

    2015-01-01

    Increased 'anaerobic' glucose metabolism is observed after traumatic brain injury (TBI) attributed to increased glycolysis. An alternative route is the pentose phosphate pathway (PPP), which generates putatively protective and reparative molecules. To compare pathways we employed microdialysis to perfuse 1,2-(13)C2 glucose into the brains of 15 TBI patients and macroscopically normal brain in six patients undergoing surgery for benign tumors, and to simultaneously collect products for nuclear magnetic resonance (NMR) analysis. (13)C enrichment for glycolytic 2,3-(13)C2 lactate was the median 5.4% (interquartile range (IQR) 4.6-7.5%) in TBI brain and 4.2% (2.4-4.4%) in 'normal' brain (P<0.01). The ratio of PPP-derived 3-(13)C lactate to glycolytic 2,3-(13)C2 lactate was median 4.9% (3.6-8.2%) in TBI brain and 6.7% (6.3-8.9%) in 'normal' brain. An inverse relationship was seen for PPP-glycolytic lactate ratio versus PbtO2 (r=-0.5, P=0.04) in TBI brain. Thus, glycolytic lactate production was significantly greater in TBI than 'normal' brain. Several TBI patients exhibited PPP-lactate elevation above the 'normal' range. There was proportionally greater PPP-derived lactate production with decreasing PbtO2. The study raises questions about the roles of the PPP and glycolysis after TBI, and whether they can be manipulated to achieve a better outcome. This study is the first direct comparison of glycolysis and PPP in human brain.

  10. 18F-fluorodeoxyglucose accumulation in the heart, brain and skeletal muscle of rats; the influence of time after injection, depressed lipid metabolism and glucose-insulin

    International Nuclear Information System (INIS)

    To study the effect of lipid depressing drugs on 18FDG myocardial concentration. The changes of 18FDG uptake in myocardium, brain and skeletal muscle of rats were compared as influenced by acipimox, tyloxapol and glucose with insulin. 5.55 MBq of 18FDG were administered to Wistar rats. Control rats were killed 15, 30, 45 and 60 minutes following intravenous injection and the radioactivity concentration (cpm/g of tissue) in relation to injected cpm was determined in a well crystal adjusted to 511 KeV in order to check the time of maximal 18FDG tissue uptake. The radioactivity in myocardium, skeletal muscle and brain in intact animals was compared with that of rats treated with tyloxapol (tritton WR 1339, 125 mg intravenously immediately before 18FDG injection), acipimox (nicotinic acid derivative, 25 mg by stomach cannula 15 minutes before 18FDG), or glucose with insulin (intravenous injection of 0.04 g and 0.04 UI immediately before 18FDG). The animals were killed 45 minutes following 18FDG injection. Tyloxapol and acipimox significantly elevated myocardial 18FDG concentration (tyloxapol +37% and acipimox +48%), but the increase in 18FDG concentration after glucose and insulin was slight and insignificant. The changes in skeletal muscle after lipid depressing agents were quite contrasting; the decrease in 18FDG concentration was -74% after tyloxapol and -44% following acipimox administration. The accumulation of 18FDG in brain was not influenced markedly by the drugs used or by glucose with insulin. The highest 18FDG uptake in myocardium could be achieved by depressing the lipid metabolism and not by administration of glucose with insulin only. A marked increase in glucose accumulation in myocardium is not possible without previous shift from the utilisation of fatty acids. This finding is fully in agreement with present knowledge about energetic metabolism of myocardium. (author)

  11. Homeostasis in anorexia nervosa

    Directory of Open Access Journals (Sweden)

    Per eSodersten

    2014-08-01

    Full Text Available Brainstem and hypothalamic orexigenic/anorexigenic networks are thought to maintain body weight homeostasis in response to hormonal and metabolic feedback from peripheral sites. This approach has not been successful in managing over- and underweight patients. It is suggested that concept of homeostasis has been misinterpreted; rather than exerting control, the brain permits eating in proportion to the amount of physical activity necessary to obtain food. In support, animal experiments have shown that while a hypothalamic orexigen excites eating when food is abundant, it inhibits eating and stimulates foraging when food is in short supply. As the physical price of food approaches zero, eating and body weight increase without constraints. Conversely, in anorexia nervosa body weight is homeostatically regulated, the high level of physical activity in anorexia is displaced hoarding for food that keeps body weight constantly low. A treatment based on this point of view, providing patients with computerized mealtime support to re-establish normal eating behavior, has brought 75% of patients with eating disorders into remission, reduced the rate of relapse to 10%, and eliminated mortality.

  12. Brain glucose metabolic changes associated with chronic spontaneous Pain due to brachial plexus avulsion:a preliminary positron emission tomography study

    Institute of Scientific and Technical Information of China (English)

    CHEN Fu-yong; TAO Wei; CHENG Xin; WANG Hong-yan; HU Yong-sheng; ZHANG Xiao-hua; LI Yong-jie

    2008-01-01

    Background Previous brain imaging studies suggested that the brain activity underlying the perception of chronic pain maV differ from that underlying acute pain.To investigate the brain regions involved in chronic spontaneous pain due to brachial plexus avulsion(BPA),fluorine-18fluorodeoxygIucose (19F-FDG) positron emission tomography (PET) scanning was applied to determine the glucose metabolic changes in patients with pain due to BPA.Methods Six right-handed patients with chronic spontaneous pain due to left-BPA and twelve right-handed age-and sex-matched healthy control subjects participated in the 18F-FDG PET study.The patients were rated by visual analog scale (VAS) during scanning and Hamilton depression scale and Hamilton anxiety scale after scanning.Statistical parametric mapping 2 (SPM2) was applied for data analysis.Results Compared with healthy subjects,the patients had significant glucose metabolism decreases in the right thalamus and S I(P<0.001,uncorrected),and significant glucose metabolism increases in the right orbitofrontaI cortex (OFC) (BA11),left rostral insula cortex and left dorsolateral prefrontal codex (DLPFC) (BA10/46) (P<0.001,uncorrected).Conclusion These findings suggest that the brain areas involved in emotion.aRention and internal modulation of pain may be related to the chronic spontaneous pain due to BPA.

  13. FDG-PET changes in brain glucose metabolism from normal cognition to pathologically verified Alzheimer's disease

    International Nuclear Information System (INIS)

    We report the first clinicopathological series of longitudinal FDG-PET scans in post-mortem (PM) verified cognitively normal elderly (NL) followed to the onset of Alzheimer's-type dementia (DAT), and in patients with mild DAT with progressive cognitive deterioration. Four NL subjects and three patients with mild DAT received longitudinal clinical, neuropsychological and dynamic FDG-PET examinations with arterial input functions. NL subjects were followed for 13 ± 5 years, received FDG-PET examinations over 7 ± 2 years, and autopsy 6 ± 3 years after the last FDG-PET. Two NL declined to mild cognitive impairment (MCI), and two developed probable DAT before death. DAT patients were followed for 9 ± 3 years, received FDG-PET examinations over 3 ± 2 years, and autopsy 7 ± 1 years after the last FDG-PET. Two DAT patients progressed to moderate-to-severe dementia and one developed vascular dementia. The two NL subjects who declined to DAT received a PM diagnosis of definite AD. Their FDG-PET scans indicated a progression of deficits in the cerebral metabolic rate for glucose (CMRglc) from the hippocampus to the parietotemporal and posterior cingulate cortices. One DAT patient showed AD with diffuse Lewy body disease (LBD) at PM, and her last in vivo PET was indicative of possible LBD for the presence of occipital as well as parietotemporal hypometabolism. Progressive CMRglc reductions on FDG-PET occur years in advance of clinical DAT symptoms in patients with pathologically verified disease. The FDG-PET profiles in life were consistent with the PM diagnosis. (orig.)

  14. Glucose Metabolic Brain Networks in Early-Onset vs. Late-Onset Alzheimer's Disease

    Science.gov (United States)

    Chung, Jinyong; Yoo, Kwangsun; Kim, Eunjoo; Na, Duk L.; Jeong, Yong

    2016-01-01

    Objective: Early-onset Alzheimer's disease (EAD) shows distinct features from late-onset Alzheimer's disease (LAD). To explore the characteristics of EAD, clinical, neuropsychological, and functional imaging studies have been conducted. However, differences between EAD and LAD are not clear, especially in terms of brain connectivity and networks. In this study, we investigated the differences in metabolic connectivity between EAD and LAD by adopting graph theory measures. Methods: We analyzed 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) images to investigate the distinct features of metabolic connectivity between EAD and LAD. Using metabolic connectivity and graph theory analysis, metabolic network differences between LAD and EAD were explored. Results: Results showed the decreased connectivity centered in the cingulate gyri and occipital regions in EAD, whereas decreased connectivity in the occipital and temporal regions as well as increased connectivity in the supplementary motor area were observed in LAD when compared with age-matched control groups. Global efficiency and clustering coefficients were decreased in EAD but not in LAD. EAD showed progressive network deterioration as a function of disease severity and clinical dementia rating (CDR) scores, mainly in terms of connectivity between the cingulate gyri and occipital regions. Global efficiency and clustering coefficients were also decreased along with disease severity. Conclusion: These results indicate that EAD and LAD have distinguished features in terms of metabolic connectivity, with EAD demonstrating more extensive and progressive deterioration. PMID:27445800

  15. Effect of Simvastatin on Glucose Homeostasis in Streptozotocin Induced Type 2 Diabetic Rats%辛伐他汀对链脲佐菌素诱导2型糖尿病大鼠血糖的影响

    Institute of Scientific and Technical Information of China (English)

    王璐璐; 逄曙光; 黄仙萍; 田玉玲; 王少莲; 王聪聪

    2013-01-01

    [目的]探讨辛伐他汀对链脲佐菌素(STZ)诱导2型糖尿病大鼠血糖的影响.[方法]选取100只Wistar雄性大鼠适应性喂养1周后随机分为4组,每组各25只.A组(正常对照组)普通饲料喂养4周后腹腔注射柠檬酸钠缓冲液;B组(糖尿病模型组)、C组(他汀早期诱导组)和D组(他汀晚期诱导组)高脂饲料喂养4周后一次腹腔注射STZ 35 mg/kg溶液建立2型糖尿病大鼠模型,C组在高脂饲料喂养的同时给予辛伐他汀10 mg/kg·d-1的剂量灌胃,D组在糖尿病模型建立后给予相同剂量辛伐他汀灌胃,B组在糖尿病模型建立后给予等量蒸馏水,成模后均连续观察4周.测定各组0、4和8周大鼠体质量、空腹血糖和血脂水平,并于第8周末行OGTT试验.[结果]在第4周末和第8周末,2型糖尿病大鼠与正常对照组大鼠相比,空腹血糖(FPG)水平均显著升高(P<0.05)、血清胰岛素(Ins)水平显著降低(P<0.05),差异有统计学意义;与糖尿病大鼠相比,第4周末他汀晚期诱导组轻微升高FPG和降低Ins (P> 0.05)、他汀早期诱导组显著升高FPG和降低Ins (P<0.001)以及更容易诱导糖尿病大鼠模型的建立;第8周末他汀晚期诱导组FPG显著高于糖尿病模型组(P<0.05).[结论]对高脂饲料喂养的大鼠进行辛伐他汀(10 mg/kg· d-1)早期诱导更容易引起胰岛β细胞功能的减退从而升高FPG和诱发糖尿病模型的建立;在糖尿病模型建立之后,对糖尿病大鼠进行他汀治疗可以引起FPG升高.%[Objective] To investigate the effect of simvastatin on glucose homeostasis in streptozotocin induced type 2 diabetic rats.[Methods] 100 male Wistar rats were randomly divided into four groups.25 control rats were fed with standard diet four weeks and were injected citrate buffered saline by a single intraperitoneal.Others were fed with high-fat diet for four weeks,then diabetes were induced by a single intraperitoneal injection of STZ at 35 mg/kg body weight in

  16. Comparing brain amyloid deposition, glucose metabolism, and atrophy in mild cognitive impairment with and without a family history of dementia.

    Science.gov (United States)

    Mosconi, Lisa; Andrews, Randolph D; Matthews, Dawn C

    2013-01-01

    This study compares the degree of brain amyloid-β (Aβ) deposition, glucose metabolism, and grey matter volume (GMV) reductions in mild cognitive impairment (MCI) patients overall and as a function of their parental history of dementia. Ten MCI with maternal history (MH), 8 with paternal history (PH), and 24 with negative family history (NH) received 11C-PiB and 18F-FDG PET and T1-MRI as part of the Alzheimer's Disease Neuroimaging Initiative. Statistical parametric mapping, voxel based morphometry, and Z-score mapping were used to compare biomarkers across MCI groups, and relative to 12 normal controls. MCI had higher PiB retention, hypometabolism, and GMV reductions in Alzheimer-vulnerable regions compared to controls. Biomarker abnormalities were more pronounced in MCI with MH than those with PH and NH. After partial volume correction of PET, Aβ load exceeded hypometabolism and atrophy with regard to the number of regions affected and magnitude of impairment in those regions. Hypometabolism exceeded atrophy in all MCI groups and exceeded Aβ load in medial temporal and posterior cingulate regions of MCI MH. While all three biomarkers were abnormal in MCI compared to controls, Aβ deposition was the most prominent abnormality, with MCI MH having the greatest degree of co-occurring hypometabolism.

  17. Cellular and molecular cues of glucose sensing in the rat olfactory bulb

    Directory of Open Access Journals (Sweden)

    Dolly eAl Koborssy

    2014-10-01

    Full Text Available In the brain, glucose homeostasis of extracellular fluid is crucial to the point that systems specifically dedicated to glucose sensing are found in areas involved in energy regulation and feeding behavior. Olfaction is a major sensory modality regulating food consumption. Nutritional status in turn modulates olfactory detection. Recently it has been proposed that some olfactory bulb (OB neurons respond to glucose similarly to hypothalamic neurons. However, the precise molecular cues governing glucose sensing in the OB are largely unknown. To decrypt these molecular mechanisms, we first used immunostaining to demonstrate a strong expression of two neuronal markers of glucose-sensitivity, insulin-dependent glucose transporter type 4 (GLUT4, and sodium glucose co-transporter type 1 (SGLT1 in specific OB layers. We showed that expression and mapping of GLUT4 but not SGLT1 were feeding state-dependent. In order to investigate the impact of metabolic status on the delivery of blood-borne glucose to the OB, we measured extracellular fluid glucose concentration using glucose biosensors simultaneously in the OB and cortex of anesthetized rats. We showed that glucose concentration in the OB is higher than in the cortex, that metabolic steady-state glucose concentration is independent of feeding state in the two brain areas, and that acute changes in glycemic conditions affect bulbar glucose concentration alone. These data provide new evidence of a direct relationship between the OB and peripheral metabolism, and emphasize the importance of glucose for the OB network, providing strong arguments toward establishing the OB as a glucose-sensing organ.

  18. Osteocalcin as a hormone regulating glucose metabolism

    Institute of Scientific and Technical Information of China (English)

    2015-01-01

    The number of patients with osteoporosis and diabetesis rapidly increasing all over the world. Bone is recentlyrecognized as an endocrine organ. Accumulatingevidence has shown that osteocalcin, which is specificallyexpressed in osteoblasts and secreted into the circulation,regulates glucose homeostasis by stimulating insulinexpression in pancreas and adiponectin expression inadipocytes, resulting in improving glucose intolerance.On the other hand, insulin and adiponectin stimulateosteocalcin expression in osteoblasts, suggesting thatpositive feedforward loops exist among bone, pancreas,and adipose tissue. In addition, recent studies haveshown that osteocalcin enhances insulin sensitivity andthe differentiation in muscle, while secreted factors frommuscle, myokines, regulate bone metabolism. Thesefindings suggest that bone metabolism and glucosemetabolism are associated with each other through theaction of osteocalcin. In this review, I describe the roleof osteocalcin in the interaction among bone, pancreas,brain, adipose tissue, and muscle.

  19. Expression of hypoxia-inducible factor 1 alpha and oligodendrocyte lineage gene-1 in cultured brain slices after oxygen-glucose deprivation

    Institute of Scientific and Technical Information of China (English)

    Hong Cui; Weijuan Han; Lijun Yang; Yanzhong Chang

    2013-01-01

    Oligodendrocyte lineage gene-1 expressed in oligodendrocytes may trigger the repair of neuronal myelin impairment, and play a crucial role in myelin repair. Hypoxia-inducible factor 1α, a transcription factor, is of great significance in premature infants with hypoxic-ischemic brain damage. There is little evidence of direct regulatory effects of hypoxia-inducible factor 1α on oligodendrocyte lineage gene-1. In this study, brain slices of Sprague-Dawley rats were cultured and subjected to oxygen-glucose deprivation. Then, slices were transfected with hypoxia-inducible factor 1α or oligodendrocyte lineage gene-1. The expression levels of hypoxia-inducible factor 1α and oligodendrocyte lineage gene-1 were significantly up-regulated in rat brains prior to transfection, as detected by immunohistochemical staining. Eight hours after transfection of slices with hypoxia-inducible factor 1α, oligodendrocyte lineage gene-1 expression was upregulated, and reached a peak 24 hours after transfection. Oligodendrocyte lineage gene-1 transfection induced no significant differences in hypoxia-inducible factor 1α levels in rat brain tissues with oxygen-glucose deprivation. These experimental findings indicate that hypoxia-inducible factor 1α can regulate oligodendrocyte lineage gene-1 expression in hypoxic brain tissue, thus repairing the neural impairment.

  20. A Fall in Plasma Free Fatty Acid (FFA) Level Activates the Hypothalamic-Pituitary-Adrenal Axis Independent of Plasma Glucose: Evidence for Brain Sensing of Circulating FFA

    Science.gov (United States)

    Oh, Young Taek; Oh, Ki-Sook; Kang, Insug

    2012-01-01

    The brain responds to a fall in blood glucose by activating neuroendocrine mechanisms for its restoration. It is unclear whether the brain also responds to a fall in plasma free fatty acids (FFA) to activate mechanisms for its restoration. We examined whether lowering plasma FFA increases plasma corticosterone or catecholamine levels and, if so, whether the brain is involved in these responses. Plasma FFA levels were lowered in rats with three independent antilipolytic agents: nicotinic acid (NA), insulin, and the A1 adenosine receptor agonist SDZ WAG 994 with plasma glucose clamped at basal levels. Lowering plasma FFA with these agents all increased plasma corticosterone, but not catecholamine, within 1 h, accompanied by increases in plasma ACTH. These increases in ACTH or corticosterone were abolished when falls in plasma FFA were prevented by Intralipid during NA or insulin infusion. In addition, the NA-induced increases in plasma ACTH were completely prevented by administration of SSR149415, an arginine vasopressin receptor antagonist, demonstrating that the hypothalamus is involved in these responses. Taken together, the present data suggest that the brain may sense a fall in plasma FFA levels and activate the hypothalamic-pituitary-adrenal axis to increase plasma ACTH and corticosterone, which would help restore FFA levels. Thus, the brain may be involved in the sensing and control of circulating FFA levels. PMID:22669895

  1. Age- and Sex-Associated Changes in Cerebral Glucose Metabolism in Normal Healthy Subjects: Statistical Parametric Mapping Analysis of F-18 Fluorodeoxyglucose Brain Positron Emission Tomography

    Energy Technology Data Exchange (ETDEWEB)

    Kim, In-Ju; Kim, Seong-Jang; Kim, Yong-Ki (Dept. of Nuclear Medicine, Pusan National Univ. Hospital, Busan (Korea); Medical Research Institute, Pusan National Univ., Busan (Korea)). e-mail: growthkim@daum.net/growthkim@pusan.ac.kr)

    2009-12-15

    Background: The age- and sex-associated changes of brain development are unclear and controversial. Several previous studies showed conflicting results of a specific pattern of cerebral glucose metabolism or no differences of cerebral glucose metabolism in association with normal aging process and sex. Purpose: To investigate the effects of age and sex on changes in cerebral glucose metabolism in healthy subjects using fluorine-18 fluorodeoxyglucose (F-18 FDG) brain positron emission tomography (PET) and statistical parametric mapping (SPM) analysis. Material and Methods: Seventy-eight healthy subjects (32 males, mean age 46.6+-18.2 years; 46 females, mean age 40.6+-19.8 years) underwent F-18 FDG brain PET. Using SPM, age- and sex-associated changes in cerebral glucose metabolism were investigated. Results: In males, a negative correlation existed in several gray matter areas, including the right temporopolar (Brodmann area [BA] 38), right orbitofrontal (BA 47), left orbitofrontal gyrus (BA 10), left dorsolateral frontal gyrus (BA 8), and left insula (BA 13) areas. A positive relationship existed in the left claustrum and left thalamus. In females, negative changes existed in the left caudate body, left temporopolar area (BA 38), right orbitofrontal gyri (BA 47 and BA 10), and right dorsolateral prefrontal cortex (BA 46). A positive association was demonstrated in the left subthalamic nucleus and the left superior frontal gyrus. In white matter, an age-associated decrease in FDG uptake in males was shown in the left insula, and increased FDG uptake was found in the left corpus callosum. The female group had an age-associated negative correlation of FDG uptake only in the right corpus callosum. Conclusion: Using SPM, we found not only similar areas of brain, but also sex-specific cerebral areas of age-associated changes of FDG uptake

  2. Age- and Sex-Associated Changes in Cerebral Glucose Metabolism in Normal Healthy Subjects: Statistical Parametric Mapping Analysis of F-18 Fluorodeoxyglucose Brain Positron Emission Tomography

    International Nuclear Information System (INIS)

    Background: The age- and sex-associated changes of brain development are unclear and controversial. Several previous studies showed conflicting results of a specific pattern of cerebral glucose metabolism or no differences of cerebral glucose metabolism in association with normal aging process and sex. Purpose: To investigate the effects of age and sex on changes in cerebral glucose metabolism in healthy subjects using fluorine-18 fluorodeoxyglucose (F-18 FDG) brain positron emission tomography (PET) and statistical parametric mapping (SPM) analysis. Material and Methods: Seventy-eight healthy subjects (32 males, mean age 46.6±18.2 years; 46 females, mean age 40.6±19.8 years) underwent F-18 FDG brain PET. Using SPM, age- and sex-associated changes in cerebral glucose metabolism were investigated. Results: In males, a negative correlation existed in several gray matter areas, including the right temporopolar (Brodmann area [BA] 38), right orbitofrontal (BA 47), left orbitofrontal gyrus (BA 10), left dorsolateral frontal gyrus (BA 8), and left insula (BA 13) areas. A positive relationship existed in the left claustrum and left thalamus. In females, negative changes existed in the left caudate body, left temporopolar area (BA 38), right orbitofrontal gyri (BA 47 and BA 10), and right dorsolateral prefrontal cortex (BA 46). A positive association was demonstrated in the left subthalamic nucleus and the left superior frontal gyrus. In white matter, an age-associated decrease in FDG uptake in males was shown in the left insula, and increased FDG uptake was found in the left corpus callosum. The female group had an age-associated negative correlation of FDG uptake only in the right corpus callosum. Conclusion: Using SPM, we found not only similar areas of brain, but also sex-specific cerebral areas of age-associated changes of FDG uptake

  3. Dynamic changes in glucose metabolism of living rat brain slices induced by hypoxia and neurotoxic chemical-loading revealed by positron autoradiography

    International Nuclear Information System (INIS)

    Fresh rat brain slices were incubated with 2-deoxy-2-[18F]-fluoro-D-glucose ([18F]FDG) in oxygenated Krebs-Ringer solution at 36 degree C, and serial two-dimensional time-resolved images of [18F]FDG uptake were obtained from these specimens on imaging plates. The fractional rate constant (= k3*) of [18F]FDG proportional to the cerebral glucose metabolic rate (CMRglc) was evaluated by applying the Gjedde-Patlak graphical method to the image data. With hypoxia loading (oxygen deprivation) or glucose metabolism inhibitors acting on oxidative phosphorylation, the k3* value increased dramatically suggesting enhanced glycolysis. After relieving hypoxia ≤10-min, the k3* value returned to the pre-loading level. In contrast, with ≥20-min hypoxia only partial or no recovery was observed, indicating that irreversible neuronal damage had been induced. However, after loading with tetrodotoxin (TTX), the k3* value also decreased but returned to the pre-loading level even after 70-min TTX-loading, reflecting a transient inhibition of neuronal activity. This technique provides a new means of quantifying dynamic changes in the regional CMRglc in living brain slices in response to various interventions such as hypoxia and neurotoxic chemical-loading as well as determining the viability and prognosis of brain tissues. (author)

  4. Voxel-based statistical analysis of cerebral glucose metabolism in the rat cortical deafness model by 3D reconstruction of brain from autoradiographic images

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Jae Sung; Park, Kwang Suk [Seoul National University College of Medicine, Department of Nuclear Medicine, 28 Yungun-Dong, Chongno-Ku, Seoul (Korea); Seoul National University College of Medicine, Department of Biomedical Engineering, Seoul (Korea); Ahn, Soon-Hyun; Oh, Seung Ha; Kim, Chong Sun; Chung, June-Key; Lee, Myung Chul [Seoul National University College of Medicine, Department of Otolaryngology, Head and Neck Surgery, Seoul (Korea); Lee, Dong Soo; Jeong, Jae Min [Seoul National University College of Medicine, Department of Nuclear Medicine, 28 Yungun-Dong, Chongno-Ku, Seoul (Korea)

    2005-06-01

    Animal models of cortical deafness are essential for investigation of the cerebral glucose metabolism in congenital or prelingual deafness. Autoradiographic imaging is mainly used to assess the cerebral glucose metabolism in rodents. In this study, procedures for the 3D voxel-based statistical analysis of autoradiographic data were established to enable investigations of the within-modal and cross-modal plasticity through entire areas of the brain of sensory-deprived animals without lumping together heterogeneous subregions within each brain structure into a large region of interest. Thirteen 2-[1-{sup 14}C]-deoxy-D-glucose autoradiographic images were acquired from six deaf and seven age-matched normal rats (age 6-10 weeks). The deafness was induced by surgical ablation. For the 3D voxel-based statistical analysis, brain slices were extracted semiautomatically from the autoradiographic images, which contained the coronal sections of the brain, and were stacked into 3D volume data. Using principal axes matching and mutual information maximization algorithms, the adjacent coronal sections were co-registered using a rigid body transformation, and all sections were realigned to the first section. A study-specific template was composed and the realigned images were spatially normalized onto the template. Following count normalization, voxel-wise t tests were performed to reveal the areas with significant differences in cerebral glucose metabolism between the deaf and the control rats. Continuous and clear edges were detected in each image after registration between the coronal sections, and the internal and external landmarks extracted from the spatially normalized images were well matched, demonstrating the reliability of the spatial processing procedures. Voxel-wise t tests showed that the glucose metabolism in the bilateral auditory cortices of the deaf rats was significantly (P<0.001) lower than that in the controls. There was no significantly reduced metabolism in

  5. Comparison of intensive insulin therapy versus conventional glucose control in traumatic brain injury patients on parenteral nutrition: A pilot randomized clinical trial

    Directory of Open Access Journals (Sweden)

    Seyedeh Neda Mousavi

    2014-01-01

    Full Text Available Background: Parenteral nutrition (PN is a valuable life saving intervention, which can improve the nutritional status of hospitalized malnourished patients. PN is associated with complications including hyperglycemia. This study was conducted to compare two methods of blood glucose control in traumatic brain injury patients on PN. Materials and Methods: A randomized, open-label, controlled trial with blinded end point assessment was designed. Traumatic brain injury patients (GCS = 4-9 on PN, without diabetes, pancreatitis, liver disease, kidney complication, were participated. Patients were randomly assigned to receive continuous insulin infusion to maintain glucose levels between 4.4 mmol/l (80 mg/dl and 6.6 mmol/l (120 mg/dl (n = 13 or conventional treatment (n = 13. Patients in the conventional group were not received insulin unless glucose levels were greater than 10 mmol/l (>180 mg/dl. These methods were done to maintain normoglycemia in ICU. The primary outcome was hypo/hyperglycemic episodes. Other factors such as C-reactive protein, blood electrolytes, liver function tests, lipid profile and mid-arm circumference were compared. Results: Mean glucose concentration were significantly lower in IIT group (118 ± 28 mg/dl vs conventional group (210 ± 31 mg/dl (P < 0.01. No hypoglycemic episode occurred in two groups. Triglyceride (P = 0.02 and C-reactive protein (P = 0.001 was decreased in the IIT group, significantly. There were also significant differences in the electrolytes, with magnesium and phosphorus being lower in the IIT group (P = 0.05. Conclusion: In this pilot study, blood glucose level, CRP and TG were lower in IIT group. Further data collection is warranted to reach definitive conclusions.

  6. Antihypertensive drugs and glucose metabolism

    Institute of Scientific and Technical Information of China (English)

    Christos; V; Rizos; Moses; S; Elisaf

    2014-01-01

    Hypertension plays a major role in the development and progression of micro-and macrovascular disease.Moreover,increased blood pressure often coexists with additional cardiovascular risk factors such as insulin resistance.As a result the need for a comprehensive management of hypertensive patients is critical.However,the various antihypertensive drug categories have different effects on glucose metabolism.Indeed,angiotensin receptor blockers as well as angiotensin converting enzyme inhibitors have been associated with beneficial effects on glucose homeostasis.Calcium channel blockers(CCBs)have an overall neutral effect on glucose metabolism.However,some members of the CCBs class such as azelnidipine and manidipine have been shown to have advantageous effects on glucose homeostasis.On the other hand,diuretics andβ-blockers have an overall disadvantageous effect on glucose metabolism.Of note,carvedilol as well as nebivolol seem to differentiate themselves from the rest of theβ-blockers class,being more attractive options regarding their effect on glucose homeostasis.The adverse effects of some blood pressure lowering drugs on glucose metabolism may,to an extent,compromise their cardiovascular protective role.As a result the effects on glucose homeostasis of the various blood pressure lowering drugs should be taken into account when selecting an antihypertensive treatment,especially in patients which are at high risk for developing diabetes.

  7. Cerebral glucose metabolism in long-term survivors of childhood primary brain tumors treated with surgery and radiotherapy

    DEFF Research Database (Denmark)

    Andersen, Preben B.; Krabbe, Katja; Leffers, Anne M.;

    2003-01-01

    a median recurrence free survival of 16 years by MRI and Positron Emission Tomography using the glucose analog 2-18F-fluoro-2-deoxy-D-glucose (18FDG). Three patients were not analyzed further due to diffuse cerebral atrophy, which might be related to previous hydrocephalus. Twenty-one patients were...

  8. Alterations in blood glucose and plasma glucagon concentrations during deep brain stimulation in the shell region of the nucleus accumbens in rats

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    Charlene eDiepenbroek

    2013-12-01

    Full Text Available Deep brain stimulation (DBS of the nucleus accumbens (NAc is an effective therapy for obsessive compulsive disorder (OCD and is currently under investigation as a treatment for eating disorders. DBS of this area is associated with altered food intake and pharmacological treatment of OCD is associated with the risk of developing type 2 diabetes. Therefore we examined if DBS of the NAc-shell (sNAc influences glucose metabolism. Male Wistar rats were subjected to DBS, or sham stimulation, for a period of one hour. To assess the effects of stimulation on blood glucose and glucoregulatory hormones, blood samples were drawn before, during and after stimulation. Subsequently, all animals were used for quantitative assessment of Fos immunoreactivity in the lateral hypothalamic area (LHA using computerized image analysis. DBS of the sNAc rapidly increased plasma concentrations of glucagon and glucose while sham stimulation and DBS outside the sNAc were ineffective. In addition, the increase in glucose was dependent on DBS intensity. In contrast, the DBS-induced increase in plasma corticosterone concentrations was independent of intensity and region, indicating that the observed DBS-induced metabolic changes were not due to corticosterone release. Stimulation of the sNAc with 200 μA increased Fos immunoreactivity in the LHA compared to sham or 100 μA stimulated animals. These data show that DBS of the sNAc alters glucose metabolism in a region- and intensity dependent manner in association with neuronal activation in the LHA. Moreover, these data illustrate the need to monitor changes in glucose metabolism during DBS-treatment of OCD patients.

  9. Alterations in blood glucose and plasma glucagon concentrations during deep brain stimulation in the shell region of the nucleus accumbens in rats.

    Science.gov (United States)

    Diepenbroek, Charlene; van der Plasse, Geoffrey; Eggels, Leslie; Rijnsburger, Merel; Feenstra, Matthijs G P; Kalsbeek, Andries; Denys, Damiaan; Fliers, Eric; Serlie, Mireille J; la Fleur, Susanne E

    2013-01-01

    Deep brain stimulation (DBS) of the nucleus accumbens (NAc) is an effective therapy for obsessive compulsive disorder (OCD) and is currently under investigation as a treatment for eating disorders. DBS of this area is associated with altered food intake and pharmacological treatment of OCD is associated with the risk of developing type 2 diabetes. Therefore we examined if DBS of the NAc-shell (sNAc) influences glucose metabolism. Male Wistar rats were subjected to DBS, or sham stimulation, for a period of 1 h. To assess the effects of stimulation on blood glucose and glucoregulatory hormones, blood samples were drawn before, during and after stimulation. Subsequently, all animals were used for quantitative assessment of Fos immunoreactivity in the lateral hypothalamic area (LHA) using computerized image analysis. DBS of the sNAc rapidly increased plasma concentrations of glucagon and glucose while sham stimulation and DBS outside the sNAc were ineffective. In addition, the increase in glucose was dependent on DBS intensity. In contrast, the DBS-induced increase in plasma corticosterone concentrations was independent of intensity and region, indicating that the observed DBS-induced metabolic changes were not due to corticosterone release. Stimulation of the sNAc with 200 μA increased Fos immunoreactivity in the LHA compared to sham or 100 μA stimulated animals. These data show that DBS of the sNAc alters glucose metabolism in a region- and intensity- dependent manner in association with neuronal activation in the LHA. Moreover, these data illustrate the need to monitor changes in glucose metabolism during DBS-treatment of OCD patients. PMID:24339800

  10. Cocaine- and amphetamine-regulated transcript: a novel regulator of energy homeostasis expressed in a subpopulation of pancreatic islet cells.

    Science.gov (United States)

    Gilon, Patrick

    2016-09-01

    Type 2 diabetes is characterised by chronic hyperglycaemia and its incidence is highly increased by exaggerated food consumption. It results from a lack of insulin action/production, but growing evidence suggests that it might also involve hyperglucagonaemia and impaired control of glucose homeostasis by the brain. In recent years, the cocaine and amphetamine-regulated transcript (CART) peptides have generated a lot of interest in the battle against obesity because, via the brain, they exert anorexic effects and they increase energy expenditure. They are also localised, outside the brain, in discrete regions of the body and play a hormonal role in controlling various functions. In this issue of Diabetologia, the Wierup group (doi: 10.1007/s00125-016-4020-6 ) shows that CART peptides are expressed heterogeneously in islet cells of various species, including humans, and that their expression is upregulated in diabetes. The authors also shine a spotlight on some interesting effects of CART peptides on islet function, including stimulation of insulin secretion and inhibition of glucagon release. CART peptides would thus be at the centre of a cooperation between the brain and the endocrine pancreas to control glucose homeostasis. Although the mechanisms of action of CART peptides remain enigmatic because no specific receptor for these peptides has so far been discovered, their potential therapeutic use is evident and represents a new challenge for future research. PMID:27421727

  11. Brain

    Science.gov (United States)

    ... will return after updating. Resources Archived Modules Updates Brain Cerebrum The cerebrum is the part of the ... the outside of the brain and spinal cord. Brain Stem The brain stem is the part of ...

  12. Lipopolysaccharide (LPS) and tumor necrosis factor alpha (TNFα) blunt the response of Neuropeptide Y/Agouti-related peptide (NPY/AgRP) glucose inhibited (GI) neurons to decreased glucose.

    Science.gov (United States)

    Hao, Lihong; Sheng, Zhenyu; Potian, Joseph; Deak, Adam; Rohowsky-Kochan, Christine; Routh, Vanessa H

    2016-10-01

    A population of Neuropeptide Y (NPY) neurons which co-express Agouti-related peptide (AgRP) in the arcuate nucleus of the hypothalamus (ARC) are inhibited at physiological levels of brain glucose and activated when glucose levels decline (e.g. glucose-inhibited or GI neurons). Fasting enhances the activation of NPY/AgRP-GI neurons by low glucose. In the present study we tested the hypothesis that lipopolysaccharide (LPS) inhibits the enhanced activation of NPY/AgRP-GI neurons by low glucose following a fast. Mice which express green fluorescent protein (GFP) on their NPY promoter were used to identify NPY/AgRP neurons. Fasting for 24h and LPS injection decreased blood glucose levels. As we have found previously, fasting increased c-fos expression in NPY/AgRP neurons and increased the activation of NPY/AgRP-GI neurons by decreased glucose. As we predicted, LPS blunted these effects of fasting at the 24h time point. Moreover, the inflammatory cytokine tumor necrosis factor alpha (TNFα) blocked the activation of NPY/AgRP-GI neurons by decreased glucose. These data suggest that LPS and TNFα may alter glucose and energy homeostasis, in part, due to changes in the glucose sensitivity of NPY/AgRP neurons. Interestingly, our findings also suggest that NPY/AgRP-GI neurons use a distinct mechanism to sense changes in extracellular glucose as compared to our previous studies of GI neurons in the adjacent ventromedial hypothalamic nucleus.

  13. Redox Homeostasis in Pancreatic Cells

    Directory of Open Access Journals (Sweden)

    Petr Ježek

    2012-01-01

    Full Text Available We reviewed mechanisms that determine reactive oxygen species (redox homeostasis, redox information signaling and metabolic/regulatory function of autocrine insulin signaling in pancreatic β cells, and consequences of oxidative stress and dysregulation of redox/information signaling for their dysfunction. We emphasize the role of mitochondrion in β cell molecular physiology and pathology, including the antioxidant role of mitochondrial uncoupling protein UCP2. Since in pancreatic β cells pyruvate cannot be easily diverted towards lactate dehydrogenase for lactate formation, the respiration and oxidative phosphorylation intensity are governed by the availability of glucose, leading to a certain ATP/ADP ratio, whereas in other cell types, cell demand dictates respiration/metabolism rates. Moreover, we examine the possibility that type 2 diabetes mellitus might be considered as an inevitable result of progressive self-accelerating oxidative stress and concomitantly dysregulated information signaling in peripheral tissues as well as in pancreatic β cells. It is because the redox signaling is inherent to the insulin receptor signaling mechanism and its impairment leads to the oxidative and nitrosative stress. Also emerging concepts, admiting participation of redox signaling even in glucose sensing and insulin release in pancreatic β cells, fit in this view. For example, NADPH has been firmly established to be a modulator of glucose-stimulated insulin release.

  14. Glucose utilization in the brain during acute seizure is a useful biomarker for the evaluation of anticonvulsants: effect of methyl ethyl ketone in lithium-pilocarpine status epilepticus rats

    Energy Technology Data Exchange (ETDEWEB)

    Yamada, Akifumi [Division of Health Sciences, Graduate School of Medicine, Osaka University, Osaka, 565-0871 (Japan)], E-mail: yamaaki@sahs.med.osaka-u.ac.jp; Momosaki, Sotaro; Hosoi, Rie [Division of Health Sciences, Graduate School of Medicine, Osaka University, Osaka, 565-0871 (Japan); Abe, Kohji [Division of Health Sciences, Graduate School of Medicine, Osaka University, Osaka, 565-0871 (Japan); Developmental Research Laboratories, Shionogi and Co., Ltd., Toyonaka, Osaka, 561-0825 (Japan); Yamaguchi, Masatoshi [Faculty of Pharmaceutical Sciences, Fukuoka University, Johnan, Fukuoka 814-0180 (Japan); Inoue, Osamu [Division of Health Sciences, Graduate School of Medicine, Osaka University, Osaka, 565-0871 (Japan)

    2009-11-15

    Enhancement of glucose utilization in the brain has been well known during acute seizure in various kinds of animal model of epilepsy. This enhancement of glucose utilization might be related to neural damage in these animal models. Recently, we found that methyl ethyl ketone (MEK) had both anticonvulsive and neuroprotective effects in lithium-pilocapine (Li-pilo) status epilepticus (SE) rat. In this article, we measured the uptake of [{sup 14}C]2-deoxyglucose ([{sup 14}C]DG) in the Li-pilo SE and Li-pilo SE with MEK rat brain in order to assess whether the glucose utilization was a useful biomarker for the detection of efficacy of anticonvulsive compounds. Significant increase of [{sup 14}C]DG uptake (45 min after the injection) in the cerebral cortex, hippocampus, amygdala and thalamus during acute seizure induced by Li-pilo were observed. On the other hand, the initial uptake of [{sup 14}C]DG (1 min after the injection) in the Li-pilo SE rats was not different from the control rats. Therefore, the enhancement of glucose metabolism during acute seizure was due to the facilitation of the rate of phosphorylation process of [{sup 14}C]DG in the brain. Pretreatment with MEK (8 mmol/kg) completely abolished the enhancement of glucose utilization in the Li-pilo SE rats. The present results indicated that glucose utilization in the brain during acute seizure might be a useful biomarker for the evaluation of efficacy of anticonvulsive compounds.

  15. Hepatic glucose sensing is required to preserve β cell glucose competence.

    OpenAIRE

    Seyer, Pascal; Vallois, David; Poitry-Yamate, Carole; Schutz, Frédéric; Metref, Salima; Tarussio, David; Maechler, Pierre; Staels, Bart; Lanz, Bernard; Grueter, Rolf; Decaris, Julie; Turner, Scott; Da Costa, Anabela; Preitner, Frédéric; Minehira, Kaori

    2013-01-01

    Liver glucose metabolism plays a central role in glucose homeostasis and may also regulate feeding and energy expenditure. Here we assessed the impact of glucose transporter 2 (Glut2) gene inactivation in adult mouse liver (LG2KO mice). Loss of Glut2 suppressed hepatic glucose uptake but not glucose output. In the fasted state, expression of carbohydrate-responsive element-binding protein (ChREBP) and its glycolytic and lipogenic target genes was abnormally elevated. Feeding, energy expenditu...

  16. In utero fuel homeostasis: Lessons for a clinician

    Directory of Open Access Journals (Sweden)

    P. N Suman Rao

    2013-01-01

    Full Text Available Fetus exists in a complex, dynamic, and yet intriguing symbiosis with its mother as far as fuel metabolism is concerned. Though the dependence on maternal fuel is nearly complete to cater for its high requirement, the fetus is capable of some metabolism of its own. The first half of gestation is a period of maternal anabolism and storage whereas the second half results in exponential fetal growth where maternal stores are mobilized. Glucose is the primary substrate for energy production in the fetus though capable of utilizing alternate sources like lactate, ketoacids, amino acids, fatty acids, and glycogen as fuel under special circumstances. Key transporters like glucose transporters (GLUT are responsible for preferential transfers, which are in turn regulated by complex interaction of maternal and fetal hormones. Amino acids are preferentially utilized for growth and essential fatty acids for development of brain and retina. Insulin, insulin like growth factors, glucagon, catecholamines, and letpin are the hormones implicated in this fascinating process. Hormonal regulation of metabolic substrate utilization and anabolism in the fetus is secondary to the supply of nutrient substrates. The knowledge of fuel homeostasis is crucial for a clinician caring for pregnant women and neonates to manage disorders of metabolism (diabetes, growth (intrauterine growth restriction, and transitional adaptation (hypoglycemia.

  17. Brain regions involved in voluntary movements as revealed by radioisotopic mapping of CBF or CMR-glucose changes

    DEFF Research Database (Denmark)

    Lassen, N A; Ingvar, D H

    1990-01-01

    Mapping of cortical and subcortical grey matter active during voluntary movements by means of measurements of local increases of CBF or CMR-Glucose is reviewed. Most of the studies concern observations in man during hand movements using the intracarotid Xenon-133 injection technique, an approach...... area SMA on both sides increase in CBF/CMR-glucose and even internally ("mentally") going through the trained movements, causes such changes; complex purposeful movements also activate the premotor cortex, a response that is bilateral with greatest response contralaterally. Studies in patients...

  18. The protective role of isorhamnetin on human brain microvascular endothelial cells from cytotoxicity induced by methylglyoxal and oxygen-glucose deprivation.

    Science.gov (United States)

    Li, Wenlu; Chen, Zhigang; Yan, Min; He, Ping; Chen, Zhong; Dai, Haibin

    2016-02-01

    As the first target of stroke, cerebral endothelial cells play a key role in brain vascular repair and maintenance, and their function is impeded in diabetes. Methylglyoxal (MGO), a reactive dicarbonyl produced during glucose metabolism, accumulates in diabetic patients. MGO and MGO-induced advanced glycation end-products (AGEs) could ameliorate stroke-induced brain vascular damage, closely related with ECs dysfunction. Using MGO plus oxygen-glucose deprivation (OGD) to mimic diabetic stroke, we reported the protective effect of isorhamnetin on OGD-induced cytotoxicity after MGO treatment on primary human brain microvascular endothelial cells (HBMEC) and explored the underlying mechanisms. Treatment of MGO for 24 h significantly enhanced 3-h OGD-induced HBMEC toxic effect, which was inhibited by pretreatment of isorhamnetin (100 μmol/L). Moreover, the protective effect of isorhamnetin is multiple function dependent, which includes anti-inflammation, anti-oxidative stress and anti-apoptosis effects. Besides its well-known inhibition on the mitochondria-dependent or intrinsic apoptotic pathway, isorhamnetin also reduced activation of the extrinsic apoptotic pathway, as characterized by the decreased expression and activity of caspase 3 and caspase 8. Furthermore, pretreatment with isorhamnetin specifically inhibited FAS/FASL expression and suppressed nuclear factor-kappa B nuclear translocation. Taken together, our results indicated that isorhamnetin protected against OGD-induced cytotoxicity after MGO treatment in cultured HBMEC due to its multiple protective effects and could inhibit Fas-mediated extrinsic apoptosis. Therefore, isorhamnetin is a promising reagent for the treatment of hyperglycemia and ischemia-induced cerebral vascular degeneration. A proposed model of the potential protective mechanism of isorhamnetin, a metabolite of quercetin, on methylglyoxal (MGO) treatment plus oxygen-glucose deprivation (OGD) exposure-induced cytotoxicity in cultured human

  19. Relationship of metabolic and endocrine parameters to brain glucose metabolism in older adults: do cognitively-normal older adults have a particular metabolic phenotype?

    Science.gov (United States)

    Nugent, S; Castellano, C A; Bocti, C; Dionne, I; Fulop, T; Cunnane, S C

    2016-02-01

    Our primary objective in this study was to quantify whole brain and regional cerebral metabolic rates of glucose (CMRg) in young and older adults in order to determine age-normalized reference CMRg values for healthy older adults with normal cognition for age. Our secondary objectives were to--(i) report a broader range of metabolic and endocrine parameters including body fat composition that could form the basis for the concept of a 'metabolic phenotype' in cognitively normal, older adults, and (ii) to assess whether medications commonly used to control blood lipids, blood pressure or thyroxine affect CMRg values in older adults. Cognition assessed by a battery of tests was normal for age and education in both groups. Compared to the young group (25 years old; n = 34), the older group (72 years old; n = 41) had ~14% lower CMRg (μmol/100 g/min) specifically in the frontal cortex, and 18% lower CMRg in the caudate. Lower grey matter volume and cortical thickness was widespread in the older group. These differences in CMRg, grey matter volume and cortical thickness were present in the absence of any known evidence for prodromal Alzheimer's disease (AD). Percent total body fat was positively correlated with CMRg in many brain regions but only in the older group. Before and after controlling for body fat, HOMA2-IR was significantly positively correlated to CMRg in several brain regions in the older group. These data show that compared to a healthy younger adult, the metabolic phenotype of a cognitively-normal 72 year old person includes similar plasma glucose, insulin, cholesterol, triglycerides and TSH, higher hemoglobin A1c and percent body fat, lower CMRg in the superior frontal cortex and caudate, but the same CMRg in the hippocampus and white matter. Age-normalization of cognitive test results is standard practice and we would suggest that regional CMRg in cognitively healthy older adults should also be age-normalized. PMID:26364049

  20. EFFECTS OF GLUCOSE-INFUSION ON HORMONE-SECRETION AND HEPATIC GLUCOSE-PRODUCTION DURING HEAVY EXERCISE

    NARCIS (Netherlands)

    WIERSMA, MML; VISSING, J; STEFFENS, AB; GALBO, H

    1993-01-01

    Blood-borne metabolic feedback vs. neural feedforward regulation of glucose homeostasis during exercise was investigated by infusing glucose and [H-3]glucose for glucose appearance determination intravenously in rats running for 20 min at 28 m/min [almost-equal-to 85% of maximal 02 consumption (VO2m

  1. Impaired Glucose Metabolism in Mice Lacking the Tas1r3 Taste Receptor Gene.

    Directory of Open Access Journals (Sweden)

    Vladimir O Murovets

    Full Text Available The G-protein-coupled sweet taste receptor dimer T1R2/T1R3 is expressed in taste bud cells in the oral cavity. In recent years, its involvement in membrane glucose sensing was discovered in endocrine cells regulating glucose homeostasis. We investigated importance of extraorally expressed T1R3 taste receptor protein in age-dependent control of blood glucose homeostasis in vivo, using nonfasted mice with a targeted mutation of the Tas1r3 gene that encodes the T1R3 protein. Glucose and insulin tolerance tests, as well as behavioral tests measuring taste responses to sucrose solutions, were performed with C57BL/6ByJ (Tas1r3+/+ inbred mice bearing the wild-type allele and C57BL/6J-Tas1r3tm1Rfm mice lacking the entire Tas1r3 coding region and devoid of the T1R3 protein (Tas1r3-/-. Compared with Tas1r3+/+ mice, Tas1r3-/- mice lacked attraction to sucrose in brief-access licking tests, had diminished taste preferences for sucrose solutions in the two-bottle tests, and had reduced insulin sensitivity and tolerance to glucose administered intraperitoneally or intragastrically, which suggests that these effects are due to absence of T1R3. Impairment of glucose clearance in Tas1r3-/- mice was exacerbated with age after intraperitoneal but not intragastric administration of glucose, pointing to a compensatory role of extraoral T1R3-dependent mechanisms in offsetting age-dependent decline in regulation of glucose homeostasis. Incretin effects were similar in Tas1r3+/+ and Tas1r3-/- mice, which suggests that control of blood glucose clearance is associated with effects of extraoral T1R3 in tissues other than the gastrointestinal tract. Collectively, the obtained data demonstrate that the T1R3 receptor protein plays an important role in control of glucose homeostasis not only by regulating sugar intake but also via its extraoral function, probably in the pancreas and brain.

  2. Glucose Intolerance, Insulin Resistance and Alzheimer’s Disease Pathology in the Baltimore Longitudinal Study of Aging

    Science.gov (United States)

    Thambisetty, M.; Metter, E.J.; Yang, A.; Dolan, H.; Marano, C.; Zonderman, A.B.; Troncoso, J.; Zhou, Y; Wong, D.F.; Ferrucci, L.; Egan, J.M.; Resnick, S.M.; OBrien, R.

    2014-01-01

    Objective To investigate associations between serial measures of glucose intolerance and insulin resistance with in vivo amyloid burden, measured with 11C-PiB, and Alzheimer’s disease (AD) pathology at autopsy in a prospective cohort from the Baltimore Longitudinal Study of Aging. Methods Brain CERAD and Braak scores were correlated with measures of hyperglycemia, hyperinsulinemia, glucose intolerance and insulin resistance in 197 participants who had come to autopsy and had two or more oral glucose tolerance tests (OGTT) during life. Glucose intolerance was measured by fasting and 120-minute post-load glucose values. Insulin resistance was measured by fasting and 120-minute post-load serum insulin values and the ratio of serum glucose to insulin at baseline and following a glucose load. In addition, the same measures of glucose intolerance and insulin resistance were correlated with brain 11C-PiB retention in 53 living subjects. Results There were no significant correlations between measures of brain AD pathology or 11C-PiB derived amyloid load and either glucose intolerance or insulin resistance in subjects who had a mean of 6.4 ± 3.2 (S.D.) OGTT evaluations over 22.1 ± 8.0 (S.D.) years of follow-up. Thirty subjects with frank diabetes on medication also had AD pathology scores that were similar to the cohort as a whole. Conclusions In this prospective cohort with multiple assessments of glucose intolerance and insulin resistance, measures of glucose and insulin homeostasis were not associated with AD pathology. PMID:23897112

  3. Age- and Brain Region-Specific Changes of Glucose Metabolic Disorder, Learning, and Memory Dysfunction in Early Alzheimer’s Disease Assessed in APP/PS1 Transgenic Mice Using 18F-FDG-PET

    Directory of Open Access Journals (Sweden)

    Xue-Yuan Li

    2016-10-01

    Full Text Available Alzheimer’s disease (AD is a leading cause of dementia worldwide, associated with cognitive deficits and brain glucose metabolic alteration. However, the associations of glucose metabolic changes with cognitive dysfunction are less detailed. Here, we examined the brains of APP/presenilin 1 (PS1 transgenic (Tg mice aged 2, 3.5, 5 and 8 months using 18F-labed fluorodeoxyglucose (18F-FDG microPET to assess age- and brain region-specific changes of glucose metabolism. FDG uptake was calculated as a relative standardized uptake value (SUVr. Morris water maze (MWM was used to evaluate learning and memory dysfunction. We showed a glucose utilization increase in multiple brain regions of Tg mice at 2 and 3.5 months but not at 5 and 8 months. Comparisons of SUVrs within brains showed higher glucose utilization than controls in the entorhinal cortex, hippocampus, and frontal cortex of Tg mice at 2 and 3.5 months but in the thalamus and striatum at 3.5, 5 and 8 months. By comparing SUVrs in the entorhinal cortex and hippocampus, Tg mice were distinguished from controls at 2 and 3.5 months. In MWM, Tg mice aged 2 months shared a similar performance to the controls (prodromal-AD. By contrast, Tg mice failed training tests at 3.5 months but failed all MWM tests at 5 and 8 months, suggestive of partial or complete cognitive deficits (symptomatic-AD. Correlation analyses showed that hippocampal SUVrs were significantly correlated with MWM parameters in the symptomatic-AD stage. These data suggest that glucose metabolic disorder occurs before onset of AD signs in APP/PS1 mice with the entorhinal cortex and hippocampus affected first, and that regional FDG uptake increase can be an early biomarker for AD. Furthermore, hippocampal FDG uptake is a possible indicator for progression of Alzheimer’s cognition after cognitive decline, at least in animals.

  4. Age- and Brain Region-Specific Changes of Glucose Metabolic Disorder, Learning, and Memory Dysfunction in Early Alzheimer’s Disease Assessed in APP/PS1 Transgenic Mice Using 18F-FDG-PET

    Science.gov (United States)

    Li, Xue-Yuan; Men, Wei-Wei; Zhu, Hua; Lei, Jian-Feng; Zuo, Fu-Xing; Wang, Zhan-Jing; Zhu, Zhao-Hui; Bao, Xin-Jie; Wang, Ren-Zhi

    2016-01-01

    Alzheimer’s disease (AD) is a leading cause of dementia worldwide, associated with cognitive deficits and brain glucose metabolic alteration. However, the associations of glucose metabolic changes with cognitive dysfunction are less detailed. Here, we examined the brains of APP/presenilin 1 (PS1) transgenic (Tg) mice aged 2, 3.5, 5 and 8 months using 18F-labed fluorodeoxyglucose (18F-FDG) microPET to assess age- and brain region-specific changes of glucose metabolism. FDG uptake was calculated as a relative standardized uptake value (SUVr). Morris water maze (MWM) was used to evaluate learning and memory dysfunction. We showed a glucose utilization increase in multiple brain regions of Tg mice at 2 and 3.5 months but not at 5 and 8 months. Comparisons of SUVrs within brains showed higher glucose utilization than controls in the entorhinal cortex, hippocampus, and frontal cortex of Tg mice at 2 and 3.5 months but in the thalamus and striatum at 3.5, 5 and 8 months. By comparing SUVrs in the entorhinal cortex and hippocampus, Tg mice were distinguished from controls at 2 and 3.5 months. In MWM, Tg mice aged 2 months shared a similar performance to the controls (prodromal-AD). By contrast, Tg mice failed training tests at 3.5 months but failed all MWM tests at 5 and 8 months, suggestive of partial or complete cognitive deficits (symptomatic-AD). Correlation analyses showed that hippocampal SUVrs were significantly correlated with MWM parameters in the symptomatic-AD stage. These data suggest that glucose metabolic disorder occurs before onset of AD signs in APP/PS1 mice with the entorhinal cortex and hippocampus affected first, and that regional FDG uptake increase can be an early biomarker for AD. Furthermore, hippocampal FDG uptake is a possible indicator for progression of Alzheimer’s cognition after cognitive decline, at least in animals. PMID:27763550

  5. The Selfish Brain: Stress and Eating Behavior

    Directory of Open Access Journals (Sweden)

    Achim ePeters

    2011-05-01

    Full Text Available The brain occupies a special hierarchical position in human energy metabolism. If cerebral homeostasis is threatened, the brain behaves in a "selfish" manner by competing for energy resources with the body. Here we present a logistic approach, which is based on the principles of supply and demand known from economics. In this "cerebral supply chain" model, the brain constitutes the final consumer. In order to illustrate the operating mode of the cerebral supply chain, we take experimental data which allow to assess the supply, demand and need of the brain under conditions of psychosocial stress. The experimental results show that the brain under conditions of psychosocial stress actively demands energy from the body, in order to cover its increased energy needs. The data demonstrate that the stressed brain uses a mechanism referred to as "cerebral insulin suppression" to limit glucose fluxes into peripheral tissue (muscle, fat and to enhance cerebral glucose supply. Furthermore psychosocial stress elicits a marked increase in eating behavior in the post-stress phase. Subjects ingested more carbohydrates without any preference for sweet ingredients. These experimentally observed changes of cerebral demand, supply and need are integrated into a logistic framework describing the supply chain of the selfish brain.

  6. HCdc14A is involved in cell cycle regulation of human brain vascular endothelial cells following injury induced by high glucose, free fatty acids and hypoxia.

    Science.gov (United States)

    Su, Jingjing; Zhou, Houguang; Tao, Yinghong; Guo, Zhuangli; Zhang, Shuo; Zhang, Yu; Huang, Yanyan; Tang, Yuping; Hu, Renming; Dong, Qiang

    2015-01-01

    Cell cycle processes play a vital role in vascular endothelial proliferation and dysfunction. Cell division cycle protein 14 (Cdc14) is an important cell cycle regulatory phosphatase. Previous studies in budding yeast demonstrated that Cdc14 could trigger the inactivation of mitotic cyclin-dependent kinases (Cdks), which are required for mitotic exit and cytokinesis. However, the exact function of human Cdc14 (hCdc14) in cell cycle regulation during vascular diseases is yet to be elucidated. There are two HCdc14 homologs: hCdc14A and hCdc14B. In the current study, we investigated the potential role of hCdc14A in high glucose-, free fatty acids (FFAs)-, and hypoxia-induced injury in cultured human brain vascular endothelial cells (HBVECs). Data revealed that high glucose, FFA, and hypoxia down-regulated hCdc14A expression remarkably, and also affected the expression of other cell cycle-related proteins such as cyclin B, cyclin D, cyclin E, and p53. Furthermore, the combined addition of the three stimuli largely blocked cell cycle progression, decreased cell proliferation, and increased apoptosis. We also determined that hCdc14A was localized mainly to centrosomes during interphase and spindles during mitosis using confocal microscopy, and that it could affect the expression of other cycle-related proteins. More importantly, the overexpression of hCdc14A accelerated cell cycle progression, enhanced cell proliferation, and promoted neoplastic transformation, whereas the knockdown of hCdc14A using small interfering RNA produced the opposite effects. Therefore, these findings provide novel evidence that hCdc14A might be involved in cell cycle regulation in cultured HBVECs during high glucose-, FFA-, and hypoxia-induced injury.

  7. Parkinson's disease-related perfusion and glucose metabolic brain patterns identified with PCASL-MRI and FDG-PET imaging

    Directory of Open Access Journals (Sweden)

    Laura K. Teune, MD, PhD

    2014-01-01

    Conclusion: We identified PD-related perfusion and metabolic brain patterns using PCASL and FDG-PET in the same patients which were comparable with results of existing research. In this respect, PCASL appears to be a promising addition in the early diagnosis of individual parkinsonian patients.

  8. 锌转运体8在胰岛功能和血糖稳态中的作用%The Role of Zinc Transporter 8 in Islet Function and Glucose Homeostasis

    Institute of Scientific and Technical Information of China (English)

    钱莉

    2011-01-01

    ZnT8( SLC30A8 )is a newly discovered islet-specific zinc transporter that controls zinc efflux into the extracellular matrix and intracellular vesicles to reduce the concentration of zinc in the cytoplasm.The polymorphism of the SLC30A8 gene is associated with susceptibility to type 2 diabetes. ZnT8 deletion decreased fasting and glucose - stimulated insulin secretion, however the blood glucose levels were not significantly changed in mice. In summary, SLC30A8 gene deletion is accompanied by a modest impairment in insulin secretion without major alterations in glucose metabolism.%锌转运体8(ZnT8)是新近发现的特异性高表达于胰岛的锌转运体,主要功能是参与锌在细胞内的区室化以及锌的外排,从而降低胞质内锌的浓度.同时,SLC30A8多态性影响2型糖尿病的易患性,与2型糖尿病的发病机制有关.虽然ZnT8全身剔除的小鼠空腹及葡萄糖刺激后胰岛素均减少,但血糖浓度无明显改变,表明了ZnT8的缺乏影响胰岛功能,而对全身血糖代谢的影响比较局限.

  9. Effects of High-Intensity Interval Exercise versus Moderate Continuous Exercise on Glucose Homeostasis and Hormone Response in Patients with Type 1 Diabetes Mellitus Using Novel Ultra-Long-Acting Insulin.

    Directory of Open Access Journals (Sweden)

    Othmar Moser

    Full Text Available We investigated blood glucose (BG and hormone response to aerobic high-intensity interval exercise (HIIE and moderate continuous exercise (CON matched for mean load and duration in type 1 diabetes mellitus (T1DM.Seven trained male subjects with T1DM performed a maximal incremental exercise test and HIIE and CON at 3 different mean intensities below (A and above (B the first lactate turn point and below the second lactate turn point (C on a cycle ergometer. Subjects were adjusted to ultra-long-acting insulin Degludec (Tresiba/ Novo Nordisk, Denmark. Before exercise, standardized meals were administered, and short-acting insulin dose was reduced by 25% (A, 50% (B, and 75% (C dependent on mean exercise intensity. During exercise, BG, adrenaline, noradrenaline, dopamine, cortisol, glucagon, and insulin-like growth factor-1, blood lactate, heart rate, and gas exchange variables were measured. For 24 h after exercise, interstitial glucose was measured by continuous glucose monitoring system.BG decrease during HIIE was significantly smaller for B (p = 0.024 and tended to be smaller for A and C compared to CON. No differences were found for post-exercise interstitial glucose, acute hormone response, and carbohydrate utilization between HIIE and CON for A, B, and C. In HIIE, blood lactate for A (p = 0.006 and B (p = 0.004 and respiratory exchange ratio for A (p = 0.003 and B (p = 0.003 were significantly higher compared to CON but not for C.Hypoglycemia did not occur during or after HIIE and CON when using ultra-long-acting insulin and applying our methodological approach for exercise prescription. HIIE led to a smaller BG decrease compared to CON, although both exercises modes were matched for mean load and duration, even despite markedly higher peak workloads applied in HIIE. Therefore, HIIE and CON could be safely performed in T1DM.ClinicalTrials.gov NCT02075567 http://www.clinicaltrials.gov/ct2/show/NCT02075567.

  10. Pre-symptomatic activation of antioxidant responses and alterations in glucose and pyruvate metabolism in Niemann-Pick Type C1-deficient murine brain.

    Directory of Open Access Journals (Sweden)

    Barry E Kennedy

    Full Text Available Niemann-Pick Type C (NPC disease is an autosomal recessive neurodegenerative disorder caused in most cases by mutations in the NPC1 gene. NPC1-deficiency is characterized by late endosomal accumulation of cholesterol, impaired cholesterol homeostasis, and a broad range of other cellular abnormalities. Although neuronal abnormalities and glial activation are observed in nearly all areas of the brain, the most severe consequence of NPC1-deficiency is a near complete loss of Purkinje neurons in the cerebellum. The link between cholesterol trafficking and NPC pathogenesis is not yet clear; however, increased oxidative stress in symptomatic NPC disease, increases in mitochondrial cholesterol, and alterations in autophagy/mitophagy suggest that mitochondria play a role in NPC disease pathology. Alterations in mitochondrial function affect energy and neurotransmitter metabolism, and are particularly harmful to the central nervous system. To investigate early metabolic alterations that could affect NPC disease progression, we performed metabolomics analyses of different brain regions from age-matched wildtype and Npc1 (-/- mice at pre-symptomatic, early symptomatic and late stage disease by (1H-NMR spectroscopy. Metabolic profiling revealed markedly increased lactate and decreased acetate/acetyl-CoA levels in Npc1 (-/- cerebellum and cerebral cortex at all ages. Protein and gene expression analyses indicated a pre-symptomatic deficiency in the oxidative decarboxylation of pyruvate to acetyl-CoA, and an upregulation of glycolytic gene expression at the early symptomatic stage. We also observed a pre-symptomatic increase in several indicators of oxidative stress and antioxidant response systems in Npc1 (-/- cerebellum. Our findings suggest that energy metabolism and oxidative stress may present additional therapeutic targets in NPC disease, especially if intervention can be started at an early stage of the disease.

  11. Ecrg4 expression and its product augurin in the choroid plexus: impact on fetal brain development, cerebrospinal fluid homeostasis and neuroprogenitor cell response to CNS injury

    Directory of Open Access Journals (Sweden)

    Gonzalez Ana

    2011-01-01

    Full Text Available Abstract Background The content and composition of cerebrospinal fluid (CSF is determined in large part by the choroid plexus (CP and specifically, a specialized epithelial cell (CPe layer that responds to, synthesizes, and transports peptide hormones into and out of CSF. Together with ventricular ependymal cells, these CPe relay homeostatic signals throughout the central nervous system (CNS and regulate CSF hydrodynamics. One new candidate signal is augurin, a newly recognized 14 kDa protein that is encoded by esophageal cancer related gene-4 (Ecrg4, a putative tumor suppressor gene whose presence and function in normal tissues remains unexplored and enigmatic. The aim of this study was to explore whether Ecrg4 and its product augurin, can be implicated in CNS development and the response to CNS injury. Methods Ecrg4 gene expression in CNS and peripheral tissues was studied by in situ hybridization and quantitative RT-PCR. Augurin, the protein encoded by Ecrg4, was detected by immunoblotting, immunohistochemistry and ELISA. The biological consequence of augurin over-expression was studied in a cortical stab model of rat CNS injury by intra-cerebro-ventricular injection of an adenovirus vector containing the Ecrg4 cDNA. The biological consequences of reduced augurin expression were evaluated by characterizing the CNS phenotype caused by Ecrg4 gene knockdown in developing zebrafish embryos. Results Gene expression and immunohistochemical analyses revealed that, the CP is a major source of Ecrg4 in the CNS and that Ecrg4 mRNA is predominantly localized to choroid plexus epithelial (CPe, ventricular and central canal cells of the spinal cord. After a stab injury into the brain however, both augurin staining and Ecrg4 gene expression decreased precipitously. If the loss of augurin was circumvented by over-expressing Ecrg4 in vivo, BrdU incorporation by cells in the subependymal zone decreased. Inversely, gene knockdown of Ecrg4 in developing

  12. Brain glucose metabolism is associated with hormone level in Cushing's disease: A voxel-based study using FDG-PET.

    Science.gov (United States)

    Liu, Shuai; Wang, Yinyan; Xu, Kaibin; Ping, Fan; Wang, Renzhi; Li, Fang; Cheng, Xin

    2016-01-01

    Chronic exposure to elevated levels of glucocorticoids can exert a neurotoxic effect in patients, possibly manifesting as molecular imaging alterations in patients. The aim of this study was to investigate the potential association between brain metabolism and elevated hormone level using (18)F-fluorodeoxyglucose positron emission tomography. We retrospectively enrolled 92 consecutive patients with confirmed diagnosis of Cushing's disease. A voxel-based analysis was performed to investigate the association between cerebral (18)F-fluorodeoxyglucose uptake and serum cortisol level. Relatively impaired metabolism of specific brain regions correlated with serum cortisol level was found. Specifically, notable correlations were found in the hippocampus, amygdala, and cerebellum, regions considered to be involved in the regulation and central action of glucocorticoids. Moreover, some hormone-associated regions were found in the frontal and occipital cortex, possibly mediating the cognitive changes seen in Cushing's disease. Our findings link patterns of perturbed brain metabolism relates to individual hormone level, thus presenting a substrate for cognitive disturbances seen in Cushing's disease patients, as well as in other conditions with abnormal cortisol levels.

  13. Brain glucose metabolism is associated with hormone level in Cushing's disease: A voxel-based study using FDG-PET.

    Science.gov (United States)

    Liu, Shuai; Wang, Yinyan; Xu, Kaibin; Ping, Fan; Wang, Renzhi; Li, Fang; Cheng, Xin

    2016-01-01

    Chronic exposure to elevated levels of glucocorticoids can exert a neurotoxic effect in patients, possibly manifesting as molecular imaging alterations in patients. The aim of this study was to investigate the potential association between brain metabolism and elevated hormone level using (18)F-fluorodeoxyglucose positron emission tomography. We retrospectively enrolled 92 consecutive patients with confirmed diagnosis of Cushing's disease. A voxel-based analysis was performed to investigate the association between cerebral (18)F-fluorodeoxyglucose uptake and serum cortisol level. Relatively impaired metabolism of specific brain regions correlated with serum cortisol level was found. Specifically, notable correlations were found in the hippocampus, amygdala, and cerebellum, regions considered to be involved in the regulation and central action of glucocorticoids. Moreover, some hormone-associated regions were found in the frontal and occipital cortex, possibly mediating the cognitive changes seen in Cushing's disease. Our findings link patterns of perturbed brain metabolism relates to individual hormone level, thus presenting a substrate for cognitive disturbances seen in Cushing's disease patients, as well as in other conditions with abnormal cortisol levels. PMID:27622138

  14. Impaired glucose metabolism treatment and carcinogenesis

    OpenAIRE

    MATYSZEWSKI, ARTUR; Czarnecka, Anna; Kawecki, Maciej; KORZEŃ, PIOTR; SAFIR, ILAN J.; Kukwa, Wojciech; SZCZYLIK, CEZARY

    2015-01-01

    Carbohydrate metabolism disorders increase the risk of carcinogenesis. Diabetes mellitus alters numerous physiological processes that may encourage cancer growth. However, treating impaired glucose homeostasis may actually promote neoplasia; maintaining proper glucose plasma concentrations reduces metabolic stresses, however, certain medications may themselves result in oncogenic effects. A number of previous studies have demonstrated that metformin reduces the cancer risk. However, the use o...

  15. The effect of fat removal on glucose tolerance is depot specific in male and female mice.

    Science.gov (United States)

    Shi, Haifei; Strader, April D; Woods, Stephen C; Seeley, Randy J

    2007-10-01

    Energy is stored predominately as lipid in white adipose tissue (WAT) in distinct anatomical locations, with each site exerting different effects on key biological processes, including glucose homeostasis. To determine the relative contributions of subcutaneous and visceral WAT on glucose homeostasis, comparable amounts of adipose tissue from abdominal subcutaneous inguinal WAT (IWAT), intra-abdominal retroperitoneal WAT (RWAT), male gonadal epididymal WAT (EWAT), or female gonadal parametrial WAT (PWAT) were removed. Gonadal fat removal in both male and female chow-fed lean mice resulted in lowered glucose levels across glucose tolerance tests. Female lean C57BL/6J mice as well as male and female lean FVBN mice significantly improved glucose tolerance, indicated by decreased areas under glucose clearance curves. For the C57BL/6J mice maintained on a high-fat butter-based diet, glucose homeostasis was improved only in female mice with PWAT removal. Removal of IWAT or RWAT did not affect glucose tolerance in either dietary condition. We conclude that WAT contribution to glucose homeostasis is depot specific, with male gonadal EWAT contributing to glucose homeostasis in the lean state, whereas female gonadal PWAT contributes to glucose homeostasis in both lean and obese mice. These data illustrate both critical differences among various WAT depots and how they influence glucose homeostasis and highlight important differences between males and females in glucose regulation. PMID:17652151

  16. Oxygen-glucose deprivation increases the enzymatic activity and the microvesicle-mediated release of ectonucleotidases in the cells composing the blood-brain barrier.

    Science.gov (United States)

    Ceruti, Stefania; Colombo, Laura; Magni, Giulia; Viganò, Francesca; Boccazzi, Marta; Deli, Mária A; Sperlágh, Beáta; Abbracchio, Maria P; Kittel, Agnes

    2011-08-01

    The blood-brain barrier (BBB), the dynamic interface between the nervous tissue and the blood, is composed by endothelial cells, pericytes and astrocytes. Extracellular nucleotides and nucleosides and their receptors (the purinergic system) constitute a widely diffused signaling system involved in many pathophysiological processes. However, the role of this system in controlling BBB functions is still largely unknown. By using cultures of these three cell types grown separately and a BBB in vitro model consisting of triple co-cultures, we studied for the first time the expression and distribution of the ecto-enzymes nucleoside triphosphate diphosphohydrolases (NTPDases, the enzymes which hydrolyze extracellular nucleotides) under control and ischemic (oxygen-glucose deprivation in vitro; OGD) conditions. NTPDase1 was detected in all three cell types, whereas NTPDase2 was expressed by astrocytes and pericytes and, to a lesser extent, by endothelial cells. Endothelial cells were extremely susceptible to cell death when OGD was applied to mimic in vitro the cytotoxicity induced by ischemia, whereas astrocytes and pericytes were more resistant. A semi-quantitative assay highlighted markedly increased e-ATPase activity following exposure to OGD in all three cell types, either when grown separately or when co-cultured together to resemble the composition of the BBB. Moreover, electron microscopy analysis showed that both endothelial cells and astrocytes shed microvesicles containing NTPDases from their membrane, which may suggest a novel mechanism to increase the breakdown of ATP released to toxic levels by damaged BBB cells. We hypothesize that this phenomenon could have a protective and/or modulatory effect for brain parenchymal cells. This in vitro model is therefore useful to study the role of extracellular nucleotides in modulating BBB responses to ischemic events, and to develop new effective purinergic-based approaches for brain ischemia.

  17. Comparing amyloid-β deposition, neuroinflammation, glucose metabolism, and mitochondrial complex I activity in brain: a PET study in aged monkeys

    Energy Technology Data Exchange (ETDEWEB)

    Tsukada, Hideo; Nishiyama, Shingo; Ohba, Hiroyuki; Kanazawa, Masakatsu; Kakiuchi, Takeharu; Harada, Norihiro [Hamamatsu Photonics K.K., Central Research Laboratory, Shizuoka (Japan)

    2014-11-15

    The aim of the present study was to compare amyloid-β (Aβ) deposition, translocator protein (TSPO) activity, regional cerebral metabolic rate of glucose (rCMRglc), and mitochondrial complex I (MC-I) activity in the brain of aged monkeys. PET scans with {sup 11}C-PIB (Aβ), {sup 18}F-BCPP-EF (MC-I), {sup 11}C-DPA-713 (TSPO), and {sup 18}F-FDG (rCMRglc) were performed in aged monkeys (Macaca mulatta) in the conscious state and under isoflurane anaesthesia. {sup 11}C-PIB binding to Aβ and {sup 11}C-DPA-713 binding to TSPO were evaluated in terms of standard uptake values (SUV). The total volume of distribution (V{sub T}) of {sup 18}F-BCPP-EF and rCMRglc with {sup 18}F-FDG were calculated using arterial blood sampling. Isoflurane did not affect MC-I activity measured in terms of {sup 18}F-BCPP-EF uptake in living brain. There was a significant negative correlation between {sup 18}F-BCPP-EF binding (V{sub T}) and {sup 11}C-PIB uptake (SUVR), and there was a significant positive correlation between {sup 11}C-DPA-713 uptake (SUV) and {sup 11}C-PIB uptake. In contrast, there was no significant correlation between rCMRglc ratio and {sup 11}C-PIB uptake. {sup 18}F-BCPP-EF could be a potential PET probe for quantitative imaging of impaired MC-I activity that is correlated with Aβ deposition in the living brain. (orig.)

  18. Glucose rapidly induces different forms of excitatory synaptic plasticity in hypothalamic POMC neurons.

    Directory of Open Access Journals (Sweden)

    Jun Hu

    Full Text Available Hypothalamic POMC neurons are required for glucose and energy homeostasis. POMC neurons have a wide synaptic connection with neurons both within and outside the hypothalamus, and their activity is controlled by a balance between excitatory and inhibitory synaptic inputs. Brain glucose-sensing plays an essential role in the maintenance of normal body weight and metabolism; however, the effect of glucose on synaptic transmission in POMC neurons is largely unknown. Here we identified three types of POMC neurons (EPSC(+, EPSC(-, and EPSC(+/- based on their glucose-regulated spontaneous excitatory postsynaptic currents (sEPSCs, using whole-cell patch-clamp recordings. Lowering extracellular glucose decreased the frequency of sEPSCs in EPSC(+ neurons, but increased it in EPSC(- neurons. Unlike EPSC(+ and EPSC(- neurons, EPSC(+/- neurons displayed a bi-phasic sEPSC response to glucoprivation. In the first phase of glucoprivation, both the frequency and the amplitude of sEPSCs decreased, whereas in the second phase, they increased progressively to the levels above the baseline values. Accordingly, lowering glucose exerted a bi-phasic effect on spontaneous action potentials in EPSC(+/- neurons. Glucoprivation decreased firing rates in the first phase, but increased them in the second phase. These data indicate that glucose induces distinct excitatory synaptic plasticity in different subpopulations of POMC neurons. This synaptic remodeling is likely to regulate the sensitivity of the melanocortin system to neuronal and hormonal signals.

  19. Glucose Tests

    Science.gov (United States)

    ... be limited. Home Visit Global Sites Search Help? Glucose Tests Share this page: Was this page helpful? ... the meaning of other test results. Fasting Blood Glucose Glucose Level Indication From 70 to 99 mg/ ...

  20. Is cerebral glucose metabolism related to blood-brain barrier dysfunction and intrathecal IgG synthesis in Alzheimer disease?: A 18F-FDG PET/CT study.

    Science.gov (United States)

    Chiaravalloti, Agostino; Fiorentini, Alessandro; Francesco, Ursini; Martorana, Alessandro; Koch, Giacomo; Belli, Lorena; Torniolo, Sofia; Di Pietro, Barbara; Motta, Caterina; Schillaci, Orazio

    2016-09-01

    The aim of this study was to investigate the relationships between blood-brain barrier (BBB) dysfunction, intrathecal IgG synthesis, and brain glucose consumption as detectable by means of serum/cerebrospinal fluid (CSF) albumin index (Qalb) and IgG index [(CSF IgG/serum IgG) × Serum albumin/CSF albumin)] and 2-deoxy-2-(F) fluoro-D-glucose (F-FDG) positron emission tomography/computed tomography (PET/CT) in a selected population affected by Alzheimer disease (AD). The study included 134 newly diagnosed AD patients according to the NINCDS-ADRDA criteria. The mean (±SD) age of the patients was 70 (±6) years; 60 were male and 64 were female. Mini mental State Examination was equal to 18.9 (±7.2). All patients underwent a CSF assay and magnetic resonance before F-FDG PET scanning. The relationships were evaluated by means of statistical parametric mapping (SPM8). We found a significant negative correlation between the increase of Qalb and F-FDG uptake in the Brodmann Area 42 and 22 that corresponds to the left superior temporal gyrus, with higher Qalb values being related to a reduced glucose consumption in these areas. No significant relationships have been found between brain glucose consumption and IgG index. The results of our study suggest that BBB dysfunction is related to reduction of cortical activity in the left temporal cortex in AD subjects. PMID:27631200

  1. Brain glucose metabolism in the early and specific diagnosis of Alzheimer's disease. FDG-PET studies in MCI and AD

    Energy Technology Data Exchange (ETDEWEB)

    Mosconi, Lisa [University of Florence, Department of Clinical Pathophysiology, Nuclear Medicine Unit (Italy); University School of Medicine, Center for Brain Health, MHL400, Department of Psychiatry New York, New York, NY (United States)

    2005-04-01

    The demographics of aging suggest a great need for the early diagnosis of dementia and the development of preventive strategies. Neuropathology and structural MRI studies have pointed to the medial temporal lobe (MTL) as the brain region earliest affected in Alzheimer's disease (AD). MRI findings provide strong evidence that in mild cognitive impairments (MCI), AD-related volume losses can be reproducibly detected in the hippocampus, the entorhinal cortex (EC) and, to a lesser extent, the parahippocampal gyrus; they also indicate that lateral temporal lobe changes are becoming increasingly useful in predicting the transition to dementia. Fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) imaging has revealed glucose metabolic reductions in the parieto-temporal, frontal and posterior cingulate cortices to be the hallmark of AD. Overall, the pattern of cortical metabolic changes has been useful for the prediction of future AD as well as in distinguishing AD from other neurodegenerative diseases. FDG-PET on average achieves 90% sensitivity in identifying AD, although specificity in differentiating AD from other dementias is lower. Moreover, recent MRI-guided FDG-PET studies have shown that MTL hypometabolism is the most specific and sensitive measure for the identification of MCI, while the utility of cortical deficits is controversial. This review highlights cross-sectional, prediction and longitudinal FDG-PET studies and attempts to put into perspective the value of FDG-PET in diagnosing AD-like changes, particularly at an early stage, and in providing diagnostic specificity. The examination of MTL structures, which has so far been exclusive to MRI protocols, is then examined as a possible strategy to improve diagnostic specificity. All told, there is considerable promise that early and specific diagnosis is feasible through a combination of imaging modalities. (orig.)

  2. FDG-PET changes in brain glucose metabolism from normal cognition to pathologically verified Alzheimer's disease

    Energy Technology Data Exchange (ETDEWEB)

    Mosconi, Lisa [New York University School of Medicine, Department of Psychiatry, New York (United States); New York University School of Medicine, Center for Brain Health, MHL 400, New York, NY (United States); Mistur, Rachel; Switalski, Remigiusz; Glodzik, Lidia; Li, Yi; Pirraglia, Elizabeth; De Santi, Susan; Reisberg, Barry [New York University School of Medicine, Department of Psychiatry, New York (United States); Tsui, Wai Hon; De Leon, Mony J. [New York University School of Medicine, Department of Psychiatry, New York (United States); Nathan Kline Institute, Orangeburg, NY (United States); Wisniewski, Thomas [New York University School of Medicine, Department of Psychiatry, New York (United States); New York University School of Medicine, Department of Neurology, New York (United States); New York University School of Medicine, Department of Pathology, New York (United States)

    2009-05-15

    We report the first clinicopathological series of longitudinal FDG-PET scans in post-mortem (PM) verified cognitively normal elderly (NL) followed to the onset of Alzheimer's-type dementia (DAT), and in patients with mild DAT with progressive cognitive deterioration. Four NL subjects and three patients with mild DAT received longitudinal clinical, neuropsychological and dynamic FDG-PET examinations with arterial input functions. NL subjects were followed for 13 {+-} 5 years, received FDG-PET examinations over 7 {+-} 2 years, and autopsy 6 {+-} 3 years after the last FDG-PET. Two NL declined to mild cognitive impairment (MCI), and two developed probable DAT before death. DAT patients were followed for 9 {+-} 3 years, received FDG-PET examinations over 3 {+-} 2 years, and autopsy 7 {+-} 1 years after the last FDG-PET. Two DAT patients progressed to moderate-to-severe dementia and one developed vascular dementia. The two NL subjects who declined to DAT received a PM diagnosis of definite AD. Their FDG-PET scans indicated a progression of deficits in the cerebral metabolic rate for glucose (CMRglc) from the hippocampus to the parietotemporal and posterior cingulate cortices. One DAT patient showed AD with diffuse Lewy body disease (LBD) at PM, and her last in vivo PET was indicative of possible LBD for the presence of occipital as well as parietotemporal hypometabolism. Progressive CMRglc reductions on FDG-PET occur years in advance of clinical DAT symptoms in patients with pathologically verified disease. The FDG-PET profiles in life were consistent with the PM diagnosis. (orig.)

  3. Effects of taurine supplementation and swimming, associated or not, on obesity and glucose homeostasis in mice = Efeito da suplementação com taurina e da natação, associadas ou não, sobre a obesidade e homeostase glicêmica em camundongos

    Directory of Open Access Journals (Sweden)

    Iris Cheng

    2012-10-01

    Full Text Available . Studies show that physical exercise (PE is associated with a reduced fat accumulation and increased insulin sensitivity, and taurine (TAU improves glucose homeostasis in lean rodents. The aim in this work was evaluate the effects of supplementing TAU and practice of PE, associated or not, on obesity and glucose homeostasis on obese MSG-mice. Neonate male Swiss mice received injections of monosodium glutamate (MSG group or saline (CON group. From the 30th to the 90th day of life, one group of animals received TAU in drinking water (MSG TAU group, another was subjected to PE (MSG PE group and a third group underwent both procedures (MSG PE TAU group. Mice treated with MSG become obese, hypertriglyceridemic, glucose intolerant and insulin resistant. The supplementation with TAU and the PE, isolated or associated, reduced the triglycerides (38%, glucose intolerance (around 30% and KITT (79% in MSG-obese animals, but did not influence the accumulation of fat. Interestingly, the combination of both strategies significantly reduced the insulin resistance, compared to animals subjected to isolated strategies. In conclusion, the supplementation with TAU and PE, isolated or associated, did not influence the accumulation of fat in MSG-obese mice, however, reduce the triglycerides and insulin resistance. O exercício físico (EF está associado à redução do acúmulo de gordura e aumento na sensibilidade à insulina e a taurina (TAU melhora a homeostase glicêmica em roedores magros. Objetivou-se avaliar os efeitos da suplementação com TAU e do EF, associados ou não, sobre a obesidade e a homeostase glicêmica em camundongos obesos-MSG. Camundongos Swiss machos neonatos receberam injeções de glutamato monossódico (grupo MSG ou salina (grupo CON. Do 30º ao 90º dia de vida, um grupo de animais MSG recebeu TAU na água de beber (MSG TAU; outro foi submetido ao EF (MSG EX e um terceiro grupo foi submetido aos dois procedimentos (MSG EX TAU

  4. Alcohol disrupts sleep homeostasis.

    Science.gov (United States)

    Thakkar, Mahesh M; Sharma, Rishi; Sahota, Pradeep

    2015-06-01

    Alcohol is a potent somnogen and one of the most commonly used "over the counter" sleep aids. In healthy non-alcoholics, acute alcohol decreases sleep latency, consolidates and increases the quality (delta power) and quantity of NREM sleep during the first half of the night. However, sleep is disrupted during the second half. Alcoholics, both during drinking periods and during abstinences, suffer from a multitude of sleep disruptions manifested by profound insomnia, excessive daytime sleepiness, and altered sleep architecture. Furthermore, subjective and objective indicators of sleep disturbances are predictors of relapse. Finally, within the USA, it is estimated that societal costs of alcohol-related sleep disorders exceeds $18 billion. Thus, although alcohol-associated sleep problems have significant economic and clinical consequences, very little is known about how and where alcohol acts to affect sleep. In this review, we have described our attempts to unravel the mechanism of alcohol-induced sleep disruptions. We have conducted a series of experiments using two different species, rats and mice, as animal models. We performed microdialysis, immunohistochemical, pharmacological, sleep deprivation and lesion studies which suggest that the sleep-promoting effects of alcohol may be mediated via alcohol's action on the mediators of sleep homeostasis: adenosine (AD) and the wake-promoting cholinergic neurons of the basal forebrain (BF). Alcohol, via its action on AD uptake, increases extracellular AD resulting in the inhibition of BF wake-promoting neurons. Since binge alcohol consumption is a highly prevalent pattern of alcohol consumption and disrupts sleep, we examined the effects of binge drinking on sleep-wakefulness. Our results suggest that disrupted sleep homeostasis may be the primary cause of sleep disruption observed following binge drinking. Finally, we have also shown that sleep disruptions observed during acute withdrawal, are caused due to impaired

  5. Water Homeostasis: Evolutionary Medicine

    OpenAIRE

    Zeidel, Mark L.

    2012-01-01

    As a major component of homeostasis, all organisms regulate the water composition of various compartments. Through the selective use of barrier membranes and surface glycoproteins, as well as aquaporin water channels, organisms ranging from Archaebacteria to humans can vary water permeabilities across their cell membranes by 4 to 5 orders of magnitude. In barrier epithelia the outer, or exofacial, leaflet acts as the main resistor to water flow; this leaflet restricts water flow by minimizing...

  6. Glucose Sensing

    CERN Document Server

    Geddes, Chris D

    2006-01-01

    Topics in Fluorescence Spectroscopy, Glucose Sensing is the eleventh volume in the popular series Topics in Fluorescence Spectroscopy, edited by Drs. Chris D. Geddes and Joseph R. Lakowicz. This volume incorporates authoritative analytical fluorescence-based glucose sensing reviews specialized enough to be attractive to professional researchers, yet also appealing to the wider audience of scientists in related disciplines of fluorescence. Glucose Sensing is an essential reference for any lab working in the analytical fluorescence glucose sensing field. All academics, bench scientists, and industry professionals wishing to take advantage of the latest and greatest in the continuously emerging field of glucose sensing, and diabetes care & management, will find this volume an invaluable resource. Topics in Fluorescence Spectroscopy Volume 11, Glucose Sensing Chapters include: Implantable Sensors for Interstitial Fluid Smart Tattoo Glucose Sensors Optical Enzyme-based Glucose Biosensors Plasmonic Glucose Sens...

  7. Homeostasis Hombre-Naturaleza

    Directory of Open Access Journals (Sweden)

    Stephano Betancourt

    2016-06-01

    Full Text Available La tendencia al equilibrio en la naturaleza y el flujo energético entre los organismos y suambiente; resulta de vital importancia para la supervivencia de estos últimos. Cuando seda una mirada antropocéntrica a esta interacción, se genera un enfoque reduccionista de losfactores que influyen para mantener la tendencia al equilibrio. Por consiguiente, el sostenerlo inteligible de las interacciones de los elementos que conforman nuestra existencia es unpunto clave de la compleja relación, entre el ser humano y su entorno, para poder permitiruna homeostasis entre ellos.

  8. G-CSF Protects Human Brain Vascular Endothelial Cells Injury Induced by High Glucose, Free Fatty Acids and Hypoxia through MAPK and Akt Signaling

    Science.gov (United States)

    Tao, Yinghong; Guo, Jingchun; Guo, Zhuangli; Zhang, Shuo; Zhang, Yu; Huang, Yanyan; Tang, Yuping; Dong, Qiang; Hu, Renming

    2015-01-01

    Granulocyte-colony stimulating factor (G-CSF) has been shown to play a neuroprotective role in ischemic stroke by mobilizing bone marrow (BM)-derived endothelial progenitor cells (EPCs), promoting angiogenesis, and inhibiting apoptosis. Impairments in mobilization and function of the BM-derived EPCs have previously been reported in animal and human studies of diabetes where there is both reduction in the levels of the BM-derived EPCs and its ability to promote angiogenesis. This is hypothesized to account for the pathogenesis of diabetic vascular complications such as stroke. Here, we sought to investigate the effects of G-CSF on diabetes-associated cerebral vascular defect. We observed that pretreatment of the cultured human brain vascular endothelial cells (HBVECs) with G-CSF largely prevented cell death induced by the combination stimulus with high glucose, free fatty acids (FFA) and hypoxia by increasing cell viability, decreasing apoptosis and caspase-3 activity. Cell ultrastructure measured by transmission electron microscope (TEM) revealed that G-CSF treatment nicely reduced combination stimulus-induced cell apoptosis. The results from fluorescent probe Fluo-3/AM showed that G-CSF greatly suppressed the levels of intracellular calcium ions under combination stimulus. We also found that G-CSF enhanced the expression of cell cycle proteins such as human cell division cycle protein 14A (hCdc14A), cyclinB and cyclinE, inhibited p53 activity, and facilitated cell cycle progression following combination stimulus. In addition, activation of extracellular signal-regulated kinase1/2 (ERK1/2) and Akt, and deactivation of c-Jun N terminal kinase (JNK) and p38 were proved to be required for the pro-survival effects of G-CSF on HBVECs exposed to combination stimulus. Overall, G-CSF is capable of alleviating HBVECs injury triggered by the combination administration with high glucose, FFA and hypoxia involving the mitogen-activated protein kinases (MAPK) and Akt signaling

  9. Dynamic modulation of intracellular glucose imaged in single cells using a FRET-based glucose nanosensor

    OpenAIRE

    John, Scott A.; Ottolia, Michela; James N Weiss; Ribalet, Bernard

    2007-01-01

    To study intracellular glucose homeostasis, the glucose nanosensor FLIPglu-600µM, which undergoes changes in fluorescence resonance energy transfer (FRET) upon interaction with glucose, was expressed in four mammalian cell lines: COS-7, CHO, HEK293, and C2C12. Upon addition of extracellular glucose, the intracellular FRET ratio decreased rapidly as intracellular glucose increased. The kinetics were fast (τ =5 to 15 s) in COS and C2C12 cells and slow (τ =20 to 40 s) in HEK and CHO cells. Upon ...

  10. Effect of latent asymptomatic toxoplasmosis on glucose metabolism in brain of mice%弓形虫慢性感染对小鼠脑内葡萄糖代谢影响的研究

    Institute of Scientific and Technical Information of China (English)

    周永华; 黄洪波; 陶永辉; 俞惠新; 许永良; 张英; 高琪

    2011-01-01

    Objective To explore the effect of latent asymptomatic Toxoplasma gondii infection on glucose metabolism in brain of mice. Methods Twenty mice were randomly divided into two groups: a Toxoplasma infected group and normal control group. The mice in the Toxoplasma infected group were inoculated with 0.3 ml of brain suspension in saline containing ten Toxoplasma gondii tissue cysts, avirulent Toxoplasma gondii Prugniaud (PRU, a Type II strain). The mice in the control group received 0.3 ml of saline orally. Six monthes after the infection, the glucose metabolism changes in the mouse brain were evaluated by Mi-croPET, then all the mice were sacrificed and the brain tissues were observed histopathologically. Results Compared with the normal controls, the infected mice demonstrated profound and widespread brain pathology, and MicroPET indicated a significant glucose metabolism reduction in the brain of asymptomatic Toxoplasma gondii infected mice. Conclusion Chronic Toxoplasma gondii infection maybe results in the glucose metabolism reduction in the brain of mice.%目的 探讨弓形虫慢性感染对小鼠脑内葡萄糖代谢的影响.方法 将30只SPF级ICR小鼠随机分成弓形虫感染组和正常对照组,感染组每只小鼠口服感染弓形虫PRU株包囊悬液0.3 ml(含包囊10个),对照组口服0.3 ml生理盐水.小鼠感染弓形虫6个月后,应用MicroPET扫描脑内葡萄糖代谢,结束后解剖小鼠进行脑组织病理学观察.结果 与正常对照组小鼠相比,弓形虫慢性感染6个月后,“无症状”的感染小鼠脑内葡萄糖代谢均显著下降,脑组织中可见大小不一、数量不等的包囊,脑膜下有大量淋巴细胞浸润、血管充血、小血管淋巴细胞袖管形成.结论 弓形虫慢性感染可造成宿主脑内葡萄糖代谢下降,神经元变性或细胞丢失.

  11. Acid-Base Homeostasis.

    Science.gov (United States)

    Hamm, L Lee; Nakhoul, Nazih; Hering-Smith, Kathleen S

    2015-12-01

    Acid-base homeostasis and pH regulation are critical for both normal physiology and cell metabolism and function. The importance of this regulation is evidenced by a variety of physiologic derangements that occur when plasma pH is either high or low. The kidneys have the predominant role in regulating the systemic bicarbonate concentration and hence, the metabolic component of acid-base balance. This function of the kidneys has two components: reabsorption of virtually all of the filtered HCO3(-) and production of new bicarbonate to replace that consumed by normal or pathologic acids. This production or generation of new HCO3(-) is done by net acid excretion. Under normal conditions, approximately one-third to one-half of net acid excretion by the kidneys is in the form of titratable acid. The other one-half to two-thirds is the excretion of ammonium. The capacity to excrete ammonium under conditions of acid loads is quantitatively much greater than the capacity to increase titratable acid. Multiple, often redundant pathways and processes exist to regulate these renal functions. Derangements in acid-base homeostasis, however, are common in clinical medicine and can often be related to the systems involved in acid-base transport in the kidneys.

  12. Ageing and water homeostasis

    Science.gov (United States)

    Robertson, David; Jordan, Jens; Jacob, Giris; Ketch, Terry; Shannon, John R.; Biaggioni, Italo

    2002-01-01

    This review outlines current knowledge concerning fluid intake and volume homeostasis in ageing. The physiology of vasopressin is summarized. Studies have been carried out to determine orthostatic changes in plasma volume and to assess the effect of water ingestion in normal subjects, elderly subjects, and patients with dysautonomias. About 14% of plasma volume shifts out of the vasculature within 30 minutes of upright posture. Oral ingestion of water raises blood pressure in individuals with impaired autonomic reflexes and is an important source of noise in blood pressure trials in the elderly. On the average, oral ingestion of 16 ounces (473ml) of water raises blood pressure 11 mmHg in elderly normal subjects. In patients with autonomic impairment, such as multiple system atrophy, strikingly exaggerated pressor effects of water have been seen with blood pressure elevations greater than 75 mmHg not at all uncommon. Ingestion of water is a major determinant of blood pressure in the elderly population. Volume homeostasis is importantly affected by posture and large changes in plasma volume may occur within 30 minutes when upright posture is assumed.

  13. Phospholipase D1 Mediates AMP-Activated Protein Kinase Signaling for Glucose Uptake

    OpenAIRE

    Jong Hyun Kim; Ji-Man Park; Kyungmoo Yea; Hyun Wook Kim; Pann-Ghill Suh; Sung Ho Ryu

    2010-01-01

    BACKGROUND: Glucose homeostasis is maintained by a balance between hepatic glucose production and peripheral glucose utilization. In skeletal muscle cells, glucose utilization is primarily regulated by glucose uptake. Deprivation of cellular energy induces the activation of regulatory proteins and thus glucose uptake. AMP-activated protein kinase (AMPK) is known to play a significant role in the regulation of energy balances. However, the mechanisms related to the AMPK-mediated control of glu...

  14. Autophagy and intestinal homeostasis.

    Science.gov (United States)

    Patel, Khushbu K; Stappenbeck, Thaddeus S

    2013-01-01

    Nutrient absorption is the basic function that drives mammalian intestinal biology. To facilitate nutrient uptake, the host's epithelial barrier is composed of a single layer of cells. This constraint is problematic, as a design of this type can be easily disrupted. The solution during the course of evolution was to add numerous host defense mechanisms that can help prevent local and systemic infection. These mechanisms include specialized epithelial cells that produce a physiochemical barrier overlying the cellular barrier, robust and organized adaptive and innate immune cells, and the ability to mount an inflammatory response that is commensurate with a specific threat level. The autophagy pathway is a critical cellular process that strongly influences all these functions. Therefore, a fundamental understanding of the components of this pathway and their influence on inflammation, immunity, and barrier function will facilitate our understanding of homeostasis in the gastrointestinal tract. PMID:23216414

  15. Astrocytes revisited: concise historic outlook on glutamate homeostasis and signaling

    OpenAIRE

    Parpura, Vladimir; VERKHRATSKY, ALEXEI

    2012-01-01

    Astroglia is a main type of brain neuroglia, which includes many cell sub-types that differ in their morphology and physiological properties and yet are united by the main function, which is the maintenance of brain homeostasis. Astrocytes employ a variety of mechanisms for communicating with neuronal networks. The communication mediated by neurotransmitter glutamate has received a particular attention. Glutamate is de novo synthesized exclusively in astrocytes; astroglia-derived glutamine is...

  16. Active transport of C-11-Methyl-D-Glucose and 3-F-18-Deoxyglucose in acute ischemic brain disease and Huntington's chorea, studied by positron-emission-tomography (PET)

    International Nuclear Information System (INIS)

    C-11-Methyl-D-Glucose (CMG) and 3-F-18-Deoxyglucose (3FDG) were demonstrated to be non-metabolizable glucose analogues which are transported across the blood-brain-barrier into and out of tissue via the glucose carrier system (GCS). These two substances were used as indicators for determining the perfusion-independent rate constant of GCS in the brain. Five normals with informed consent, 12 patients with acute ischemic brain disease and 9 patients with initial and advanced Huntington's chorea were examined by PET after i.v. application of 5 mCi of GMG or 3FDG. In each patient 30 transaxial images were registered in 1 selected plane, image collection time being 1 min. Time-activity curves were created from different regions of interest. The slope to tracer steady state between tissue and blood yields the perfusion-independent rate constant of GCS from tissue to blood (k/sub 2/). In normals k/sub 2/ for CMG was 0.235 +- 0.03/min, as expected, and for 3FDG 0.47 +- 0.07/min indicating a higher affinity to GCS for 3FDG than CMG. In acute ischemic brain disease k/sub 2/ was normal or reduced at the site of insult for both CMG and 3FDG. In Huntington's chorea, k/sub 2/ was reduced in the basal ganglia but normal or occasionally significantly increased in frontal or occipital cortical areas, for CMG and 3FDG. The authors conclude that CMG permits noninvasive analysis of the perfusion-independent rate constant of CCS. 3FDG shows a higher affinity for CCS than CMC but gives comparable information

  17. The hypothalamic clock and its control of glucose homeostasis

    NARCIS (Netherlands)

    A. Kalsbeek; C.X. Yi; S.E. la Fleur; E. Fliers

    2010-01-01

    The everyday life of mammals, including humans, exhibits many behavioral, physiological and endocrine oscillations. The major timekeeping mechanism for these rhythms is contained in the central nervous system (CNS). The output of the CNS clock not only controls daily rhythms in sleep/wake (or feedin

  18. Glucagon-like peptide-1, glucose homeostasis and diabetes

    DEFF Research Database (Denmark)

    Holst, Jens Juul; Deacon, Carolyn F; Vilsbøll, Tina;

    2008-01-01

    pancreatic beta cells, and inhibits glucagon secretion, gastric emptying and food intake, leading to weight loss. GLP-1 mimetics, which are stable-peptide-based activators of the GLP-1 receptor, and incretin enhancers, which inhibit the incretin-degrading enzyme dipeptidyl peptidase-4, have emerged...

  19. Glucose Homeostasis and Sympathoadrenal Activity in Mercaptoacetate-Treated Rats

    NARCIS (Netherlands)

    Dijk, Gertjan van; Scheurink, Anton; Ritter, Sue; Steffens, Anton

    1995-01-01

    The effect of the fatty acid oxidation inhibitor, sodium mercaptoacetate (MA, 600 µmol/kg) on peripheral energy substrate metabolism was investigated in rats with permanent heart catheters. Rats were either fed, 48-h food deprived, or exercising for 30 min. Before and after intravenous MA injection,

  20. Change in hexose distribution volume and fractional utilization of ( sup 18 F)-2-deoxy-2-fluoro-D-glucose in brain during acute hypoglycemia in humans

    Energy Technology Data Exchange (ETDEWEB)

    Shapiro, E.T.; Cooper, M.; Chen, C.T.; Given, B.D.; Polonsky, K.S. (Univ. of Chicago, IL (USA))

    1990-02-01

    We used positron emission tomography (PET) to study the effects of mild hypoglycemia on cerebral glucose uptake and metabolism. Nine healthy men were studied under basal saline-infusion conditions, and during euglycemic and hypoglycemic clamp studies. Insulin was infused at the same rate (1 mU.kg-1.min-1) in both clamp studies. In euglycemic clamp studies, glucose was infused at a rate sufficient to maintain the basal plasma glucose concentration, whereas in hypoglycemic clamp studies, the glucose infusion rate was reduced to maintain the plasma glucose at 3.1 mM. Each study lasted 3 h and included a 30-min baseline period and a subsequent 150-min period in which insulin or glucose was administered. Blood samples for measurement of insulin, glucose, cortisol, growth hormone, and glucagon were obtained at 20- to 30-min intervals. A bolus injection of 5-10 mCi (18F)-2-deoxy-2-fluoro-D-glucose (2-DFG) was administered 120 min after initiation of the study, and plasma radioactivity and dynamic PET scans were obtained at frequent intervals for the remaining 40-60 min of the study. Cerebral regions of interest were defined, and concentrations of radioactivity were calculated and used in the three-compartment model of 2-DFG distribution described by Sokoloff. Glucose levels were similar during saline-infusion (4.9 +/- 0.1 mM) and euglycemic clamp (4.8 +/- 0.1 mM) studies, whereas the desired degree of mild hypoglycemia was achieved during the hypoglycemic clamp study (3.1 +/- 0.1 mM, P less than 0.05). The insulin level during saline infusion was 41 +/- 7 pM.

  1. Change in hexose distribution volume and fractional utilization of [18F]-2-deoxy-2-fluoro-D-glucose in brain during acute hypoglycemia in humans

    International Nuclear Information System (INIS)

    We used positron emission tomography (PET) to study the effects of mild hypoglycemia on cerebral glucose uptake and metabolism. Nine healthy men were studied under basal saline-infusion conditions, and during euglycemic and hypoglycemic clamp studies. Insulin was infused at the same rate (1 mU.kg-1.min-1) in both clamp studies. In euglycemic clamp studies, glucose was infused at a rate sufficient to maintain the basal plasma glucose concentration, whereas in hypoglycemic clamp studies, the glucose infusion rate was reduced to maintain the plasma glucose at 3.1 mM. Each study lasted 3 h and included a 30-min baseline period and a subsequent 150-min period in which insulin or glucose was administered. Blood samples for measurement of insulin, glucose, cortisol, growth hormone, and glucagon were obtained at 20- to 30-min intervals. A bolus injection of 5-10 mCi [18F]-2-deoxy-2-fluoro-D-glucose (2-DFG) was administered 120 min after initiation of the study, and plasma radioactivity and dynamic PET scans were obtained at frequent intervals for the remaining 40-60 min of the study. Cerebral regions of interest were defined, and concentrations of radioactivity were calculated and used in the three-compartment model of 2-DFG distribution described by Sokoloff. Glucose levels were similar during saline-infusion (4.9 +/- 0.1 mM) and euglycemic clamp (4.8 +/- 0.1 mM) studies, whereas the desired degree of mild hypoglycemia was achieved during the hypoglycemic clamp study (3.1 +/- 0.1 mM, P less than 0.05). The insulin level during saline infusion was 41 +/- 7 pM

  2. In Alzheimer’s Disease, 6-Month Treatment with GLP-1 Analog Prevents Decline of Brain Glucose Metabolism: Randomized, Placebo-Controlled, Double-Blind Clinical Trial

    Science.gov (United States)

    Gejl, Michael; Gjedde, Albert; Egefjord, Lærke; Møller, Arne; Hansen, Søren B.; Vang, Kim; Rodell, Anders; Brændgaard, Hans; Gottrup, Hanne; Schacht, Anna; Møller, Niels; Brock, Birgitte; Rungby, Jørgen

    2016-01-01

    In animal models, the incretin hormone GLP-1 affects Alzheimer’s disease (AD). We hypothesized that treatment with GLP-1 or an analog of GLP-1 would prevent accumulation of Aβ and raise, or prevent decline of, glucose metabolism (CMRglc) in AD. In this 26-week trial, we randomized 38 patients with AD to treatment with the GLP-1 analog liraglutide (n = 18), or placebo (n = 20). We measured Aβ load in brain with tracer [11C]PIB (PIB), CMRglc with [18F]FDG (FDG), and cognition with the WMS-IV scale (ClinicalTrials.gov NCT01469351). The PIB binding increased significantly in temporal lobe in placebo and treatment patients (both P = 0.04), and in occipital lobe in treatment patients (P = 0.04). Regional and global increases of PIB retention did not differ between the groups (P ≥ 0.38). In placebo treated patients CMRglc declined in all regions, significantly so by the following means in precuneus (P = 0.009, 3.2 μmol/hg/min, 95% CI: 5.45; 0.92), and in parietal (P = 0.04, 2.1 μmol/hg/min, 95% CI: 4.21; 0.081), temporal (P = 0.046, 1.54 μmol/hg/min, 95% CI: 3.05; 0.030), and occipital (P = 0.009, 2.10 μmol/hg/min, 95% CI: 3.61; 0.59) lobes, and in cerebellum (P = 0.04, 1.54 μmol/hg/min, 95% CI: 3.01; 0.064). In contrast, the GLP-1 analog treatment caused a numerical but insignificant increase of CMRglc after 6 months. Cognitive scores did not change. We conclude that the GLP-1 analog treatment prevented the decline of CMRglc that signifies cognitive impairment, synaptic dysfunction, and disease evolution. We draw no firm conclusions from the Aβ load or cognition measures, for which the study was underpowered. PMID:27252647

  3. Effects of glucose load on cognitive functions in elderly people

    NARCIS (Netherlands)

    Zwaluw, N.L. van der; Rest, O. van de; Kessels, R.P.C.; Groot, L.C.P.G.M. de

    2015-01-01

    Glucose is the main fuel for the brain, and manipulation of the glucose supply may consequently affect brain function. The present review was conducted to provide an overview of studies that investigated the acute effects of glucose load on memory and other cognitive functions in elderly people. The

  4. of Energy Homeostasis

    Directory of Open Access Journals (Sweden)

    Xian Liu

    2015-01-01

    Full Text Available Sex differences exist in the complex regulation of energy homeostasis that utilizes central and peripheral systems. It is widely accepted that sex steroids, especially estrogens, are important physiological and pathological components in this sex-specific regulation. Estrogens exert their biological functions via estrogen receptors (ERs. ERα, a classic nuclear receptor, contributes to metabolic regulation and sexual behavior more than other ER subtypes. Physiological and molecular studies have identified multiple ERα-rich nuclei in the hypothalamus of the central nervous system (CNS as sites of actions that mediate effects of estrogens. Much of our understanding of ERα regulation has been obtained using transgenic models such as ERα global or nuclei-specific knockout mice. A fundamental question concerning how ERα is regulated in wild-type animals, including humans, in response to alterations in steroid hormone levels, due to experimental manipulation (i.e., castration and hormone replacement or physiological stages (i.e., puberty, pregnancy, and menopause, lacks consistent answers. This review discusses how different sex hormones affect ERα expression in the hypothalamus. This information will contribute to the knowledge of estrogen action in the CNS, further our understanding of discrepancies in correlation of altered sex hormone levels with metabolic disturbances when comparing both sexes, and improve health issues in postmenopausal women.

  5. Role of serotonin and/or norepinephrine in the MDMA-induced increase in extracellular glucose and glycogenolysis in the rat brain

    OpenAIRE

    Pachmerhiwala, Rashida; Bhide, Nirmal; Straiko, Megan; Gudelsky, Gary A.

    2010-01-01

    The acute administration of MDMA has been shown to promote glycogenolysis and increase the extracellular concentration of glucose in the striatum. In the present study the role of serotonergic and/or noradrenergic mechanisms in the MDMA-induced increase in extracellular glucose and glycogenolysis was assessed. The relationship of these responses to the hyperthermia produced by MDMA also was examined. The administration of MDMA (10 mg/kg, i.p.) resulted in a significant and sustained increase ...

  6. Brain peroxisomes.

    Science.gov (United States)

    Trompier, D; Vejux, A; Zarrouk, A; Gondcaille, C; Geillon, F; Nury, T; Savary, S; Lizard, G

    2014-03-01

    Peroxisomes are essential organelles in higher eukaryotes as they play a major role in numerous metabolic pathways and redox homeostasis. Some peroxisomal abnormalities, which are often not compatible with life or normal development, were identified in severe demyelinating and neurodegenerative brain diseases. The metabolic roles of peroxisomes, especially in the brain, are described and human brain peroxisomal disorders resulting from a peroxisome biogenesis or a single peroxisomal enzyme defect are listed. The brain abnormalities encountered in these disorders (demyelination, oxidative stress, inflammation, cell death, neuronal migration, differentiation) are described and their pathogenesis are discussed. Finally, the contribution of peroxisomal dysfunctions to the alterations of brain functions during aging and to the development of Alzheimer's disease is considered.

  7. GDH-Dependent Glutamate Oxidation in the Brain Dictates Peripheral Energy Substrate Distribution

    DEFF Research Database (Denmark)

    Karaca, Melis; Frigerio, Francesca; Migrenne, Stephanie;

    2015-01-01

    Glucose, the main energy substrate used in the CNS, is continuously supplied by the periphery. Glutamate, the major excitatory neurotransmitter, is foreseen as a complementary energy contributor in the brain. In particular, astrocytes actively take up glutamate and may use it through oxidative...... glutamate dehydrogenase (GDH) activity. Here, we investigated the significance of glutamate as energy substrate for the brain. Upon glutamate exposure, astrocytes generated ATP in a GDH-dependent way. The observed lack of glutamate oxidation in brain-specific GDH null CnsGlud1(-/-) mice resulted....... Our data reveal the importance of glutamate as necessary energy substrate for the brain and the role of central GDH in the regulation of whole-body energy homeostasis....

  8. Glucose enhancement of human memory: A comprehensive research review of the glucose memory facilitation effect

    OpenAIRE

    Smith, Michael; Riby, Leigh; van Eekelen, Anke; Foster, Jonathan

    2011-01-01

    The brain relies upon glucose as its primary fuel. In recent years, a rich literature has developed from both human and animal studies indicating that increases in circulating blood glucose can facilitate cognitive functioning. This phenomenon has been termed the ‘glucose memory facilitation effect’. The purpose of this review is to discuss a number of salient studies which have investigated the influence of glucose ingestion on neurocognitive performance in individuals with (a) compromised n...

  9. Glucagon-like peptide-1 decreases intracerebral glucose content by activating hexokinase and changing glucose clearance during hyperglycemia

    DEFF Research Database (Denmark)

    Gejl, Michael; Egefjord, Lærke; Lerche, Susanne;

    2012-01-01

    Type 2 diabetes and hyperglycemia with the resulting increase of glucose concentrations in the brain impair the outcome of ischemic stroke, and may increase the risk of developing Alzheimer's disease (AD). Reports indicate that glucagon-like peptide-1 (GLP-1) may be neuroprotective in models of AD...... in the actions of GLUT1 and glucose metabolism: GLP-1 ensures less fluctuation of brain glucose levels in response to alterations in plasma glucose, which may prove to be neuroprotective during hyperglycemia....

  10. POSTNATAL GLUCOSE KINETICS IN NEWBORNS OF TIGHTLY CONTROLLED INSULIN-DEPENDENT DIABETIC MOTHERS

    NARCIS (Netherlands)

    Baarsma, R; Reijngoud, DJ; van Asselt, Wilhelmina; van Doormaal, JJ; Berger, Rudolf; Okken, Albert

    1993-01-01

    Infants of diabetic mothers are at risk of developing hypoglycemia postnatally. Strict control of blood glucose during pregnancy might result in adequate glucose homeostasis in the neonate. We followed 15 mother-infant pairs from the beginning of pregnancy until birth. Glucose kinetics in the infant

  11. Lipoproteins, cholesterol homeostasis and cardiac health

    Directory of Open Access Journals (Sweden)

    Tyler F. Daniels, Karen M. Killinger, Jennifer J. Michal, Raymond W. Wright Jr., Zhihua Jiang

    2009-01-01

    Full Text Available Cholesterol is an essential substance involved in many functions, such as maintaining cell membranes, manufacturing vitamin D on surface of the skin, producing hormones, and possibly helping cell connections in the brain. When cholesterol levels rise in the blood, they can, however, have dangerous consequences. In particular, cholesterol has generated considerable notoriety for its causative role in atherosclerosis, the leading cause of death in developed countries around the world. Homeostasis of cholesterol is centered on the metabolism of lipoproteins, which mediate transport of the lipid to and from tissues. As a synopsis of the major events and proteins that manage lipoprotein homeostasis, this review contributes to the substantial attention that has recently been directed to this area. Despite intense scrutiny, the majority of phenotypic variation in total cholesterol and related traits eludes explanation by current genetic knowledge. This is somewhat disappointing considering heritability estimates have established these traits as highly genetic. Thus, the continued search for candidate genes, mutations, and mechanisms is vital to our understanding of heart disease at the molecular level. Furthermore, as marker development continues to predict risk of vascular illness, this knowledge has the potential to revolutionize treatment of this leading human disease.

  12. Perturbed cholesterol homeostasis in aging spinal cord.

    Science.gov (United States)

    Parkinson, Gemma M; Dayas, Christopher V; Smith, Doug W

    2016-09-01

    The spinal cord is vital for the processing of sensorimotor information and for its propagation to and from both the brain and the periphery. Spinal cord function is affected by aging, however, the mechanisms involved are not well-understood. To characterize molecular mechanisms of spinal cord aging, microarray analyses of gene expression were performed on cervical spinal cords of aging rats. Of the metabolic and signaling pathways affected, cholesterol-associated pathways were the most comprehensively altered, including significant downregulation of cholesterol synthesis-related genes and upregulation of cholesterol transport and metabolism genes. Paradoxically, a significant increase in total cholesterol content was observed-likely associated with cholesterol ester accumulation. To investigate potential mechanisms for the perturbed cholesterol homeostasis, we quantified the expression of myelin and neuroinflammation-associated genes and proteins. Although there was minimal change in myelin-related expression, there was an increase in phagocytic microglial and astrogliosis markers, particularly in the white matter. Together, these results suggest that perturbed cholesterol homeostasis, possibly as a result of increased inflammatory activation in spinal cord white matter, may contribute to impaired spinal cord function with aging. PMID:27459933

  13. Consciousness, endogenous generation of goals and homeostasis

    Science.gov (United States)

    Tsitolovsky, Lev E.

    2015-08-01

    Behaviour can be both unpredictable and goal directed, as animals act in correspondence with their motivation. Motivation arises when neurons in specific brain areas leave the state of homeostatic equilibrium and are injured. The basic goal of organisms and living cells is to maintain their life and their functional state is optimal if it does not lead to physiological damage. This can somehow be sensed by neurons and the occurrence of damage elicits homeostatic protection to recover excitability and the ability to produces spikes. It can be argued that the neuron's activity is guided on the scale of "damage-protection" and it behaves as an object possessing minimum awareness. The approach of death increases cellular efforts to operate. Thus, homeostasis may evidently produce both maintenance of life and will. The question is - how does homeostasis reach the optimum? We have no possibility of determining how the cell evaluates its own states, e.g. as "too little free energy" or in terms of "threat" to life. In any case, the approach of death increases cellular efforts to operate. For the outside observer, this is reminiscent of intentional action and a manifestation of will.

  14. Maternal dietary restriction alters offspring's sleep homeostasis.

    Directory of Open Access Journals (Sweden)

    Noriyuki Shimizu

    Full Text Available Nutritional state in the gestation period influences fetal growth and development. We hypothesized that undernutrition during gestation would affect offspring sleep architecture and/or homeostasis. Pregnant female mice were assigned to either control (fed ad libitum; AD or 50% dietary restriction (DR groups from gestation day 12 to parturition. After parturition, dams were fed AD chow. After weaning, the pups were also fed AD into adulthood. At adulthood (aged 8-9 weeks, we carried out sleep recordings. Although offspring mice displayed a significantly reduced body weight at birth, their weights recovered three days after birth. Enhancement of electroencephalogram (EEG slow wave activity (SWA during non-rapid eye movement (NREM sleep was observed in the DR mice over a 24-hour period without changing the diurnal pattern or amounts of wake, NREM, or rapid eye movement (REM sleep. In addition, DR mice also displayed an enhancement of EEG-SWA rebound after a 6-hour sleep deprivation and a higher threshold for waking in the face of external stimuli. DR adult offspring mice exhibited small but significant increases in the expression of hypothalamic peroxisome proliferator-activated receptor α (Pparα and brain-specific carnitine palmitoyltransferase 1 (Cpt1c mRNA, two genes involved in lipid metabolism. Undernutrition during pregnancy may influence sleep homeostasis, with offspring exhibiting greater sleep pressure.

  15. Brain glycogen

    DEFF Research Database (Denmark)

    Obel, Linea Lykke Frimodt; Müller, Margit S; Walls, Anne B;

    2012-01-01

    Glycogen is a complex glucose polymer found in a variety of tissues, including brain, where it is localized primarily in astrocytes. The small quantity found in brain compared to e.g., liver has led to the understanding that brain glycogen is merely used during hypoglycemia or ischemia....... In this review evidence is brought forward highlighting what has been an emerging understanding in brain energy metabolism: that glycogen is more than just a convenient way to store energy for use in emergencies-it is a highly dynamic molecule with versatile implications in brain function, i.e., synaptic...... activity and memory formation. In line with the great spatiotemporal complexity of the brain and thereof derived focus on the basis for ensuring the availability of the right amount of energy at the right time and place, we here encourage a closer look into the molecular and subcellular mechanisms...

  16. Transmissible microbial and metabolomic remodeling by soluble dietary fiber improves metabolic homeostasis

    OpenAIRE

    He, Baokun; Nohara, Kazunari; Ajami, Nadim J.; Michalek, Ryan D.; Tian, Xiangjun; Wong, Matthew; Losee-Olson, Susan H.; Petrosino, Joseph F; Yoo, Seung-Hee; Shimomura, Kazuhiro; Chen, Zheng

    2015-01-01

    Dietary fibers are increasingly appreciated as beneficial nutritional components. However, a requisite role of gut microbiota in fiber function and the overall impact of fibers on metabolomic flux remain unclear. We herein showed enhancing effects of a soluble resistant maltodextrin (RM) on glucose homeostasis in mouse metabolic disease models. Remarkably, fecal microbiota transplantation (FMT) caused pronounced and time-dependent improvement in glucose tolerance in RM recipient mice, indicat...

  17. Homeostasis of T Cell Diversity

    Institute of Scientific and Technical Information of China (English)

    Vinay S. Mahajan; Ilya B. Leskov; Jianzhu Chen

    2005-01-01

    T cell homeostasis commonly refers to the maintenance of relatively stable T cell numbers in the peripheral lymphoid organs. Among the large numbers of T cells in the periphery, T cells exhibit structural diversity, I.e., the expression of a diverse repertoire of T cell receptors (TCRs), and functional diversity, I.e., the presence of T cells at na(I)ve, effector, and memory developmental stages. Although the homeostasis of T cell numbers has been extensively studied, investigation of the mechanisms underlying the maintenance of structural and functional diversity of T cells is still at an early stage. The fundamental feature throughout T cell development is the interaction between the TCR and either self or foreign peptides in association with MHC molecules. In this review, we present evidence showing that homeostasis of T cell number and diversity is mediated through competition for limiting resources.The number of T cells is maintained through competition for limiting cytokines, whereas the diversity of T cells is maintained by competition for self-peptide-MHC complexes. In other words, diversity of the self-peptide repertoire limits the structural (TCR) diversity of a T cell population. We speculate that cognate low affinity self-peptides,acting as weak agonists and antagonists, regulate the homeostasis of T cell diversity whereas non-cognate or null peptides which are extremely abundant for any given TCR, may contribute to the homeostasis of T cell number by providing survival signals. Moreover, self-peptides and cytokines may form specialized niches for the regulation of T cell homeostasis.

  18. Homeostasis of T Cell Diversity

    Institute of Scientific and Technical Information of China (English)

    VinayS.Mahajan; IlyaB.Leskov; JianzhuChen

    2005-01-01

    T cell homeostasis commonly refers to the maintenance of relatively stable T cell numbers in the peripheral lymphoid organs. Among the large numbers of T cells in the periphery, T cells exhibit structural diversity, i.e., the expression of a diverse repertoire of T cell receptors (TCRs), and functional diversity, i.e., the presence of T cells at naive, effector, and memory developmental stages. Although the homeostasis of T cell numbers has been extensively studied, investigation of the mechanisms underlying the maintenance of structural and functional diversity of T cells is still at an early stage. The fundamental feature throughout T cell development is the interaction between the TCR and either self or foreign peptides in association with MHC molecules. In this review, we present evidence showing that homeostasis of T cell number and diversity is mediated through competition for limiting resources. The number of T cells is maintained through competition for limiting cytokines, whereas the diversity of T cells is maintained by competition for self-peptide-MHC complexes. In other words, diversity of the self-peptide repertoire limits the structural (TCR) diversity of a T cell population. We speculate that cognate low affinity self-peptides, acting as weak agonists and antagonists, regulate the homeostasis of T cell diversity whereas non-cognate or null peptides which are extremely abundant for any given TCR, may contribute to the homeostasis of T cell number by providing survival signals. Moreover, self-peptides and cytokines may form specialized niches for the regulation of T cell homeostasis. Cellular & Molecular Immunology. 2005;2(1): 1-10.

  19. Leptin and Hormones: Energy Homeostasis.

    Science.gov (United States)

    Triantafyllou, Georgios A; Paschou, Stavroula A; Mantzoros, Christos S

    2016-09-01

    Leptin, a 167 amino acid adipokine, plays a major role in human energy homeostasis. Its actions are mediated through binding to leptin receptor and activating JAK-STAT3 signal transduction pathway. It is expressed mainly in adipocytes, and its circulating levels reflect the body's energy stores in adipose tissue. Recombinant methionyl human leptin has been FDA approved for patients with generalized non-HIV lipodystrophy and for compassionate use in subjects with congenital leptin deficiency. The purpose of this review is to outline the role of leptin in energy homeostasis, as well as its interaction with other hormones. PMID:27519135

  20. Increased expression of aquaporin-4 in human traumatic brain injury and brain tumors

    Institute of Scientific and Technical Information of China (English)

    HuaHu; Wei-PingZhang; LeiZhang; ZhongChen; Er-QingWei

    2004-01-01

    Aquaporin-4 (AQP4) is one of the aquaporins (AQPs), a water channel family. In the brain, AQP4 is expressed in astroeyte foot processes, and plays an important role in water homeostasis and in the formation of brain edema. In our study, AQP4 expression in human brain specimens from patients with traumatic brain injury or different brain tumors was detected

  1. Glucose allostasis

    DEFF Research Database (Denmark)

    Stumvoll, Michael; Tataranni, P Antonio; Stefan, Norbert;

    2003-01-01

    concentration assumed to remain constant along the hyperbola. Conceivably, glucose is one of the signals stimulating AIR in response to decreasing M. Hypothetically, as with any normally functioning feed-forward system, AIR should not fully compensate for worsening M, since this would remove the stimulus...... (insulin resistance), we propose to use the term "glucose allostasis." Allostasis (stability through change) ensures the continued homeostatic response (stability through staying the same) to acute stress at some cumulative costs to the system. With increasing severity and over time, the allostatic load...

  2. Type 1 cannabinoid receptor mapping with [18F]MK-9470 PET in the rat brain after quinolinic acid lesion: a comparison to dopamine receptors and glucose metabolism

    International Nuclear Information System (INIS)

    Several lines of evidence imply early alterations in metabolic, dopaminergic and endocannabinoid neurotransmission in Huntington's disease (HD). Using [18F]MK-9470 and small animal PET, we investigated cerebral changes in type 1 cannabinoid (CB1) receptor binding in the quinolinic acid (QA) rat model of HD in relation to glucose metabolism, dopamine D2 receptor availability and amphetamine-induced turning behaviour. Twenty-one Wistar rats (11 QA and 10 shams) were investigated. Small animal PET acquisitions were conducted on a Focus 220 with approximately 18 MBq of [18F]MK-9470, [18F]FDG and [11C]raclopride. Relative glucose metabolism and parametric CB1 receptor and D2 binding images were anatomically standardized to Paxinos space and analysed voxel-wise using Statistical Parametric Mapping (SPM2). In the QA model, [18F]MK-9470 uptake, glucose metabolism and D2 receptor binding were reduced in the ipsilateral caudate-putamen by 7, 35 and 77%, respectively (all p -5), while an increase for these markers was observed on the contralateral side (>5%, all p -4). [18F]MK-9470 binding was also increased in the cerebellum (p = 2.10-5), where it was inversely correlated to the number of ipsiversive turnings (p = 7.10-6), suggesting that CB1 receptor upregulation in the cerebellum is related to a better functional outcome. Additionally, glucose metabolism was relatively increased in the contralateral hippocampus, thalamus and sensorimotor cortex (p = 1.10-6). These data point to in vivo changes in endocannabinoid transmission, specifically for CB1 receptors in the QA model, with involvement of the caudate-putamen, but also distant regions of the motor circuitry, including the cerebellum. These data also indicate the occurrence of functional plasticity on metabolism, D2 and CB1 neurotransmission in the contralateral hemisphere. (orig.)

  3. Electroacupuncture Treatment Improves Learning-Memory Ability and Brain Glucose Metabolism in a Mouse Model of Alzheimer’s Disease: Using Morris Water Maze and Micro-PET

    OpenAIRE

    Jing Jiang; Kai Gao; Yuan Zhou; Anping Xu; Suhua Shi; Gang Liu; Zhigang Li

    2015-01-01

    Introduction. Alzheimer’s disease (AD) causes progressive hippocampus dysfunctions leading to the impairment of learning and memory ability and low level of uptake rate of glucose in hippocampus. What is more, there is no effective treatment for AD. In this study, we evaluated the beneficial and protective effects of electroacupuncture in senescence-accelerated mouse prone 8 (SAMP8). Method. In the electroacupuncture paradigm, electroacupuncture treatment was performed once a day for 15 days ...

  4. Repeated intraperitoneal injections of interleukin 1 beta induce glucose intolerance in normal rats

    DEFF Research Database (Denmark)

    Wogensen, L; Reimers, J; Mandrup-Poulsen, T;

    1991-01-01

    . An ip glucose tolerance test (0.2 g D-glucose/100 g) was performed 2 h after injection of rIL-1 beta. A single injection of rIL-1 beta caused a mild depression in blood glucose and an improved glucose tolerance. Multiple injections of rIL-1 beta induced a diminished weight gain, a 24-28% reduction...... in food intake, a lasting mild depression of blood glucose (7 days) and a transiently impaired glucose tolerance on day 5. We conclude that systemic IL-1 should be considered an important regulator of glucose homeostasis in vivo....

  5. WSB1: from homeostasis to hypoxia.

    Science.gov (United States)

    Haque, Moinul; Kendal, Joseph Keith; MacIsaac, Ryan Matthew; Demetrick, Douglas James

    2016-01-01

    The wsb1 gene has been identified to be important in developmental biology and cancer. A complex transcriptional regulation of wsb1 yields at least three functional transcripts. The major expressed isoform, WSB1 protein, is a substrate recognition protein within an E3 ubiquitin ligase, with the capability to bind diverse targets and mediate ubiquitinylation and proteolytic degradation. Recent data suggests a new role for WSB1 as a component of a neuroprotective pathway which results in modification and aggregation of neurotoxic proteins such as LRRK2 in Parkinson's Disease, via an unusual mode of protein ubiquitinylation.WSB1 is also involved in thyroid hormone homeostasis, immune regulation and cellular metabolism, particularly glucose metabolism and hypoxia. In hypoxia, wsb1 is a HIF-1 target, and is a regulator of the degradation of diverse proteins associated with the cellular response to hypoxia, including HIPK2, RhoGDI2 and VHL. Major roles are to both protect HIF-1 function through degradation of VHL, and decrease apoptosis through degradation of HIPK2. These activities suggest a role for wsb1 in cancer cell proliferation and metastasis. As well, recent work has identified a role for WSB1 in glucose metabolism, and perhaps in mediating the Warburg effect in cancer cells by maintaining the function of HIF1. Furthermore, studies of cancer specimens have identified dysregulation of wsb1 associated with several types of cancer, suggesting a biologically relevant role in cancer development and/or progression.Recent development of an inducible expression system for wsb1 could aid in the further understanding of the varied functions of this protein in the cell, and roles as a potential oncogene and neuroprotective protein. PMID:27542736

  6. Geniposide regulates glucose-stimulated insulin secretion possibly through controlling glucose metabolism in INS-1 cells.

    Directory of Open Access Journals (Sweden)

    Jianhui Liu

    Full Text Available Glucose-stimulated insulin secretion (GSIS is essential to the control of metabolic fuel homeostasis. The impairment of GSIS is a key element of β-cell failure and one of causes of type 2 diabetes mellitus (T2DM. Although the KATP channel-dependent mechanism of GSIS has been broadly accepted for several decades, it does not fully describe the effects of glucose on insulin secretion. Emerging evidence has suggested that other mechanisms are involved. The present study demonstrated that geniposide enhanced GSIS in response to the stimulation of low or moderately high concentrations of glucose, and promoted glucose uptake and intracellular ATP levels in INS-1 cells. However, in the presence of a high concentration of glucose, geniposide exerted a contrary role on both GSIS and glucose uptake and metabolism. Furthermore, geniposide improved the impairment of GSIS in INS-1 cells challenged with a high concentration of glucose. Further experiments showed that geniposide modulated pyruvate carboxylase expression and the production of intermediates of glucose metabolism. The data collectively suggest that geniposide has potential to prevent or improve the impairment of insulin secretion in β-cells challenged with high concentrations of glucose, likely through pyruvate carboxylase mediated glucose metabolism in β-cells.

  7. β-Hydroxybutyrate is the preferred substrate for GABA and glutamate synthesis while glucose is indispensable during depolarization in cultured GABAergic neurons.

    Science.gov (United States)

    Lund, Trine M; Obel, Linea F; Risa, Øystein; Sonnewald, Ursula

    2011-08-01

    The ketogenic diet has multiple beneficial effects not only in treatment of epilepsy, but also in that of glucose transporter 1 deficiency, cancer, Parkinson's disease, obesity and pain. Thus, there is an increasing interest in understanding the mechanism behind this metabolic therapy. Patients on a ketogenic diet reach high plasma levels of ketone bodies, which are used by the brain as energy substrates. The interaction between glucose and ketone bodies is complex and there is still controversy as to what extent it affects the homeostasis of the neurotransmitters glutamate, aspartate and GABA. The present study was conducted to study this metabolic interaction in cultured GABAergic neurons exposed to different combinations of (13)C-labeled and unlabeled glucose and β-hydroxybutyrate. Depolarization was induced and the incorporation of (13)C into glutamate, GABA and aspartate was analyzed. The presence of β-hydroxybutyrate together with glucose did not affect the total GABA content but did, however, decrease the aspartate content to a lower value than when either glucose or β-hydroxybutyrate was employed alone. When combinations of the two substrates were used (13)C-atoms from β-hydroxybutyrate were found in all three amino acids to a greater extent than (13)C-atoms from glucose, but only the (13)C contribution from [1,6-(13)C]glucose increased upon depolarization. In conclusion, β-hydroxybutyrate was preferred over glucose as substrate for amino acid synthesis but the total content of aspartate decreased when both substrates were present. Furthermore only the use of glucose increased upon depolarization. PMID:21684314

  8. A comparative study in Alzheimer's and normal brains of trace element distribution using PIXE and INA analyses and glucose metabolism by positron emission tomography

    NARCIS (Netherlands)

    Cutts, DA; Maguire, RP; Stedman, JD; Leenders, KL; Spyrou, NM

    1999-01-01

    The onset of Alzheimer's disease has been shown to affect trace element concentrations in the brain when compared to "normal" subjects in ex vivo samples. The techniques used to determine trace element concentrations were proton-induced X-ray emission and instrumental neutron activation analysis. Wi

  9. Hyperbaric oxygen therapy or hydroxycobalamin attenuates surges in brain interstitial lactate and glucose; and hyperbaric oxygen improves respiratory status in cyanide-intoxicated rats

    DEFF Research Database (Denmark)

    Lawson-Smith, P; Olsen, Niels Vidiendal; Hyldegaard, Ole

    2011-01-01

    Cyanide (CN) intoxication inhibits cellular oxidative metabolism and may result in brain damage. Hydroxycobalamin (OHCob) is one among other antidotes that may be used following intoxication with CN. Hyperbaric oxygen (HBO2) is recommended when supportive measures or antidotes fail. However...

  10. Development and potential role of type-2 sodium-glucose transporter inhibitors for management of type 2 diabetes

    OpenAIRE

    Hardman, Timothy Colin; Dubrey, Simon William

    2011-01-01

    There is a recognized need for new treatment options for type 2 diabetes mellitus (T2DM). Recovery of glucose from the glomerular filtrate represents an important mechanism in maintaining glucose homeostasis and represents a novel target for the management of T2DM. Recovery of glucose from the glomerular filtrate is executed principally by the type 2 sodium-glucose cotransporter (SGLT2). Inhibition of SGLT2 promotes glucose excretion and normalizes glycemia in animal models. First reports of ...

  11. The Whole-Brain "Global" Signal from Resting State fMRI as a Potential Biomarker of Quantitative State Changes in Glucose Metabolism.

    Science.gov (United States)

    Thompson, Garth J; Riedl, Valentin; Grimmer, Timo; Drzezga, Alexander; Herman, Peter; Hyder, Fahmeed

    2016-07-01

    The evolution of functional magnetic resonance imaging to resting state (R-fMRI) allows measurement of changes in brain networks attributed to state changes, such as in neuropsychiatric diseases versus healthy controls. Since these networks are observed by comparing normalized R-fMRI signals, it is difficult to determine the metabolic basis of such group differences. To investigate the metabolic basis of R-fMRI network differences within a normal range, eyes open versus eyes closed in healthy human subjects was used. R-fMRI was recorded simultaneously with fluoro-deoxyglucose positron emission tomography (FDG-PET). Higher baseline FDG was observed in the eyes open state. Variance-based metrics calculated from R-fMRI did not match the baseline shift in FDG. Functional connectivity density (FCD)-based metrics showed a shift similar to the baseline shift of FDG, however, this was lost if R-fMRI "nuisance signals" were regressed before FCD calculation. Average correlation with the mean R-fMRI signal across the whole brain, generally regarded as a "nuisance signal," also showed a shift similar to the baseline of FDG. Thus, despite lacking a baseline itself, changes in whole-brain correlation may reflect changes in baseline brain metabolism. Conversely, variance-based metrics may remain similar between states due to inherent region-to-region differences overwhelming the differences between normal physiological states. As most previous studies have excluded the spatial means of R-fMRI metrics from their analysis, this work presents the first evidence of a potential R-fMRI biomarker for baseline shifts in quantifiable metabolism between brain states. PMID:27029438

  12. Glucose-lowering effects of intestinal bile acid sequestration through enhancement of splanchnic glucose utilization.

    Science.gov (United States)

    Prawitt, Janne; Caron, Sandrine; Staels, Bart

    2014-05-01

    Intestinal bile acid (BA) sequestration efficiently lowers plasma glucose concentrations in type 2 diabetes (T2D) patients. Because BAs act as signaling molecules via receptors, including the G protein-coupled receptor TGR5 and the nuclear receptor FXR (farnesoid X receptor), to regulate glucose homeostasis, BA sequestration, which interrupts the entero-hepatic circulation of BAs, constitutes a plausible action mechanism of BA sequestrants. An increase of intestinal L-cell glucagon-like peptide-1 (GLP-1) secretion upon TGR5 activation is the most commonly proposed mechanism, but recent studies also argue for a direct entero-hepatic action to enhance glucose utilization. We discuss here recent findings on the mechanisms of sequestrant-mediated glucose lowering via an increase of splanchnic glucose utilization through entero-hepatic FXR signaling.

  13. 葡萄糖稳态的中枢调控作用机制——2014年美国糖尿病协会“杰出科学成就奖”演讲报告解读%The mechanisms of central nervous system in the control of glucose homeostasis——A summary of 2014 ADA "Outstanding Scientific Achievement Award" Lecture

    Institute of Scientific and Technical Information of China (English)

    郑佳; 肖新华

    2014-01-01

    At the American Diabetes Association's 74th Scientific Sessions in 2014,professor Joel K.Elmquist from the university of Texas southwestern medical center was awarded the American Diabetes Association's Outstanding Scientific Achievement Award.Dr.Elmquist presented the Outstanding Scientific Achievement Award Lecture," Claude Bernard Was Right:Brain Control of Glucose Homeostasis" at the Scientific Sessions.Here briefly interpretaed his award lecture which focused on the mechanisms of central nervous system on the regulation in glucose homeostasis.%2014年第74届美国糖尿病协会年会上,美国德克萨斯大学西南医学中心Joel K.Elmquist教授获得了杰出科学成就奖,并发表了关于“Claude Bernard是正确的——葡萄糖稳态的大脑调控(Claude Bernard Was Right——Brain Control of Glucose Homeostasis)”的获奖演讲.现对其演讲报告作一简短的解读,探讨中枢神经系统对葡萄糖稳态的调控作用机制.

  14. Electroacupuncture Treatment Improves Learning-Memory Ability and Brain Glucose Metabolism in a Mouse Model of Alzheimer’s Disease: Using Morris Water Maze and Micro-PET

    Directory of Open Access Journals (Sweden)

    Jing Jiang

    2015-01-01

    Full Text Available Introduction. Alzheimer’s disease (AD causes progressive hippocampus dysfunctions leading to the impairment of learning and memory ability and low level of uptake rate of glucose in hippocampus. What is more, there is no effective treatment for AD. In this study, we evaluated the beneficial and protective effects of electroacupuncture in senescence-accelerated mouse prone 8 (SAMP8. Method. In the electroacupuncture paradigm, electroacupuncture treatment was performed once a day for 15 days on 7.5-month-old SAMP8 male mice. In the normal control paradigm and AD control group, 7.5-month-old SAMR1 male mice and SAMP8 male mice were grabbed and bandaged while electroacupuncture group therapy, in order to ensure the same treatment conditions, once a day, 15 days. Results. From the Morris water maze (MWM test, we found that the treatment of electroacupuncture can improve the spatial learning and memory ability of SAMP8 mouse, and from the micro-PET test, we proved that after the electroacupuncture treatment the level of uptake rate of glucose in hippocampus was higher than normal control group. Conclusion. These results suggest that the treatment of electroacupuncture may provide a viable treatment option for AD.

  15. Bang to the Brain: What We Know about Concussions

    Science.gov (United States)

    ... later leads to an even steeper drop in glucose use and memory problems that last longer. But when the brain has several days to recover, and the use of glucose returns to normal, a second mild brain injury ...

  16. Zinc bioavailability and homeostasis1234

    OpenAIRE

    Hambidge, K Michael; Miller, Leland V; Westcott, Jamie E; Sheng, Xiaoyang; Krebs, Nancy F.

    2010-01-01

    Zinc has earned recognition recently as a micronutrient of outstanding and diverse biological, clinical, and global public health importance. Regulation of absorption by zinc transporters in the enterocyte, together with saturation kinetics of the absorption process into and across the enterocyte, are the principal means by which whole-body zinc homeostasis is maintained. Several physiologic factors, most notably the quantity of zinc ingested, determine the quantity of zinc absorbed and the e...

  17. Transmissible microbial and metabolomic remodeling by soluble dietary fiber improves metabolic homeostasis.

    Science.gov (United States)

    He, Baokun; Nohara, Kazunari; Ajami, Nadim J; Michalek, Ryan D; Tian, Xiangjun; Wong, Matthew; Losee-Olson, Susan H; Petrosino, Joseph F; Yoo, Seung-Hee; Shimomura, Kazuhiro; Chen, Zheng

    2015-01-01

    Dietary fibers are increasingly appreciated as beneficial nutritional components. However, a requisite role of gut microbiota in fiber function and the overall impact of fibers on metabolomic flux remain unclear. We herein showed enhancing effects of a soluble resistant maltodextrin (RM) on glucose homeostasis in mouse metabolic disease models. Remarkably, fecal microbiota transplantation (FMT) caused pronounced and time-dependent improvement in glucose tolerance in RM recipient mice, indicating a causal relationship between microbial remodeling and metabolic efficacy. Microbial 16S sequencing revealed transmissible taxonomic changes correlated with improved metabolism, notably enrichment of probiotics and reduction of Alistipes and Bacteroides known to associate with high fat/protein diets. Metabolomic profiling further illustrated broad changes, including enrichment of phenylpropionates and decreases in key intermediates of glucose utilization, cholesterol biosynthesis and amino acid fermentation. These studies elucidate beneficial roles of RM-dependent microbial remodeling in metabolic homeostasis, and showcase prevalent health-promoting potentials of dietary fibers. PMID:26040234

  18. Regulatory T Cells in Post-stroke Immune Homeostasis.

    Science.gov (United States)

    Liesz, Arthur; Kleinschnitz, Christoph

    2016-08-01

    The secondary neuroinflammatory response has come into focus of experimental stroke research. Immunological mechanisms after acute stroke are being investigated in the hope to identify novel and druggable pathways that contribute to secondary infarct growth after stroke. Among a variety of neuroimmunological events after acute brain ischemia, including microglial activation, brain leukocyte invasion, and secretion of pro-inflammatory factors, lymphocytes have been identified as the key leukocyte subpopulation driving the neuroinflammatory response and contributing to stroke outcome. Several studies have shown that pro-inflammatory lymphocyte subpopulations worsen stroke outcome and that inhibiting their invasion to the injured brain is neuroprotective. In contrast to the effector functions of pro-inflammatory lymphocytes, regulatory T cells (Treg) are critically involved in maintaining immune homeostasis and have been characterized as disease-limiting protective cells in several inflammatory conditions, particularly in primary inflammatory diseases of the central nervous system (CNS). However, due to the complex function of regulatory cells in immune homeostasis and disease, divergent findings have been described for the role of Treg in stroke models. Emerging evidence suggests that this discrepancy arises from potentially differing functions of Treg depending on the predominant site of action within the neurovascular unit and the surrounding inflammatory milieu. This article will provide a comprehensive review of current findings on Treg in brain ischemia models and discuss potential reasons for the observed discrepancies. PMID:27030356

  19. Pattern of cerebral glucose metabolism on F-18 FDG brain PET during vomiting and symptom free periods in cyclic vomiting syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Yu Kyeong; Lee, Dong Soo; Kang, Eun Joo; Seo, Jeong Kee; Yeo, Jeong Seok; Chung, June Key; Lee, Myung Chul [College of Medicine, Seoul National Univ., Seoul (Korea, Republic of)

    2001-06-01

    Cyclic Vomiting Syndrome (CVS) is characterized by recurrent, periodic, self-limiting vomiting. However, its pathogenesis is not yet established. We investigated the changes of the cerebral glucose metabolism using F-18 FDG during the vomiting attack and symptom free period in two children with CVS. FDG PET study showed the markedly increased metabolism in both temporal lobes and also in the medulla and cerebellum during the vomiting period. Also, FDG PET showed the decreased metabolism in the parieto-occipital and occipital areas during the in vomiting period. The area with decreased metabolism seemed to be related with the region showing abnormalities in EEG and perfusion SPECT studies. We expect that what we observed would be a helpful finding in clarifying the pathogenesis of the CVS.

  20. Sex Hormones and Their Receptors Regulate Liver Energy Homeostasis

    Directory of Open Access Journals (Sweden)

    Minqian Shen

    2015-01-01

    Full Text Available The liver is one of the most essential organs involved in the regulation of energy homeostasis. Hepatic steatosis, a major manifestation of metabolic syndrome, is associated with imbalance between lipid formation and breakdown, glucose production and catabolism, and cholesterol synthesis and secretion. Epidemiological studies show sex difference in the prevalence in fatty liver disease and suggest that sex hormones may play vital roles in regulating hepatic steatosis. In this review, we summarize current literature and discuss the role of estrogens and androgens and the mechanisms through which estrogen receptors and androgen receptors regulate lipid and glucose metabolism in the liver. In females, estradiol regulates liver metabolism via estrogen receptors by decreasing lipogenesis, gluconeogenesis, and fatty acid uptake, while enhancing lipolysis, cholesterol secretion, and glucose catabolism. In males, testosterone works via androgen receptors to increase insulin receptor expression and glycogen synthesis, decrease glucose uptake and lipogenesis, and promote cholesterol storage in the liver. These recent integrated concepts suggest that sex hormone receptors could be potential promising targets for the prevention of hepatic steatosis.

  1. GLUT, SGLT, and SWEET: Structural and mechanistic investigations of the glucose transporters.

    Science.gov (United States)

    Deng, Dong; Yan, Nieng

    2016-03-01

    Glucose is the primary fuel to life on earth. Cellular uptake of glucose is a fundamental process for metabolism, growth, and homeostasis. Three families of secondary glucose transporters have been identified in human, including the major facilitator superfamily glucose facilitators GLUTs, the sodium-driven glucose symporters SGLTs, and the recently identified SWEETs. Structures of representative members or their prokaryotic homologs of all three families were obtained. This review focuses on the recent advances in the structural elucidation of the glucose transporters and the mechanistic insights derived from these structures, including the molecular basis for substrate recognition, alternating access, and stoichiometric coupling of co-transport. PMID:26650681

  2. Hyperbaric oxygen therapy or hydroxycobalamin attenuates surges in brain interstitial lactate and glucose; and hyperbaric oxygen improves respiratory status in cyanide-intoxicated rats

    DEFF Research Database (Denmark)

    Lawson-Smith, P; Olsen, Niels Vidiendal; Hyldegaard, O

    2011-01-01

    Cyanide (CN) intoxication inhibits cellular oxidative metabolism and may result in brain damage. Hydroxycobalamin (OHCob) is one among other antidotes that may be used following intoxication with CN. Hyperbaric oxygen (HBO2) is recommended when supportive measures or antidotes fail. However...... to four groups receiving potassium CN (KCN) 5.4 mg/kg or vehicle intra-arterially: 1) vehicle-treated control rats; 2) KCN-poisoned rats; 3) KCN-poisoned rats receiving hydroxycobalamin (25 mg); and 4) KCN-poisoned rats treated with HBO2 (284 kPa for 90 minutes). KCN alone caused a prompt increase...

  3. At the centennial of Michaelis and Menten, competing Michaelis-Menten steps explain effect of GLP-1 on blood-brain transfer and metabolism of glucose

    DEFF Research Database (Denmark)

    Jensen, Michael Gejl; Rungby, Jørgen; Brock, Birgitte;

    2014-01-01

    mellitus. GLP-1 interacts with peripheral functions in which the autonomic nervous system plays an important role, and emerging preclinical findings indicate a potential neuroprotective role of the peptide, e.g., in models of stroke and in neurodegenerative disorders. A century ago, Leonor Michaelis......Glucagon-like peptide-1 (GLP-1) is a potent insulinotropic incretin hormone with pancreatic and extrapancreatic effects. Studies reveal significant effects in regions of brain tissue that regulate appetite and satiety. The effects cause that mimetics of GLP-1 serves as treatment of type 2 diabetes...

  4. Regulation of systemic energy homeostasis by serotonin in adipose tissues.

    Science.gov (United States)

    Oh, Chang-Myung; Namkung, Jun; Go, Younghoon; Shong, Ko Eun; Kim, Kyuho; Kim, Hyeongseok; Park, Bo-Yoon; Lee, Ho Won; Jeon, Yong Hyun; Song, Junghan; Shong, Minho; Yadav, Vijay K; Karsenty, Gerard; Kajimura, Shingo; Lee, In-Kyu; Park, Sangkyu; Kim, Hail

    2015-04-13

    Central serotonin (5-HT) is an anorexigenic neurotransmitter in the brain. However, accumulating evidence suggests peripheral 5-HT may affect organismal energy homeostasis. Here we show 5-HT regulates white and brown adipose tissue function. Pharmacological inhibition of 5-HT synthesis leads to inhibition of lipogenesis in epididymal white adipose tissue (WAT), induction of browning in inguinal WAT and activation of adaptive thermogenesis in brown adipose tissue (BAT). Mice with inducible Tph1 KO in adipose tissues exhibit a similar phenotype as mice in which 5-HT synthesis is inhibited pharmacologically, suggesting 5-HT has localized effects on adipose tissues. In addition, Htr3a KO mice exhibit increased energy expenditure and reduced weight gain when fed a high-fat diet. Treatment with an Htr2a antagonist reduces lipid accumulation in 3T3-L1 adipocytes. These data suggest important roles for adipocyte-derived 5-HT in controlling energy homeostasis.

  5. Effect of Cinnamon Tea on Postprandial Glucose Concentration

    OpenAIRE

    Maria Alexandra Bernardo; Maria Leonor Silva; Elisabeth Santos; Margarida Maria Moncada; José Brito; Luis Proença; Jaipaul Singh; Maria Fernanda de Mesquita

    2015-01-01

    Glycaemic control, in particular at postprandial period, has a key role in prevention of different diseases, including diabetes and cardiovascular events. Previous studies suggest that postprandial high blood glucose levels (BGL) can lead to an oxidative stress status, which is associated with metabolic alterations. Cinnamon powder has demonstrated a beneficial effect on postprandial glucose homeostasis in animals and human models. The purpose of this study is to investigate the effect of cin...

  6. Fat Distribution and Glucose Intolerance Among Greenland Inuit

    OpenAIRE

    Jørgensen, Marit Eika; Borch-Johnsen, Knut; Stolk, Ronald; Bjerregaard, Peter

    2013-01-01

    OBJECTIVE A high amount of subcutaneous fat is suggested to explain the observation of lower obesity-associated metabolic risk among Inuit than among Europeans. We examined the association between measures of obesity (visceral adipose tissue [VAT], subcutaneous adipose tissue [SAT], BMI, waist circumference [WC], and percentage of body fat) and the indices of glucose metabolism (fasting and 2-h glucose levels, insulin resistance per homeostasis model assessment [HOMA-IR], and the insulin sens...

  7. Metabolomic Profiling of Post-Mortem Brain Reveals Changes in Amino Acid and Glucose Metabolism in Mental Illness Compared with Controls.

    Science.gov (United States)

    Zhang, Rong; Zhang, Tong; Ali, Ali Muhsen; Al Washih, Mohammed; Pickard, Benjamin; Watson, David G

    2016-01-01

    Metabolomic profiling was carried out on 53 post-mortem brain samples from subjects diagnosed with schizophrenia, depression, bipolar disorder (SDB), diabetes, and controls. Chromatography on a ZICpHILIC column was used with detection by Orbitrap mass spectrometry. Data extraction was carried out with m/z Mine 2.14 with metabolite searching against an in-house database. There was no clear discrimination between the controls and the SDB samples on the basis of a principal components analysis (PCA) model of 755 identified or putatively identified metabolites. Orthogonal partial least square discriminant analysis (OPLSDA) produced clear separation between 17 of the controls and 19 of the SDB samples (R2CUM 0.976, Q2 0.671, p-value of the cross-validated ANOVA score 0.0024). The most important metabolites producing discrimination were the lipophilic amino acids leucine/isoleucine, proline, methionine, phenylalanine, and tyrosine; the neurotransmitters GABA and NAAG and sugar metabolites sorbitol, gluconic acid, xylitol, ribitol, arabinotol, and erythritol. Eight samples from diabetic brains were analysed, six of which grouped with the SDB samples without compromising the model (R2 CUM 0.850, Q2 CUM 0.534, p-value for cross-validated ANOVA score 0.00087). There appears on the basis of this small sample set to be some commonality between metabolic perturbations resulting from diabetes and from SDB. PMID:27076878

  8. Alpha Klotho and phosphate homeostasis

    OpenAIRE

    Bian, Ao; Xing, Changying; Hu, Ming Chang

    2014-01-01

    The Klotho family consists of three single-pass transmembrane proteins—αKlotho, βKlotho and γKlotho. Each of them combines with fibroblast growth factor (FGF) receptors (FGFRs) to form receptor complexes for various FGF’s. αKlotho is a co-receptor for physiological FGF23 signaling and appears essential for FGF23-mediated regulation of mineral metabolism. αKlotho protein also plays a FGF23-independent role in phosphate homeostasis. Animal experimental studies and clinical observations have dem...

  9. Direct neuronal glucose uptake Heralds activity-dependent increases in cerebral metabolism

    DEFF Research Database (Denmark)

    Lundgaard, Iben; Li, Baoman; Xie, Lulu;

    2015-01-01

    Metabolically, the brain is a highly active organ that relies almost exclusively on glucose as its energy source. According to the astrocyte-to-neuron lactate shuttle hypothesis, glucose is taken up by astrocytes and converted to lactate, which is then oxidized by neurons. Here we show, using two...... of glucose uptake as visualized by functional brain imaging....

  10. A physiologist's view of homeostasis.

    Science.gov (United States)

    Modell, Harold; Cliff, William; Michael, Joel; McFarland, Jenny; Wenderoth, Mary Pat; Wright, Ann

    2015-12-01

    Homeostasis is a core concept necessary for understanding the many regulatory mechanisms in physiology. Claude Bernard originally proposed the concept of the constancy of the "milieu interieur," but his discussion was rather abstract. Walter Cannon introduced the term "homeostasis" and expanded Bernard's notion of "constancy" of the internal environment in an explicit and concrete way. In the 1960s, homeostatic regulatory mechanisms in physiology began to be described as discrete processes following the application of engineering control system analysis to physiological systems. Unfortunately, many undergraduate texts continue to highlight abstract aspects of the concept rather than emphasizing a general model that can be specifically and comprehensively applied to all homeostatic mechanisms. As a result, students and instructors alike often fail to develop a clear, concise model with which to think about such systems. In this article, we present a standard model for homeostatic mechanisms to be used at the undergraduate level. We discuss common sources of confusion ("sticky points") that arise from inconsistencies in vocabulary and illustrations found in popular undergraduate texts. Finally, we propose a simplified model and vocabulary set for helping undergraduate students build effective mental models of homeostatic regulation in physiological systems.

  11. Delayed ß-cell response and glucose intolerance in young women with Turner syndrome

    DEFF Research Database (Denmark)

    Hjerrild, Britta Eilersen; Holst, Jens Juul; Juhl, Claus;

    2011-01-01

    BACKGROUND: To investigate glucose homeostasis in detail in Turner syndrome (TS), where impaired glucose tolerance (IGT) and type 2 diabetes are frequent. METHODS: Cross sectional study of women with Turner syndrome (TS)(n = 13) and age and body mass index matched controls (C) (n = 13), evaluated...

  12. Experimental Periodontitis Results in Prediabetes and Metabolic Alterations in Brain, Liver and Heart: Global Untargeted Metabolomic Analyses

    Science.gov (United States)

    Ilievski, Vladimir; Kinchen, Jason M; Prabhu, Ramya; Rim, Fadi; Leoni, Lara; Unterman, Terry G.; Watanabe, Keiko

    2016-01-01

    Results from epidemiological studies suggest that there is an association between periodontitis and prediabetes, however, causality is not known. The results from our previous studies suggest that induction of periodontitis leads to hyperinsulinemia glucose intolerance and insulin resistance, all hallmarks of prediabetes. However, global effects of periodontitis on critical organs in terms of metabolic alterations are unknown. We determined the metabolic effects of periodontitis on brain, liver, heart and plasma resulting from Porphyromonas gingivalis induced periodontitis in mice. Periodontitis was induced by oral application of the periodontal pathogen, Porphyromonas gingivalis for 22 weeks. Global untargeted biochemical profiles in samples from these organs/plasma were determined by liquid and gas chromatography/mass spectrometry and compared between controls and animals with periodontitis. Oral application of Porphyromonas gingivalis induced chronic periodontitis and hallmarks of prediabetes. The results of sample analyses indicated a number of changes in metabolic readouts, including changes in metabolites related to glucose and arginine metabolism, inflammation and redox homeostasis. Changes in biochemicals suggested subtle systemic effects related to periodontal disease, with increases in markers of inflammation and oxidative stress most prominent in the liver. Signs of changes in redox homeostasis were also seen in the brain and heart. Elevated bile acids in liver were suggestive of increased biosynthesis, which may reflect changes in liver function. Interestingly, signs of decreasing glucose availability were seen in the brain. In all three organs and plasma, there was a significant increase in the microbiome-derived bioactive metabolite 4-ethylphenylsulfate sulfate in animals with periodontitis. The results of metabolic profiling suggest that periodontitis/bacterial products alter metabolomic signatures of brain, heart, liver, and plasma in the

  13. Parkin Protects against Oxygen-Glucose Deprivation/Reperfusion Insult by Promoting Drp1 Degradation

    Science.gov (United States)

    Tang, Jiayu; Hu, Zhiping; Tan, Jieqiong; Yang, Sonlin

    2016-01-01

    Ischemic stroke results in severe brain damage and remains one of the leading causes of death and disability worldwide. Effective neuroprotective therapies are needed to reduce brain damage resulting from ischemic stroke. Mitochondria are crucial for cellular energy production and homeostasis. Modulation of mitochondrial function mediates neuroprotection against ischemic brain damage. Dynamin-related protein 1 (Drp1) and parkin play a key role in regulating mitochondrial dynamics. They are potential therapeutic targets for neuroprotection in ischemic stroke. Protective effects of parkin-Drp1 pathway on mitochondria were assessed in a cellular ischemia-reperfusion injury model. Mouse neuroblastoma Neuro2a (N2a) cells were subjected to oxygen-glucose deprivation/reperfusion (OGDR) insult. OGDR induces mitochondrial fragmentation. The expression of Drp1 protein is increased after OGDR insult, while the parkin protein level is decreased. The altered protein level of Drp1 after OGDR injury is mediated by parkin through ubiquitin proteasome system (UPS). Drp1 depletion protects against OGDR induced mitochondrial damage and apoptosis. Meanwhile, parkin overexpression protects against OGDR induced apoptosis and mitochondrial dysfunction, which is attenuated by increased expression of Drp1. Our data demonstrate that parkin protects against OGDR insult through promoting degradation of Drp1. This neuroprotective potential of parkin-Drp1 pathway against OGDR insult will pave the way for developing novel neuroprotective agents for cerebral ischemia-reperfusion related disorders. PMID:27597885

  14. Glucose test (image)

    Science.gov (United States)

    ... person with diabetes constantly manages their blood's sugar (glucose) levels. After a blood sample is taken and tested, it is determined whether the glucose levels are low or high. If glucose levels ...

  15. Low Blood Glucose (Hypoglycemia)

    Science.gov (United States)

    ... Other Dental Problems Diabetic Eye Disease Low Blood Glucose (Hypoglycemia) What is hypoglycemia? Hypoglycemia, also called low ... actions can also help prevent hypoglycemia: Check blood glucose levels Knowing your blood glucose level can help ...

  16. Epigenetic Regulation of Cholesterol Homeostasis

    Directory of Open Access Journals (Sweden)

    Steve eMeaney

    2014-09-01

    Full Text Available Although best known as a risk factor for cardiovascular disease, cholesterol is a vital component of all mammalian cells. In addition to key structural roles, cholesterol is a vital biochemical precursor for numerous biologically important compounds including oxysterols and bile acids, as well as acting as an activator of critical morphogenic systems (e.g. the Hedgehog system. A variety of sophisticated regulatory mechanisms interact to coordinate the overall level of cholesterol in cells, tissues and the entire organism. Accumulating evidence indicates that in additional to the more ‘traditional’ regulatory schemes, cholesterol homeostasis is also under the control of epigenetic mechanisms such as histone acetylation and DNA methylation. The available evidence supporting a role for these mechanisms in the control of cholesterol synthesis, elimination, transport and storage are the focus of this review.

  17. Copper Homeostasis in Mycobacterium tuberculosis

    Science.gov (United States)

    Shi, Xiaoshan; Darwin, K. Heran

    2015-01-01

    Copper (Cu) is a trace element essential for the growth and development of almost all organisms, including bacteria. However, Cu overload in most systems is toxic. Studies show Cu accumulates in macrophage phagosomes infected with bacteria, suggesting Cu provides an innate immune mechanism to combat invading pathogens. To counteract the host-supplied Cu, increasing evidence suggests that bacteria have evolved Cu resistance mechanisms to facilitate their pathogenesis. In particular, Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, has evolved multiple pathways to respond to Cu. Here, we summarize what is currently known about Cu homeostasis in Mtb and discuss potential sources of Cu encountered by this and other pathogens in a mammalian host. PMID:25614981

  18. Increased postabsorptive and exercise-induced whole-body glucose production in patients with chronic obstructive pulmonary disease

    NARCIS (Netherlands)

    F.M.E. Franssen; H.P. Sauerwein; M.T. Ackermans; E.P.A. Rutten; E.F.M. Wouters; A.M.W.J. Schols

    2011-01-01

    Skeletal muscle biopsy studies have consistently shown a decreased oxidative phenotype in patients with moderate to severe chronic obstructive pulmonary disease (COPD). Limited information is available regarding potential adaptations or abnormalities in anaerobic metabolism and glucose homeostasis.

  19. The Role of PAS Kinase in PASsing the Glucose Signal

    Directory of Open Access Journals (Sweden)

    Julianne H. Grose

    2010-06-01

    Full Text Available PAS kinase is an evolutionarily conserved nutrient responsive protein kinase that regulates glucose homeostasis. Mammalian PAS kinase is activated by glucose in pancreatic beta cells, and knockout mice are protected from obesity, liver triglyceride accumulation, and insulin resistance when fed a high-fat diet. Yeast PAS kinase is regulated by both carbon source and cell integrity stress and stimulates the partitioning of glucose toward structural carbohydrate biosynthesis. In our current model for PAS kinase regulation, a small molecule metabolite binds the sensory PAS domain and activates the enzyme. Although bona fide PAS kinase substrates are scarce, in vitro substrate searches provide putative targets for exploration.

  20. Hydrogen sulfide induced disruption of Na+ homeostasis in the cortex.

    Science.gov (United States)

    Chao, Dongman; He, Xiaozhou; Yang, Yilin; Balboni, Gianfranco; Salvadori, Severo; Kim, Dong H; Xia, Ying

    2012-07-01

    Maintenance of ionic balance is essential for neuronal functioning. Hydrogen sulfide (H(2)S), a known toxic environmental gaseous pollutant, has been recently recognized as a gasotransmitter involved in numerous biological processes and is believed to play an important role in the neural activities under both physiological and pathological conditions. However, it is unclear if it plays any role in maintenance of ionic homeostasis in the brain under physiological/pathophysiological conditions. Here, we report by directly measuring Na(+) activity using Na(+) selective electrodes in mouse cortical slices that H(2)S donor sodium hydrosulfide (NaHS) increased Na(+) influx in a concentration-dependent manner. This effect could be partially blocked by either Na(+) channel blocker or N-methyl-D-aspartate receptor (NMDAR) blocker alone or almost completely abolished by coapplication of both blockers but not by non-NMDAR blocker. These data suggest that increased H(2)S in pathophysiological conditions, e.g., hypoxia/ischemia, potentially causes a disruption of ionic homeostasis by massive Na(+) influx through Na(+) channels and NMDARs, thus injuring neural functions. Activation of delta-opioid receptors (DOR), which reduces Na(+) currents/influx in normoxia, had no effect on H(2)S-induced Na(+) influx, suggesting that H(2)S-induced disruption of Na(+) homeostasis is resistant to DOR regulation and may play a major role in neuronal injury in pathophysiological conditions, e.g., hypoxia/ischemia.

  1. 2维和3维采集对脑葡萄糖代谢半定量指标的影响%Effect on Semiquantitive Analysis for Brain Glucose Metabolism with 2 or 3 Dimensional PET Scan Respectively

    Institute of Scientific and Technical Information of China (English)

    苏玉盛; 马云川; 李德鹏; 张琳瑛; 尚建文

    2001-01-01

    目的研究2维(2D)和3维(3D)采集对脑葡萄糖代谢半定量指标有无明显影响,在实际工作中可否灵活采用.方法 36例无神经疾病病史、症状和体征;脑磁共振成像无异常的受检者分为2组,其中2D组15例,3D组21例.静脉注射18F-FDG后行PET脑断层显像,经计算机滤波反投影重建获得横断面、冠状面、矢状面断层影像.横断面影像经处理层厚为0.5cm,按常规分别选取代表双侧额叶、顶叶、颞叶、枕叶、小脑皮质的三层影像,勾画出各结构的边界,依据体重和注射剂量等参数求出平均SUV值.将上述各部位的平均SUV值进行左右比较,计算出比值,称R(L/R).将各脑叶的平均SUV值与小脑平均SUV值进行比较,计算出比值,称R(C/Cb).上述数据进行统计学处理.结果 2D和3D两组双侧额叶、顶叶、颞叶、枕叶、小脑皮质的平均SUV值,R(L/R)和R(C/Cb)皆差异无显著性.结论 2D和3D采集各有优缺点,当采用SUV作为半定量指标对脑葡萄糖代谢状况进行评价时,两种采集方式对结果无明显影响,故可根据实际情况,灵活选择不同的采集方式.%objective To explore the effect on semiquantitive analysis for brain glucose metabolism with 2 or 3 dimensional PET scan respectively.Methods 36 normal persons were divided into two group,15 for 2D,21 for 3D.PET scans were done after 40 minutes of injection of FDG .The transaxial,the coronal,the saggital were gotten through computer reconstruction. The transaxial slice density was 0.5cm. The borders ofbilateral frontal lobes , bilateral parietal lobes , bilateral tempt lobes ,bilateral occipital lobes and bilateral cerebellum were drawn. According to ROI, weight and injection dose of FDG,mean SUVs in all above lobes were gotten. R(L/R)s from Mean SUVs in the left lobes via those in the right were caculated. R(C/CB)s from mean SUVs in different brain lobes via those different

  2. Metabolic Alterations Associated to Brain Dysfunction in Diabetes

    OpenAIRE

    João M N Duarte

    2015-01-01

    From epidemiological studies it is known that diabetes patients display increased risk of developing dementia. Moreover, cognitive impairment and Alzheimer’s disease (AD) are also accompanied by impaired glucose homeostasis and insulin signalling. Although there is plenty of evidence for a connection between insulin-resistant diabetes and AD, definitive linking mechanisms remain elusive. Cerebrovascular complications of diabetes, alterations in glucose homeostasis and insulin signalling, as w...

  3. Gut Microbiota: The Brain Peacekeeper

    OpenAIRE

    Mu, Chunlong; Yang, Yuxiang; Zhu, Weiyun

    2016-01-01

    Gut microbiota regulates intestinal and extraintestinal homeostasis. Accumulating evidence suggests that the gut microbiota may also regulate brain function and behavior. Results from animal models indicate that disturbances in the composition and functionality of some microbiota members are associated with neurophysiological disorders, strengthening the idea of a microbiota–gut–brain axis and the role of microbiota as a “peacekeeper” in the brain health. Here, we review recent discoveries on...

  4. Regulation of plasma lipid homeostasis by hepatic lipoprotein lipase in adult mice.

    Science.gov (United States)

    Liu, Gan; Xu, Jun-Nan; Liu, Dong; Ding, Qingli; Liu, Meng-Na; Chen, Rong; Fan, Mengdi; Zhang, Ye; Zheng, Chao; Zou, Da-Jin; Lyu, Jianxin; Zhang, Weiping J

    2016-07-01

    LPL is a pivotal rate-limiting enzyme to catalyze the hydrolysis of TG in circulation, and plays a critical role in regulating lipid metabolism. However, little attention has been paid to LPL in the adult liver due to its relatively low expression. Here we show that endogenous hepatic LPL plays an important physiological role in plasma lipid homeostasis in adult mice. We generated a mouse model with the Lpl gene specifically ablated in hepatocytes with the Cre/LoxP approach, and found that specific deletion of hepatic Lpl resulted in a significant decrease in plasma LPL contents and activity. As a result, the postprandial TG clearance was markedly impaired, and plasma TG and cholesterol levels were significantly elevated. However, deficiency of hepatic Lpl did not change the liver TG and cholesterol contents or glucose homeostasis. Taken together, our study reveals that hepatic LPL is involved in the regulation of plasma LPL activity and lipid homeostasis. PMID:27234787

  5. Regulation of. beta. -cell glucose transporter gene expression

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Ling; Alam, Tausif; Johnson, J.H.; Unger, R.H. (Univ. of Texas Southwestern Medical Center, Dallas (USA) Department of Veterans Affairs Medical Center, Dallas, TX (USA)); Hughes, S.; Newgard, C.B. (Univ. of Texas Southwestern Medical Center, Dallas (USA))

    1990-06-01

    It has been postulated that a glucose transporter of {beta} cells (GLUT-2) may be important in glucose-stimulated insulin secretion. To determine whether this transporter is constitutively expressed or regulated, the authors subjected conscious unrestrained Wistar rats to perturbations in glucose homeostasis and quantitated {beta}-cell GLUT-2 mRNA by in situ hybridization. After 3 hr of hypoglycemia, GLUT-2 and proinsulin mRNA signal densities were reduced by 25% of the level in control rats. After 4 days, GLUT-2 and proinsulin mRNA densities were reduced by 85% and 65%, respectively. After 12 days of hypoglycemia, the K{sub m} for 3-O-methyl-D-glucose transport in isolated rat islets, normally 18-20 mM, was 2.5 mM. This provides functional evidence of a profound reduction of high K{sub m} glucose transporter in {beta} cells. In contrast, GLUT-2 was only slightly reduced by hypoglycemia in liver. To determine the effect of prolonged hyperglycemia, they also infused animals with 50% (wt/vol) glucose for 5 days. Hyperglycemic clamping increased GLUT-2 mRNA by 46% whereas proinsulin mRNA doubled. They conclude that GLUT-2 expression in {beta} cells, but not liver, is subject to regulation by certain perturbations in blood glucose homeostasis.

  6. Regulation of β-cell glucose transporter gene expression

    International Nuclear Information System (INIS)

    It has been postulated that a glucose transporter of β cells (GLUT-2) may be important in glucose-stimulated insulin secretion. To determine whether this transporter is constitutively expressed or regulated, the authors subjected conscious unrestrained Wistar rats to perturbations in glucose homeostasis and quantitated β-cell GLUT-2 mRNA by in situ hybridization. After 3 hr of hypoglycemia, GLUT-2 and proinsulin mRNA signal densities were reduced by 25% of the level in control rats. After 4 days, GLUT-2 and proinsulin mRNA densities were reduced by 85% and 65%, respectively. After 12 days of hypoglycemia, the Km for 3-O-methyl-D-glucose transport in isolated rat islets, normally 18-20 mM, was 2.5 mM. This provides functional evidence of a profound reduction of high Km glucose transporter in β cells. In contrast, GLUT-2 was only slightly reduced by hypoglycemia in liver. To determine the effect of prolonged hyperglycemia, they also infused animals with 50% (wt/vol) glucose for 5 days. Hyperglycemic clamping increased GLUT-2 mRNA by 46% whereas proinsulin mRNA doubled. They conclude that GLUT-2 expression in β cells, but not liver, is subject to regulation by certain perturbations in blood glucose homeostasis

  7. Neuronal expression of glucosylceramide synthase in central nervous system regulates body weight and energy homeostasis.

    Directory of Open Access Journals (Sweden)

    Viola Nordström

    Full Text Available Hypothalamic neurons are main regulators of energy homeostasis. Neuronal function essentially depends on plasma membrane-located gangliosides. The present work demonstrates that hypothalamic integration of metabolic signals requires neuronal expression of glucosylceramide synthase (GCS; UDP-glucose:ceramide glucosyltransferase. As a major mechanism of central nervous system (CNS metabolic control, we demonstrate that GCS-derived gangliosides interacting with leptin receptors (ObR in the neuronal membrane modulate leptin-stimulated formation of signaling metabolites in hypothalamic neurons. Furthermore, ganglioside-depleted hypothalamic neurons fail to adapt their activity (c-Fos in response to alterations in peripheral energy signals. Consequently, mice with inducible forebrain neuron-specific deletion of the UDP-glucose:ceramide glucosyltransferase gene (Ugcg display obesity, hypothermia, and lower sympathetic activity. Recombinant adeno-associated virus (rAAV-mediated Ugcg delivery to the arcuate nucleus (Arc significantly ameliorated obesity, specifying gangliosides as seminal components for hypothalamic regulation of body energy homeostasis.

  8. Chromium supplementation improved post-stroke brain infarction and hyperglycemia.

    Science.gov (United States)

    Chen, Wen-Ying; Mao, Frank Chiahung; Liu, Chia-Hsin; Kuan, Yu-Hsiang; Lai, Nai-Wei; Wu, Chih-Cheng; Chen, Chun-Jung

    2016-04-01

    Hyperglycemia is common after acute stroke and is associated with a worse outcome of stroke. Thus, a better understanding of stress hyperglycemia is helpful to the prevention and therapeutic treatment of stroke. Chromium is an essential nutrient required for optimal insulin activity and normal carbohydrate and lipid metabolism. Beyond its nutritional effects, dietary supplement of chromium causes beneficial outcomes against several diseases, in particular diabetes-associated complications. In this study, we investigated whether post-stroke hyperglycemia involved chromium dynamic mobilization in a rat model of permanent focal cerebral ischemia and whether dietary supplement of chromium improved post-stroke injury and alterations. Stroke rats developed brain infarction, hyperglycemia, hyperinsulinemia, glucose intolerance, and insulin resistance. Post-stroke hyperglycemia was accompanied by elevated secretion of counter-regulatory hormones including glucagon, corticosterone, and norepinephrine, decreased insulin signaling in skeletal muscles, and increased hepatic gluconeogenesis. Correlation studies revealed that counter-regulatory hormone secretion showed a positive correlation with chromium loss and blood glucose increased together with chromium loss. Daily chromium supplementation increased tissue chromium levels, attenuated brain infarction, improved hyperglycemia, and decreased plasma levels of glucagon and corticosterone in stroke rats. Our findings suggest that stroke rats show disturbance of tissue chromium homeostasis with a net loss through urinary excretion and chromium mobilization and loss might be an alternative mechanism responsible for post-stroke hyperglycemia. PMID:26477944

  9. Hypothalamic BOLD response to glucose intake and hypothalamic volume are similar in anorexia nervosa and healthy control subjects

    Directory of Open Access Journals (Sweden)

    Anna M Van Opstal

    2015-05-01

    Full Text Available Background. Inconsistent findings about the neurobiology of Anorexia Nervosa (AN hinder the development of effective treatments for this severe mental disorder. Therefore the need arises for elucidation of neurobiological factors involved in the pathophysiology of AN. The hypothalamus plays a key role in the neurobiological processes that govern food intake and energy homeostasis, processes that are disturbed in anorexia nervosa (AN. The present study will assess the hypothalamic response to energy intake and the hypothalamic structure in patients with AN and healthy controls. Methods. 10 women aged 18-30 years diagnosed with AN and 11 healthy, lean (BMI <23 kg/m2 women in the same age range were recruited. We used functional magnetic resonance imaging (MRI to determine function of the hypothalamus in response to glucose. Structural MRI was used to determine differences in hypothalamic volume and local grey volume using manual segmentation and voxel-based morphometry.Results. No differences were found in hypothalamic volume and neuronal activity in response to a glucose load between the patients and controls. Whole brain structural analysis showed a significant decrease in grey matter volume in the cingulate cortex in the AN patients, bilaterally.Conclusions. We argue that in spite of various known changes in the hypothalamus the direct hypothalamic response to glucose intake is similar in AN patients and healthy controls.

  10. Calcium homeostasis modulator (CALHM) ion channels.

    Science.gov (United States)

    Ma, Zhongming; Tanis, Jessica E; Taruno, Akiyuki; Foskett, J Kevin

    2016-03-01

    Calcium homeostasis modulator 1 (CALHM1), formerly known as FAM26C, was recently identified as a physiologically important plasma membrane ion channel. CALHM1 and its Caenorhabditis elegans homolog, CLHM-1, are regulated by membrane voltage and extracellular Ca(2+) concentration ([Ca(2+)]o). In the presence of physiological [Ca(2+)]o (∼1.5 mM), CALHM1 and CLHM-1 are closed at resting membrane potentials but can be opened by strong depolarizations. Reducing [Ca(2+)]o increases channel open probability, enabling channel activation at negative membrane potentials. Together, voltage and Ca(2+) o allosterically regulate CALHM channel gating. Through convergent evolution, CALHM has structural features that are reminiscent of connexins and pannexins/innexins/LRRC8 (volume-regulated anion channel (VRAC)) gene families, including four transmembrane helices with cytoplasmic amino and carboxyl termini. A CALHM1 channel is a hexamer of CALHM1 monomers with a functional pore diameter of ∼14 Å. CALHM channels discriminate poorly among cations and anions, with signaling molecules including Ca(2+) and ATP able to permeate through its pore. CALHM1 is expressed in the brain where it plays an important role in cortical neuron excitability induced by low [Ca(2+)]o and in type II taste bud cells in the tongue that sense sweet, bitter, and umami tastes where it functions as an essential ATP release channel to mediate nonsynaptic neurotransmitter release. CLHM-1 is expressed in C. elegans sensory neurons and body wall muscles, and its genetic deletion causes locomotion defects. Thus, CALHM is a voltage- and Ca(2+) o-gated ion channel, permeable to large cations and anions, that plays important roles in physiology. PMID:26603282

  11. Diabetic ketoacidosis, sodium glucose transporter-2 inhibitors and the kidney.

    Science.gov (United States)

    Palmer, Biff F; Clegg, Deborah J; Taylor, Simeon I; Weir, Matthew R

    2016-08-01

    Diabetic ketoacidosis is a serious metabolic condition that may occur in patients with either Type 1 or Type 2 diabetes. The accumulation of ketoacids in the serum is a consequence of insulin deficiency and glucagon excess. Sodium Glucose Transporter 2 (SGLT2) inhibitors are novel therapeutic treatments for improving glucose homeostasis in patients with diabetes. Through reductions in glucose reabsorption by the kidney, they lower serum glucose in patients with Type 2 diabetes and they improve glucose control whether used alone or in combination with other therapies. Mechanistically, these drugs increase serum ketoacids and increase glucagon production, which in some individuals, can lead to formation of diabetic ketoacidosis. This review will first focus in how the kidney normally handles ketoacids, and second will discuss how the SGLT2 inhibitors affect the kidney in such a way so as to enhance the risk for development of ketoacidosis in susceptible individuals.

  12. Central role of maladapted astrocytic plasticity in ischemic brain edema formation

    Directory of Open Access Journals (Sweden)

    Yu-Feng eWang

    2016-05-01

    Full Text Available Brain edema formation and the ensuing brain damages are the major cause of high mortality and long term disability following the occurrence of ischemic stroke. In this process, oxygen and glucose deprivation and the ensuing reperfusion injury play primary roles. In response to the ischemic insult, the neurovascular unit experiences both intracellular and extracellular edemas; the two processes are interactive closely under the driving of maladapted astrocytic plasticity. The astrocytic plasticity includes both morphologic and functional plasticity. The former involves a reactive gliosis and the ensuing glial retraction. It relates to the capacity of astrocytes to buffer changes in extracellular chemical levels, particularly K+ and glutamate, as well as the integrity of the blood-brain barrier. The latter involves the expression and activity of a series of ion and water transport proteins. These molecules are grouped together around glial fibrillary acidic protein and water channel protein aquaporin 4 to form functional networks, regulate hydromineral balance across cell membranes and maintain the integrity of the blood-brain barrier. Intense ischemic challenges can disrupt these capacities of astrocytes and result in their maladaptation. The maladapted astrocytic plasticity in ischemic stroke cannot only disrupt the hydromineral homeostasis across astrocyte membrane and the blood-brain barrier, but also lead to disorders of the whole neurovascular unit. This review focuses on how the maladapted astrocytic plasticity in ischemic stroke plays the central role in the brain edema formation.

  13. Blood Test: Glucose

    Science.gov (United States)

    ... Things to Know About Zika & Pregnancy Blood Test: Glucose KidsHealth > For Parents > Blood Test: Glucose Print A A A Text Size What's in ... de sangre: glucosa What It Is A blood glucose test measures the amount of glucose (the main ...

  14. Microbiota and the gut-brain axis.

    Science.gov (United States)

    Bienenstock, John; Kunze, Wolfgang; Forsythe, Paul

    2015-08-01

    Changes in gut microbiota can modulate the peripheral and central nervous systems, resulting in altered brain functioning, and suggesting the existence of a microbiota gut-brain axis. Diet can also change the profile of gut microbiota and, thereby, behavior. Effects of bacteria on the nervous system cannot be disassociated from effects on the immune system since the two are in constant bidirectional communication. While the composition of the gut microbiota varies greatly among individuals, alterations to the balance and content of common gut microbes may affect the production of molecules such as neurotransmitters, e.g., gamma amino butyric acid, and the products of fermentation, e.g., the short chain fatty acids butyrate, propionate, and acetate. Short chain fatty acids, which are pleomorphic, especially butyrate, positively influence host metabolism by promoting glucose and energy homeostasis, regulating immune responses and epithelial cell growth, and promoting the functioning of the central and peripheral nervous systems. In the future, the composition, diversity, and function of specific probiotics, coupled with similar, more detailed knowledge about gut microbiota, will potentially help in developing more effective diet- and drug-based therapies. PMID:26175487