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Sample records for abnormal glucose regulation

  1. Activin A Levels Are Associated With Abnormal Glucose Regulation in Patients With Myocardial Infarction

    Andersen, Geir Ø.; Ueland, Thor; Knudsen, Eva C.; Scholz, Hanne; Yndestad, Arne; Sahraoui, Afaf; Smith, Camilla; Lekva, Tove; Otterdal, Kari; Halvorsen, Bente; Seljeflot, Ingebjørg; Aukrust, Pål

    2011-01-01

    OBJECTIVE On the basis of the role of activin A in inflammation, atherogenesis, and glucose homeostasis, we investigated whether activin A could be related to glucometabolic abnormalities in patients with acute myocardial infarction (MI). RESEARCH DESIGN AND METHODS Activin A measurement and oral glucose tolerance tests (OGTTs) were performed in patients (n = 115) with acute MI, without previously known diabetes, and repeated after 3 months. Release of activin A and potential anti-inflammatory effects of activin A were measured in human endothelial cells. Activin A effects on insulin secretion and inflammation were tested in human pancreatic islet cells. RESULTS 1) In patients with acute MI, serum levels of activin A were significantly higher in those with abnormal glucose regulation (AGR) compared with those with normal glucose regulation. Activin A levels were associated with the presence of AGR 3 months later (adjusted odds ratio 5.1 [95% CI 1.73–15.17], P = 0.003). 2) In endothelial cells, glucose enhanced the release of activin A, whereas activin A attenuated the release of interleukin (IL)-8 and enhanced the mRNA levels of the antioxidant metallothionein. 3) In islet cells, activin A attenuated the suppressive effect of inflammatory cytokines on insulin release, counteracted the ability of these inflammatory cytokines to induce mRNA expression of IL-8, and induced the expression of transforming growth factor-β. CONCLUSIONS We found a significant association between activin A and newly detected AGR in patients with acute MI. Our in vitro findings suggest that this association represents a counteracting mechanism to protect against inflammation, hyperglycemia, and oxidative stress. PMID:21464440

  2. Association between extraversion personality and abnormal glucose regulation in young Korean women.

    Shim, Unjin; Oh, Jee-Young; Lee, Hyejin; Sung, Yeon-Ah; Kim, Han-Na; Kim, Hyung-Lae

    2014-01-01

    Depression and psychological distress are known to be associated with diabetes development as well as the disease progression including glycemic control and chronic complication, but relationship of personality with diabetes is controversial. We examined whether personality trait and the presence of abnormal glucose regulation (AGR; diabetes and pre-diabetes) are associated in young women. A total of 1,617 young women aged 19-39 years without previously diagnosed diabetes were participated voluntarily. Personality trait was assessed by self-reported questionnaire using the five-factor model (neuroticism, extraversion, openness to experience, agreeableness and conscientiousness) consisting of five-point scale ranging from 'strongly disagreeable' to 'strongly agreeable.' Glucose tolerance status was assessed by standard 75-g oral glucose tolerance test. One hundred and eleven women were newly diagnosed with AGR (6.9 %). Among five factors, only extraversion trait was significantly associated with AGR. Multiple linear regression analysis showed significant negative association between extraversion trait and 2-h post-load glucose after adjustment for age, BMI, systolic blood pressure, triglycerides, HDL cholesterol and family history of diabetes (β = -0.16, P = 0.026). Multiple logistic regression showed extraversion trait having a significant association with the presence of AGR after adjustment for the same covariates (OR 0.97, 95 % CI 0.95-0.99, P = 0.011). The frequency of AGR was significantly increased according to the decrease in extraversion score (P for trend with exact test = 0.047). In conclusion, extraversion may be an important personality trait having a beneficial effect on decreasing the risk of AGR.

  3. High prevalence of abnormal circadian blood pressure regulation and impaired glucose tolerance in adults with hypopituitarism.

    Krzyzanowska, K; Schnack, C; Mittermayer, F; Kopp, H P; Hofer, M; Kann, T; Schernthaner, G

    2005-09-01

    Patients with hypopituitarism have an increased mortality from cardiovascular events. Reduced nocturnal blood pressure decline (non-dipping) and impaired glucose tolerance are considered as cardiovascular risk factors. To evaluate the role of these risk factors in patients with hypopituitarism we determined the 24-hour blood pressure regulation and glucose tolerance status in hypopituitary patients with and without growth hormone (GH) deficiency. Sixty-one hypopituitary subjects 5 +/- 3 years after brain surgery because of macroadenoma, 61 patients with type 2 diabetes mellitus (T2DM), and 20 healthy controls were included. Forty-four hypopituitary patients were GH deficient and 28 of these on GH treatment. Non-dipping was observed in 41 % (n = 7) of hypopituitary subjects with normal GH release, in 46 % (n = 13) of patients on GH therapy, and in 69 % (n = 11) of untreated GH deficient patients. Untreated GH deficient patients had a higher systolic night/day ratio (1.00 +/- 0.03) compared to non GH deficient (0.92 +/- 0.02; p < 0.02) and GH treated hypopituitary patients (0.93 +/- 0.01; p < 0.02). The rate of non-dipping in hypopituitarism was comparable to that in T2DM. Pathologic glucose tolerance was diagnosed in 30 % of the hypopituitary patients. The prevalence of non-dipping was independent of glucose metabolism in hypopituitary patients. All controls had normal night time blood pressure fall and glucose metabolism. The high prevalence of nocturnal non-dipping and glucose intolerance detected in this cohort might contribute to the increased cardiovascular risk of hypopituitary patients.

  4. Impact of polymorphisms in WFS1 on prediabetic phenotypes in a population-based sample of middle-aged people with normal and abnormal glucose regulation

    Sparsø, T; Andersen, G; Albrechtsen, Anders

    2008-01-01

    interaction of WFS1 rs734312 on insulin release and insulin resistance we introduced Hotelling's T (2) test. Assuming bivariate normal distribution, we constructed standard error ellipses of the insulinogenic index and HOMA-IR when stratified according to glucose tolerance status around the means of each WFS1...... rs734312 genotype level. The interaction term between individuals with normal glucose tolerance and abnormal glucose regulation on the insulinogenic index and HOMA-IR was significantly associated with the traits (p = 0.0017). CONCLUSIONS/INTERPRETATION: Type 2 diabetes-associated risk alleles of WFS1...... are associated with estimates of a decreased pancreatic beta cell function among middle-aged individuals with abnormal glucose regulation....

  5. Treatment of Abnormal Glucose Regulation and Huge Ovarian Cysts with High Dose Insulin Glargine in an Infant with Leprechaunism - Case Report

    Ayşe Yasemin Çelik

    2010-12-01

    Full Text Available Introduction: Leprechaunism is a rare autosomal recessive disorder caused by mutations in the insulin receptor gene. In this report; we present a 75 days old infant with leprecahunism treated by high dose insulin glargine.Case Report: Yetmiş day old girl was diagnosed as leprechaunism because of the hyperglycemia, ketoacidosis and dysmorphic appearance. Huge cysts with multiple septa were determined in her ovaries. High dose insulin glargine were adjusted to achieve target blood glucose regulation. Huge ovarian cysts resolved by this treatment.Conclusion: Leprechaunism is characterized by intra-uterine and postnatal growth restriction, lipo-atrophy, characteristic facial features, severe acanthosis nigricans, abnormal glucose homeostasis, clitoromegaly and hirsutism. It is usually fatal within the 1st year of life because of diabetic ketoacidosis or recurrent infections. (Journal of Current Pediatrics 2010; 8: 119-22

  6. 妊娠期糖尿病高危因素与产后早发糖代谢异常的关系%Relationship between Risk Factors of GDM and Postpartum Early Abnormal Glucose Regulation

    莫小庆; 王子莲; 曹筱佩; 肖海鹏; 李延兵

    2011-01-01

    [Objective] To investigate the relationship between traditional risk factors of gestational diabetes mellitus (GDM) and pregnancy outcome as well as postpartum early abnormal glucose regulation. [Methods] Risk factors or 50 g oral glucose tolerance test (OGTT) were used to scan GDM in 3017 pregnant women, the 75 g OGTT were performed to confirm the diagnosis of GDM in those with positive results. GDM women were divided into two groups; women with risk factors (n = 143) and without risk factors (re = 175). All GDM women were recruited to take 75 g OGTT at 6-8 weeks and 6-12 months after delivery. [Results] Total 318 GDM were confirmed in those 3017 pregnant women. The prevalence of GDM in women with risk factors were higher than those without risk factors (41.81% vs 6.54%, P<0.01). Additionally, compare to those without risk factors, women with risk factors has higher pregnant complications, higher premature birth rate, and birth-weight. Also a higher incidence of early postpartum abnormal glucose tolerance was observed in those with GDM risk factors. Logistic regression analysis indicated that family history of diabetes and positive uric glucose were relative to the early postpartum abnormal glucose tolerance. [Conclusions] The GDM risk factors are not only the predictor of GDM, but also are relative to postpartum early abnormal glucose regulation. Among these risk factors, family history of diabetes and positive uric glucose are of greater contribution.%[目的]探讨妊娠期糖尿病(GDM)传统高危因素与妊娠结局及产后早发糖代谢异常的关系.[方法]3 017名孕妇以高危因素或50 g葡萄糖筛查试验进行GDM筛查,阳性者行75 g口服葡萄糖耐量试验(OGTT)确诊GDM,GDM孕妇分为高危因素组(G1组,n=143)与非高危因素组(G2组,n=175),并于产后6~8周及产后6~ 12月复查OGTT.[结果]3 017名孕妇中318例确诊GDM,存在高因危素的孕妇GDM患病率明显高于无高危因素的孕妇(41.81% VS 6.54

  7. Dietary Patterns and Glucose Tolerance Abnormalities in Chinese Adults

    He, Y.; Ma, G.; Zhai, F.; Li, Y.; Hu, Y.; Feskens, E.J.M.; Yang, X.

    2009-01-01

    OBJECTIVE To investigate the association of the dietary pattern with the presence of newly diagnosed glucose tolerance abnormalities among Chinese adults. RESEARCH DESIGN AND METHODS A total of 20,210 adults aged 45–69 years from the 2002 China National Nutrition and Health Survey were included. Inf

  8. Glucose abnormalities in Asian patients with chronic hepatitis C

    Bo Q

    2015-11-01

    Full Text Available Qingyan Bo,1 Roberto Orsenigo,2 Junyi Wang,1 Louis Griffel,3 Clifford Brass3 1Beijing Novartis Pharma Co. Ltd., Shanghai, People’s Republic of China; 2Novartis Pharma AG, Basel, Switzerland; 3Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA Abstract: Many studies have demonstrated a potential association between type 2 diabetes (T2D and hepatitis C virus infection in Western countries, while similar evidence is limited in Asia. We compared the prevalence of glucose abnormalities (impaired fasting glucose [IFG] and T2D and their risk factors between Asian and non-Asian chronic hepatitis C (CHC patients, and evaluated whether glucose abnormalities impacted the viral responses to peginterferon plus ribavirin treatment (current standard of care in most Asian countries. This study retrospectively analyzed data of 1,887 CHC patients from three Phase II/III studies with alisporivir (DEB025 as treatment for CHC. The chi-square test was used to compare the prevalence of IFG/T2D between Asian and non-Asian CHC patients, and logistic regression was used to adjust for sex, age, and cirrhosis status. Risk factors for IFG/T2D were evaluated using univariate and multivariate analysis. Our results indicated that the prevalence of IFG/T2D was high in both Asian and non-Asian CHC patients (23.0% vs 20.9%, and no significant difference was found between these two populations (adjusted odds ratio: 1.3, 95% confidence interval: 0.97, 1.7; P=0.08. Age, sex, and cirrhosis status were risk factors for IFG/T2D in both populations, while body mass index was positively associated with IFG/T2D in non-Asian but not in Asian participants. No significant differences in sustained virological response rates were seen between patients with normal fasting glucose and patients with IFG/T2D for both populations. These results demonstrate that the prevalence of glucose abnormalities in Asian CHC patients was similar to that in non-Asians, and glucose abnormalities had

  9. Cerebral glucose metabolic abnormality in patients with congenital scoliosis

    Nam, H. Y.; Seo, G. T.; Lee, J. S.; Kim, S. C.; Kim, I. J.; Kim, Y. K.; Jeon, S. M. [Pusan National University Hospital, Pusan (Korea, Republic of)

    2007-07-01

    A possible association between congenital scoliosis and low mental status has been recognized, but there are no reports describing the mental status or cerebral metabolism in patients with congenital scoliosis in detail. We investigated the mental status using a mini-mental status exam as well as the cerebral glucose metabolism using F-18 fluorodeoxyglucose brain positron emission tomography in 12 patients with congenital scoliosis and compared them with those of 14 age-matched patients with adolescent idiopathic scoliosis. The mean mini-mental status exam score in the congenital scoliosis group was significantly lower than that in the adolescent idiopathic scoliosis group. Group analysis found that various brain areas of patients with congenital scoliosis showed glucose hypometabolisms in the left prefrontal cortex (Brodmann area 10), right orbitofrontal cortex (Brodmann area 11), left dorsolateral prefrontal cortex (Brodmann area 9), left anterior cingulate gyrus (Brodmann area 24) and pulvinar of the left thalamus. From this study, we could find the metabolic abnormalities of brain in patients with congenital scoliosis and suggest the possible role of voxel-based analysis of brain fluorodeoxyglucose positron emission tomography.

  10. Noninvasive skin fluorescence spectroscopy for detection of abnormal glucose tolerance

    Edward L. Hull, PhD

    2014-09-01

    Full Text Available The ENGINE study evaluated noninvasive skin fluorescence spectroscopy (SFS for detection of abnormal glucose tolerance (AGT. The AGT detection performance of SFS was compared to fasting plasma glucose (FPG and hemoglobin A1C (A1C. The study was a head-to-head comparison of SFS to FPG and A1C in an at-risk population of 507 subjects, with no prior diagnosis of diabetes, each of whom received a 75 g, two-hour oral glucose tolerance test (OGTT. Subjects were measured by SFS on multiple days in fasting and non-fasting states. SFS data were acquired and analyzed with the SCOUT DS® device (VeraLight, Albuquerque, NM, USA. Disease truth was AGT, defined as OGTT ≥ 7.8 mmol/L. Sensitivity, false positive rate (FPR, ROC area, and equal error rate (EER for detection of AGT were computed. The reproducibility of SFS and FPG was assessed. The AGT sensitivity of SFS at the device's recommended screening threshold of 50 was 75.2%, higher than that of FPG (thresholds of 5.6 mmol/L or 6.1 mmol/L and A1C (thresholds of 5.7% or 6.0%. The SFS FPR was 42.1%, comparable to an A1C threshold of 5.7% (FPR = 43.5%. The EERs of SFS, FPG and A1C were similar, as were the partial ROC areas for FPRs of 20–50%. The reproducibility of SFS was 7.7% versus 8.1% for FPG. SFS had similar AGT detection performance to FPG and A1C and is a viable alternative to screening individuals for AGT.

  11. [Glucose homeostasis in children. I. Regulation of blood glucose].

    Otto Buczkowska, E; Szirer, G; Jarosz-Chobot, P

    2001-01-01

    The amount of glucose in the circulation depends on its absorption from the intestine, uptake by and release from the liver and uptake by peripheral tissues. Insulin and glucagon together control the metabolities required by peripheral tissues and both are involved in maintaining glucose homeostasis. Insulin is considered to be an anabolic hormone in that it promotes the synthesis of protein, lipid and glycogen. The key target tissues for insulin are liver, muscles and adipose tissue. Glucagon acts largely to increase catabolic processes. Between meals or during fast, the most tightly regulated process is the release of glucose from the liver. During fasting glucose is produced from glycogen and is formed by enzymes on the gluconeogenic pathway. Fetal metabolism is directed to ensure anabolism with formation of glycogen, fat and protein. Glucogen is stored in the liver and serves as the immediate source of new glucose during first few hours after birth. Glucose is the most important substrate for brain metabolism. Due to the large size of neonatal brain in relation to body weight cerebral glucose consumption is particularly high. Postnatal hormonal changes have a central role in regulating glucose mobilization through glycogenolysis and gluconeogenesis. The initial glucagon surge is the key adaptive change which triggers the switch to glucose production. The control of insulin and glucagon secretion is of fundamental importance during first hours after birth. Children have a decreased tolerance to starvation when compared with adults, they are more prone to develop hypoglycaemia after short fasting. The faster rate in the fall of blood glucose and gluconeogenic substrates and rapid rate of ketogenesis are characteristic features of fasting adaptation in children.

  12. Value of fructosamine measurement in pregnant women with abnormal glucose tolerance

    LI Kui; YANG Hui-xia

    2006-01-01

    Background The concentration of serum fructosamine is correlated with plasma glucose level. The aim of this study was to determine whether the level of serum fructosamine can be diagnostic for abnormal glucose tolerance in pregnant women.Methods Serum samples were collected from 161 pregnant women between November 2004 and April 2005.The women were divided into three groups according to the gestational age (16-20 weeks group, 56 patients; 28-34 weeks group, 72; and 37-41 weeks group, 33). Each group was subdivided into normal and abnormal glucose tolerance subgroups. The levels of serum fructosamine were measured. Differences among the groups were assessed by ANOVA and Student-Newman-Keuls test. Correlations between the level of fructosamine and other variables including the results of glucose challenge test (GCT), oral glucose tolerance test (OGTT), and glycosylated hemoglobin (HbA1c) test, and infant's birth weight were analyzed by Pearson correlation.Results The level of serum fructosamine decreased with gestational age [(223.25 ±48.90) μmol/L, (98.44±29.57)μmol/L, and (53.99±29.94) μmol/L, respectively. P<0.05]. It was higher in women with abnormal glucose tolerance than that in women with normal glucose tolerance, however, the difference reached statistical significance only in the 28-34 weeks group (P<0.05). In this group, the level of serum fructosamine correlated positively with the GCT result (r=0.28, P<0.05). No correlation was found between fructosamine level and OGTT result, HbA1c level, or neonatal weight.Conclusions Fructosamine can be used to monitor the glucose level of pregnant women with abnormal glucose tolerance, and to identify the patients at high risk of abnormal glucose tolerance, but can not be used to predict gestational diabetes mellitus (GDM) in early stage of pregnancy.

  13. Persistent abnormal coronary flow reserve in association with abnormal glucose metabolism affects prognosis in acute myocardial infarction

    Løgstrup, Brian B; Høfsten, Dan E; Christophersen, Thomas B

    2011-01-01

    Objectives: To evaluate changes in coronary flow reserve (CFR) over time after acute myocardial infarction (AMI) in relation to left ventricular (LV) function and glucometabolic state and prognostic implication of abnormal CFR. Methods: 154 patients with first time AMI had a comprehensive...... baseline CFR (P = 0.004), S' (P = 0.045) and abnormal glucose metabolism (P = 0.001) were predictors of a decreased CFR at 3 months of follow-up. In multivariate analyses abnormal glucose metabolism (OR: 5.3; 95%CI: 1.9-14.4; P = 0.001) remained a predictor of decreased CFR at follow-up, furthermore...... baseline CFR (OR: 0.5; 95%CI: 0.25-0.94; P = 0.032) and S' (OR: 0.67; 95% CI: 0.47-0.94; P = 0.021) was predictors of decreased CFR. Finally, CFR was associated with a lower risk of cardiac events in patients with normal glucose metabolism (HR: 0.64; 95% CI: 0.22-1.9; P = 0.42) than in patients...

  14. FOXN3 regulates hepatic glucose utilization

    Karanth, Santhosh; Zinkhan, Erin K.; Hill, Jonathon T.; Yost, H. Joseph; Schlegel, Amnon

    2016-01-01

    SUMMARY A SNP (rs8004664) in the first intron of the FOXN3 gene is associated with human fasting blood glucose. We find that carriers of the risk allele have higher hepatic expression of the transcriptional repressor FOXN3. Rat Foxn3 protein and zebrafish foxn3 transcripts are downregulated during fasting, a process recapitulated in human HepG2 hepatoma cells. Transgenic overexpression of zebrafish foxn3 or human FOXN3 increases zebrafish hepatic gluconeogenic gene expression, whole-larval free glucose, and adult fasting blood glucose, and also decreases expression of glycolytic genes. Hepatic FOXN3 overexpression suppresses expression of mycb, whose ortholog MYC is known to directly stimulate expression of glucose-utilization enzymes. Carriers of the rs8004664 risk allele have decreased MYC transcript abundance. Human FOXN3 binds DNA sequences in the human FOXN3 and zebrafish mycb loci. We conclude that the rs8004664 risk allele drives excessive expression of FOXN3 during fasting and that FOXN3 regulates fasting blood glucose. PMID:27292639

  15. Osteocalcin as a hormone regulating glucose metabolism

    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.

  16. Clinical Analysis of Wine age and Metabolic Syndrome and Abnormal Glucose Regulation Ties%酒龄与代谢综合征及糖调节异常的关系探讨

    彭达平

    2014-01-01

    Objective:To explore the relationship of wine age and metabolic syndrome(MS)and glucose regulation (IGR)relationship.Method:309 males with different wine age were selected and analyzed. They were divided into three groups(A1-A3)accordance their drinking time. 103 cases of remaining non-drinking history were set up the control group. Drinking relationship with MS were analyzed through 412 cases of the research object of test results.Result:The longer the wine age men,their BMI,TGL and equivalents increased,while HDL-C was gradually reduced,the differences were statistically significant(P<0.01).Conclusion:With the probability of prolonge alcohol consumption of time,MS and other diseases is increasing. The efficient by limiting alcohol consumption can be prevented.%目的:探讨酒龄与代谢综合征(MS)及糖调节异常(IGR)的关系。方法:本次研究对象为309例男性,均有不同的酒龄。按照其饮酒的时间分三组(A1~A3)。其余无饮酒史的103例男性为对照组。通过412例研究对象的检测结果分析饮酒与MS等的关系。结果:酒龄越长的男性,其BMI、TGL以及等值均增加,而HDL-C却逐渐降低,差异均有统计学意义(P<0.01)。结论:随着饮酒时间的延长,MS等疾病的几率逐渐增加。而通过限制饮酒可以高效地对其进行预防。

  17. The Role of Helicobacter pylori Seropositivity in Insulin Sensitivity, Beta Cell Function, and Abnormal Glucose Tolerance

    Lou Rose Malamug

    2014-01-01

    Full Text Available Infection, for example, Helicobacter pylori (H. pylori, has been thought to play a role in the pathogenesis of type 2 diabetes mellitus (T2DM. Our aim was to determine the role of H. pylori infection in glucose metabolism in an American cohort. We examined data from 4,136 non-Hispanic white (NHW, non-Hispanic black (NHB, and Mexican Americans (MA aged 18 and over from the NHANES 1999-2000 cohort. We calculated the odds ratios for states of glucose tolerance based on the H. pylori status. We calculated and compared homeostatic model assessment insulin resistance (HOMA-IR and beta cell function (HOMA-B in subjects without diabetes based on the H. pylori status. The results were adjusted for age, body mass index (BMI, poverty index, education, alcohol consumption, tobacco use, and physical activity. The H. pylori status was not a risk factor for abnormal glucose tolerance. After adjustment for age and BMI and also adjustment for all covariates, no difference was found in either HOMA-IR or HOMA-B in all ethnic and gender groups except for a marginally significant difference in HOMA-IR in NHB females. H. pylori infection was not a risk factor for abnormal glucose tolerance, nor plays a major role in insulin resistance or beta cell dysfunction.

  18. Abnormal glycosylated hemoglobin as a predictive factor for glucose metabolism disorders in antipsychotic treatment

    XU Leping; JI Juying; DUAN Yiyang; SHI Hui; ZHANG Bin; SHAO Yaqin; SUN Jian

    2007-01-01

    The aim of this study was to observe the changes in glucose metabolism after antipsychotic(APS)therapy,to note the influencing factors,as well as to dicuss the relationship between the occurrence of glucose metabolism disorders of APS origin and abnormal glycosylated hemoglobin(HbA1c)levels.One hundred and fifty-two patients with schizophrenia,whose fasting plasma glucose(FPG)and 2-h plasma glucose (2hPG)in the oral glucose tolerance test(2HPG)were normal,were grouped according to the HbA1c levels,one normal and the other abnormal,and were randomly enrolled into risperidone,clozapine and chlorpromazine treatment for six weeks.The FPG and 2hPG were measured at the baseline and at the end of the study.In the group with abnormal HbA1c and clozapine therapy,2HPG was higher after the study[(9.5±1.8)mmol/L]than that before the study[(7.2±1.4)mmol/L]and the difierence was statistically significant(P<0.01).FPG had no statistically significant difference before and after the study in any group(P>0.05).HbA1c levels and drugs contributing to 2HPG at the end of study had statistical cross-action(P<0.01).In the abnormal HbA1c group,2HPG after the study was higher in the clozapine treatment group [(9.5±1.8)mmol/L]than in the risperidone treatment group [(7.4±1.7)mmol/L]and the chlorpromazine treatment group[(7.3±1.6)mmol/L].The differences were statistically significant(P<0.01).In the normal HbA1c group there was no statistically significant difierence before and after the study in any group(P>0.05).2HPG before[(7.1±1.6)mmol/L]and after the study[(8.1±1.9)mmol/L]was higher in the abnormal HbA1c group than in the normal HbA1c group[(6.2±1.4)mmol/L vs(6.5±1.4)mmol/L]with the difierence being statistically significant(P<0.01 vs P<0.001).As compared with normal HbA1c group,the relative risk (RR)of glucose metabolism disease occurrence was 4.7 in the abnormal HDA1C group wlth the difierence being statistically significant(P<0.001).Patients with abnormal HbA1c

  19. Abnormal Glucose Tolerance Is Associated with a Reduced Myocardial Metabolic Flexibility in Patients with Dilated Cardiomyopathy.

    Tricò, Domenico; Baldi, Simona; Frascerra, Silvia; Venturi, Elena; Marraccini, Paolo; Neglia, Danilo; Natali, Andrea

    2016-01-01

    Dilated cardiomyopathy (DCM) is characterized by a metabolic shift from fat to carbohydrates and failure to increase myocardial glucose uptake in response to workload increments. We verified whether this pattern is influenced by an abnormal glucose tolerance (AGT). In 10 patients with DCM, 5 with normal glucose tolerance (DCM-NGT) and 5 with AGT (DCM-AGT), and 5 non-DCM subjects with AGT (N-AGT), we measured coronary blood flow and arteriovenous differences of oxygen and metabolites during Rest, Pacing (at 130 b/min), and Recovery. Myocardial lactate exchange and oleate oxidation were also measured. At Rest, DCM patients showed a reduced nonesterified fatty acids (NEFA) myocardial uptake, while glucose utilization increased only in DCM-AGT. In response to Pacing, glucose uptake promptly rose in N-AGT (from 72 ± 21 to 234 ± 73 nmol/min/g, p equivalents, p metabolism and the reduced myocardial metabolic flexibility in response to an increased workload. This trial is registered with ClinicalTrial.gov NCT02440217.

  20. Abnormal Glucose Tolerance Is Associated with a Reduced Myocardial Metabolic Flexibility in Patients with Dilated Cardiomyopathy

    Domenico Tricò

    2016-01-01

    Full Text Available Dilated cardiomyopathy (DCM is characterized by a metabolic shift from fat to carbohydrates and failure to increase myocardial glucose uptake in response to workload increments. We verified whether this pattern is influenced by an abnormal glucose tolerance (AGT. In 10 patients with DCM, 5 with normal glucose tolerance (DCM-NGT and 5 with AGT (DCM-AGT, and 5 non-DCM subjects with AGT (N-AGT, we measured coronary blood flow and arteriovenous differences of oxygen and metabolites during Rest, Pacing (at 130 b/min, and Recovery. Myocardial lactate exchange and oleate oxidation were also measured. At Rest, DCM patients showed a reduced nonesterified fatty acids (NEFA myocardial uptake, while glucose utilization increased only in DCM-AGT. In response to Pacing, glucose uptake promptly rose in N-AGT (from 72 ± 21 to 234 ± 73 nmol/min/g, p<0.05, did not change in DCM-AGT, and slowly increased in DCM-NGT. DCM-AGT sustained the extra workload by increasing NEFA oxidation (from 1.3 ± 0.2 to 2.9 ± 0.1 μmol/min/gO2 equivalents, p<0.05, while DCM-NGT showed a delayed increase in glucose uptake. Substrate oxidation rates paralleled the metabolites data. The presence of AGT in patients with DCM exacerbates both the shift from fat to carbohydrates in resting myocardial metabolism and the reduced myocardial metabolic flexibility in response to an increased workload. This trial is registered with ClinicalTrial.gov NCT02440217.

  1. Abnormal glucose metabolism in acute myocardial infarction: influence on left ventricular function and prognosis

    Høfsten, Dan E; Løgstrup, Brian B; Møller, Jacob E

    2009-01-01

    tolerance test before discharge. LV function was assessed using echocardiographic measurements (LV end-diastolic volume, LV end-systolic volume, LV ejection fraction, restrictive diastolic filling pattern, early transmitral flow velocity to early diastolic mitral annular velocity ratio [E/e'], and left...... atrial volume index) and by measuring plasma N-terminal pro-B-type natriuretic peptide levels. RESULTS: After adjustment for age and gender, a linear relationship between the degree of abnormal glucose metabolism was observed for each marker of LV dysfunction (p(trend)

  2. Morphological and glucose metabolism abnormalities in alcoholic Korsakoff's syndrome: group comparisons and individual analyses.

    Anne-Lise Pitel

    Full Text Available BACKGROUND: Gray matter volume studies have been limited to few brain regions of interest, and white matter and glucose metabolism have received limited research attention in Korsakoff's syndrome (KS. Because of the lack of brain biomarkers, KS was found to be underdiagnosed in postmortem studies. METHODOLOGY/PRINCIPAL FINDINGS: Nine consecutively selected patients with KS and 22 matched controls underwent both structural magnetic resonance imaging and (18F-fluorodeoxyglucose positron emission tomography examinations. Using a whole-brain analysis, the between-group comparisons of gray matter and white matter density and relative glucose uptake between patients with KS and controls showed the involvement of both the frontocerebellar and the Papez circuits, including morphological abnormalities in their nodes and connection tracts and probably resulting hypometabolism. The direct comparison of the regional distribution and degree of gray matter hypodensity and hypometabolism within the KS group indicated very consistent gray matter distribution of both abnormalities, with a single area of significant difference in the middle cingulate cortex showing greater hypometabolism than hypodensity. Finally, the analysis of the variability in the individual patterns of brain abnormalities within our sample of KS patients revealed that the middle cingulate cortex was the only brain region showing significant GM hypodensity and hypometabolism in each of our 9 KS patients. CONCLUSIONS/SIGNIFICANCE: These results indicate widespread brain abnormalities in KS including both gray and white matter damage mainly involving two brain networks, namely, the fronto-cerebellar circuit and the Papez circuit. Furthermore, our findings suggest that the middle cingulate cortex may play a key role in the pathophysiology of KS and could be considered as a potential in vivo brain biomarker.

  3. Regulation of Intestinal Glucose Absorption by Ion Channels and Transporters.

    Chen, Lihong; Tuo, Biguang; Dong, Hui

    2016-01-14

    The absorption of glucose is electrogenic in the small intestinal epithelium. The major route for the transport of dietary glucose from intestinal lumen into enterocytes is the Na⁺/glucose cotransporter (SGLT1), although glucose transporter type 2 (GLUT2) may also play a role. The membrane potential of small intestinal epithelial cells (IEC) is important to regulate the activity of SGLT1. The maintenance of membrane potential mainly depends on the activities of cation channels and transporters. While the importance of SGLT1 in glucose absorption has been systemically studied in detail, little is currently known about the regulation of SGLT1 activity by cation channels and transporters. A growing line of evidence suggests that cytosolic calcium ([Ca(2+)]cyt) can regulate the absorption of glucose by adjusting GLUT2 and SGLT1. Moreover, the absorption of glucose and homeostasis of Ca(2+) in IEC are regulated by cation channels and transporters, such as Ca(2+) channels, K⁺ channels, Na⁺/Ca(2+) exchangers, and Na⁺/H⁺ exchangers. In this review, we consider the involvement of these cation channels and transporters in the regulation of glucose uptake in the small intestine. Modulation of them may be a potential strategy for the management of obesity and diabetes.

  4. Regulation of Intestinal Glucose Absorption by Ion Channels and Transporters

    Lihong Chen

    2016-01-01

    Full Text Available The absorption of glucose is electrogenic in the small intestinal epithelium. The major route for the transport of dietary glucose from intestinal lumen into enterocytes is the Na+/glucose cotransporter (SGLT1, although glucose transporter type 2 (GLUT2 may also play a role. The membrane potential of small intestinal epithelial cells (IEC is important to regulate the activity of SGLT1. The maintenance of membrane potential mainly depends on the activities of cation channels and transporters. While the importance of SGLT1 in glucose absorption has been systemically studied in detail, little is currently known about the regulation of SGLT1 activity by cation channels and transporters. A growing line of evidence suggests that cytosolic calcium ([Ca2+]cyt can regulate the absorption of glucose by adjusting GLUT2 and SGLT1. Moreover, the absorption of glucose and homeostasis of Ca2+ in IEC are regulated by cation channels and transporters, such as Ca2+ channels, K+ channels, Na+/Ca2+ exchangers, and Na+/H+ exchangers. In this review, we consider the involvement of these cation channels and transporters in the regulation of glucose uptake in the small intestine. Modulation of them may be a potential strategy for the management of obesity and diabetes.

  5. The Real Culprit in Systemic Lupus Erythematosus: Abnormal Epigenetic Regulation

    Haijing Wu

    2015-05-01

    Full Text Available Systemic lupus erythematosus (SLE is an autoimmune disease involving multiple organs and the presence of anti-nuclear antibodies. The pathogenesis of SLE has been intensively studied but remains far from clear. B and T lymphocyte abnormalities, dysregulation of apoptosis, defects in the clearance of apoptotic materials, and various genetic and epigenetic factors are attributed to the development of SLE. The latest research findings point to the association between abnormal epigenetic regulation and SLE, which has attracted considerable interest worldwide. It is the purpose of this review to present and discuss the relationship between aberrant epigenetic regulation and SLE, including DNA methylation, histone modifications and microRNAs in patients with SLE, the possible mechanisms of immune dysfunction caused by epigenetic changes, and to better understand the roles of aberrant epigenetic regulation in the initiation and development of SLE and to provide an insight into the related therapeutic options in SLE.

  6. Effect of ghrelin on glucose regulation in mice

    Chacko, Shaji K.; Haymond, Morey W.; Sun, Yuxiang; Marini, Juan C.; Sauer, Pieter J. J.; Ma, Xiaojun; Sunehag, Agneta L.

    2012-01-01

    Chacko SK, Haymond MW, Sun Y, Marini JC, Sauer PJJ, Ma X, Sunehag AL. Effect of ghrelin on glucose regulation in mice. Am J Physiol Endocrinol Metab 302: E1055-E1062, 2012. First published February 14, 2011; doi:10.1152/ajpendo.00445.2011.-Improvement of glucose metabolism after bariatric surgery ap

  7. Intra- and intercellular mechanisms regulating glucose metabolism in the liver.

    E. Casteleijn (Eric)

    1988-01-01

    textabstractThe regulation of glucose metabolism in the liver by intraand intercellular mechanisms was studied. Fructose-1,6-bisphosphatase, an enzyme involved in de novo synthesis of glucose was found to be stimulated by glucagon in isolated parenchym~l liver cells. Glucagon increased the Vmax of f

  8. High incidence of abnormal glucose metabolism in acute coronary syndrome patients at a moderate altitude: A sub-Himalayan study

    Mokta, Jitender; Kumar, Subash; Ganju, Neeraj; Mokta, Kiran; Panda, Prashant Kumar; Gupta, Swatantra

    2017-01-01

    Background: Abnormal glucose metabolic status at admission is an important marker of future cardiovascular events and long-term mortality after acute coronary syndrome (ACS), whether or not they are known diabetics. Objective: The aims were to study the prevalence of abnormal glucose metabolism in ACS patients and to compare the different methods of diagnosing diabetes in ACS patients. Methods: We did a prospective study. About 250 consecutive nondiabetic patients (200 men and 50 women) with ACS admitted to a tertiary care institute of Himachal Pradesh in 1 year were enrolled. Admission plasma glucose, next morning fasting plasma glucose (FPG), A1C, and a standardized 75-g oral glucose tolerance test (OGTT) 72 h after admission were done. Glucose metabolism was categorized as normal glucose metabolism, impaired glucose metabolism (impaired fasting glucose or impaired glucose tolerance [IGT]), and diabetes. Diabetes was arbitrarily classified further as undiagnosed (HBA1c ≥6.5%) or possibly stress diabetes (HBA1c <6.5%). A repeat OGTT after 3 months in objects with IGT and stress hyperglycemia at a time of admission was done. Results: The mean age was 54 ± 12.46 years. The mean plasma glucose at admission was 124 ± 53.96 mg/dL, and the mean FPG was 102 ± 27.07 mg/dL. The mean 2-h postglucose load concentration was 159.5 ± 56.58 mg/dL. At baseline, 95 (38%) had normal glucose metabolism, 95 (38%) had impaired glucose metabolism (IGT and or IGT) and 60 (24%) had diabetes; 48 (19.2%) were undiagnosed diabetes and 12 (4.8%) had stress hyperglycemia. At follow up 58.66% and 55.55% of patients with impaired glucose tolerance and stress hyperglycemia continued to have impaired glucose tolerance respectively. About 75 gm OGTT has highest sensitivity and specificity to diagnose diabetes, whereas A1C most specific to rule out stress hyperglycemia. Conclusions: In this small hilly state of India, abnormal glucose metabolism (previously undiagnosed diabetes and IGT) is

  9. Plasma myeloperoxidase is inversely associated with endothelium-dependent vasodilation in elderly subjects with abnormal glucose metabolism.

    van der Zwan, Leonard P; Teerlink, Tom; Dekker, Jacqueline M; Henry, Ronald M A; Stehouwer, Coen D A; Jakobs, Cornelis; Heine, Robert J; Scheffer, Peter G

    2010-12-01

    Myeloperoxidase (MPO), a biomarker related to inflammation, oxidative stress, and nitric oxide scavenging, has been shown to impair endothelium-dependent vasodilation. Because elevated hydrogen peroxide concentrations in diabetic vessels may enhance MPO activity, we hypothesized that a stronger association of MPO with flow-mediated dilation (FMD) may be found in subjects with abnormal glucose metabolism. Myeloperoxidase concentrations were measured in EDTA plasma samples from participants of a population-based cohort study, including 230 subjects with normal glucose metabolism and 386 with abnormal glucose metabolism. Vascular function was expressed as FMD and nitroglycerin-mediated dilation of the brachial artery. In subjects with abnormal glucose metabolism, MPO was negatively associated with FMD (-20.9 [95% confidence interval {CI}, -41.7 to -0.2] -μm change in FMD per SD increment of MPO). This association remained significant after adjustment for nitroglycerin-mediated dilation (-31.1 [95% CI, -50.0 to -12.3]) and was not attenuated after further adjustment for established risk factors. In subjects with normal glucose metabolism, MPO was not significantly associated with FMD (2.0 [95% CI, -16.0 to 20.0]). In conclusion, in subjects with abnormal glucose metabolism, plasma levels of MPO are inversely associated with endothelium-dependent vasodilation, possibly reflecting enhancement of MPO activity by vascular oxidative stress.

  10. Regulation of endogenous glucose production in glucose transporter 4 over-expressing mice.

    Eric D Berglund

    Full Text Available Strategies to amplify whole-body glucose disposal are key therapies to treat type 2 diabetes. Mice that over-express glucose transporter 4 (Glut4 in skeletal muscle, heart, and adipose tissue (G4Tg exhibit increased fasting glucose disposal and thus lowered blood glucose. Intriguingly, G4Tg mice also exhibit improved insulin-stimulated suppression of endogenous glucose production even though Glut4 is not present in the liver. It is unclear, however, if hepatic gluco-regulation is altered in G4Tg mice in the basal, non-insulin-stimulated state. The current studies were performed to examine fasting hepatic glucose metabolism in G4Tg mice and to determine whether gluco-regulatory adaptations exist in the non-insulin-stimulated condition. To test this question, phloridzin-glucose clamps were used to match blood glucose and pancreatic hormone levels while tracer dilution techniques were used to measure glucose flux. These techniques were performed in chronically-catheterized, conscious, and un-stressed 5h-fasted G4Tg and wild-type (WT littermates. Results show reduced blood glucose, hepatic glycogen content, and hepatic glucokinase (GK activity/expression as well as higher endogenous glucose production, glucose disposal, arterial glucagon, and hepatic glucose-6-phosphatase (G6Pase activity/expression in G4Tg mice versus WT controls. Clamping blood glucose for 90 min at ~115 mg/dLin G4Tg and WT mice normalized nearly all variables. Notably, however, net hepatic glycogen synthetic rates were disproportionately elevated compared to changes in blood glucose. In conclusion, these studies demonstrate that basal improvements in glucose tolerance due to increased uptake in extra-hepatic sites provoke important gluco-regulatory adaptations in the liver. Although changes in blood glucose underlie the majority of these adaptations, net hepatic glycogen synthesis is sensitized. These data emphasize that anti-diabetic therapies that target skeletal muscle, heart

  11. Glucose Regulates the Expression of the Apolipoprotein A5 Gene

    Fruchart, Jamila; Nowak, Maxime; Helleboid-Chapman, Audrey; Jakel, Heidelinde; Moitrot, Emmanuelle; Rommens, Corinne; Pennacchio, Len A.; Fruchart-Najib, Jamila; Fruchart, Jean-Charles

    2008-04-07

    The apolipoprotein A5 gene (APOA5) is a key player in determining triglyceride concentrations in humans and mice. Since diabetes is often associated with hypertriglyceridemia, this study explores whether APOA5 gene expression is regulated by alteration in glucose homeostasis and the related pathways. D-glucose activates APOA5 gene expression in a time- and dose-dependent manner in hepatocytes, and the glycolytic pathway involved was determined using D-glucose analogs and metabolites. Together, transient transfections, electrophoretic mobility shift assays and chromatin immunoprecipitation assays show that this regulation occurs at the transcriptional level through an increase of USF1/2 binding to an E-box in the APOA5 promoter. We show that this phenomenon is not due to an increase of mRNA or protein expression levels of USF. Using protein phosphatases 1 and 2A inhibitor, we demonstrate that D-glucose regulates APOA5 gene via a dephosphorylation mechanism, thereby resulting in an enhanced USF1/2-promoter binding. Last, subsequent suppressions of USF1/2 and phosphatases mRNA through siRNA gene silencing abolished the regulation. We demonstrate that APOA5 gene is up regulated by D-glucose and USF through phosphatase activation. These findings may provide a new cross talk between glucose and lipid metabolism.

  12. Postprandial glucose regulation and diabetic complications.

    Ceriello, Antonio; Hanefeld, Markolf; Leiter, Lawrence; Monnier, Louis; Moses, Alan; Owens, David; Tajima, Naoko; Tuomilehto, Jaakko

    2004-10-25

    Atherosclerotic disease accounts for much of the increased mortality and morbidity associated with type 2 diabetes. Epidemiological studies support the potential of improved glycemic control to reduce cardiovascular complications. An association between glycosylated hemoglobin (HbA(1c)) level and the risk for cardiovascular complications has frequently been reported. Most epidemiological data implicate postprandial hyperglycemia in the development of cardiovascular disease, whereas the link between fasting glycemia and diabetic complications is inconclusive. Moreover, in many studies, postprandial glycemia is a better predictor of cardiovascular risk than HbA(1c) level. Postprandial glucose may have a direct toxic effect on the vascular endothelium, mediated by oxidative stress that is independent of other cardiovascular risk factors such as hyperlipidemia. Postprandial hyperglycemia also may exert its effects through its substantial contribution to total glycemic exposure. The present review examines the hypothesis that controlling postprandial glucose level is an important strategy in the prevention of cardiovascular complications associated with diabetes.

  13. SREBP-1c regulates glucose-stimulated hepatic clusterin expression

    Kim, Gukhan [Department of Pharmacology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 138-736 (Korea, Republic of); Kim, Geun Hyang; Oh, Gyun-Sik; Yoon, Jin [Department of Pharmacology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 138-736 (Korea, Republic of); Bio-Medical Institute of Technology, University of Ulsan College of Medicine, Seoul 138-736 (Korea, Republic of); Kim, Hae Won [Department of Pharmacology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 138-736 (Korea, Republic of); Kim, Min-Seon [Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul 138-736 (Korea, Republic of); Kim, Seung-Whan, E-mail: swkim7@amc.seoul.kr [Department of Pharmacology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 138-736 (Korea, Republic of); Bio-Medical Institute of Technology, University of Ulsan College of Medicine, Seoul 138-736 (Korea, Republic of)

    2011-05-20

    Highlights: {yields} This is the first report to show nutrient-regulated clusterin expression. {yields} Clusterin expression in hepatocytes was increased by high glucose concentration. {yields} SREBP-1c is directly involved in the transcriptional activation of clusterin by glucose. {yields} This glucose-stimulated activation process is mediated through tandem E-box motifs. -- Abstract: Clusterin is a stress-response protein that is involved in diverse biological processes, including cell proliferation, apoptosis, tissue differentiation, inflammation, and lipid transport. Its expression is upregulated in a broad spectrum of diverse pathological states. Clusterin was recently reported to be associated with diabetes, metabolic syndrome, and their sequelae. However, the regulation of clusterin expression by metabolic signals was not addressed. In this study we evaluated the effects of glucose on hepatic clusterin expression. Interestingly, high glucose concentrations significantly increased clusterin expression in primary hepatocytes and hepatoma cell lines, but the conventional promoter region of the clusterin gene did not respond to glucose stimulation. In contrast, the first intronic region was transcriptionally activated by high glucose concentrations. We then defined a glucose response element (GlRE) of the clusterin gene, showing that it consists of two E-box motifs separated by five nucleotides and resembles carbohydrate response element (ChoRE). Unexpectedly, however, these E-box motifs were not activated by ChoRE binding protein (ChREBP), but were activated by sterol regulatory element binding protein-1c (SREBP-1c). Furthermore, we found that glucose induced recruitment of SREBP-1c to the E-box of the clusterin gene intronic region. Taken together, these results suggest that clusterin expression is increased by glucose stimulation, and SREBP-1c plays a crucial role in the metabolic regulation of clusterin.

  14. Clustering of hypertension, abnormal glucose tolerance, hypercholesterolaemia and obesity in Malaysian adult population.

    Lim, T O; Ding, L M; Zaki, M; Merican, I; Kew, S T; Maimunah, A H; Rozita, H H; Rugayah, B

    2000-06-01

    We determine the prevalence and determinants of clustering of hypertension, abnormal glucose tolerance, hypercholesterolaemia and overweight in Malaysia. A national probability sample of 17,392 individuals aged 30 years or older had usable data. 61% of adults had at least one risk factor, 27% had 2 or more risk factors. The observed frequency of 4 factors cluster was 6 times greater than that expected by chance. Indian and Malay women were at particular high risk of risk factors clustering. Individuals with a risk factor had 1.5 to 3 times higher prevalence of other risk factors. Ordinal regression analyses show that higher income, urban residence and physical inactivity were independently associated with risk factors clustering, lending support to the hypotheses that risk factors clustering is related to lifestyle changes brought about by modernisation and urbanisation. In conclusion, risk factor clustering is highly prevalent among Malaysian adults. Treatment and prevention programme must emphasise the multiple risk factor approach.

  15. Abnormal Glucose Metabolism in Alzheimer’s Disease: Relation to Autophagy/Mitophagy and Therapeutic Approaches

    Banerjee, Kalpita; Munshi, Soumyabrata; Frank, David E.; Gibson, Gary E.

    2015-01-01

    Diminished glucose metabolism accompanies many neurodegenerative diseases including Alzheimer’s disease. An understanding of the relation of these metabolic changes to the disease will enable development of novel therapeutic strategies. Following a metabolic challenge, cells generally conserve energy to preserve viability. This requires activation of many cellular repair/regenerative processes such as mitophagy/autophagy and fusion/fission. These responses may diminish cell function in the long term. Prolonged fission induces mitophagy/autophagy which promotes repair but if prolonged progresses to mitochondrial degradation. Abnormal glucose metabolism alters protein signaling including the release of proteins from the mitochondria or migration of proteins from the cytosol to the mitochondria or nucleus. This overview provides an insight into the different mechanisms of autophagy/mitophagy and mitochondrial dynamics in response to the diminished metabolism that occurs with diseases, especially neurodegenerative diseases such as Alzheimer's disease. The review discusses multiple aspects of mitochondrial responses including different signaling proteins and pathways of mitophagy and mitochondrial biogenesis. Improving cellular bioenergetics and mitochondrial dynamics will alter protein signaling and improve cellular/mitochondrial repair and regeneration. An understanding of these changes will suggest new therapeutic strategies. PMID:26077923

  16. Preliminary validation of an exercise program suitable for pregnant women with abnormal glucose metabolism: inhibitory effects of Tai Chi Yuttari-exercise on plasma glucose elevation

    Yamamoto, Sachina; Kagawa, Kyoko; Hori, Naohi; Akezaki, Yoshiteru; Mori, Kohei; Nomura, Takuo

    2016-01-01

    [Purpose] There is insufficient evidence related to exercise programs that are safe and efficacious for pregnant women with abnormal glucose metabolism. Tai Chi Yuttari-exercise is an exercise program with validated safety and efficacy in improving physical function in the elderly. In this study, we investigated this program’s inhibitory effects on plasma glucose elevation when it was adapted to a pregnancy model. [Subjects and Methods] Twelve 18- to 19-year-old females without a history of pregnancy were randomly assorted into two groups: an intervention group, for which six subjects were outfitted with mock-pregnancy suits and asked to perform Tai Chi Yuttari-exercise, and a control group who did not perform exercise. The intervention group had a mean Borg Scale score of 11.1 ± 0.9 during the exercise. [Results] No significant intragroup differences were observed in fasting, baseline, or post-intervention/observation plasma glucose levels. On the other hand, the intergroup change in plasma glucose levels after intervention/observation was significant when comparing the intervention and control groups: −1.66 ± 7.0 and 9.42 ± 6.57 mg/dl, respectively. [Conclusion] Tai Chi Yuttari-exercise appears to effectively inhibit plasma glucose elevation at intensity and movement levels that can be safely applied to pregnant women with abnormal glucose metabolism. PMID:28174463

  17. Regulation of GLUT4 and Insulin-Dependent Glucose Flux

    Ann Louise Olson

    2012-01-01

    GLUT4 has long been known to be an insulin responsive glucose transporter. Regulation of GLUT4 has been a major focus of research on the cause and prevention of type 2 diabetes. Understanding how insulin signaling alters the intracellular trafficking of GLUT4 as well as understanding the fate of glucose transported into the cell by GLUT4 will be critically important for seeking solutions to the current rise in diabetes and metabolic disease.

  18. Glucose 6-phosphate regulates hepatic glycogenolysis through inactivation of phosphorylase.

    Aiston, Susan; Andersen, Birgitte; Agius, Loranne

    2003-06-01

    High glucose concentration suppresses hepatic glycogenolysis by allosteric inhibition and dephosphorylation (inactivation) of phosphorylase-a. The latter effect is attributed to a direct effect of glucose on the conformation of phosphorylase-a. Although glucose-6-phosphate (G6P), like glucose, stimulates dephosphorylation of phosphorylase-a by phosphorylase phosphatase, its physiological role in regulating glycogenolysis in intact hepatocytes has not been tested. We show in this study that metabolic conditions associated with an increase in G6P, including glucokinase overexpression and incubation with octanoate or dihydroxyacetone, cause inactivation of phosphorylase. The latter conditions also inhibit glycogenolysis. The activity of phosphorylase-a correlated inversely with the G6P concentration within the physiological range. The inhibition of glycogenolysis and inactivation of phosphorylase-a caused by 10 mmol/l glucose can be at least in part counteracted by inhibition of glucokinase with 5-thioglucose, which lowers G6P. In conclusion, metabolic conditions that alter the hepatic G6P content affect glycogen metabolism not only through regulation of glycogen synthase but also through regulation of the activation state of phosphorylase. Dysregulation of G6P in diabetes by changes in activity of glucokinase or glucose 6-phosphatase may be a contributing factor to impaired suppression of glycogenolysis by hyperglycemia.

  19. Regulation of glucose homeostasis by KSR1 and MARK2.

    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.

  20. Leptin regulates glutamate and glucose transporters in hypothalamic astrocytes

    Fuente-Martín, Esther; García-Cáceres, Cristina; Granado, Miriam; de Ceballos, María L.; Sánchez-Garrido, Miguel Ángel; Sarman, Beatrix; Liu, Zhong-Wu; Dietrich, Marcelo O.; Tena-Sempere, Manuel; Argente-Arizón, Pilar; Díaz, Francisca; Argente, Jesús; Horvath, Tamas L.; Chowen, Julie A.

    2012-01-01

    Glial cells perform critical functions that alter the metabolism and activity of neurons, and there is increasing interest in their role in appetite and energy balance. Leptin, a key regulator of appetite and metabolism, has previously been reported to influence glial structural proteins and morphology. Here, we demonstrate that metabolic status and leptin also modify astrocyte-specific glutamate and glucose transporters, indicating that metabolic signals influence synaptic efficacy and glucose uptake and, ultimately, neuronal function. We found that basal and glucose-stimulated electrical activity of hypothalamic proopiomelanocortin (POMC) neurons in mice were altered in the offspring of mothers fed a high-fat diet. In adulthood, increased body weight and fasting also altered the expression of glucose and glutamate transporters. These results demonstrate that whole-organism metabolism alters hypothalamic glial cell activity and suggest that these cells play an important role in the pathology of obesity. PMID:23064363

  1. Glucose regulates lipid metabolism in fasting king penguins.

    Bernard, Servane F; Orvoine, Jord; Groscolas, René

    2003-08-01

    This study aims to determine whether glucose intervenes in the regulation of lipid metabolism in long-term fasting birds, using the king penguin as an animal model. Changes in the plasma concentration of various metabolites and hormones, and in lipolytic fluxes as determined by continuous infusion of [2-3H]glycerol and [1-14C]palmitate, were examined in vivo before, during, and after a 2-h glucose infusion under field conditions. All the birds were in the phase II fasting status (large fat stores, protein sparing) but differed by their metabolic and hormonal statuses, being either nonstressed (NSB; n = 5) or stressed (SB; n = 5). In both groups, glucose infusion at 5 mg.kg-1.min-1 induced a twofold increase in glycemia. In NSB, glucose had no effect on lipolysis (maintenance of plasma concentrations and rates of appearance of glycerol and nonesterified fatty acids) and no effect on the plasma concentrations of triacylglycerols (TAG), glucagon, insulin, or corticosterone. However, it limited fatty acid (FA) oxidation, as indicated by a 25% decrease in the plasma level of beta-hydroxybutyrate (beta-OHB). In SB, glucose infusion induced an approximately 2.5-fold decrease in lipolytic fluxes and a large decrease in FA oxidation, as reflected by a 64% decrease in the plasma concentration of beta-OHB. There were also a 35% decrease in plasma TAG, a 6.5- and 2.8-fold decrease in plasma glucagon and corticosterone, respectively, and a threefold increase in insulinemia. These data show that in fasting king penguins, glucose regulates lipid metabolism (inhibition of lipolysis and/or of FA oxidation) and affects hormonal status differently in stressed vs. nonstressed individuals. The results also suggest that in birds, as in humans, the availability of glucose, not of FA, is an important determinant of the substrate mix (glucose vs. FA) that is oxidized for energy production.

  2. DLK1 regulates whole body glucose metabolism

    Abdallah, Basem; Ditzel, Nicholas; Laborda, Jorge

    2015-01-01

    The endocrine role of the skeleton in regulating energy metabolism is supported by a feed forward loop between circulating osteoblasts (OBs)-derived undercaboxylated osteocalcin (Glu-OCN) and pancreatic β-cell-insulin; in turn insulin favors osteocalcin bioactivity. These data suggest the existence...... cells acts as a negative feedback mechanism to counteract the stimulatory effects of insulin on osteoblast production of Glu-OCN, a potential mechanism preventing OCN-induced hypoglycemia....

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

    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.

  4. The Impact of Abnormal Glucose Tolerance and Obesity on Fetal Growth

    Erin Graves

    2015-01-01

    Full Text Available Objective. Factors linked with insulin resistance were examined for their association with large-for-gestational-age (LGA infant birth weight and gestational diabetes. Study Design. Data came from a longitudinal cohort study of 2,305 subjects without overt diabetes, analyzed using multinomial logistic and linear regression. Results. High maternal BMI (OR=1.53 (1.11, 2.12, height (1.98 (1.62, 2.42, antidepressant use (1.71 (1.20, 2.44, pregnancy weight-gain exceeding 40 pounds (1.79 (1.25, 2.57, and high blood sugar (2.68, (1.53, 5.27 were all positively associated with LGA birth. Strikingly, the difference in risk from diagnosed and treated gestational diabetes compared to women with a single abnormal glucose tolerance test (but no diagnosis of gestational diabetes was significant (OR=0.65, p=0.12 versus OR=2.84, p<0.01. When weight/length ratio was used instead, different factors were found to be significant. BMI and pregnancy weight-gain were found to influence the development of gestational diabetes, through an additive interaction. Conclusions. High prepregnancy BM, height, antidepressant use, pregnancy weight-gain exceeding 40 pounds, and high blood sugar were associated with LGA birth, but not necessarily infant weight/length ratio. An additive interaction between BMI and pregnancy weight-gain influenced gestational diabetes development.

  5. Impact of diet composition on blood glucose regulation

    Russell, W.R.; Baka, A.; Bjorck, I.; Delzenne, N.; Gao, D.; Griffiths, H.R.; Hadjilucas, E.; Juvonen, K.; Lahtinen, S.; Lansink, M.; van Loon, L.; Mykkanen, H.; Ostman, E.; Riccardi, G.; Vinoy, S.; Weickert, M.O.

    2013-01-01

    Abstract Nutritional management of blood glucose levels is a strategic target in the prevention and management of type 2 diabetes mellitus (T2DM). To implement such an approach it is essential to understand the effect of food on glycaemic regulation and on the underlying metabolic derangements. This

  6. Abnormal release of incretins and cortisol after oral glucose in subjects with insulin-resistant myotonic dystrophy

    Johansson, Asa; Olsson, Tommy; Cederquist, Kristina;

    2002-01-01

    OBJECTIVE: Although the incretins, gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), as well as glucagon and cortisol, are known to influence islet function, the role of these hormones in conditions of insulin resistance and development of type 2 diabetes is unknown...... response. Furthermore, cortisol and ACTH levels increased paradoxically in patients after glucose; this was more pronounced in patients with long CTG repeat expansions. CONCLUSIONS: This study showed that the GLP-1 and ACTH/cortisol responses to oral glucose are abnormal in insulin-resistant DM1 patients...

  7. The yeast Sks1p kinase signaling network regulates pseudohyphal growth and glucose response.

    Cole Johnson

    2014-03-01

    Full Text Available The yeast Saccharomyces cerevisiae undergoes a dramatic growth transition from its unicellular form to a filamentous state, marked by the formation of pseudohyphal filaments of elongated and connected cells. Yeast pseudohyphal growth is regulated by signaling pathways responsive to reductions in the availability of nitrogen and glucose, but the molecular link between pseudohyphal filamentation and glucose signaling is not fully understood. Here, we identify the glucose-responsive Sks1p kinase as a signaling protein required for pseudohyphal growth induced by nitrogen limitation and coupled nitrogen/glucose limitation. To identify the Sks1p signaling network, we applied mass spectrometry-based quantitative phosphoproteomics, profiling over 900 phosphosites for phosphorylation changes dependent upon Sks1p kinase activity. From this analysis, we report a set of novel phosphorylation sites and highlight Sks1p-dependent phosphorylation in Bud6p, Itr1p, Lrg1p, Npr3p, and Pda1p. In particular, we analyzed the Y309 and S313 phosphosites in the pyruvate dehydrogenase subunit Pda1p; these residues are required for pseudohyphal growth, and Y309A mutants exhibit phenotypes indicative of impaired aerobic respiration and decreased mitochondrial number. Epistasis studies place SKS1 downstream of the G-protein coupled receptor GPR1 and the G-protein RAS2 but upstream of or at the level of cAMP-dependent PKA. The pseudohyphal growth and glucose signaling transcription factors Flo8p, Mss11p, and Rgt1p are required to achieve wild-type SKS1 transcript levels. SKS1 is conserved, and deletion of the SKS1 ortholog SHA3 in the pathogenic fungus Candida albicans results in abnormal colony morphology. Collectively, these results identify Sks1p as an important regulator of filamentation and glucose signaling, with additional relevance towards understanding stress-responsive signaling in C. albicans.

  8. Ghrelin's second life: From appetite stimulator to glucose regulator

    Pieter-Jan Verhulst; Inge Depoortere

    2012-01-01

    Ghrelin,a 28 amino acid peptide hormone produced by the stomach,was the first orexigenic hormone to be discovered from the periphery.The octanoyl modification at Ser3,mediated by ghrelin O-acyltransferase (GOAT),is essential for ghrelin's biological activity.Ghrelin stimulates food intake through binding to its receptor (GRLN-R) on neurons in the arcuate nucleus of the hypothalamus.Ghrelin is widely expressed throughout the body; accordingly,it is implicated in several other physiological functions,which include growth hormone release,gastric emptying,and body weight regulation.Ghrelin and GRLN-R expression are also found in the pancreas,suggesting a local physiological role.Accordingly,several recent studies now point towards an important role for ghrelin and its receptor in the regulation of blood glucose homeostasis,which is the main focus of this review.Several mechanisms of this regulation by ghrelin have been proposed,and one possibility is through the regulation of insulin secretion.Despite some controversy,most studies suggest that ghrelin exerts an inhibitory effect on insulin secretion,resulting in increased circulating glucose levels.Ghrelin may thus be a diabetogenic factor.Obesity-related type 2 diabetes has become an increasingly important health problem,almost reaching epidemic proportions in the world; therefore,antagonists of the ghrelin-GOAT signaling pathway,which will tackle both energy-and glucose homeostasis,may be considered as promising new therapies for this disease.

  9. Regulation of Glucose Utilization by Estradiol in Breast Cancer

    2014-10-01

    uptake or glycolysis (Fig. 5D, 5E). We believe that this disparity may be because of the relative potency of PFK158 which competitively but not completely...E2) to estrogen receptor-positive (ER+) breast cancer patients increases glucose uptake by tumors. Accordingly, downstream metabolic regulators of E2...appendix 1). 15. SUBJECT TERMS Estradiol, Glycolysis, Estrogen receptor, PFKFB3, Cancer metabolism 16. SECURITY CLASSIFICATION OF: 17. LIMITATION

  10. PREVALENCE OF IMPAIRED GLUCOSE REGULATION IN THE POPULATION OF TIANJIN

    Xin-yue Zhi; Jian-hua Wang

    2008-01-01

    Objective To investigate the prevalence of impaired glucose regulation (IGR) in the population of Tianjin.Methods A cross-sectional study was conducted in Tianjin from June to September in 2005.The multi-phasic stratified cluster sampling method was adopted.Totally,21454 people were selected as survey sample.Information on risk factors was collected through face-to-face questionnaire interview.Fasting capillary whole blood glucose level and other clinical indexes were tested.Results The prevalence of impaired fasting glucose (IFG) in the population was 5.61% (5.32% in male,5.89% in female).The prevalence of impaired glucose tolerance (IGT) was 2.91% (2.59% in male,3.20% in female) in whole population,and the prevalence of female was significantly higher than that of male (P=0.04).The prevalences of IFG and IGT increased with the increasing of age.And the prevalences were also influenced by the profession,educational level,and income level.Conclusion The prevalences oflGT and IFG in Tianjin are similar to those in the other big cities of China.

  11. Valine Pyrrolidide Preserves Intact Glucose-Dependent Insulinotropic Peptide and Improves Abnormal Glucose Tolerance in Minipigs With Reduced β-Cell Mass

    Larsen, Marianne Olholm; Rolin, Bidda; Ribel, Ulla; Wilken, Michael; Deacon, Carolyn F; Svendsen, Ove; Gotfredsen, Carsten F.; Carr, Richard David

    2003-01-01

    The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are important in blood glucose regulation.However, both incretin hormones are rapidly degraded by the enzyme dipeptidyl peptidase IV (DPPIV). The concept of DPPIV inhibition as a treatment for type 2 diabetes was evaluated in a new large animal model of insulin-deficient diabetes and reduced β-cell mass, the nicotinamide (NIA) (67 mg/kg) and streptozotocin (STZ) (125 mg/kg)–treated min...

  12. Dietary intake, food pattern, and abnormal blood glucose status of middle-aged adults: a cross-sectional community-based study in Myanmar

    Hlaing Hlaing Hlaing

    2016-05-01

    Full Text Available Background: Lifestyle changes, particularly dietary intake, had resulted in increasing trends of type-2 diabetes mellitus worldwide. However, dietary intake is diverse across country contexts. This study aimed to compare the dietary intake, food patterns, and blood glucose among middle-aged adults living in urban and suburban areas in Mandalay city, Myanmar, and explore their relationships. Methods: A cross-sectional community-based study was conducted during June–November 2014. Adults aged 35–64 were randomly selected and requested to record all food they ate in a 4-day diary. Fasting and 2-hour postprandial blood glucose values were measured over two consecutive days. Dietary intakes were calculated in terms of energy, macronutrients, glycemic index, and glycemic load, and food patterns were identified by factor analysis. The relationships between food pattern, dietary intake, and blood glucose were assessed. Results: Of 440 participants, dietary intake between urban and suburban residents was significantly different. Six food patterns were identified. There was no difference in fasting and 2-hour postprandial blood glucose between urban and suburban residents, but a strong correlation between fasting blood glucose and 2-hour postprandial blood glucose was found (correlation coefficient=0.8. Identification of abnormal blood glucose status using original fasting and converted 2-hour postprandial values showed substantial agreement (prevalence-adjusted bias-adjusted Kappa= 0.8. Relationships between food patterns and blood glucose or abnormal blood glucose status were not found. Conclusion: Food patterns were associated with dietary intake, not with abnormal blood glucose status. Two-hour postprandial blood glucose was highly correlated with fasting blood glucose and may be used for identifying abnormal blood glucose status.

  13. Insulin signalling and the regulation of glucose and lipid metabolism

    Saltiel, Alan R.; Kahn, C. Ronald

    2001-12-01

    The epidemic of type 2 diabetes and impaired glucose tolerance is one of the main causes of morbidity and mortality worldwide. In both disorders, tissues such as muscle, fat and liver become less responsive or resistant to insulin. This state is also linked to other common health problems, such as obesity, polycystic ovarian disease, hyperlipidaemia, hypertension and atherosclerosis. The pathophysiology of insulin resistance involves a complex network of signalling pathways, activated by the insulin receptor, which regulates intermediary metabolism and its organization in cells. But recent studies have shown that numerous other hormones and signalling events attenuate insulin action, and are important in type 2 diabetes.

  14. Quantitative proteomics identifies unanticipated regulators of nitrogen- and glucose starvation

    Rødkær, Steven V; Pultz, Dennis; Brusch, Michelle;

    2014-01-01

    starvation. We identify nearly 1400 phosphorylation sites of which more than 500 are regulated in a temporal manner in response to glucose- or nitrogen starvation. By bioinformatics and network analyses, we have identified the cyclin-dependent kinase (CDK) inhibitor Sic1, the Hsp90 co-chaperone Cdc37......, and the Hsp90 isoform Hsp82 to putatively mediate some of the starvation responses. Consistently, quantitative expression analyses showed that Sic1, Cdc37, and Hsp82 are required for normal expression of nutrient-responsive genes. Collectively, we therefore propose that Sic1, Cdc37, and Hsp82 may orchestrate...... parts of the cellular starvation response by regulating transcription factor- and kinase activities....

  15. Prevalence of glucose tolerance test abnormalities in women with polycystic ovarian syndrome

    Leila J. Gracelyn

    2015-12-01

    Conclusions: High prevalence of IGT and Non-Insulin Dependent Diabetes Mellitus (NIDDM in women with PCOS was observed than expected. They have accelerated conversion from IGT to NIDDM. IGT is often asymptomatic and is a known risk factor for type 2 DM and cardiovascular disease. OGTT with 75 gms of glucose is the best screening method for glucose intolerance and a good measure to diagnose type 2 DM in PCOS women. [Int J Reprod Contracept Obstet Gynecol 2015; 4(6.000: 1739-1745

  16. Integration of Transcriptional and Posttranslational Regulation in a Glucose Signal Transduction Pathway in Saccharomyces cerevisiae

    Kim, Jeong-Ho; Brachet, Valérie; Moriya, Hisao; Johnston, Mark

    2006-01-01

    Expression of the HXT genes encoding glucose transporters in the budding yeast Saccharomyces cerevisiae is regulated by two interconnected glucose-signaling pathways: the Snf3/Rgt2-Rgt1 glucose induction pathway and the Snf1-Mig1 glucose repression pathway. The Snf3 and Rgt2 glucose sensors in the membrane generate a signal in the presence of glucose that inhibits the functions of Std1 and Mth1, paralogous proteins that regulate the function of the Rgt1 transcription factor, which binds to th...

  17. Is contraction-stimulated glucose transport feedforward regulated by Ca2+?

    Jensen, Thomas Elbenhardt; Angin, Yeliz; Sylow, Lykke

    2014-01-01

    feedforward regulator of the translocation of glucose transporter 4 to the cell surface to facilitate transmembrane glucose transport. This review summarizes the evidence supporting the Ca(2+) feedforward model and its proposed signalling links to regulation of glucose transport in skeletal muscle and other......-stimulated glucose transport. A revised working model is proposed, in which muscle glucose transport during contraction is not directly regulated by SR Ca(2+) release but rather responds exclusively to feedback signals activated secondary to cross-bridge cycling and tension development....

  18. Stretch-stimulated glucose transport in skeletal muscle is regulated by Rac1

    Sylow, Lykke; Møller, Lisbeth L V; Kleinert, Maximilian;

    2015-01-01

    -stimulated glucose transport by 30-40% in tension developing muscle, but did not affect contraction-stimulated glucose transport in muscles in which force development was prevented. Our findings suggest that Rac1 and the actin cytoskeleton regulate stretch-stimulated glucose transport and that Rac1 is a required......Alternatives to the canonical insulin signaling pathway for glucose transport are muscle contraction/exercise. Mechanical stress is an integrated part of the muscle contraction/relaxation cycle and passive stretch has been shown to increase muscle glucose transport. However, the signaling mechanism...... regulating stretch-stimulated glucose transport is not well understood. We recently reported that the actin cytoskeleton regulating GTPase, Rac1 was activated in mouse muscle in response to stretching. Rac1 is a regulator of contraction- and insulin-stimulated glucose transport but its role in stretch...

  19. 葡萄糖调节受损的研究现状%Impaired glucose regulation

    张静漪; 刘树琴

    2010-01-01

    葡萄糖调节受损(IGR)是介于正常血糖与糖尿病之间的一种中间状态.它同样具有2型糖尿病的两大基本特征:胰岛素抵抗和β细胞分泌功能受损.但它包括的两种血糖异常状态即空腹血糖受损和糖耐量减低具有不同的胰岛素抵抗和β细胞分泌功能特征及流行病学特征.我国普通成年人中15.5%发生IGR.IGR独立于代谢综合征的其他组分而与动脉粥样硬化性心血管疾病密切相关,采取生活方式及适当药物早期干预IGR可有效防治糖尿病及心血管疾病的发生.%Impaired glucose regulation (IGR) is a condition between normal blood glucose and diabetes mellitus. IGR also has two basic features of type 2 diabetes mellilus: insulin resistance and islet β cell dysfunction. On the other hand, IGR includes two different abnormal glycetnia conditions-impaired fasting glucose (IFG) and impaired glucose tolerance (IGT), which have distinct degrees on insulin resistance and islet β cell dysfunction and different epidemiological features. 15. 5% of Chinese ordinary adults developed ICR. IGR is significantly related with atherosclerotic cardiovascular diseases that independent of components of metabolic syndrome. Lifestyle intervention and relevant pharmacotherapy earlier are effective in reducing the incidence of diabetes and cardiovascular diseases in subjects with pre-diabetes.

  20. A comprehensive compartmental model of blood glucose regulation for healthy and type 2 diabetic subjects

    Vahidi, O; Kwok, K E; Gopaluni, R B

    2016-01-01

    We have expanded a former compartmental model of blood glucose regulation for healthy and type 2 diabetic subjects. The former model was a detailed physiological model which considered the interactions of three substances, glucose, insulin and glucagon on regulating the blood sugar. The main...... drawback of the former model was its restriction on the route of glucose entrance to the body which was limited to the intravenous glucose injection. To handle the oral glucose intake, we have added a model of glucose absorption in the gastrointestinal tract to the former model to address the resultant...... variations of blood glucose concentrations following an oral glucose intake. Another model representing the incretins production in the gastrointestinal tract along with their hormonal effects on boosting pancreatic insulin production is also added to the former model. We have used two sets of clinical data...

  1. Glucose utilization rates regulate intake levels of artificial sweeteners.

    Tellez, Luis A; Ren, Xueying; Han, Wenfei; Medina, Sara; Ferreira, Jozélia G; Yeckel, Catherine W; de Araujo, Ivan E

    2013-11-15

    It is well established that animals including humans attribute greater reinforcing value to glucose-containing sugars compared to their non-caloric counterparts, generally termed 'artificial sweeteners'. However, much remains to be determined regarding the physiological signals and brain systems mediating the attribution of greater reinforcing value to sweet solutions that contain glucose. Here we show that disruption of glucose utilization in mice produces an enduring inhibitory effect on artificial sweetener intake, an effect that did not depend on sweetness perception or aversion. Indeed, such an effect was not observed in mice presented with a less palatable, yet caloric, glucose solution. Consistently, hungry mice shifted their preferences away from artificial sweeteners and in favour of glucose after experiencing glucose in a hungry state. Glucose intake was found to produce significantly greater levels of dopamine efflux compared to artificial sweetener in dorsal striatum, whereas disrupting glucose oxidation suppressed dorsal striatum dopamine efflux. Conversely, inhibiting striatal dopamine receptor signalling during glucose intake in sweet-naïve animals resulted in reduced, artificial sweetener-like intake of glucose during subsequent gluco-deprivation. Our results demonstrate that glucose oxidation controls intake levels of sweet tastants by modulating extracellular dopamine levels in dorsal striatum, and suggest that glucose utilization is one critical physiological signal involved in the control of goal-directed sweetener intake.

  2. Rac1- a novel regulator of contraction-stimulated glucose uptake in skeletal muscle

    Sylow, Lykke; Møller, Lisbeth L V; Kleinert, Maximilian

    2014-01-01

    Muscle contraction stimulates muscle glucose uptake by facilitating translocation of the glucose transporter 4 from intracellular locations to the cell surface, which allows for diffusion of glucose into the myofibers. However, the intracellular mechanisms regulating this process are not well....../contraction-stimulated glucose uptake in skeletal muscle, since muscle-specific Rac1 knockout mice display reduced ex vivo contraction- and in vivo exercise-stimulated glucose uptake in skeletal muscle. The molecular mechanisms by which Rac1 regulate glucose uptake is presently unknown. However, recent studies link Rac1...... to the actin cytoskeleton, the small GTPase RalA, and/or free radical production, which have previously been shown to be regulators of glucose uptake in muscle. We propose a model in which Rac1 is activated by contraction- and exercise-induced stretch signals and that Rac1 in conjunction with other signaling...

  3. Geniposide regulates glucose-stimulated insulin secretion possibly through controlling glucose metabolism in INS-1 cells.

    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.

  4. Evaluation of glucose metabolic abnormality in postlingually deaf patients using F-18-FDG positron emission tomography and statistical parametric mapping

    Lee, Jae Sung; Lee, Dong Soo; Oh, Seung Ha; Kim, Chong Sun; Park, Kwang Suk; Chung, June Key; Lee, Myung Chul [College of Medicine, Seoul National Univ., Seoul (Korea, Republic of)

    2000-07-01

    We have previously reported the prognostic relevance of cross-modal cortical plasticity in prelingual deaf patients revealed by F-18-FDG PET and SPM analysis. In this study, we investigated metabolic abnormality in postlingual deaf patients, whose clinical features are different from prelingual deafness. Nine postlingual deaf patients (age: 30.5 {+-}14.0) were performed on F-18-FDG brain PET. We compared their PET images with those of age-matched 20 normal controls (age: 27.1 {+-}8.6), and performed correlation analysis to investigate the relationship between glucose metabolism and deaf duration using SPM99. Glucose metabolism of deaf patients was significantly (p<0.05, corrected) decreased in both anterior cingulate, inferior frontal cortices, and superior temporal cortices, and left hippocampus. Metabolism in both superior temporal cortices and association area in inferior parietal cortices showed significant (p<0.01, uncorrected) positive correlation with deaf duration. Decreased metabolism in hippocampus accompanied with hypometabolism in auditory related areas can be explained by recent finding of anatomical connectivity between them, and may be the evidence indicating their functional connectivity. Metabolism recovery in auditory cortex after long deaf duration suggests that cortical plasticity takes place also in postlingual deafness.

  5. Dietary antioxidants: Do they have a role to play in the ongoing fight against abnormal glucose metabolism?

    Avignon, Antoine; Hokayem, Marie; Bisbal, Catherine; Lambert, Karen

    2012-07-01

    Overfeeding, an increased intake of saturated fatty acids, and sugary foods are key dietary changes that have occurred in recent decades in addition to the emergence of the obesity epidemic. In addition to an increase in energy storage as fat, these dietary changes are accompanied by an increase in mitochondrial macronutrient oxidation, leading to an excessive free radical production and, hence, oxidative stress. The latter has long been considered a central mechanism linking nutrient overload, insulin resistance, the metabolic syndrome, and diabetes. However, food, through fruit and vegetable consumption, also can be a great source of antioxidants that protect the body against oxidative damage and insulin resistance and thus help cope with the metabolic backlash of the energy-dense Westernized diet. Experimental data are in favor of the beneficial role conveyed by antioxidants in glucose metabolism, but clinical data in humans remain controversial. This review therefore aimed to sort out any underlying discrepancies and provide an overall clear view of the role of antioxidants in the ongoing fight against abnormal glucose metabolism.

  6. Objective 3D surface evaluation of intracranial electrophysiologic correlates of cerebral glucose metabolic abnormalities in children with focal epilepsy.

    Jeong, Jeong-Won; Asano, Eishi; Kumar Pilli, Vinod; Nakai, Yasuo; Chugani, Harry T; Juhász, Csaba

    2017-03-21

    To determine the spatial relationship between 2-deoxy-2[(18) F]fluoro-D-glucose (FDG) metabolic and intracranial electrophysiological abnormalities in children undergoing two-stage epilepsy surgery, statistical parametric mapping (SPM) was used to correlate hypo- and hypermetabolic cortical regions with ictal and interictal electrocorticography (ECoG) changes mapped onto the brain surface. Preoperative FDG-PET scans of 37 children with intractable epilepsy (31 with non-localizing MRI) were compared with age-matched pseudo-normal pediatric control PET data. Hypo-/hypermetabolic maps were transformed to 3D-MRI brain surface to compare the locations of metabolic changes with electrode coordinates of the ECoG-defined seizure onset zone (SOZ) and interictal spiking. While hypometabolic clusters showed a good agreement with the SOZ on the lobar level (sensitivity/specificity = 0.74/0.64), detailed surface-distance analysis demonstrated that large portions of ECoG-defined SOZ and interictal spiking area were located at least 3 cm beyond hypometabolic regions with the same statistical threshold (sensitivity/specificity = 0.18-0.25/0.94-0.90 for overlap 3-cm distance); for a lower threshold, sensitivity for SOZ at 3 cm increased to 0.39 with a modest compromise of specificity. Performance of FDG-PET SPM was slightly better in children with smaller as compared with widespread SOZ. The results demonstrate that SPM utilizing age-matched pseudocontrols can reliably detect the lobe of seizure onset. However, the spatial mismatch between metabolic and EEG epileptiform abnormalities indicates that a more complete SOZ detection could be achieved by extending intracranial electrode coverage at least 3 cm beyond the metabolic abnormality. Considering that the extent of feasible electrode coverage is limited, localization information from other modalities is particularly important to optimize grid coverage in cases of large hypometabolic cortex. Hum Brain Mapp, 2017. © 2017

  7. Dietary thylakoids suppress blood glucose and modulate appetite-regulating hormones in pigs exposed to oral glucose tolerance test

    Montelius, Caroline; Szwiec, Katarzyna; Kardas, Marek

    2014-01-01

    BACKGROUND & AIMS: Dietary chloroplast thylakoids have previously been found to reduce food intake and body weight in animal models, and to change metabolic profiles in humans in mixed-food meal studies. The aim of this study was to investigate the modulatory effects of thylakoids on glucose...... metabolism and appetite-regulating hormones during an oral glucose tolerance test in pigs fed a high fat diet. METHODS: Six pigs were fed a high fat diet (36 energy% fat) for one month before oral glucose tolerance test (1 g/kg d-glucose) was performed. The experiment was designed as a cross-over study......, and decreased late postprandial secretion of ghrelin. CONCLUSION: Dietary thylakoids may be a novel agent in reducing the glycaemic responses to high carbohydrate and high glycaemic index foods. Thylakoids may in the future be promising for treatment and prevention of diabetes, overweight and obesity....

  8. Abnormal Cardiac Autonomic Regulation in Mice Lacking ASIC3

    Ching-Feng Cheng

    2014-01-01

    Full Text Available Integration of sympathetic and parasympathetic outflow is essential in maintaining normal cardiac autonomic function. Recent studies demonstrate that acid-sensing ion channel 3 (ASIC3 is a sensitive acid sensor for cardiac ischemia and prolonged mild acidification can open ASIC3 and evoke a sustained inward current that fires action potentials in cardiac sensory neurons. However, the physiological role of ASIC3 in cardiac autonomic regulation is not known. In this study, we elucidate the role of ASIC3 in cardiac autonomic function using Asic3−/− mice. Asic3−/− mice showed normal baseline heart rate and lower blood pressure as compared with their wild-type littermates. Heart rate variability analyses revealed imbalanced autonomic regulation, with decreased sympathetic function. Furthermore, Asic3−/− mice demonstrated a blunted response to isoproterenol-induced cardiac tachycardia and prolonged duration to recover to baseline heart rate. Moreover, quantitative RT-PCR analysis of gene expression in sensory ganglia and heart revealed that no gene compensation for muscarinic acetylcholines receptors and beta-adrenalin receptors were found in Asic3−/− mice. In summary, we unraveled an important role of ASIC3 in regulating cardiac autonomic function, whereby loss of ASIC3 alters the normal physiological response to ischemic stimuli, which reveals new implications for therapy in autonomic nervous system-related cardiovascular diseases.

  9. Acute and chronic effects of glyceryl trinitrate therapy on insulin and glucose regulation in humans.

    Jedrzkiewicz, Sean; Parker, John D

    2013-05-01

    This study examined the effect of acute and sustained transdermal glyceryl trinitrate (GTN) therapy on insulin and glucose regulation. Totally, 12 males (18-30 years) underwent a glucose tolerance test at baseline (visit 1), 90 minutes after acute transdermal GTN 0.6 mg/h (visit 2), following 7 days of continuous GTN (visit 3), and 2 to 3 days after stopping GTN (visit 4). At each visit, plasma glucose and insulin concentrations were measured before and 30, 60, 90, and 120 minutes after a 75-g oral glucose load. Indices of glucose metabolism that were examined included the insulin sensitivity index, the homeostasis model assessment of insulin resistance (HOMA-IR), and the insulinogenic index. The acute administration of GTN had no effect on glucose and insulin responses (visit 2). However, after 7 days of GTN exposure (visit 3) there was an increase in the mean glucose concentration measured after the oral glucose load. On visit 1, the mean glucose concentration (± standard deviation) following the 75 g oral glucose challenge was 5.7 ± 0.5 µmol/L. On visit 3, after 7 days of transdermal GTN therapy, the mean glucose concentration after the oral glucose was significantly higher; 6.2 ± 0.5 µmol/L (P GTN therapy modifies glucose metabolism causing evidence of increased insulin resistance during sustained therapy in normal humans.

  10. Regulation of glucose and glycogen metabolism during and after exercise

    Jensen, Thomas Elbenhardt; Richter, Erik

    2012-01-01

    Utilization of carbohydrate in the form of intramuscular glycogen stores and glucose delivered from plasma becomes an increasingly important energy substrate to the working muscle with increasing exercise intensity. This review gives an update on the molecular signals by which glucose transport...... in the post-exercise period which can result in an overshoot of intramuscular glycogen resynthesis post exercise (glycogen supercompensation)....

  11. Impact of cereal fibre on glucose-regulating factors

    Weickert, M O; Mohlig, M; Koebnick, C

    2005-01-01

    AIMS/HYPOTHESIS: Insoluble dietary fibre intake is associated, by unknown mechanisms, with a reduced risk of type 2 diabetes. We investigated whether a short-term dietary intervention with purified insoluble fibres influences acute and delayed responses of glucose, insulin, glucose-dependent insu...

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

    Pichette, Jennifer; Gagnon, Jeffrey

    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.

  13. Abnormality of peripheral nerve conduction velocity associated with illness course, symptoms and fasting blood glucose in patients with type 2 diabetes mellitus

    Suijing Cui; Jinhua Qiu; Weiliang Luo

    2006-01-01

    BACKGROUND: It has shown that abnormality of peripheral nerve conduction velocity during onset of diabetes mellitus is not related to age and sex, but to symptoms, illness course and level of fasting blood glucose.OBJECTIVE: To measure correlation of abnormality of peripheral nerve conduction velocity with various illness courses, symptoms and levels of fasting blood glucose of patients with type 2 diabetes mellitus.DESIGN: Case analysis.SETTING: Department of Neurology, Central People's Hospital of Huizhou.PARTICIPANTS: A total of 128 patients who were diagnosed as type 2 diabetes mellitus were selected from Central People's Hospital of Huizhou from September 2001 to October 2005. There were 75 males and 53 females aged 32-83 years and the illness course ranged from 1 month to 20 years.METHODS: All 128 patients with type 2 diabetes mellitus received neuro-electrophysiological study and their clinical data were retrospectively analyzed to measure peripheral nerve conduction velocity and fasting blood glucose so as to investigate the correlation of peripheral nerve conduction velocity with clinical symptoms,illness course and levels of fasting blood glucose.MAIN OUTCOME MEASURES: Correlation of peripheral nerve conduction velocity with clinical symptoms, illness course and levels of fasting blood glucose.RESULTS: All 128 patients with type 2 diabetes mellitus were involved in the final analysis. ① Among 128patients, 114 patients had abnormality of peripheral nerve conduction velocity; 110 patients had clinical symptoms, including 102 patients having abnormality of peripheral nerve conduction velocity; 18 patients did not have clinical symptoms, including 12 patients having abnormality of peripheral nerve conduction velocity.There were significant differences between them (x2=8.275, P=0.04). ② Among 128 patients, illness course of 75 patients was equal to or less than 5 years, including 27 patients having abnormality of peripheral nerve conduction velocity

  14. Blood glucose regulation mechanism in depressive disorder animal model during hyperglycemic states.

    Lim, Su-Min; Park, Soo-Hyun; Sharma, Naveen; Kim, Sung-Su; Lee, Jae-Ryeong; Jung, Jun-Sub; Suh, Hong-Won

    2016-06-01

    Depression is more common among diabetes people than in the general population. In the present study, blood glucose change in depression animal model was characterized by various types of hyperglycemia models such as d-glucose-fed-, immobilization stress-, and drug-induced hyperglycemia models. First, the ICR mice were enforced into chronic restraint stress for 2h daily for 2 weeks to produce depression animal model. The animals were fed with d-glucose (2g/kg), forced into restraint stress for 30min, or administered with clonidine (5μg/5μl) supraspinally or spinally to produce hyperglycemia. The blood glucose level in depression group was down-regulated compared to that observed in the normal group in d-glucose-fed-, restraint stress-, and clonidine-induced hyperglycemia models. The up-regulated corticosterone level induced by d-glucose feeding or restraint stress was reduced in the depression group while the up-regulation of plasma corticosterone level is further elevated after i.t. or i.c.v. clonidine administration in the depression group. The up-regulated insulin level induced by d-glucose feeding or restraint stress was reduced in the depression group. On the other hand, blood corticosterone level in depression group was up-regulated compared to the normal group after i.t. or i.c.v. clonidine administration. Whereas the insulin level in depression group was not altered when mice were administered clonidine i.t. or i.c.v. Our results suggest that the blood glucose level in depression group is down-regulated compared to the normal group during d-glucose-fed-, immobilization stress-, and clonidine-induced hyperglycemia in mice. The down-regulation of the blood glucose level might be one of the important pathophysiologic changes in depression.

  15. Upper intestinal lipids trigger a gut-brain-liver axis to regulate glucose production.

    Wang, Penny Y T; Caspi, Liora; Lam, Carol K L; Chari, Madhu; Li, Xiaosong; Light, Peter E; Gutierrez-Juarez, Roger; Ang, Michelle; Schwartz, Gary J; Lam, Tony K T

    2008-04-24

    Energy and glucose homeostasis are regulated by food intake and liver glucose production, respectively. The upper intestine has a critical role in nutrient digestion and absorption. However, studies indicate that upper intestinal lipids inhibit food intake as well in rodents and humans by the activation of an intestine-brain axis. In parallel, a brain-liver axis has recently been proposed to detect blood lipids to inhibit glucose production in rodents. Thus, we tested the hypothesis that upper intestinal lipids activate an intestine-brain-liver neural axis to regulate glucose homeostasis. Here we demonstrate that direct administration of lipids into the upper intestine increased upper intestinal long-chain fatty acyl-coenzyme A (LCFA-CoA) levels and suppressed glucose production. Co-infusion of the acyl-CoA synthase inhibitor triacsin C or the anaesthetic tetracaine with duodenal lipids abolished the inhibition of glucose production, indicating that upper intestinal LCFA-CoAs regulate glucose production in the preabsorptive state. Subdiaphragmatic vagotomy or gut vagal deafferentation interrupts the neural connection between the gut and the brain, and blocks the ability of upper intestinal lipids to inhibit glucose production. Direct administration of the N-methyl-d-aspartate ion channel blocker MK-801 into the fourth ventricle or the nucleus of the solitary tract where gut sensory fibres terminate abolished the upper-intestinal-lipid-induced inhibition of glucose production. Finally, hepatic vagotomy negated the inhibitory effects of upper intestinal lipids on glucose production. These findings indicate that upper intestinal lipids activate an intestine-brain-liver neural axis to inhibit glucose production, and thereby reveal a previously unappreciated pathway that regulates glucose homeostasis.

  16. Glucose level regulation via integral high-order sliding modes.

    Dorel, Lela

    2011-04-01

    Diabetes is a condition in which the body either does not produce enough insulin, or does not properly respond to it. This causes the glucose level in blood to increase. An algorithm based on Integral High-Order Sliding Mode technique is proposed, which keeps the normal blood glucose level automatically releasing insulin into the blood. The system is highly insensitive to inevitable parametric and model uncertainties, measurement noises and small delays.

  17. Effect of ghrelin on glucose regulation in mice.

    Chacko, Shaji K; Haymond, Morey W; Sun, Yuxiang; Marini, Juan C; Sauer, Pieter J J; Ma, Xiaojun; Sunehag, Agneta L

    2012-05-15

    Improvement of glucose metabolism after bariatric surgery appears to be from the composite effect of the alterations in multiple circulating gut hormone concentrations. However, their individual effect on glucose metabolism during different conditions is not clear. The objective of this study was to determine whether ghrelin has an impact on glycogenolysis, gluconeogenesis, and insulin sensitivity (using a mice model). Rate of appearance of glucose, glycogenolysis, and gluconeogenesis were measured in wild-type (WT), ghrelin knockout (ghrelin(-/-)), and growth hormone secretagogue receptor knockout (Ghsr(-/-)) mice in the postabsorptive state. The physiological nature of the fasting condition was ascertained by a short-term fast commenced immediately at the end of the dark cycle. Concentrations of glucose and insulin were measured, and insulin resistance and hepatic insulin sensitivity were calculated. Glucose concentrations were not different among the groups during the food-deprived period. However, plasma insulin concentrations were lower in the ghrelin(-/-) and Ghsr(-/-) than WT mice. The rates of gluconeogenesis, glycogenolysis, and indexes of insulin sensitivity were higher in the ghrelin(-/-) and Ghsr(-/-) than WT mice during the postabsorptive state. Insulin receptor substrate 1 and glucose transporter 2 gene expressions in hepatic tissues of the ghrelin(-/-) and Ghsr(-/-) were higher compared with that in WT mice. This study demonstrates that gluconeogenesis and glycogenolysis are increased and insulin sensitivity is improved by the ablation of the ghrelin or growth hormone secretagogue receptor in mice.

  18. A karyopherin alpha2 nuclear transport pathway is regulated by glucose in hepatic and pancreatic cells.

    Cassany, Aurélia; Guillemain, Ghislaine; Klein, Christophe; Dalet, Véronique; Brot-Laroche, Edith; Leturque, Armelle

    2004-01-01

    We studied the role of the karyopherin alpha2 nuclear import carrier (also known as importin alpha2) in glucose signaling. In mhAT3F hepatoma cells, GFP-karyopherin alpha2 accumulated massively in the cytoplasm within minutes of glucose extracellular addition and returned to the nucleus after glucose removal. In contrast, GFP-karyopherin alpha1 distribution was unaffected regardless of glucose concentration. Glucose increased GFP-karyopherin alpha2 nuclear efflux by a factor 80 and its shuttling by a factor 4. These glucose-induced movements were not due to glycolytic ATP production. The mechanism involved was leptomycin B-insensitive, but phosphatase- and energy-dependent. HepG2 and COS-7 cells displayed no glucose-induced GFP-karyopherin alpha2 movements. In pancreatic MIN-6 cells, the glucose-induced movements of karyopherin alpha2 and the stimulation of glucose-induced gene transcription were simultaneously lost between passages 28 and 33. Thus, extracellular glucose regulates a nuclear transport pathway by increasing the nuclear efflux and shuttling of karyopherin alpha2 in cells in which glucose can stimulate the transcription of sugar-responsive genes.

  19. Mathematical analysis of a model for glucose regulation.

    Fessel, Kimberly; Gaither, Jeffrey B; Bower, Julie K; Gaillard, Trudy; Osei, Kwame; Rempala, Grzegorz A

    2016-02-01

    Diabetes affects millions of Americans, and the correct identification of individuals afflicted with this disease, especially of those in early stages or in progression towards diabetes, remains an active area of research. The minimal model is a simplified mathematical construct for understanding glucose-insulin interactions. Developed by Bergman, Cobelli, and colleagues over three decades ago, this system of coupled ordinary differential equations prevails as an important tool for interpreting data collected during an intravenous glucose tolerance test (IVGTT). In this study we present an explicit solution to the minimal model which allows for separating the glucose and insulin dynamics of the minimal model and for identifying patient-specific parameters of glucose trajectories from IVGTT. As illustrated with patient data, our approach seems to have an edge over more complicated methods currently used. Additionally, we also present an application of our method to prediction of the time to baseline recovery and calculation of insulin sensitivity and glucose effectiveness, two quantities regarded as significant in diabetes diagnostics.

  20. Expression and Location of Glucose-regulated Protein 78 in Testis and Epididymis

    W Wang

    2014-04-01

    Full Text Available Objective: To know the role of glucose-regulated protein 78 (GRP78/BiP/HSPA5 in spermatogenesis and its expression and location in the testis and epididymis. Methods: Immunohistochemistry and Western blot were used to detect GRP78 location and expression in the testis and epididymis. Results: Glucose-regulated protein 78 was observed in spermatocytes, round spermatids and interstitial cells of the testis and in principal cells of the epididymis. Glucose-regulated protein 78 was first detected in the rat testis at postnatal day 14. Thereafter, the protein level increased gradually with age and was maintained at a high and stable state after postnatal day 28. In the rat, GRP78 was expressed in the principal cells but not in clear cells of the epididymis. Conclusion: Glucose-regulated protein 78 participates in the process of spermatogenesis.

  1. Significance of adiponectin in the risk of coronary lesions in patients with impaired glucose regulation

    黄珊

    2013-01-01

    Objective To investigate the association of impaired glucose regulation and adiponectin(APN) with the clinical severity of coronary lesions. Methods A total of 210 cases of suspected coronary heart disease were examined

  2. The Rab-GTPase-activating protein TBC1D1 regulates skeletal muscle glucose metabolism

    Szekeres, Ferenc; Chadt, Alexandra; Tom, Robby Z

    2012-01-01

    The Rab-GTPase-activating protein TBC1D1 has emerged as a novel candidate involved in metabolic regulation. Our aim was to determine whether TBC1D1 is involved in insulin as well as energy-sensing signals controlling skeletal muscle metabolism. TBC1D1-deficient congenic B6.SJL-Nob1.10 (Nob1.10(SJL...... be explained partly by a 50% reduction in GLUT4 protein, since proximal signaling at the level of Akt, AMPK, and acetyl-CoA carboxylase (ACC) was unaltered. Paradoxically, in vivo insulin-stimulated 2-deoxyglucose uptake was increased in EDL and tibialis anterior muscle from TBC1D1-deficient mice......)) and wild-type littermates were studied. Glucose and insulin tolerance, glucose utilization, hepatic glucose production, and tissue-specific insulin-mediated glucose uptake were determined. The effect of insulin, AICAR, or contraction on glucose transport was studied in isolated skeletal muscle. Glucose...

  3. Burden and Socio-Behavioral Correlates of Uncontrolled Abnormal Glucose Metabolism in an Urban Population of India

    Mahapatra, Tanmay; Chakraborty, Kaushik; Mahapatra, Sanchita; Mahapatra, Umakanta; Pandey, Naren; Thomson, Peter L.; Musk, Arthur W.; Mitra, Ramendra N.

    2016-01-01

    Background Progressive burden of diabetes mellitus is a major concern in India. Data on the predictors of poor glycemic control among diabetics are scanty. A population-based cross-sectional study nested in an urban cohort was thus conducted in West Bengal, India to determine the burden and correlates of total and uncontrolled abnormalities in glucose metabolism (AGM) in a representative population. Methods From 9046 adult cohort-members, 269 randomly selected consenting subjects (non-response = 7.24%) were interviewed, examined [blood pressure (BP), anthropometry], tested for fasting plasma glucose (FPG) and glycosylated hemoglobin (HbA1C). Those having pre-diagnosed diabetes or FPG ≥126 or HbA1c≥6.5 were defined as diabetic. Among non-diabetics, subjects with FPG (mg/dl) = 100–125 or HbA1C(%) = 5.7–6.4 were defined as pre-diabetic. Pre-diagnosed cases with current FPG ≥126 were defined as uncontrolled AGM. Descriptive and regression analyses were conducted using SAS-9.3.2. Results Among participants, 28.62% [95% Confidence Interval (95%CI) = 23.19–34.06)] were overweight [body mass index(BMI) = (25–29.99)kg/meter2], 7.81% (4.58–11.03) were obese(BMI≥30kg/meter2), 20.82% (15.93–25.70) were current smokers, 12.64% (8.64–16.64) were current alcohol-drinkers and 46.32% of responders (39.16–53.47) had family history of diabetes. 17.84% (13.24–22.45) had stage-I [140≤average systolic BP (AvSBP in mm of mercury)business-owners [OR = 25.53(24.91–16.18)], retired [OR = 46.53(45.38–47.72)], ex-smokers [OR = 4.75(1.09–20.78)], ex-drinkers [OR = 22.43(4.62–108.81)] and hypertensives [ORStage II = 13.17(1.29–134.03)] were more likely to have uncontrolled AGM. Conclusions Burden of uncontrolled AGM was high among participants. Efforts to curb the diabetes epidemic in urban India should include interventions targeting appropriate diabetic control among relatively older persons, unemployed, business-owners, retired, ex-smokers, ex

  4. Regulation of aflatoxin biosynthesis: effect of glucose on activities of various glycolytic enzymes.

    Buchanan, R L; Lewis, D F

    1984-08-01

    Catabolism of carbohydrates has been implicated in the regulation of aflatoxin synthesis. To characterize this effect further, the activities of various enzymes associated with glucose catabolism were determined in Aspergillus parasiticus organisms that were initially cultured in peptone-mineral salts medium and then transferred to glucose-mineral salts and peptone-mineral salts media. After an initial increase in activity, the levels of glucose 6-phosphate dehydrogenase, mannitol dehydrogenase, and malate dehydrogenase were lowered in the presence of glucose. Phosphofructokinase activity was greater in the peptone-grown mycelium, but fructose diphosphatase was largely unaffected by carbon source. Likewise, carbon source had relatively little effect on the activities of pyruvate kinase, malic enzyme, isocitrate-NADP dehydrogenase, and isocitrate-NAD dehydrogenase. The results suggest that glucose may, in part, regulate aflatoxin synthesis via a carbon catabolite repression of NADPH-generating and tricarboxylic acid cycle enzymes.

  5. Glucose regulates diacylglycerol intracellular levels and protein kinase C activity by modulating diacylglycerol kinase subcellular localization.

    Miele, Claudia; Paturzo, Flora; Teperino, Raffaele; Sakane, Fumio; Fiory, Francesca; Oriente, Francesco; Ungaro, Paola; Valentino, Rossella; Beguinot, Francesco; Formisano, Pietro

    2007-11-02

    Although chronic hyperglycemia reduces insulin sensitivity and leads to impaired glucose utilization, short term exposure to high glucose causes cellular responses positively regulating its own metabolism. We show that exposure of L6 myotubes overexpressing human insulin receptors to 25 mm glucose for 5 min decreased the intracellular levels of diacylglycerol (DAG). This was paralleled by transient activation of diacylglycerol kinase (DGK) and of insulin receptor signaling. Following 30-min exposure, however, both DAG levels and DGK activity returned close to basal levels. Moreover, the acute effect of glucose on DAG removal was inhibited by >85% by the DGK inhibitor R59949. DGK inhibition was also accompanied by increased protein kinase C-alpha (PKCalpha) activity, reduced glucose-induced insulin receptor activation, and GLUT4 translocation. Glucose exposure transiently redistributed DGK isoforms alpha and delta, from the prevalent cytosolic localization to the plasma membrane fraction. However, antisense silencing of DGKdelta, but not of DGKalpha expression, was sufficient to prevent the effect of high glucose on PKCalpha activity, insulin receptor signaling, and glucose uptake. Thus, the short term exposure of skeletal muscle cells to glucose causes a rapid induction of DGK, followed by a reduction of PKCalpha activity and transactivation of the insulin receptor signaling. The latter may mediate, at least in part, glucose induction of its own metabolism.

  6. Adipocyte glucose transport regulation by eicosanoid precursors and inhibitors

    Lee, H.C.C.

    1987-01-01

    Glucose uptake and free fatty acid release by adipocytes are increased by catecholamines. The mechanism of the stimulatory action of catecholamines on glucose uptake may be via eicosanoid production from release fatty acids. Rats were fed iso-nutrient diets with high or low safflower oil. After one month, 5 rats per diet group were fed diets with aspirin or without aspirin for 2 days. Isolated adipocytes from epididymal fat pads were incubated at 37/sup 0/C, gassed with 95% O/sub 2/-5% CO/sub 2/ in KRB buffer with 3% bovine serum albumin and with or without eicosanoid modifiers; a stimulator (10/sup -5/ M norepinephrine, N), or inhibitors (167 ..mu..l of antiserum to prostaglandin E (AntiE) per 1600 ..mu..l or 23mM Asp), or combinations of these. At 2-, 5-, and 10-min incubation, samples of incubation mixtures were taken to measure 2-deoxy glucose transport using /sup 3/H-2-deoxy glucose, /sup 14/C-inulin, and liquid scintillation counter.

  7. Polyamines regulate cell growth and cellular methylglyoxal in high-glucose medium independently of intracellular glutathione.

    Kwak, Min-Kyu; Lee, Mun-Hyoung; Park, Seong-Jun; Shin, Sang-Min; Liu, Rui; Kang, Sa-Ouk

    2016-03-01

    Polyamines can presumably inhibit protein glycation, when associated with the methylglyoxal inevitably produced during glycolysis. Herein, we hypothesized a nonenzymatic interaction between putrescine and methylglyoxal in putrescine-deficient or -overexpressing Dictyostelium cells in high-glucose medium, which can control methylglyoxal production. Putrescine was essentially required for growth rescue accompanying methylglyoxal detoxification when cells underwent growth defect and cell cycle G1-arrest when supplemented with high glucose. Furthermore, methylglyoxal regulation by putrescine seemed to be a parallel pathway independent of the changes in cellular glutathione content in high-glucose medium. Consequently, we suggest that Dictyostelium cells need polyamines for normal growth and cellular methylglyoxal regulation.

  8. Yeast HXK2 gene reverts glucose regulation mutation of penicillin biosynthesis in P. chrysogenum

    Edmundo A. Pérez

    2014-09-01

    Full Text Available The mutant Penicillium chrysogenum strain dogR5, derived from strain AS-P-78, does not respond to glucose regulation of penicillin biosynthesis and β-galactosidase, and is partially deficient in D-glucose phosphorilating activity. We have transformed strain dogR5 with the (hexokinase hxk2 gene from Saccharomyces cerevisiae. Transformants recovered glucose control of penicillin biosynthesis in different degrees, and acquired a hexokinase (fructose phosphorylating activity absent in strains AS- P-78 and dogR5. Interestingly, they also recovered glucose regulation of β-galactosidase. On the other hand, glucokinase activity was affected in different ways in the transformants; one of which showed a lower activity than the parental dogR5, but normal glucose regulation of penicillin biosynthesis. Our results show that Penicillium chrysogenum AS-P-78 and dogR5 strains lack hexokinase, and suggest that an enzyme with glucokinase activity is involved in glucose regulation of penicillin biosynthesis and β-galactosidase, thus signaling glucose in both primary and secondary metabolism; however, catalytic and signaling activities seem to be independent.

  9. Yeast HXK2 gene reverts glucose regulation mutation of penicillin biosynthesis in P. chrysogenum.

    Pérez, Edmundo A; Fernández, Francisco J; Fierro, Francisco; Mejía, Armando; Marcos, Ana T; Martín, Juan F; Barrios-González, Javier

    2014-01-01

    The mutant Penicillium chrysogenum strain dogR5, derived from strain AS-P-78, does not respond to glucose regulation of penicillin biosynthesis and β-galactosidase, and is partially deficient in D-glucose phosphorilating activity. We have transformed strain dogR5 with the (hexokinase) hxk2 gene from Saccharomyces cerevisiae. Transformants recovered glucose control of penicillin biosynthesis in different degrees, and acquired a hexokinase (fructose phosphorylating) activity absent in strains AS- P-78 and dogR5. Interestingly, they also recovered glucose regulation of β-galactosidase. On the other hand, glucokinase activity was affected in different ways in the transformants; one of which showed a lower activity than the parental dogR5, but normal glucose regulation of penicillin biosynthesis. Our results show that Penicillium chrysogenum AS-P-78 and dogR5 strains lack hexokinase, and suggest that an enzyme with glucokinase activity is involved in glucose regulation of penicillin biosynthesis and β-galactosidase, thus signaling glucose in both primary and secondary metabolism; however, catalytic and signaling activities seem to be independent.

  10. Detection of glycemic abnormalities in adolescents with beta thalassemia using continuous glucose monitoring and oral glucose tolerance in adolescents and young adults with β-thalassemia major: Pilot study

    Ashraf T Soliman

    2013-01-01

    Full Text Available Background: Both insulin deficiency and resistance are reported in patients with β-thalassemia major (BTM. The use of continuous blood glucose monitoring (CGM, among the different methods for early detection of glycemic abnormalities, has not been studied thoroughly in these adolescents. Materials and Methods: To assess the oralglucose tolerance (OGT and 72-h continuous glucose concentration by the continuous glucose monitoring system (CGMS and calculate homeostatic model assessment (HOMA, and the quantitative insulin sensitivity check index (QUICKI was conducted in 16 adolescents with BTM who were receiving regular blood transfusions every 2-4 weeks and iron-chelation therapy since early childhood. Results: Sixteen adolescents with BTM (age: 19.75 ± 3 years were investigated. Using OGTT, (25% had impaired fasting blood (plasma glucose concentration (BG (>5.6 mmol/L. 2-h after the glucose load, one of them had BG = 16.2 mmol/L (diabetic and two had impaired glucose tolerance (IGT (BG > 7.8 and 11.1 mmol/L and 9 with IGT (56%. HOMA and QUICKI revealed levels 0.33 (0.36 ± 0.03, respectively, ruling out significant insulin resistance in these adolescents. There was a significant negative correlation between the β-cell function (B% on one hand and the fasting and the 2-h BG (r=−0.6, and − 0.48, P < 0.01, respectively on the other hand. Neither fasting serum insulin nor c-peptide concentrations were correlated with fasting BG or ferritin levels. The average and maximum blood glucose levels during CGM were significantly correlated with the fasting BG (r = 0.68 and 0.39, respectively, with P < 0.01 and with the BG at 2-hour after oral glucose intake (r = 0.87 and 0.86 respectively, with P < 0.001. Ferritin concentrations were correlated with the fasting BG and the 2-h blood glucose levels in the OGTT (r = 0.52, and r = 0.43, respectively, P < 0.01 as well as with the average BG recorded by CGM (r = 0.75, P < 0.01. Conclusion: CGM has proven to

  11. Comparative study of different control techniques for the regulation of blood glucose level in diabetic patients.

    Ibbini, Mohammed S

    2009-01-01

    Blood glucose regulation is of a great concern for insulin-dependant patients with excessive glucose in blood (hyperglycaemia), or low glucose profile (hypoglycaemia) due to excess insulin delivery. Both conditions can cause dangerous complications for diabetic patients, and hence glucose regulation in blood is of prime importance. Insulin pumps are used to deliver insulin in small quantities, allowing the glucose level to remain as close as possible to that of non-diabetics (near 100 mg dl(-1)). Different control techniques are used to maintain the glucose level and most of them depend on an exact mathematical or empirical model of insulin-glucose interaction. Recently, we have proposed different controllers that are based on fuzzy logic and so do not use mathematical modelling, which in general is nonlinear, complex and suffers from uncertainties. PI fuzzy controllers are physically related to classical PI and PID controllers, which are extremely popular. The parameter settings of classical and fuzzy logic controllers are based on deep common physical background. In this manuscript, a comparative study is proposed to evaluate the use of fuzzy logic controllers over other conventional controllers such as PI and PID controllers to maintain the blood glucose level within a normoglycaemic average especially when a diabetic patient is subjected to different conditions.

  12. Hormonal regulation of glucose clearance in lactating northern elephant seals (Mirounga angustirostris).

    Fowler, Melinda A; Champagne, Cory D; Houser, Dorian S; Crocker, Daniel E

    2008-09-01

    Northern elephant seals exhibit the rare strategy of fasting and lactating concomitantly. We investigated hormonal regulation of glucose clearance in northern elephant seals using glucose tolerance tests (GTT) performed early in lactation and again just prior to weaning. For comparison, identical measurements were made on separate females late in the molt fast. Serial blood samples were used to assess glucose clearance and hormone responses for 3 h post glucose injection. Plasma glucose remained elevated at the end of the sampling period in all groups. Glucose clearance rates were not significantly different among test groups. A significant insulin response was observed in early lactation, no significant response was observed late in lactation and an intermediate response was observed late in the molt fast. The insulin response to a glucose load decreased with adipose tissue proportions. Plasma glucagon decreased significantly following GTT in early and late lactation, although the magnitude of the depression was small in comparison to other species. Hypoinsulemia may be critical to facilitate net lipolysis late in lactation. Consistently low glucose clearance among test groups suggests insulin insensitivity within peripheral tissues. Glucagon suppression independent of insulin release suggests modification of the typical insulin-glucagon counter-regulation. These findings suggest that metabolic features of diabetic-like conditions may be adaptive in the context of long-term fasting.

  13. Progression to impaired glucose regulation and diabetes in the population-based Inter99 study

    Engberg, Susanne; Vistisen, Dorte; Lau, Cathrine;

    2009-01-01

    Objective: To estimate the progression rates to impaired glucose regulation (impaired fasting glucose or impaired glucose tolerance) and diabetes in the Danish population-based Inter99 study and in a high-risk subpopulation, separately. Research Design and Methods: From a population-based primary...... glucose regulation using the current World Health Organization classification criteria were calculated for the first time in a large European population-based study. The progression rates to diabetes show the same pattern as seen in the few similar European studies.......Objective: To estimate the progression rates to impaired glucose regulation (impaired fasting glucose or impaired glucose tolerance) and diabetes in the Danish population-based Inter99 study and in a high-risk subpopulation, separately. Research Design and Methods: From a population-based primary...... prevention study, the Inter99 study, 4,615 individuals without diabetes at baseline and with relevant follow-up data were divided into a low- and a high-risk group based on a risk estimate of ischemic heart disease or the presence of risk factors (smoking, hypertension, hypercholesterolemia, obesity...

  14. Rac1 is a novel regulator of contraction-stimulated glucose uptake in skeletal muscle.

    Sylow, Lykke; Jensen, Thomas E; Kleinert, Maximilian; Mouatt, Joshua R; Maarbjerg, Stine J; Jeppesen, Jacob; Prats, Clara; Chiu, Tim T; Boguslavsky, Shlomit; Klip, Amira; Schjerling, Peter; Richter, Erik A

    2013-04-01

    In skeletal muscle, the actin cytoskeleton-regulating GTPase, Rac1, is necessary for insulin-dependent GLUT4 translocation. Muscle contraction increases glucose transport and represents an alternative signaling pathway to insulin. Whether Rac1 is activated by muscle contraction and regulates contraction-induced glucose uptake is unknown. Therefore, we studied the effects of in vivo exercise and ex vivo muscle contractions on Rac1 signaling and its regulatory role in glucose uptake in mice and humans. Muscle Rac1-GTP binding was increased after exercise in mice (~60-100%) and humans (~40%), and this activation was AMP-activated protein kinase independent. Rac1 inhibition reduced contraction-stimulated glucose uptake in mouse muscle by 55% in soleus and by 20-58% in extensor digitorum longus (EDL; P contraction-stimulated increment in glucose uptake was decreased by 27% (P = 0.1) and 40% (P muscles, respectively, of muscle-specific inducible Rac1 knockout mice. Furthermore, depolymerization of the actin cytoskeleton decreased contraction-stimulated glucose uptake by 100% and 62% (P muscles, respectively. These are the first data to show that Rac1 is activated during muscle contraction in murine and human skeletal muscle and suggest that Rac1 and possibly the actin cytoskeleton are novel regulators of contraction-stimulated glucose uptake.

  15. TAp63 is a master transcriptional regulator of lipid and glucose metabolism

    Su, Xiaohua; Gi, Young Jin; Chakravarti, Deepavali; Chan, Io Long; Zhang, Aijun; Xia, Xuefeng; Tsai, Kenneth Y.; Flores, Elsa R.

    2012-01-01

    TAp63 prevents premature aging suggesting a link to genes that regulate longevity. Further characterization of TAp63−/− mice revealed that these mice develop obesity, insulin resistance, and glucose intolerance, similar to those seen in mice lacking two key metabolic regulators, Silent information regulator T1 (Sirt1) and AMPK. While the roles of Sirt1 and AMPK in metabolism have been well studied, their upstream regulators are not well understood. We found that TAp63 is important in regulati...

  16. Genetically obese rats with (SHR/N-cp) and without diabetes (LA/N-cp) share abnormal islet responses to glucose.

    Timmers, K I; Voyles, N R; Recant, L

    1992-10-01

    To assess the effect of hyperglycemia on the function of islets obtained from obese rats, the behavior of isolated islets from LA/N-corpulent (nondiabetic obese) and SHR/N-corpulent (diabetic obese) male rats was examined and compared. Islets from both genetic models showed a left-shifted glucose dose-response curve for insulin release (concentrations for half-maximal release, 5 to 6 mmol/L v 12 to 13 mmol/L in LA/N lean littermates and 3 mmol/L v 10 mmol/L in lean SHR/N). When insulin release was expressed per unit islet volume, the fourfold to fivefold enlarged islets from both obese diabetic and obese nondiabetic rats showed decreased insulin secretory response in high (16.5 to 28 mmol/L) glucose concentrations, although the decrease was more severe in the diabetic rats. Glucose-stimulated insulin release by islets from both models was relatively resistant to inhibition by 1.2 mmol/L mannoheptulose (eg, 82% +/- 3% inhibition in LA/N lean v 16% +/- 8% in LA/N obese), although nearly complete inhibition was observed with 16 mmol/L mannoheptulose (96% v 85%, NS). Islets of obese diabetic rats were also resistant to the calcium-channel blocker, verapamil, suggesting an abnormal pathway of stimulus-secretion coupling for glucose. Glucose oxidation to carbon dioxide was increased in both obese models at all glucose concentrations when expressed per islet. In data expressed per unit volume, the larger islets from the obese-nondiabetic rats showed a left-shifted dose-response curve with an unchanged maximum rate of glucose oxidation at high (16.5 mmol/L) glucose concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

  17. Abnormal glucose metabolism is associated with reduced left ventricular contractile reserve and exercise intolerance in patients with chronic heart failure

    Egstrup, M; Kistorp, C N; Schou, M;

    2013-01-01

    years, 69% male, 59% had ischaemic heart disease, mean LV ejection fraction (LVEF) 37 ± 9%). Thirty-four (21%) patients had known diabetes mellitus (DM). Oral glucose tolerance testing (OGTT) classified patients without a prior DM diagnosis as normal glucose tolerance (NGT), impaired glucose tolerance......AIMS: To investigate the associations between glucose metabolism, left ventricular (LV) contractile reserve, and exercise capacity in patients with chronic systolic heart failure (HF). METHODS AND RESULTS: From an outpatient HF clinic, 161 patients with systolic HF were included (mean age 70 ± 10...... detected by OGTT, is independently associated with reduced LV contractile reserve and exercise...

  18. High Glucose Enhances Isoflurane-Induced Neurotoxicity by Regulating TRPC-Dependent Calcium Influx.

    Liu, ZhongJie; Ma, ChangQing; Zhao, Wei; Zhang, QingGuo; Xu, Rui; Zhang, HongFei; Lei, HongYi; Xu, ShiYuan

    2017-01-06

    Isoflurane is a commonly used inhalational anesthetic that can induce neurotoxicity via elevating cytosolic calcium (Ca(2+)). High glucose regulates the expression of a family of non-selective cation channels termed transient receptor potential canonical (TRPC) channels that may contribute to Ca(2+) influx. In the present study, we investigated whether high glucose enhances isoflurane-induced neurotoxicity by regulating TRPC-dependent Ca(2+) influx. First, we evaluated toxic damage in mice primary cultured hippocampal neurons and human neuroblastoma cells (SH-SY5Y cells) after hyperglycemia and isoflurane exposure. Next, we investigated cytosolic Ca(2+) concentrations, TRPC mRNA expression levels and tested the effect of the TRPC channel blocker SKF96365 on cytosolic Ca(2+) levels in cells treated with high glucose or/and isoflurane. Finally, we employed knocked down TRPC6 to demonstrate the role of TRPC in high glucose-mediated enhancement of isoflurane-induced neurotoxicity. The results showed that high glucose could enhance isoflurane-induecd toxic damage in primary hippocampal neurons and SH-SY5Y cells. High glucose enhanced the isoflurane-induced increase of cytosolic Ca(2+) in SH-SY5Y cells. High glucose elevated TRPC mRNA expression, especially that of TRPC6. SKF96365 and knock down of TRPC6 were able to inhibit the high glucose-induced increase of cytosolic Ca(2+) and decrease isoflurane-induced neurotoxicity in SH-SY5Y cells cultured with high glucose. Our findings indicate that high glucose could elevate TRPC expression, thus increasing Ca(2+) influx and enhancing isoflurane-induced neurotoxicity.

  19. Glucokinase expression is regulated by glucose through O-GlcNAc glycosylation.

    Baldini, Steffi F; Steenackers, Agata; Olivier-Van Stichelen, Stéphanie; Mir, Anne-Marie; Mortuaire, Marlène; Lefebvre, Tony; Guinez, Céline

    2016-09-16

    Blood glucose fluctuates with the fasting-feeding cycle. One of the liver's functions is to maintain blood glucose concentrations within a physiological range. Glucokinase (GCK) or hexokinase IV, is the main enzyme that regulates the flux and the use of glucose in the liver leading to a compensation of hyperglycemia. In hepatocytes, GCK catalyzes the phosphorylation of glucose into glucose-6-phosphate. This critical enzymatic reaction is determinant for the metabolism of glucose in the liver which includes glycogen synthesis, glycolysis, lipogenesis and gluconeogenesis. In liver, simultaneous increase of glucose and insulin enhances GCK activity and gene expression, changes its subcellular location and interaction with regulatory proteins. The post-translational O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) acts as a glucose-sensitive modification and is believed to take part in hepatic glucose sensing by modifying key regulatory proteins. Therefore, we aimed to determine whether GCK is modified by O-GlcNAcylation in the liver of mice and investigated the role that this modification plays in regulating GCK protein expression. We demonstrated that endogenous GCK expression correlated with O-GlcNAc levels in the pathophysiological model ob/ob mice. More specifically, in response to the pharmacological inhibition of O-GlcNAcase (OGA) contents of GCK increased. Using the GlcNAc specific lectin succinylated-WGA and click chemistry labeling approaches, we demonstrated that GCK is modified by O-GlcNAcylation. Further, we demonstrated that siRNA-mediated Ogt knock-down not only decreases O-GlcNAc content but also GCK protein level. Altogether, our in vivo and in vitro results demonstrate that GCK expression is regulated by nutrient-sensing O-GlcNAc cycling in liver.

  20. Relationships between glucose excursion and the activation of oxidative stress in patients with newly diagnosed type 2 diabetes or impaired glucose regulation.

    Zheng, Fenping; Lu, Weina; Jia, Chengfang; Li, Hong; Wang, Zhou; Jia, Weiping

    2010-02-01

    The effect of glucose excursions on oxidative stress is an important topic in diabetes research. We investigated this relationship by analyzing markers of oxidative stress and glycemic data from a continuous glucose monitoring system (CGMS) in 30 individuals with normal glucose regulation (NGR), 27 subjects with impaired glucose regulation (IGR), and 27 patients with newly diagnosed type 2 diabetes (T2DM). We compared the mean amplitude of glycemic excursion (MAGE), mean postprandial glucose excursion (MPPGE), and mean postprandial incremental area under the curve (IAUC) with plasma levels of oxidative stress markers 8-iso-PGF2α, 8-OH-dG, and protein carbonyl content in the study subjects. Patients with T2DM or IGR had significantly higher glucose excursions and plasma levels of oxidative stress markers compared to normal controls (P oxidative stress.

  1. The Lin28/let-7 Axis Regulates Glucose Metabolism

    Zhu, Hao; Shyh-Chang, Ng; Segre, Ayellet V.; Shinoda, Gen; Shah, Samar P.; Einhorn, William S.; Takeuchi, Ayumu; Engreitz, Jesse M.; Hagan, John P.; Kharas, Michael G.; Urbach, Achia; Thornton, James E.; Triboulet, Robinson; Gregory, Richard I.; Altshuler, David; Daley, George Q.

    2011-01-01

    The let-7 tumor suppressor microRNAs are known for their regulation of oncogenes, while the RNA-binding proteins Lin28a/b promote malignancy by inhibiting let-7 biogenesis. We have uncovered unexpected roles for the Lin28/let-7 pathway in regulating-metabolism. When overexpressed in mice, both Lin28

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

    Lekva, Tove; Bollerslev, Jens; Sahraoui, Afaf; Scholz, Hanne; Bøyum, Hege; Evang, Johan Arild; Godang, Kristin; Aukrust, Pål; Ueland, Thor

    2013-01-01

    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.

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

    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.

  4. Cumulative glycemia and microangiopathy in subjects with impaired glucose regulation in the Inter99 study

    Munch, Inger Christine; Larsen, Michael; Kessel, Line

    2011-01-01

    participants. RESULTS: Lens fluorescence, a quantitative index of life-long cumulative glycemia, was increased by 7.5% (CI(95) 0.37-15.1%) in subjects with impaired fasting glucose, by 13.0% (CI(95) 5.5-21%) in subjects with combined impaired fasting glucose and impaired glucose tolerance (IFG+IGT), and by 11......AIMS: To assess cumulative glycemia, microvascular characteristics, and associated risk factors for diabetes in subjects with impaired glucose regulation. METHODS: Cross-sectional, population-based study comprising systemic characteristics in 6487 participants and ocular characteristics in 970.......8% (CI(95) 6.8-17.1%) in subjects with screen-detected diabetes compared to normoglycemic subjects, adjusted for age, sex, and smoking. The prevalences of microalbuminuria and retinopathy were significantly increased in subjects with screen-detected diabetes after adjusting for age, sex and systolic...

  5. CcpA-independent glucose regulation of lactate dehydrogenase 1 in Staphylococcus aureus.

    Adrianne K Crooke

    Full Text Available Lactate Dehydrogenase 1 (Ldh1 is a key enzyme involved in Staphylococcus aureus NO·-resistance. Full ldh1-induction requires the presence of glucose, and mutants lacking the Carbon-Catabolite Protein (CcpA exhibit decreased ldh1 transcription and diminished Ldh1 activity. The redox-regulator Rex represses ldh1 directly by binding to Rex-sites within the ldh1 promoter (P(ldh1. In the absence of Rex, neither glucose nor CcpA affect ldh1 expression implying that glucose/CcpA-mediated activation requires Rex activity. Rex-mediated repression of ldh1 depends on cellular redox status and is maximal when NADH levels are low. However, compared to WT cells, the ΔccpA mutant exhibited impaired redox balance with relatively high NADH levels, yet ldh1 was still poorly expressed. Furthermore, CcpA did not drastically alter Rex transcript levels, nor did glucose or CcpA affect the expression of other Rex-regulated genes indicating that the glucose/CcpA effect is specific for P(ldh1. A putative catabolite response element (CRE is located ∼30 bp upstream of the promoter-distal Rex-binding site in P(ldh1. However, CcpA had no affinity for P(ldh1 in vitro and a genomic mutation of CRE upstream of P(ldh1 in S. aureus had no affect on Ldh1 expression in vivo. In contrast to WT, ΔccpA S. aureus preferentially consumes non-glycolytic carbon sources. However when grown in defined medium with glucose as the primary carbon source, ΔccpA mutants express high levels of Ldh1 compared to growth in media devoid of glucose. Thus, the actual consumption of glucose stimulates Ldh1 expression rather than direct CcpA interaction at P(ldh1.

  6. Skeletal muscle glucose uptake during contraction is regulated by nitric oxide and ROS independently of AMPK.

    Merry, Troy L; Steinberg, Gregory R; Lynch, Gordon S; McConell, Glenn K

    2010-03-01

    Reactive oxygen species (ROS) and nitric oxide (NO) have been implicated in the regulation of skeletal muscle glucose uptake during contraction, and there is evidence that they do so via interaction with AMP-activated protein kinase (AMPK). In this study, we tested the hypothesis that ROS and NO regulate skeletal muscle glucose uptake during contraction via an AMPK-independent mechanism. Isolated extensor digitorum longus (EDL) and soleus muscles from mice that expressed a muscle-specific kinase dead AMPKalpha2 isoform (AMPK-KD) and wild-type litter mates (WT) were stimulated to contract, and glucose uptake was measured in the presence or absence of the antioxidant N-acetyl-l-cysteine (NAC) or the nitric oxide synthase (NOS) inhibitor N(G)-monomethyl-l-arginine (l-NMMA). Contraction increased AMPKalpha2 activity in WT but not AMPK-KD EDL muscles. However, contraction increased glucose uptake in the EDL and soleus muscles of AMPK-KD and WT mice to a similar extent. In EDL muscles, NAC and l-NMMA prevented contraction-stimulated increases in oxidant levels (dichloroflourescein fluorescence) and NOS activity, respectively, and attenuated contraction-stimulated glucose uptake in both genotypes to a similar extent. In soleus muscles of AMPK-KD and WT mice, NAC prevented contraction-stimulated glucose uptake and l-NMMA had no effect. This is likely attributed to the relative lack of neuronal NOS in the soleus muscles compared with EDL muscles. Contraction increased AMPKalpha Thr(172) phosphorylation in EDL and soleus muscles of WT but not AMPK-KD mice, and this was not affected by NAC or l-NMMA treatment. In conclusion, ROS and NO are involved in regulating skeletal muscle glucose uptake during contraction via an AMPK-independent mechanism.

  7. Caffeamide 36-13 Regulates the Antidiabetic and Hypolipidemic Signs of High-Fat-Fed Mice on Glucose Transporter 4, AMPK Phosphorylation, and Regulated Hepatic Glucose Production

    Yueh-Hsiung Kuo

    2014-01-01

    Full Text Available This study was to investigate the antidiabetic and antihyperlipidemic effects of (E-3-[3, 4-dihydroxyphenyl-1-(piperidin-1-ylprop-2-en-1-one] (36-13 (TS, one of caffeic acid amide derivatives, on high-fat (HF- fed mice. The C57BL/6J mice were randomly divided into the control (CON group and the experimental group, which was firstly fed a HF diet for 8 weeks. Then, the HF group was subdivided into four groups and was given TS orally (including two doses or rosiglitazone (Rosi or vehicle for 4 weeks. Blood, skeletal muscle, and tissues were examined by measuring glycaemia and dyslipidemia-associated events. TS effectively prevented HF diet-induced increases in the levels of blood glucose, triglyceride, insulin, leptin, and free fatty acid (FFA and weights of visceral fa; moreover, adipocytes in the visceral depots showed a reduction in size. TS treatment significantly increased the protein contents of glucose transporter 4 (GLUT4 in skeletal muscle; TS also significantly enhanced Akt phosphorylation in liver, whereas it reduced the expressions of phosphoenolpyruvate carboxykinase (PEPCK and glucose-6-phosphatase (G6Pase. Moreover, TS enhanced phosphorylation of AMP-activated protein kinase (phospho-AMPK both in skeletal muscle and liver tissue. Therefore, it is possible that the activation of AMPK by TS resulted in enhanced glucose uptake in skeletal muscle, contrasting with diminished gluconeogenesis in liver. TS exhibits hypolipidemic effect by decreasing the expressions of fatty acid synthase (FAS. Thus, antidiabetic properties of TS occurred as a result of decreased hepatic glucose production by PEPCK and G6Pase downregulation and improved insulin sensitization. Thus, amelioration of diabetic and dyslipidemic state by TS in HF-fed mice occurred by regulation of GLUT4, G6Pase, and FAS and phosphorylation of AMPK.

  8. Boron-doped graphene quantum dots for selective glucose sensing based on the "abnormal" aggregation-induced photoluminescence enhancement.

    Zhang, Li; Zhang, Zhi-Yi; Liang, Ru-Ping; Li, Ya-Hua; Qiu, Jian-Ding

    2014-05-06

    A hydrothermal approach for the cutting of boron-doped graphene (BG) into boron-doped graphene quantum dots (BGQDs) has been proposed. Various characterizations reveal that the boron atoms have been successfully doped into graphene structures with the atomic percentage of 3.45%. The generation of boronic acid groups on the BGQDs surfaces facilitates their application as a new photoluminescence (PL) probe for label free glucose sensing. It is postulated that the reaction of the two cis-diol units in glucose with the two boronic acid groups on the BGQDs surfaces creates structurally rigid BGQDs-glucose aggregates, restricting the intramolecular rotations and thus resulting in a great boost in the PL intensity. The present unusual "aggregation-induced PL increasing" sensing process excludes any saccharide with only one cis-diol unit, as manifested by the high specificity of BGQDs for glucose over its close isomeric cousins fructose, galactose, and mannose. It is believed that the doping of boron can introduce the GQDs to a new kind of surface state and offer great scientific insights to the PL enhancement mechanism with treatment of glucose.

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

    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...

  10. Effects of exercise training on regulation of skeletal muscle glucose metabolism in elderly men

    Biensø, Rasmus Sjørup; Olesen, Jesper; Gliemann, Lasse

    2015-01-01

    BACKGROUND: The aim was to investigate the molecular mechanisms behind exercise training-induced improvements in glucose regulation in aged subjects. METHODS: Twelve elderly male subjects completed 8 weeks of exercise training. Before and after the training period, the subjects completed an oral ...

  11. SIK2 regulates CRTCs, HDAC4 and glucose uptake in adipocytes

    Henriksson, Emma; Säll, Johanna; Gormand, Amélie

    2015-01-01

    regulation in human adipocytes, strengthening the physiological relevance of our findings. Collectively, we demonstrate that SIK2 acts directly on CRTC2, CRTC3 and HDAC4, and that cAMP/PKA reduces the interaction of SIK2 with CRTCs and PP2A. Downstream, SIK2 promotes GLUT4 levels and glucose uptake...

  12. Differential role of SH2-B and APS in regulating energy and glucose homeostasis.

    Li, Minghua; Ren, Decheng; Iseki, Masanori; Takaki, Satoshi; Rui, Liangyou

    2006-05-01

    SH2-B and APS, two members of a pleckstrin homology and SH2 domain-containing adaptor family, promote both insulin and leptin signaling in a similar fashion in cultured cells. In addition, APS mediates insulin-stimulated activation of the c-Cbl/CAP/TC10 pathway in cultured adipocytes. Here we characterized genetically modified mice lacking SH2-B, APS, or both to determine the physiological roles of these two proteins in animals. Disruption of the SH2-B gene resulted in obesity, hyperglycemia, hyperinsulinemia, and glucose intolerance. Conversely, deletion of the APS gene did not alter adiposity, energy balance, and glucose metabolism. Energy intake, energy expenditure, fat content, body weight, and plasma insulin, leptin, glucose, and lipid levels were similar between APS(-/-) and WT littermates fed either normal chow or a high-fat diet. Moreover, deletion of APS failed to alter insulin and glucose tolerance. APS(-/-)/SH2-B(-/-) double knockout mice also developed energy imbalance, obesity, hyperleptinemia, hyperinsulinemia, hyperglycemia, and glucose intolerance; however, plasma leptin and insulin levels were significantly lower in APS(-/-)/SH2-B(-/-) than in SH2-B(-/-) mice. These results suggest that SH2-B, but not APS, is a key positive regulator of energy and glucose metabolism in mice.

  13. Ghrelin signalling in β-cells regulates insulin secretion and blood glucose.

    Yada, T; Damdindorj, B; Rita, R S; Kurashina, T; Ando, A; Taguchi, M; Koizumi, M; Sone, H; Nakata, M; Kakei, M; Dezaki, K

    2014-09-01

    Insulin secretion from pancreatic islet β-cells is stimulated by glucose. Glucose-induced insulin release is potentiated or suppressed by hormones and neural substances. Ghrelin, an acylated 28-amino acid peptide, was isolated from the stomach in 1999 as the endogenous ligand for the growth hormone (GH) secretagogue-receptor (GHS-R). Circulating ghrelin is produced predominantly in the stomach and to a lesser extent in the intestine, pancreas and brain. Ghrelin, initially identified as a potent stimulator of GH release and feeding, has been shown to suppress glucose-induced insulin release. This insulinostatic action is mediated by Gα(i2) subtype of GTP-binding proteins and delayed outward K⁺ (Kv) channels. Interestingly, ghrelin is produced in pancreatic islets. The ghrelin originating from islets restricts insulin release and thereby upwardly regulates the systemic glucose level. Furthermore, blockade or elimination of ghrelin enhances insulin release, which can ameliorate glucose intolerance in high-fat diet fed mice and ob/ob mice. This review focuses on the insulinostatic action of ghrelin, its signal transduction mechanisms in islet β-cells, ghrelin's status as an islet hormone, physiological roles of ghrelin in regulating systemic insulin levels and glycaemia, and therapeutic potential of the ghrelin-GHS-R system as the target to treat type 2 diabetes.

  14. Electroacupuncture regulates glucose-inhibited neurons in treatment of simple obesity

    Zhi Yu; Youbing Xia; Chuanhui Ju; Qinghua Shao; Zhen Mao; Yun Gu; Bin Xu

    2013-01-01

    The glucose-inhibited neurons present in the lateral hypothalamic area are regarded as glucose detectors. This structure is involved in the regulation of food intake through extracellular blood glucose concentrations, and plays a crucial role in obesity onset. In the present study, obesity models established with high fat feeding were treated with electroacupuncture at Zusanli (ST36)/ Inner Court (ST44) on the left side and Tianshu (ST25) bilaterally. We found that electroacupuncture could effectively reduce body weight and the fat-weight ratio, and decrease serum leptin, resistin, tumor necrosis factor alpha, and neuropeptide Y levels, while increase serum adiponectin and cholecystokinin-8 levels. This treatment altered the electrical activity of glucose-inhibited neurons in the lateral hypothalamic area, with electroacupuncture at Zusanli/ Inner Court exerting an inhibitory effect, while electroacupuncture at bilateral Tianshu exerting an excitatory effect. These data suggest that electroacupuncture at the lower limbs and abdominal cavity is an effective means for regulating the activity of glucose-inhibited neurons in the lateral hypothalamic area and for improving the secretory function of adipose tissue.

  15. Effects of glucose, ethanol and acetic acid on regulation of ADH2 gene from Lachancea fermentati

    Yaacob, Norhayati; Salleh, Abu Bakar; Abdul Rahman, Nor Aini

    2016-01-01

    Background. Not all yeast alcohol dehydrogenase 2 (ADH2) are repressed by glucose, as reported in Saccharomyces cerevisiae. Pichia stipitis ADH2 is regulated by oxygen instead of glucose, whereas Kluyveromyces marxianus ADH2 is regulated by neither glucose nor ethanol. For this reason, ADH2 regulation of yeasts may be species dependent, leading to a different type of expression and fermentation efficiency. Lachancea fermentati is a highly efficient ethanol producer, fast-growing cells and adapted to fermentation-related stresses such as ethanol and organic acid, but the metabolic information regarding the regulation of glucose and ethanol production is still lacking. Methods. Our investigation started with the stimulation of ADH2 activity from S. cerevisiae and L. fermentati by glucose and ethanol induction in a glucose-repressed medium. The study also embarked on the retrospective analysis of ADH2 genomic and protein level through direct sequencing and sites identification. Based on the sequence generated, we demonstrated ADH2 gene expression highlighting the conserved NAD(P)-binding domain in the context of glucose fermentation and ethanol production. Results. An increase of ADH2 activity was observed in starved L. fermentati (LfeADH2) and S. cerevisiae (SceADH2) in response to 2% (w/v) glucose induction. These suggest that in the presence of glucose, ADH2 activity was activated instead of being repressed. An induction of 0.5% (v/v) ethanol also increased LfeADH2 activity, promoting ethanol resistance, whereas accumulating acetic acid at a later stage of fermentation stimulated ADH2 activity and enhanced glucose consumption rates. The lack in upper stream activating sequence (UAS) and TATA elements hindered the possibility of Adr1 binding to LfeADH2. Transcription factors such as SP1 and RAP1 observed in LfeADH2 sequence have been implicated in the regulation of many genes including ADH2. In glucose fermentation, L. fermentati exhibited a bell-shaped ADH2

  16. Effects of glucose, ethanol and acetic acid on regulation of ADH2 gene from Lachancea fermentati

    Norhayati Yaacob

    2016-03-01

    Full Text Available Background. Not all yeast alcohol dehydrogenase 2 (ADH2 are repressed by glucose, as reported in Saccharomyces cerevisiae. Pichia stipitis ADH2 is regulated by oxygen instead of glucose, whereas Kluyveromyces marxianus ADH2 is regulated by neither glucose nor ethanol. For this reason, ADH2 regulation of yeasts may be species dependent, leading to a different type of expression and fermentation efficiency. Lachancea fermentati is a highly efficient ethanol producer, fast-growing cells and adapted to fermentation-related stresses such as ethanol and organic acid, but the metabolic information regarding the regulation of glucose and ethanol production is still lacking. Methods. Our investigation started with the stimulation of ADH2 activity from S. cerevisiae and L. fermentati by glucose and ethanol induction in a glucose-repressed medium. The study also embarked on the retrospective analysis of ADH2 genomic and protein level through direct sequencing and sites identification. Based on the sequence generated, we demonstrated ADH2 gene expression highlighting the conserved NAD(P-binding domain in the context of glucose fermentation and ethanol production. Results. An increase of ADH2 activity was observed in starved L. fermentati (LfeADH2 and S. cerevisiae (SceADH2 in response to 2% (w/v glucose induction. These suggest that in the presence of glucose, ADH2 activity was activated instead of being repressed. An induction of 0.5% (v/v ethanol also increased LfeADH2 activity, promoting ethanol resistance, whereas accumulating acetic acid at a later stage of fermentation stimulated ADH2 activity and enhanced glucose consumption rates. The lack in upper stream activating sequence (UAS and TATA elements hindered the possibility of Adr1 binding to LfeADH2. Transcription factors such as SP1 and RAP1 observed in LfeADH2 sequence have been implicated in the regulation of many genes including ADH2. In glucose fermentation, L. fermentati exhibited a bell

  17. Trefoil factor 3 (TFF3 expression is regulated by insulin and glucose

    Girolamo Jose Barrera Roa

    2013-04-01

    Full Text Available Introduction: Trefoil factors are effector molecules in gastrointestinal tract physiology. They are classified into three groups: the gastric peptides (TFF1, spasmolytic peptide (TFF2 and intestinal trefoil factor (TFF3. Previous studies have shown that trefoil factors are located and expressed in human endocrine pancreas suggesting that TFF3 play a role in: a pancreatic cells migration, b β-cell mitosis, and c pancreatic cells regeneration. We speculated that the presence of TFF3 in pancreas, could be associated to a possible regulation mechanism by insulin and glucose. To date, there are not reports whether the unbalance in carbohydrate metabolism observed in diabetes could affect the production or expression of TFF3.Methods: We determined the TFF3 levels and expression by immunoassay (ELISA and semi-quantitative RT-PCR technique respectively, of intestinal epithelial cells (HT-29 treated with glucose and insulin. Also,Real Time-PCR (RTq-PCR was done.Results: Increasing concentrations of glucose improved TFF3 expression and these levels were further elevated after insulin treatment. Insulin treatment also led to the up-regulation of human sodium/glucose transporter 1 (hSGLT1, which further increases intracellular glucose levels. Finally, we investigated theTFF3 levels in serum of diabetes mellitus type 1 (T1DM and healthy patients. Here we shown that serum TFF3 levels were down-regulated in T1DM and this levels were up-regulated after insulin treatment. Also, the TFF3 levels of healthy donors were up-regulated 2 h after breakfast.Conclusion: Our fi ndings suggest for the fi rst time that insulin signaling is important for TFF3 optimal expression in serum and intestinal epithelial cells.

  18. Gluco-incretins regulate beta-cell glucose competence by epigenetic silencing of Fxyd3 expression.

    David Vallois

    Full Text Available Gluco-incretin hormones increase the glucose competence of pancreatic beta-cells by incompletely characterized mechanisms.We searched for genes that were differentially expressed in islets from control and Glp1r-/-; Gipr-/- (dKO mice, which show reduced glucose competence. Overexpression and knockdown studies; insulin secretion analysis; analysis of gene expression in islets from control and diabetic mice and humans as well as gene methylation and transcriptional analysis were performed.Fxyd3 was the most up-regulated gene in glucose incompetent islets from dKO mice. When overexpressed in beta-cells Fxyd3 reduced glucose-induced insulin secretion by acting downstream of plasma membrane depolarization and Ca++ influx. Fxyd3 expression was not acutely regulated by cAMP raising agents in either control or dKO adult islets. Instead, expression of Fxyd3 was controlled by methylation of CpGs present in its proximal promoter region. Increased promoter methylation reduced Fxyd3 transcription as assessed by lower abundance of H3K4me3 at the transcriptional start site and in transcription reporter assays. This epigenetic imprinting was initiated perinatally and fully established in adult islets. Glucose incompetent islets from diabetic mice and humans showed increased expression of Fxyd3 and reduced promoter methylation.Because gluco-incretin secretion depends on feeding the epigenetic regulation of Fxyd3 expression may link nutrition in early life to establishment of adult beta-cell glucose competence; this epigenetic control is, however, lost in diabetes possibly as a result of gluco-incretin resistance and/or de-differentiation of beta-cells that are associated with the development of type 2 diabetes.

  19. Conservation of the Nrf2-Mediated Gene Regulation of Proteasome Subunits and Glucose Metabolism in Zebrafish

    Vu Thanh Nguyen

    2016-01-01

    Full Text Available The Keap1-Nrf2 system is an evolutionarily conserved defense mechanism against oxidative and xenobiotic stress. Besides the exogenous stress response, Nrf2 has been found to regulate numerous cellular functions, including protein turnover and glucose metabolism; however, the evolutionary origins of these functions remain unknown. In the present study, we searched for novel target genes associated with the zebrafish Nrf2 to answer this question. A microarray analysis of zebrafish embryos that overexpressed Nrf2 revealed that 115 candidate genes were targets of Nrf2, including genes encoding proteasome subunits and enzymes involved in glucose metabolism. A real-time quantitative PCR suggested that the expression of 3 proteasome subunits (psma3, psma5, and psmb7 and 2 enzymes involved in glucose metabolism (pgd and fbp1a were regulated by zebrafish Nrf2. We thus next examined the upregulation of these genes by an Nrf2 activator, diethyl maleate, using Nrf2 mutant zebrafish larvae. The results of real-time quantitative PCR and whole-mount in situ hybridization showed that all of these 5 genes were upregulated by diethyl maleate treatment in an Nrf2-dependent manner, especially in the liver. These findings implied that the Nrf2-mediated regulation of the proteasome subunits and glucose metabolism is evolutionarily conserved among vertebrates.

  20. DHHC7 Palmitoylates Glucose Transporter 4 (Glut4) and Regulates Glut4 Membrane Translocation.

    Du, Keyong; Murakami, Shoko; Sun, Yingmin; Kilpatrick, Casey L; Luscher, Bernhard

    2017-02-17

    Insulin-dependent translocation of glucose transporter 4 (Glut4) to the plasma membrane plays a key role in the dynamic regulation of glucose homeostasis. We recently showed that this process is critically dependent on palmitoylation of Glut4 at Cys-223. To gain further insights into the regulation of Glut4 palmitoylation, we set out to identify the palmitoyl acyltransferase (PAT) involved. Here we report that among 23 mammalian DHHC proteins, DHHC7 is the major Glut4 PAT, based on evidence that ectopic expression of DHHC7 increased Glut4 palmitoylation, whereas DHHC7 knockdown in 3T3-L1 adipocytes and DHHC7 KO in adipose tissue and muscle decreased Glut4 palmitoylation. Moreover, inactivation of DHHC7 suppressed insulin-dependent Glut4 membrane translocation in both 3T3-L1 adipocytes and primary adipocytes. Finally, DHHC7 KO mice developed hyperglycemia and glucose intolerance, thereby confirming that DHHC7 represents the principal PAT for Glut4 and that this mechanism is essential for insulin-regulated glucose homeostasis.

  1. Blood glucose regulation during fasting in rats under food restriction since birth

    Adriana de Souza Vitoriano

    2011-02-01

    Full Text Available The effect of severe food restriction since birth on regulation of fasting glycemia in male Wistar rats was investigated. The control group (CG had free supply of chow, while the restriction group (RG received 50% of the amount ingested by the CG. The experiments were done in adult (60 days overnight fasted rats in which glycemia, liver free glucose levels and hepatic glycogen concentration were measured. In part of the experiments in situ liver perfusion was done. The results showed that livers from the RG had higher glycogenolysis rates but lower gluconeogenesis rates from L-alanine (10 mM. Since RG showed maintained glycemia during fasting, it could be concluded that livers from RG produced glucose preferentially from glycogenolysis in detriment of gluconeogenesis. These findings demonstrated that in spite of severe caloric restriction, the metabolic adaptations of the liver did exist to assure the maintenance of blood glucose for brain supply during fasting.

  2. Effects of glucose and insulin on the H9c2 (2-1) cell proliferation may be mediated through regulating glucose transporter 4 expression

    LIU Qian; HUANG Qing-xian; LOU Fu-chen; ZHANG Li; WANG Kun; YU Shan; XU Hua

    2013-01-01

    RNA level in HG1 group was higher on the first day but lower on the second and third day (P <0.05).In HG1,HG2 and HG3 groups,GLUT4 mRNA level had a negative correlation with the level of glucose (P <0.05).GLUT4 mRNA in INSc subgroups was lower than that in INSh subgroups (P <0.05).The expression of GLUT4 protein was similar to that of GLUT4 mRNA.There was a positive correlation between H9c2 cell proliferation and GLUT4 expression (P <0.02).Conclusions Glucose levels could regulate glucose uptake in myocardial cells through influencing GLUT4 expression,and thus affected the cell proliferation and cell function.Insulin levels could affect the myocardial cell function by regulating GLUT4 expression.Effects of glucose and insulin on the myocardial cells proliferation might be mediated through regulating GLUT4 expression.There may be a mechanism of hyperglycemia pre-accommodation (HGPA) in myocardial cells mediated through regulation of GLUT4 expression.

  3. Long-term exposure to abnormal glucose levels alters drug metabolism pathways and insulin sensitivity in primary human hepatocytes

    Davidson, Matthew D.; Ballinger, Kimberly R.; Khetani, Salman R.

    2016-06-01

    Hyperglycemia in type 2 diabetes mellitus has been linked to non-alcoholic fatty liver disease, which can progress to inflammation, fibrosis/cirrhosis, and hepatocellular carcinoma. Understanding how chronic hyperglycemia affects primary human hepatocytes (PHHs) can facilitate the development of therapeutics for these diseases. Conversely, elucidating the effects of hypoglycemia on PHHs may provide insights into how the liver adapts to fasting, adverse diabetes drug reactions, and cancer. In contrast to declining PHH monocultures, micropatterned co-cultures (MPCCs) of PHHs and 3T3-J2 murine embryonic fibroblasts maintain insulin-sensitive glucose metabolism for several weeks. Here, we exposed MPCCs to hypo-, normo- and hyperglycemic culture media for ~3 weeks. While albumin and urea secretion were not affected by glucose level, hypoglycemic MPCCs upregulated CYP3A4 enzyme activity as compared to other glycemic states. In contrast, hyperglycemic MPCCs displayed significant hepatic lipid accumulation in the presence of insulin, while also showing decreased sensitivity to insulin-mediated inhibition of glucose output relative to a normoglycemic control. In conclusion, we show for the first time that PHHs exposed to hypo- and hyperglycemia can remain highly functional, but display increased CYP3A4 activity and selective insulin resistance, respectively. In the future, MPCCs under glycemic states can aid in novel drug discovery and mechanistic investigations.

  4. Transcriptional coactivator p300 regulates glucose-induced gene expression in endothelial cells.

    Chen, Shali; Feng, Biao; George, Biju; Chakrabarti, Rana; Chen, Megan; Chakrabarti, Subrata

    2010-01-01

    Sustained hyperglycemia in diabetes causes alteration of a large number of transcription factors and mRNA transcripts, leading to tissue damage. We investigated whether p300, a transcriptional coactivator with histone acetyl transferase activity, regulates glucose-induced activation of transcription factors and subsequent upregulation of vasoactive factors and extracellular matrix (ECM) proteins in human umbilical vein endothelial cells (HUVECs). HUVECs were incubated in varied glucose concentrations and were studied after p300 small interfering RNA (siRNA) transfection, p300 overexpression, or incubation with the p300 inhibitor curcumin. Histone H2AX phosphorylation and lysine acetylation were examined for oxidative DNA damage and p300 activation. Screening for transcription factors was performed with the Luminex system. Alterations of selected transcription factors were validated. mRNA expression of p300, endothelin-1 (ET-1), vascular endothelial growth factor (VEGF), and fibronectin (FN) and its splice variant EDB(+)FN and FN protein production were analyzed. HUVECs in 25 mmol/l glucose showed increased p300 production accompanied by increased binding of p300 to ET-1 and FN promoters, augmented histone acetylation, H2AX phosphorylation, activation of multiple transcription factors, and increased mRNA expression of vasoactive factors and ECM proteins. p300 overexpression showed a glucose-like effect on the mRNA expression of ET-1, VEGF, and FN. Furthermore, siRNA-mediated p300 blockade or chemical inhibitor of p300 prevented such glucose-induced changes. Similar mRNA upregulation was also seen in the organ culture of vascular tissues, which was prevented by p300 siRNA transfection. Data from these studies suggest that glucose-induced p300 upregulation is an important upstream epigenetic mechanism regulating gene expression of vasoactive factors and ECM proteins in endothelial cells and is a potential therapeutic target for diabetic complications.

  5. Insulin-coated gold nanoparticles as a new concept for personalized and adjustable glucose regulation

    Shilo, Malka; Berenstein, Peter; Dreifuss, Tamar; Nash, Yuval; Goldsmith, Guy; Kazimirsky, Gila; Motiei, Menachem; Frenkel, Dan; Brodie, Chaya; Popovtzer, Rachela

    2015-12-01

    Diabetes mellitus is a chronic metabolic disease, characterized by high blood glucose levels, affecting millions of people around the world. Currently, the main treatment for diabetes requires multiple daily injections of insulin and self-monitoring of blood glucose levels, which markedly affect patients' quality of life. In this study we present a novel strategy for controlled and prolonged glucose regulation, based on the administration of insulin-coated gold nanoparticles (INS-GNPs). We show that both intravenous and subcutaneous injection of INS-GNPs into a mouse model of type 1 diabetes decreases blood glucose levels for periods over 3 times longer than free insulin. We further showed that conjugation of insulin to GNPs prevented its rapid degradation by the insulin-degrading-enzyme, and thus allows controlled and adjustable bio-activity. Moreover, we assessed different sizes and concentrations of INS-GNPs, and found that both parameters have a critical effect in vivo, enabling specific adjustment of blood glucose levels. These findings have the potential to improve patient compliance in diabetes mellitus.

  6. Retinal proteins associated with redox regulation and protein folding play central roles in response to high glucose conditions.

    Wang, Ssu-Han; Lee, Wen-Chi; Chou, Hsiu-Chuan

    2015-03-01

    Diabetic retinopathy typically causes poor vision and blindness. A previous study revealed that a high blood glucose concentration induces glycoxidation and weakens the retinal capillaries. Nevertheless, the molecular mechanisms underlying the effects of high blood glucose induced diabetic retinopathy remain to be elucidated. In the present study, we cultured the retinal pigmented epithelial cell line ARPE-19 in mannitol-balanced 5.5, 25, and 100 mM glucose media and investigated protein level alterations. Proteomic analysis revealed significant changes in 137 protein features, of which 124 demonstrated changes in a glucose concentration dependent manner. Several proteins functionally associated with redox regulation, protein folding, or the cytoskeleton are affected by increased glucose concentrations. Additional analyses also revealed that cellular oxidative stress, including endoplasmic reticulum stress, was significantly increased after treatment with high glucose concentrations. However, the mitochondrial membrane potential and cell survival remained unchanged during treatment with high glucose concentrations. To summarize, in this study, we used a comprehensive retinal pigmented epithelial cell based proteomic approach for identifying changes in protein expression associated retinal markers induced by high glucose concentrations. Our results revealed that a high glucose condition can induce cellular oxidative stress and modulate the levels of proteins with functions in redox regulation, protein folding, and cytoskeleton regulation; however, cell viability and mitochondrial integrity are not significantly disturbed under these high glucose conditions.

  7. Symposium: Normal and abnormal REM sleep regulation: REM sleep in depression-an overview.

    Berger; Riemann

    1993-12-01

    Abnormalities of REM sleep, i.e. shortening of REM latency, lengthening of the duration of the first REM period and heightening of REM density, which are frequently observed in patients with a major depressive disorder (MDD), have attracted considerable interest. Initial hopes that these aberrant patterns of sleep constitute specific markers for the primary/endogenous sub-type of depression have not been fulfilled. The specificity of REM sleep disinhibition for depression in comparison with other psychopathological groups is challenged as well. Demographic variables like age and sex exert strong influences on sleep physiology and must be controlled when searching for specific markers of depressed sleep. It is still an open question whether abnormalities of sleep are state- or trait-markers of depression. Beyond baseline studies, the cholinergic REM induction test (CRIT) indicated a heightened responsitivity of the REM sleep system to cholinergic challenge in depression compared with healthy controls and other psychopathological groups, with the exception of schizophrenia. A special role for REM sleep in depression is supported by the well-known REM sleep suppressing effect of most antidepressants. The antidepressant effect of selective REM deprivation by awakenings stresses the importance of mechanisms involved in REM sleep regulation for the understanding of the pathophysiology of depressive disorders. The positive effect of total sleep deprivation on depressive mood which can be reversed by daytime naps, furthermore emphasizes relationships between sleep and depression. Experimental evidence as described above instigated several theories like the REM deprivation hypothesis, the 2-process model and the reciprocal interaction model of nonREM-REM sleep regulation to explain the deviant sleep pattern of depression. The different models will be discussed with reference to empirical data gathered in the field.

  8. The Role of Gut–brain Axis in Regulating Glucose Metabolism After Acute Pancreatitis

    Pendharkar, Sayali A; Asrani, Varsha M; Murphy, Rinki; Cutfield, Richard; Windsor, John A; Petrov, Maxim S

    2017-01-01

    Objectives: Diabetes has become an epidemic in developed and developing countries alike, with an increased demand for new efficacious treatments. A large body of pre-clinical evidence suggests that the gut–brain axis may be exploited as a potential therapeutic target for defective glucose homeostasis. This clinical study aimed to investigate a comprehensive panel of glucoregulatory peptides, released by both the gut and brain, in individuals after acute pancreatitis. Methods: Fasting levels of glucagon-like peptide-1 (GLP-1), glicentin, oxyntomodulin, peptide YY, ghrelin, cholecystokinin, vasoactive intestinal peptide (VIP), and secretin were studied. Modified Poisson and multivariable linear regression analyses were conducted. Pre-determined concentration ranges were used to categorize each peptide into quartiles. Results: A total of 83 individuals were included, of who 30 (36%) developed abnormal glucose metabolism (AGM) after acute pancreatitis. In individuals with AGM, the highest quartile of oxyntomodulin differed most significantly from the lowest quartile with a prevalence ratio (PR; 95% confidence interval) of 0.50 (0.21, 1.20; P=0.005); of glicentin with a PR of 0.26 (0.13, 0.54; Pcholecystokinin, ghrelin, and secretin were not significantly associated with AGM. Conclusions: Fasting circulating oxyntomodulin, glicentin, and VIP levels are significantly decreased in patients with defective glucose homeostasis after acute pancreatitis. Oxyntomodulin appears to be a promising therapeutic target for future clinical studies on diabetes associated with diseases of the exocrine pancreas. PMID:28055028

  9. Discovery of novel glucose-regulated proteins in isolated human pancreatic islets using LC-MS/MS-based proteomics.

    Schrimpe-Rutledge, Alexandra C; Fontès, Ghislaine; Gritsenko, Marina A; Norbeck, Angela D; Anderson, David J; Waters, Katrina M; Adkins, Joshua N; Smith, Richard D; Poitout, Vincent; Metz, Thomas O

    2012-07-06

    The prevalence of diabetes mellitus is increasing dramatically throughout the world, and the disease has become a major public health issue. The most common form of the disease, type 2 diabetes, is characterized by insulin resistance and insufficient insulin production from the pancreatic beta-cell. Since glucose is the most potent regulator of beta-cell function under physiological conditions, identification of the insulin secretory defect underlying type 2 diabetes requires a better understanding of glucose regulation of human beta-cell function. To this aim, a bottom-up LC-MS/MS-based proteomics approach was used to profile pooled islets from multiple donors under basal (5 mM) or high (15 mM) glucose conditions. Our analysis discovered 256 differentially abundant proteins (∼p < 0.05) after 24 h of high glucose exposure from more than 4500 identified in total. Several novel glucose-regulated proteins were elevated under high glucose conditions, including regulators of mRNA splicing (pleiotropic regulator 1), processing (retinoblastoma binding protein 6), and function (nuclear RNA export factor 1), in addition to neuron navigator 1 and plasminogen activator inhibitor 1. Proteins whose abundances markedly decreased during incubation at 15 mM glucose included Bax inhibitor 1 and synaptotagmin-17. Up-regulation of dicer 1 and SLC27A2 and down-regulation of phospholipase Cβ4 were confirmed by Western blots. Many proteins found to be differentially abundant after high glucose stimulation are annotated as uncharacterized or hypothetical. These findings expand our knowledge of glucose regulation of the human islet proteome and suggest many hitherto unknown responses to glucose that require additional studies to explore novel functional roles.

  10. MAPK/ERK signaling regulates insulin sensitivity to control glucose metabolism in Drosophila.

    Wei Zhang

    2011-12-01

    Full Text Available The insulin/IGF-activated AKT signaling pathway plays a crucial role in regulating tissue growth and metabolism in multicellular animals. Although core components of the pathway are well defined, less is known about mechanisms that adjust the sensitivity of the pathway to extracellular stimuli. In humans, disturbance in insulin sensitivity leads to impaired clearance of glucose from the blood stream, which is a hallmark of diabetes. Here we present the results of a genetic screen in Drosophila designed to identify regulators of insulin sensitivity in vivo. Components of the MAPK/ERK pathway were identified as modifiers of cellular insulin responsiveness. Insulin resistance was due to downregulation of insulin-like receptor gene expression following persistent MAPK/ERK inhibition. The MAPK/ERK pathway acts via the ETS-1 transcription factor Pointed. This mechanism permits physiological adjustment of insulin sensitivity and subsequent maintenance of circulating glucose at appropriate levels.

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

    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.

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

    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

  13. Reciprocal regulation of insulin and plasma 5'-AMP in glucose homeostasis in mice.

    Xia, Lin; Wang, Zhongqiu; Zhang, Ying; Yang, Xiao; Zhan, Yibei; Cheng, Rui; Wang, Shiming; Zhang, Jianfa

    2015-03-01

    A previous investigation has demonstrated that plasma 5'-AMP (pAMP) exacerbates and causes hyperglycemia in diabetic mice. However, the crosstalk between pAMP and insulin signaling to regulate glucose homeostasis has not been investigated in depth. In this study, we showed that the blood glucose level was more dependent on the ratio of insulin to pAMP than on the absolute level of these two factors. Administration of 5'-AMP significantly attenuated the insulin-stimulated insulin receptor (IR) autophosphorylation in the liver and muscle tissues, resulting in the inhibition of downstream AKT phosphorylation. A docking analysis indicated that adenosine was a potential inhibitor of IR tyrosine kinase. Moreover, the 5'-AMP treatment elevated the ATP level in the pancreas and in the isolated islets, stimulating insulin secretion and increasing the plasma level of insulin. The insulin administration decreased the 5'-AMP-induced hyper-adenosine level by the up-regulation of adenosine kinase activities. Our results indicate that blood glucose homeostasis is reciprocally regulated by pAMP and insulin.

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

    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.

  15. C-myb Regulates Autophagy for Pulp Vitality in Glucose Oxidative Stress.

    Lee, Y H; Kim, H S; Kim, J S; Yu, M K; Cho, S D; Jeon, J G; Yi, H K

    2016-04-01

    Diabetes mellitus is closely related to oral-complicated diseases by oxidative stress. This study investigates whether cellular myeloblastosis (c-myb) could protect human dental pulp cells against glucose oxidative stress and regulate autophagy activity for pulp vitality. Diabetes mellitus was induced by streptozotocin in Sprague-Dawley rats, and their pulp tissue in teeth was analyzed in terms of pulp cavity and molecules by hematoxylin and eosin and immunohistochemistry staining. Human dental pulp cells were serially subcultured and treated with glucose oxidase in the presence of elevated glucose to generate glucose oxidative stress. The replication-deficient adenovirus c-myb and small interfering RNA c-myb were introduced for c-myb expression. The pulp tissue from the diabetic rats was structurally different from normal tissue in terms of narrow pulp capacity, reduced c-myb, and dentinogenesis molecules. Glucose oxidase treatment decreased c-myb and dentinogenesis molecules (bone morphogenetic protein 2 and 7, dentin matrix protein 1, and dentin sialophosphoprotein) in human dental pulp cells. However, overexpression of c-myb by adenovirus c-myb increased dentinogenesis, autophagy molecules (autophagy protein 5, microtubule-associated protein 1A/1B-light chain 3, and Beclin-1), and cell survival via p-AMPK/AKT signaling even with glucose oxidative stress. In contrast, the lack of c-myb decreased the above molecules and cell survival by downregulating p-AMPK/AKT signaling. The results indicate that diabetes leads to irreversible damage to dental pulp, which is related to downexpression of autophagy via the p-AMPK/AKT pathway by decline of c-myb. The findings of this study provide a new insight that c-myb could ameliorate autophagy activity and that it is applicable for monitoring complicated diseases of dental pulp. The involvement of c-myb in pulp pathology could serve a therapeutic target in oral-complicated diseases.

  16. Regulation of Glucose Oxidase Activity through Interaction with Fullerene Derivatives%Regulation of Glucose Oxidase Activity through Interaction with Fullerene Derivatives

    Gao, Yunyan; Wang, Zhongli; Ou, Zhize; Li, Yi; Wang, Xuesong; Yang, Guoqiang

    2012-01-01

    The 2-(hydroxymethyl)pyridine modified C60 (PY-C60) and methoxydiglycol modified C60 (MDG-C60) are synthesized using Bingel-Hirsch reaction and characterized by nuclear magnetic resonance (NMR) and mass spectra. PY-C60 and MDG-C60 can bind to glucose oxidase (GOx) and quench the fluorescence of tryptophan (Trp) residue in GOx through static mechanism. The conformation of GOx is disturbed after formation of complex with these fullerene derivatives. Kinetic analysis indicates that PY-C60 and MDG-C60 may affect the catalytic activity of GOx with a partial mixed-type inhibition mechanism. In the plasma glucose concentration range (3.6--5.2 mmol·L-1), PY-C60 may significantly accelerate the catalytic velocity of GOx, however, MDG-C60 exerts almost no obvious change to the initial velocity of GOx, suggesting that elaborate design of molecular structure of fullerene derivative is very important for regulating the biological activity of fullerene-enzyme complex.

  17. TAp63 is a master transcriptional regulator of lipid and glucose metabolism

    Su, Xiaohua; Gi, Young Jin; Chakravarti, Deepavali; Chan, Io Long; Zhang, Aijun; Xia, Xuefeng; Tsai, Kenneth Y.; Flores, Elsa R.

    2012-01-01

    SUMMARY TAp63 prevents premature aging suggesting a link to genes that regulate longevity. Further characterization of TAp63−/− mice revealed that these mice develop obesity, insulin resistance, and glucose intolerance, similar to those seen in mice lacking two key metabolic regulators, Silent information regulator T1 (Sirt1) and AMPK. While the roles of Sirt1 and AMPK in metabolism have been well studied, their upstream regulators are not well understood. We found that TAp63 is important in regulating energy metabolism by accumulating in response to metabolic stress and transcriptionally activating Sirt1, AMPKα2, and LKB1 resulting in increased fatty acid synthesis and decreased fatty acid oxidation. Moreover, we found that TAp63 lowers blood glucose levels in response to metformin. Restoration of Sirt1, AMPKα2, and LKB1 in TAp63−/− mice rescued some of the metabolic defects of the TAp63−/− mice. Our study defines a role for TAp63 in metabolism and weight control. PMID:23040072

  18. Discovery of novel glucose-regulated proteins in isolated human pancreatic islets using LC-MS/MS-based proteomics

    Rutledge, Alexandra C.; Fontes, Ghislaine; Gritsenko, Marina A.; Norbeck, Angela D.; Anderson, David J.; Waters, Katrina M.; Adkins, Joshua N.; Smith, Richard D.; Poitout, Vincent; Metz, Thomas O.

    2012-07-06

    The prevalence of diabetes mellitus is increasing dramatically throughout the world, and the disease has become a major public health issue. The most common form of the disease, type 2 diabetes, is due in part to insufficient insulin production from the pancreatic beta-cell. Since glucose is the most potent and physiologically important regulators of beta-cell function under physiological conditions, understanding the insulin secretory defect underlying type 2 diabetes requires a better understanding of glucose regulation of beta-cell function. To this aim, a bottom-up LC-MS/MS-based proteomics approach was used to profile pooled islets from multiple donors under basal (5 mM) or high (15 mM) glucose conditions. Our analysis discovered 256 differentially abundant proteins ({approx}p < 0.05) after 24 h of high glucose exposure from more than 4500 identified in total. Several novel glucose-regulated proteins were elevated under high glucose conditions, including regulators of mRNA splicing (Pleiotropic regulator 1), processing (Retinoblastoma binding protein 6), and function (Nuclear RNA export factor 1), in addition to Neuron navigator 1 and Plasminogen activator inhibitor 1. Proteins whose abundances markedly decreased during incubation at 15 mM glucose included Bax inhibitor 1 and Synaptotagmin-17. Many proteins found to be differentially abundant after high glucose stimulation were uncharacterized or hypothetical. These findings expand our knowledge of glucose regulation of the human islet proteome and suggest many hitherto unknown responses to glucose that require additional studies to explore novel functional roles.

  19. Translocator protein (18 kDa) as a pharmacological target in adipocytes to regulate glucose homeostasis.

    Li, Jiehan; Papadopoulos, Vassilios

    2015-09-01

    As a major regulator in obesity and its associated metabolic complications, the proper functioning of adipocytes is crucial for health maintenance, thus serving as an important target for the development of anti-obese and anti-diabetic therapies. There is increasing evidence that mitochondrial malfunction is a pivotal event in disturbing adipocyte cell homeostasis. Among major mitochondrial structure components, the high-affinity drug- and cholesterol-binding outer mitochondrial membrane translocator protein (18 kDa; TSPO) has shown importance across a broad spectrum of mitochondrial functions. Recent studies demonstrated the presence of TSPO in white adipocyte mitochondria of mice, and administration of TSPO drug ligands to obese mice reduced weight gain and lowered glucose level. Therefore, it is of great interest to assess whether TSPO in adipocytes could serve as a drug target to regulate adipocyte activities with potential influence on weight control and glucose metabolism. Two structurally distinct TSPO drug ligands, PK 11195 and FGIN-1-27, improved the intracellular dynamics of 3T3-L1 adipocytes, such as the production and release of adipokines, glucose uptake, and adipogenesis. TSPO knockdown in either differentiated adipocytes or preadipocytes impaired these functions. Findings from 3T3-L1 cells were related to human primary cells, where TSPO expression was tightly associated with the metabolic state of primary adipocytes and the differentiation of primary preadipocytes. These results suggest that TSPO expression is essential to safeguard healthy adipocyte functions, and that TSPO activation in adipocytes improves their metabolic status in regulating glucose homeostasis. Adipocyte TSPO may serve as a pharmacologic target for the treatment of obesity and diabetes.

  20. Decreased glucose uptake by hyperglycemia is regulated by different mechanisms in human cancer cells and monocytes

    Kim, Chae Kyun; Chung, June Key; Lee, Yong Jin; Hong, Mee Kyoung; Jeong, Jae Min; Lee, Dong Soo; Lee, Myung Chul [College of Medicine, Seoul National Univ., Seoul (Korea, Republic of)

    2002-04-01

    To clarify the difference in glucose uptake between human cancer cells and monocytes, we studied ({sup 18}F) fluorodeoxyglucose (FDG) uptake in three human colon cancer cell lines (SNU-C2A, SNU-C4, SNU-C5), one human lung cancer cell line (NCI-H522), and human peripheral blood monocytes. The FDG uptake of both cancer cells and monocytes was increased in glucose-free medium, but decreased in the medium containing 16.7 mM glucose (hyperglycemic). The level of Glut1 mRNA decreased in human colon cancer cells and NCI-H522 under hyperglycemic condition. Glut1 protein expression was also decreased in the four human cancer cell lines under hyperglycemic condition, whereas it was consistently undetectable in monocytes. SNU-C2A, SNU-C4 and NCI-H522 showed a similar level of hexokinase activity (7.5-10.8 mU/mg), while SNU-C5 and moncytes showed lower range of hexokinase activity (4.3-6.5 mU/mg). These data suggest that glucose uptake is regulated by different mechanisms in human cancer cells and monocytes.

  1. Developmental role for endocannabinoid signaling in regulating glucose metabolism and growth.

    Li, Zhiying; Schmidt, Sarah F; Friedman, Jeffrey M

    2013-07-01

    Treatment of ob/ob (obese) mice with a cannabinoid receptor 1 (Cnr1) antagonist reduces food intake, suggesting a role for endocannabinoid signaling in leptin action. We further evaluated the role of endocannabinoid signaling by analyzing the phenotype of Cnr1 knockout ob/ob mice. Double mutant animals show a more severe growth retardation than ob/ob mice with similar levels of adiposity and reduced IGF-I levels without alterations of growth hormone (GH) levels. The double mutant mice are also significantly more glucose intolerant than ob/ob mice. This is in contrast to treatment of ob/ob mice with a Cnr1 antagonist that had no effect on glucose metabolism, suggesting a possible requirement for endocannabinoid signaling during development for normal glucose homeostasis. Double mutant animals also showed similar leptin sensitivity as ob/ob mice, suggesting that there are developmental changes that compensate for the loss of Cnr1 signaling. These data establish a role for Cnr1 during development and suggest that compensatory changes during development may mitigate the requirement for Cnr1 in mediating the effects of leptin. The data also suggest a developmental role for Cnr1 to promote growth, regulate the GH/IGF-I axis, and improve β-cell function and glucose homeostasis in the setting of leptin deficiency.

  2. Health technology assessment review : Computerized glucose regulation in the intensive care unit - how to create artificial control

    Hoekstra, Miriam; Vogelzang, Mathijs; Verbitskiy, Evgeny; Nijsten, Maarten W.N.

    2009-01-01

    Current care guidelines recommend glucose control (GC) in critically ill patients. To achieve GC, many ICUs have implemented a (nurse-based) protocol on paper. However, such protocols are often complex, time-consuming, and can cause iatrogenic hypoglycaemia. Computerized glucose regulation protocols

  3. 冠心病糖代谢异常患者血浆Ghrelin水平及临床意义%Plasma ghrelin level in patients with coronary heart disease with abnormal glucose metabolism and its clinical significance

    庞军刚; 徐新; 唐良秋; 张社兵; 江志平

    2012-01-01

    目的:探讨冠心病糖代谢异常患者血浆胃饥饿素(Ghrelin)水平及其相关临床意义.方法:将纳入研究对象依据相关检验及检查结果分为正常对照组、冠心病组(冠心病糖代谢正常组和冠心病糖代谢异常组)、单纯糖代谢异常组.收集所有入选对象人院第2天清晨空腹血样,采用ELISA方法同批检测血浆Ghrelin水平.结果:①冠心病组及单纯糖代谢异常组血浆Ghrelin水平均显著低于正常对照组.②冠心病糖代谢异常组血浆Ghrelin水平显著低于冠心病糖代谢正常组及单纯糖代谢异常组.③析因分析结果显示:冠心病与糖代谢异常在对血浆Ghrelin水平影响方面不存在交互作用.然而,糖代谢异常比冠心病对血浆Ghrelin水平的影响更明显.结论:冠心病糖代谢异常患者血浆Ghrelin水平显著下降,且糖代谢异常对Ghrelin的影响更明显.%AIM: To study plasma ghrelin level distribution in patients with coronary heart disease (CHD) with abnormal glucose metabolism and to discuss its clinical significance. METHODS; According to laboratory examination results, subjects were divided into control group, coronary heart disease with normal glucose metabolism group, coronary heart disease with abnormal glucose metabolism group and abnormal glucose metabolism group. Fasting blood samples were collected the morning after admission with EDTA-2K anticoagulation tubes. Blood samples were then transferred to centrifuge tubes containing aprotinin and were centrifuged to extract plasma for cryopreservation. All blood plasma ghrelin levels were tested with ELISA. RESULTS: Compared with those in control group, ghrelin levels were significantly reduced in the group with CHD with normal glucose metabolism, group of CHD with abnormal glucose metabolism and group with abnormal glucose metabolism. Compared with those in the group of CHD with normal glucose metabolism, levels of ghrelin were significantly reduced in patients with

  4. ChREBP, but not LXRs, is required for the induction of glucose-regulated genes in mouse liver

    Denechaud, Pierre-Damien; Bossard, Pascale; Lobaccaro, Jean-Marc A.; Millatt, Lesley; Staels, Bart; Girard, Jean; Postic, Catherine

    2008-01-01

    The transcription factor carbohydrate-responsive element–binding protein (ChREBP) has emerged as a central regulator of lipid synthesis in liver because it is required for glucose-induced expression of the glycolytic enzyme liver–pyruvate kinase (L-PK) and acts in synergy with SREBP to induce lipogenic genes such as acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS). Liver X receptors (LXRs) are also important regulators of the lipogenic pathway, and the recent finding that ChREBP is a direct target of LXRs and that glucose itself can bind and activate LXRs prompted us to study the role of LXRs in the induction of glucose-regulated genes in liver. Using an LXR agonist in wild-type mice, we found that LXR stimulation did not promote ChREBP phosphorylation or nuclear localization in the absence of an increased intrahepatic glucose flux. Furthermore, the induction of ChREBP, L-PK, and ACC by glucose or high-carbohydrate diet was similar in LXRα/β knockout compared with wild-type mice, suggesting that the activation of these genes by glucose occurs by an LXR-independent mechanism. We used fluorescence resonance energy transfer analysis to demonstrate that glucose failed to promote the interaction of LXRα/β with specific cofactors. Finally, siRNA silencing of ChREBP in LXRα/β knockout hepatocytes abrogated glucose-induced expression of L-PK and ACC, further demonstrating the central role of ChREBP in glucose signaling. Taken together, our results demonstrate that glucose is required for ChREBP functional activity and that LXRs are not necessary for the induction of glucose-regulated genes in liver. PMID:18292813

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

    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.

  6. Adaptive evolution for fast growth on glucose and the effects on the regulation of glucose transport system in Clostridium tyrobutyricum.

    Jiang, Ling; Li, Shuang; Hu, Yi; Xu, Qing; Huang, He

    2012-03-01

    Laboratory adaptive evolution of microorganisms offers the possibility of relating acquired mutations to increased fitness of the organism under the conditions used. By combining a fibrous-bed bioreactor, we successfully developed a simple and valuable adaptive evolution strategy in repeated-batch fermentation mode with high initial substrate concentration and evolved Clostridium tyrobutyricum mutant with significantly improved butyric acid volumetric productivity up to 2.25 g/(L h), which is the highest value in batch fermentation reported so far. Further experiments were conducted to pay attention to glucose transport system in consideration of the high glucose consumption rate resulted from evolution. Complete characterization and comparison of the glucose phosphoenolpyruvate (PEP)-dependent phosphotransferase system (PTS) were carried out in the form of toluene-treated cells and cell-free extracts derived from both C. tyrobutyricum wide-type and mutant, while an alternative glucose transport route that requires glucokinase was confirmed by the phenomena of resistance to the glucose analogue 2-deoxyglucose and ATP-dependent glucose phosphorylation. Our results suggest that C. tyrobutyricum mutant is defective in PTS activity and compensates for this defect with enhanced glucokinase activity, resulting in the efficient uptake and consumption of glucose during the whole metabolism.

  7. High glucose induced alteration of SIRTs in endothelial cells causes rapid aging in a p300 and FOXO regulated pathway.

    Rokhsana Mortuza

    Full Text Available In diabetes, some of the cellular changes are similar to aging. We hypothesized that hyperglycemia accelerates aging-like changes in the endothelial cells (ECs and tissues leading to structural and functional damage. We investigated glucose-induced aging in 3 types of ECs using senescence associated β-gal (SA β-gal staining and cell morphology. Alterations of sirtuins (SIRTs and their downstream mediator FOXO and oxidative stress were investigated. Relationship of such alteration with histone acetylase (HAT p300 was examined. Similar examinations were performed in tissues of diabetic animals. ECs in high glucose (HG showed evidence of early senescence as demonstrated by increased SA β-gal positivity and reduced replicative capacities. These alterations were pronounced in microvascular ECs. They developed an irregular and hypertrophic phenotype. Such changes were associated with decreased SIRT (1-7 mRNA expressions. We also found that p300 and SIRT1 regulate each other in such process, as silencing one led to increase of the others' expression. Furthermore, HG caused reduction in FOXO1's DNA binding ability and antioxidant target gene expressions. Chemically induced increased SIRT1 activity and p300 knockdown corrected these abnormalities slowing aging-like changes. Diabetic animals showed increased cellular senescence in renal glomerulus and retinal blood vessels along with reduced SIRT1 mRNA expressions in these tissues. Data from this study demonstrated that hyperglycemia accelerates aging-like process in the vascular ECs and such process is mediated via downregulation of SIRT1, causing reduction of mitochondrial antioxidant enzyme in a p300 and FOXO1 mediated pathway.

  8. Zinc finger protein 407 (ZFP407) regulates insulin-stimulated glucose uptake and glucose transporter 4 (Glut4) mRNA.

    Buchner, David A; Charrier, Alyssa; Srinivasan, Ethan; Wang, Li; Paulsen, Michelle T; Ljungman, Mats; Bridges, Dave; Saltiel, Alan R

    2015-03-06

    The glucose transporter GLUT4 facilitates insulin-stimulated glucose uptake in peripheral tissues including adipose, muscle, and heart. GLUT4 function is impaired in obesity and type 2 diabetes leading to hyperglycemia and an increased risk of cardiovascular disease and neuropathy. To better understand the regulation of GLUT4 function, a targeted siRNA screen was performed and led to the discovery that ZFP407 regulates insulin-stimulated glucose uptake in adipocytes. The decrease in insulin-stimulated glucose uptake due to ZFP407 deficiency was attributed to a reduction in GLUT4 mRNA and protein levels. The decrease in GLUT4 was due to both decreased transcription of Glut4 mRNA and decreased efficiency of Glut4 pre-mRNA splicing. Interestingly, ZFP407 coordinately regulated this decrease in transcription with an increase in the stability of Glut4 mRNA, resulting in opposing effects on steady-state Glut4 mRNA levels. More broadly, transcriptome analysis revealed that ZFP407 regulates many peroxisome proliferator-activated receptor (PPAR) γ target genes beyond Glut4. ZFP407 was required for the PPARγ agonist rosiglitazone to increase Glut4 expression, but was not sufficient to increase expression of a PPARγ target gene reporter construct. However, ZFP407 and PPARγ co-overexpression synergistically activated a PPARγ reporter construct beyond the level of PPARγ alone. Thus, ZFP407 may represent a new modulator of the PPARγ signaling pathway.

  9. 妊娠期糖代谢异常的相关危险因素分析%Risk Factors of Abnormal Glucose Metabolism in Gestation Period

    代明甫; 李倩; 钟思燕; 杨霜雪; 邬小臣

    2015-01-01

    Objective:To explore risk factors of abnormal glucose metabolism in gestation period, and provide the theory basis for the clinical prevention and treatment of gestational diabetes mellitus ( GDM ) . Method:A case-control study was conducted on 100 pregnant women with clinically confirmed gestational abnormal glucose metabolism as study group, and 100 pregnant women of same gestational weeks with normal glucose metabolism as control group from Jun.2011 to May 2014.The general information, gestational mate-rials and behaviors of the two groups were investigated and the risk factors of abnormal glucose metabolism in gestation period were analyzed.Result:Multi-factor logistic regression analysis showed that diabetes family history ( OR =2.398, 95%CI 1.042~5.012) , age was more than 28 years ( OR=1.413, 95%CI 1.322~4. 352) , BMI>24 ( OR=6.543, 95%CI 0.782~2.320) , abortion history ( OR=0.212, 95%CI 0.025~2. 256) , smoking history ( OR=0.246, 95%CI 0.045~3.452) were the risk factor of GDM morbidity.Con-clusion:Pregnant women with diabetes family history,>28 years, BMI>24,history of abortion and smoking should undergo gestational diabetes screening during early trimester of pregency.%目的:探讨妇女妊娠期糖代谢异常分布情况及发病的相关危险因素,为预防和控制妊娠期糖尿病提供理论依据。方法:以我院2011年6月至2014年5月保健门诊确诊的妊娠期糖代谢异常的孕产妇100例为病例组,以糖代谢正常及孕周相同的孕产妇100例为对照组。调查两组孕产妇一般情况,分析妊娠期糖代谢异常相关因素。结果:Logistic回归分析发现糖尿病遗传史( OR=2.398,95%, CI:1.042~5.012)、年龄>28岁( OR=1.413,95%,CI:1.322~4.352)、体质指数>24( OR=6.543,95%, CI:0.782~2.320)、流产史( OR=0.212,95%,CI:0.025~2.256)、吸烟史( OR=0.246,95%,CI:0.045~3.452)是妊娠

  10. Leptin signaling regulates glucose homeostasis, but not adipostasis, in the zebrafish.

    Michel, Maximilian; Page-McCaw, Patrick S; Chen, Wenbiao; Cone, Roger D

    2016-03-15

    Leptin is the primary adipostatic factor in mammals. Produced largely by adipocytes in proportion to total adipose mass, the hormone informs the brain regarding total energy stored as triglycerides in fat cells. The hormone acts on multiple circuits in the brain to regulate food intake, autonomic outflow, and endocrine function to maintain energy balance. In addition to regulating adipose mass, mammalian leptin also plays a role in the regulation of glucose homeostasis and as a gating factor in reproductive competence. Leptin-deficient mice and people exhibit early onset profound hyperphagia and obesity, diabetes, and infertility. Although leptin and the leptin receptor are found in fish, the hormone is not expressed in adipose tissue, but is found in liver and other tissues. Here, we show that adult zebrafish lacking a functional leptin receptor do not exhibit hyperphagia or increased adiposity, and exhibit normal fertility. However, leptin receptor-deficient larvae have increased numbers of β-cells and increased levels of insulin mRNA. Furthermore, larval zebrafish have been shown to exhibit β-cell hyperplasia in response to high fat feeding or peripheral insulin resistance, and we show here that leptin receptor is required for this response. Adult zebrafish also have increased levels of insulin mRNA and other alterations in glucose homeostasis. Thus, a role for leptin in the regulation of β-cell mass and glucose homeostasis appears to be conserved across vertebrates, whereas its role as an adipostatic factor is likely to be a secondary role acquired during the evolution of mammals.

  11. Branched-chain amino acid metabolism in rat muscle: abnormal regulation in acidosis

    May, R.C.; Hara, Y.; Kelly, R.A.; Block, K.P.; Buse, M.G.; Mitch, W.E.

    1987-06-01

    Branched-chain amino acid (BCAA) metabolism is frequently abnormal in pathological conditions accompanied by chronic metabolic acidosis. To study how metabolic acidosis affects BCAA metabolism in muscle, rats were gavage fed a 14% protein diet with or without 4 mmol NH/sub 4/Cl x 100 g body wt/sup -1/ x day/sup -1/. Epitrochlearis muscles were incubated with L-(1-/sup 14/C)-valine and L-(1-/sup 14/C)leucine, and rates of decarboxylation, net transamination, and incorporation into muscle protein were measured. Plasma and muscle BCAA levels were lower in acidotic rats. Rates of valine and leucine decarboxylation and net transamination were higher in muscles from acidotic rats; these differences were associated with a 79% increase in the total activity of branched-chain ..cap alpha..-keto acid dehydrogenase and a 146% increase in the activated form of the enzyme. They conclude that acidosis affects the regulation of BCAA metabolism by enhancing flux through the transaminase and by directly stimulating oxidative catabolism through activation of branched-chain ..cap alpha..-keto acid dehydrogenase.

  12. Down-regulation of EPHX2 gene transcription by Sp1 under high-glucose conditions.

    Oguro, Ami; Oida, Shoko; Imaoka, Susumu

    2015-09-15

    sEH (soluble epoxide hydrolase), which is encoded by the EPHX2 gene, regulates the actions of bioactive lipids, EETs (epoxyeicosatrienoic acids). Previously, we found that high-glucose-induced oxidative stress suppressed sEH levels in a hepatocarcinoma cell line (Hep3B) and sEH was decreased in streptozotocin-induced diabetic mice in vivo. In the present study, we investigated the regulatory mechanisms underlying EPHX2 transcriptional suppression under high-glucose conditions. The decrease in sEH was prevented by an Sp1 (specificity protein 1) inhibitor, mithramycin A, and overexpression or knockdown of Sp1 revealed that Sp1 suppressively regulated sEH expression, in contrast with the general role of Sp1 on transcriptional activation. In addition, we found that AP2α (activating protein 2α) promoted EPHX2 transcription. The nuclear transport of Sp1, but not that of AP2α, was increased under high glucose concomitantly with the decrease in sEH. Within the EPHX2 promoter -56/+32, five Sp1-binding sites were identified, and the mutation of each of these sites showed that the first one (SP1_1) was important in both suppression by Sp1 and activation by AP2α. Furthermore, overexpression of Sp1 diminished the binding of AP2α by DNA-affinity precipitation assay and ChIP, suggesting competition between Sp1 and AP2α on the EPHX2 promoter. These findings provide novel insights into the role of Sp1 in transcriptional suppression, which may be applicable to the transcriptional regulation of other genes.

  13. The expression of glucose regulated protein-94 in colorectal carcinoma cells treated by sodium butyrate

    2000-01-01

    The expression of glucose regulated protein 94 (GRP94)during the treatment of human colorectal carcinoma cell lineClone A cells with sodium butyrate was studied. Sodium butyrate (SB) can cause functional and morphological effects on Clone A cells including growth arrest at G0/G1 stage and cell differentiation as observed by morphological changes, MTT and flow cytometry assays, as well as reduced Grp94 gene expression as shown by Northern blot and Western blot assays. The possible mechanism of the correlation between Grp94 gene expression and tumor growth inhibition and cell differentiation is briefly discussed.

  14. The expression of glucose regulated protein—94 in colorectal carcinoma cells treated by sodium butyrate

    WUYIDI; JINDANSONG

    2000-01-01

    The expression of glucose regulated protein 94 (GPR94) during the treatment of human colorectal carcinoma cell lineClone A cells with codium butyrate was studied.Dodium butyrate (SB) can cause functional and morphological effects on Clone A cells including growth arrest at G0/G1 stage and cell differentiation as observed by morphological changes,MTT and flow cytometry assays,as well as reduced Grp94 gene expression as shown by Northern blot and Western blot assays.The possible mechanism of the correlation between Grp94 gene expression and tumor growth inhibition and cell differentiation is briefly discussed.

  15. Involvement of atypical protein kinase C in the regulation of cardiac glucose and long-chain fatty acid uptake

    Habets, Daphna D J; Luiken, Joost J F P; Ouwens, Margriet;

    2012-01-01

    Aim: The signaling pathways involved in the regulation of cardiac GLUT4 translocation/glucose uptake and CD36 translocation/long-chain fatty acid uptake are not fully understood. We compared in heart/muscle-specific PKC-¿ knockout mice the roles of atypical PKCs (PKC-¿ and PKC-¿) in regulating ca...... to allow optimal stimulation of glucose and fatty acid uptake, indicating that atypical PKCs are necessary but not rate-limiting in the regulation of cardiac substrate uptake and that PKC-¿ and PKC-¿ have interchangeable functions in these processes.......Aim: The signaling pathways involved in the regulation of cardiac GLUT4 translocation/glucose uptake and CD36 translocation/long-chain fatty acid uptake are not fully understood. We compared in heart/muscle-specific PKC-¿ knockout mice the roles of atypical PKCs (PKC-¿ and PKC-¿) in regulating...... cardiac glucose and fatty acid uptake. Results: Neither insulin-stimulated nor AMPK-mediated glucose and fatty acid uptake were inhibited upon genetic PKC-¿ ablation in cardiomyocytes. In contrast, myristoylated PKC-¿ pseudosubstrate inhibited both insulin-stimulated and AMPK-mediated glucose and fatty...

  16. "Glucose and ethanol-dependent transcriptional regulation of the astaxanthin biosynthesis pathway in Xanthophyllomyces dendrorhous"

    Cifuentes Víctor

    2011-08-01

    Full Text Available Abstract Background The yeast Xanthophyllomyces dendrorhous is one of the most promising and economically attractive natural sources of astaxanthin. The biosynthesis of this valuable carotenoid is a complex process for which the regulatory mechanisms remain mostly unknown. Several studies have shown a strong correlation between the carbon source present in the medium and the amount of pigments synthesized. Carotenoid production is especially low when high glucose concentrations are used in the medium, while a significant increase is observed with non-fermentable carbon sources. However, the molecular basis of this phenomenon has not been established. Results In this work, we showed that glucose caused transcriptional repression of the three genes involved in the synthesis of astaxanthin from geranylgeranyl pyrophosphate in X. dendrorhous, which correlates with a complete inhibition of pigment synthesis. Strikingly, this regulatory response was completely altered in mutant strains that are incapable of synthesizing astaxanthin. However, we found that addition of ethanol caused the induction of crtYB and crtS gene expression and promoted de novo synthesis of carotenoids. The induction of carotenogenesis was noticeable as early as 24 h after ethanol addition. Conclusion For the first time, we demonstrated that carbon source-dependent regulation of astaxanthin biosynthesis in X. dendrorhous involves changes at the transcriptional level. Such regulatory mechanism provides an explanation for the strong and early inhibitory effect of glucose on the biosynthesis of this carotenoid.

  17. Oxygen-glucose deprivation regulates BACE1 expression through induction of autophagy in Neuro-2a/APP695 cells.

    Chen, Rong-Fu; Zhang, Ting; Sun, Yin-Yi; Sun, Ya-Meng; Chen, Wen-Qi; Shi, Nan; Shen, Fang; Zhang, Yan; Liu, Kang-Yong; Sun, Xiao-Jiang

    2015-09-01

    Our previous findings have demonstrated that autophagy regulation can alleviate the decline of learning and memory by eliminating deposition of extracellular beta-amyloid peptide (Aβ) in the brain after stroke, but the exact mechanism is unclear. It is presumed that the regulation of beta-site APP-cleaving enzyme 1 (BACE1), the rate-limiting enzyme in metabolism of Aβ, would be a key site. Neuro-2a/amyloid precursor protein 695 (APP695) cell models of cerebral ischemia were established by oxygen-glucose deprivation to investigate the effects of Rapamycin (an autophagy inducer) or 3-methyladenine (an autophagy inhibitor) on the expression of BACE1. Either oxygen-glucose deprivation or Rapamycin down-regulated the expression of BACE1 while 3-methyladenine up-regulated BACE1 expression. These results confirm that oxygen-glucose deprivation down-regulates BACE1 expression in Neuro-2a/APP695 cells through the introduction of autophagy.

  18. Regulation of glucose transport by ROCK1 differs from that of ROCK2 and is controlled by actin polymerization.

    Chun, Kwang-Hoon; Araki, Kazushi; Jee, Yuna; Lee, Dae-Ho; Oh, Byung-Chul; Huang, Hu; Park, Kyong Soo; Lee, Sam W; Zabolotny, Janice M; Kim, Young-Bum

    2012-04-01

    A role of Rho-associated coiled-coil-containing protein kinase (ROCK)1 in regulating whole-body glucose homeostasis has been reported. However, cell-autonomous effects of ROCK1 on insulin-dependent glucose transport in adipocytes and muscle cells have not been elucidated. To determine the specific role of ROCK1 in glucose transport directly, ROCK1 expression in 3T3-L1 adipocytes and L6 myoblasts was biologically modulated. Here, we show that small interfering RNA-mediated ROCK1 depletion decreased insulin-induced glucose transport in adipocytes and myoblasts, whereas adenovirus-mediated ROCK1 expression increased this in a dose-dependent manner, indicating that ROCK1 is permissive for glucose transport. Inhibition of ROCK1 also impaired glucose transporter 4 translocation in 3T3-L1 adipocytes. Importantly, the ED₅₀ of insulin for adipocyte glucose transport was reduced when ROCK1 was expressed, leading to hypersensitivity to insulin. These effects are dependent on actin cytoskeleton remodeling, because inhibitors of actin polymerization significantly decreased ROCK1's effect to promote insulin-stimulated glucose transport. Unlike ROCK2, ROCK1 binding to insulin receptor substrate (IRS)-1 was not detected by immunoprecipitation, although cell fractionation demonstrated both ROCK isoforms localize with IRS-1 in low-density microsomes. Moreover, insulin's ability to increase IRS-1 tyrosine 612 and serine 632/635 phosphorylation was attenuated by ROCK1 suppression. Replacing IRS-1 serine 632/635 with alanine reduced insulin-stimulated phosphatidylinositol 3-kinase activation and glucose transport in 3T3-L1 adipocytes, indicating that phosphorylation of these serine residues of IRS-1, which are substrates of the ROCK2 isoform in vitro, are crucial for maximal stimulation of glucose transport by insulin. Our studies identify ROCK1 as an important positive regulator of insulin action on glucose transport in adipocytes and muscle cells.

  19. Impact of Glucose Tolerance Status, Sex, and Body Size on Glucose Absorption Patterns During OGTTs

    Faerch, K.; Pacini, G.; Nolan, J. J.;

    2013-01-01

    OBJECTIVEWe studied whether patterns of glucose absorption during oral glucose tolerance tests (OGTTs) were abnormal in individuals with impaired glucose regulation and whether they were related to sex and body size (height and fat-free mass). We also examined how well differences in insulin......), isolated impaired fasting glucose (i-IFG), or isolated impaired glucose tolerance (i-IGT). Insulin sensitivity and -cell function were measured with the euglycemic-hyperinsulinemic clamp and intravenous glucose tolerance tests, respectively. Surrogate markers of both conditions were calculated from OGTTs...... size were taken into account (P > 0.28). Faster glucose absorption was related to higher fasting (P = 0.001) and lower 2-h (P = 0.001) glucose levels and to greater height and fat-free mass (P

  20. Prevalence of Blood Pressure, Blood Glucose and Serum Lipids Abnormalities Among Ethiopian Immigrants: A Community-Based Cross-Sectional Study.

    Ghobadzadeh, Maryam; Demerath, Ellen W; Tura, Yisehak

    2015-08-01

    The main objective of this study was to investigate the prevalence of hypertension, glucose and blood lipid abnormalities among a community of Ethiopian immigrants in Minnesota. This cross-sectional study used data from the parish nursing program 2007-2012. A total of 673 encounters were included in this study. Various dependent variables including systolic blood pressure (SBP), diastolic blood pressure (DBP), blood glucose (BG), and serum lipids were examined. High blood pressure was defined as a mean SBP equal to or higher than 140 mm/Hg and/or DBP equal to or higher than 90 mmHg. Elevated fasting glucose defined as levels equal to or higher than 126 mg/dL. High level of total cholesterol (TC), total triglyceride (TG), low-density lipoprotein (LDL) cholesterol, and low high-density lipoprotein (HDL) cholesterol were defined as ≥240, ≥200, ≥160 and ≤40 mg/dL, respectively. General linear regression models were used to investigate the relationship of participants' age and gender, to the continuously distributed response variables, which included systolic and DBP, BG, TC, TG, LDL cholesterol and HDL cholesterol. This is a nonrandom sample of adult Ethiopian church members who were invited to participate in a parish nurse cardiovascular disease (CVD) risk factor screening program. Participants in this sample were 43 % male and 57 % female. The overall prevalence of hypertension was 30.1 % with a cut off mark of 140/90 mm/Hg. The prevalence of hypertension was 33 and 24 % among men than among women, respectively (p 240 mg/dL) were observed in 15 % of the women and 10 % of the men (p = 0.2). Higher SBP and DBP were significantly higher in male participants than their female counterparts (p  0.05). This opportunity sample suggests high prevalence of CVD risk factors in a community of Ethiopian-American adults, and a pressing need for more comprehensive and systematic assessment of chronic disease health needs in this growing community.

  1. Adr1 and Cat8 mediate coactivator recruitment and chromatin remodeling at glucose-regulated genes.

    Rhiannon K Biddick

    Full Text Available BACKGROUND: Adr1 and Cat8 co-regulate numerous glucose-repressed genes in S. cerevisiae, presenting a unique opportunity to explore their individual roles in coactivator recruitment, chromatin remodeling, and transcription. METHODOLOGY/PRINCIPAL FINDINGS: We determined the individual contributions of Cat8 and Adr1 on the expression of a cohort of glucose-repressed genes and found three broad categories: genes that need both activators for full derepression, genes that rely mostly on Cat8 and genes that require only Adr1. Through combined expression and recruitment data, along with analysis of chromatin remodeling at two of these genes, ADH2 and FBP1, we clarified how these activators achieve this wide range of co-regulation. We find that Adr1 and Cat8 are not intrinsically different in their abilities to recruit coactivators but rather, promoter context appears to dictate which activator is responsible for recruitment to specific genes. These promoter-specific contributions are also apparent in the chromatin remodeling that accompanies derepression: ADH2 requires both Adr1 and Cat8, whereas, at FBP1, significant remodeling occurs with Cat8 alone. Although over-expression of Adr1 can compensate for loss of Cat8 at many genes in terms of both activation and chromatin remodeling, this over-expression cannot complement all of the cat8Delta phenotypes. CONCLUSIONS/SIGNIFICANCE: Thus, at many of the glucose-repressed genes, Cat8 and Adr1 appear to have interchangeable roles and promoter architecture may dictate the roles of these activators.

  2. Obestatin and Ghrelin in Regulation of Blood Glucose%Obestatin、Ghrelin与血糖调节

    孙杰辉

    2011-01-01

    Obestatin and ghrelin participate and antagonize each other in blood glucose regulation. Obestatin inhibits food intake, gastrointestinal evacuation and motility, and increases insulin secretion from pancreatic β-cells, whereas ghrelin enhances appetite, gastrointestinal emptying and motility, decreases fat consumption, prevents apoptosis of pancreatic (β-cells and human islets thereby controlling insulin secretion. However, the mechanisms of both obestatin and ghrelin in blood glucose regulation remain controversial.%肥胖抑制素(obestatin)和生长激素释放肽(ghrelin)能互相拮抗,参与血糖的调节.其中obestatin与GPR-39(G-protein-coupled receptor 39)结合抑制摄食和胃肠排空、促进胰岛β细胞功能,影响胰岛素的分泌;而ghrelin与生长激素促分泌受体(GHSR1a)结合,促进食欲和胃肠排空,减少脂肪的利用,抑制胰岛细胞凋亡,调节胰岛素的分泌.但两者参与血糖调节的具体机制尚存在争议.

  3. Schisandra polysaccharide increased glucose consumption by up-regulating the expression of GLUT-4.

    Jin, Dun; Zhao, Ting; Feng, Wei-Wei; Mao, Guang-Hua; Zou, Ye; Wang, Wei; Li, Qian; Chen, Yao; Wang, Xin-Tong; Yang, Liu-Qing; Wu, Xiang-Yang

    2016-06-01

    In our previous study, a polysaccharide was extracted from Schisandra Chinensis (Trucz.) Baill and found with anti-diabetic effects. The aim of this study was to investigate the anti-diabetic effects of the low weight molecular polysaccharide (SCPP11) purified from crude Schisandra polysaccharide and illustrate the underlying mechanism in buffalo rat liver cells. The insulin resistance model of BRL cells was established by incubating with insulin solution for 24h. The effects of SCPP11 on regulating related protein and mRNA expression in an insulin and AMPK signal pathway were investigated by western blot and RT-PCR analysis. SCPP11 showed no cytotoxicity to BRL cells and could improve the glucose consumption in BRL cells. SCPP11 increased the protein expression of Akt, p-AMPK and GLUT-4 in BRL cells. Moreover, SCPP11 could enhance the mRNA expression levels of IRS-1, PI3K, Akt, GLUT-4, AMPKα and PPAR-γ in BRL cells at the same time. In conclusion, SCPP11 possessed effects in improving glucose consumption by up-regulating the expression of GLUT-4 which might occur via insulin and AMPK signal pathway and could be a potential functional food to prevent and mitigate the insulin resistance condition.

  4. Adiponectin regulates expression of hepatic genes critical for glucose and lipid metabolism.

    Liu, Qingqing; Yuan, Bingbing; Lo, Kinyui Alice; Patterson, Heide Christine; Sun, Yutong; Lodish, Harvey F

    2012-09-04

    The effects of adiponectin on hepatic glucose and lipid metabolism at transcriptional level are largely unknown. We profiled hepatic gene expression in adiponectin knockout (KO) and wild-type (WT) mice by RNA sequencing. Compared with WT mice, adiponectin KO mice fed a chow diet exhibited decreased mRNA expression of rate-limiting enzymes in several important glucose and lipid metabolic pathways, including glycolysis, tricarboxylic acid cycle, fatty-acid activation and synthesis, triglyceride synthesis, and cholesterol synthesis. In addition, binding of the transcription factor Hnf4a to DNAs encoding several key metabolic enzymes was reduced in KO mice, suggesting that adiponectin might regulate hepatic gene expression via Hnf4a. Phenotypically, adiponectin KO mice possessed smaller epididymal fat pads and showed reduced body weight compared with WT mice. When fed a high-fat diet, adiponectin KO mice showed significantly reduced lipid accumulation in the liver. These lipogenic defects are consistent with the down-regulation of lipogenic genes in the KO mice.

  5. The 78-kD Glucose-Regulated Protein Regulates Endoplasmic Reticulum Homeostasis and Distal Epithelial Cell Survival during Lung Development.

    Flodby, Per; Li, Changgong; Liu, Yixin; Wang, Hongjun; Marconett, Crystal N; Laird-Offringa, Ite A; Minoo, Parviz; Lee, Amy S; Zhou, Beiyun

    2016-07-01

    Bronchopulmonary dysplasia (BPD), a chronic lung disease of prematurity, has been linked to endoplasmic reticulum (ER) stress. To investigate a causal role for ER stress in BPD pathogenesis, we generated conditional knockout (KO) mice (cGrp78(f/f)) with lung epithelial cell-specific KO of Grp78, a gene encoding the ER chaperone 78-kD glucose-regulated protein (GRP78), a master regulator of ER homeostasis and the unfolded protein response (UPR). Lung epithelial-specific Grp78 KO disrupted lung morphogenesis, causing developmental arrest, increased alveolar epithelial type II cell apoptosis, and decreased surfactant protein and type I cell marker expression in perinatal lungs. cGrp78(f/f) pups died immediately after birth, likely owing to respiratory distress. Importantly, Grp78 KO triggered UPR activation with marked induction of the proapoptotic transcription factor CCAAT/enhancer-binding proteins (C/EBP) homologous protein (CHOP). Increased expression of genes involved in oxidative stress and cell death and decreased expression of genes encoding antioxidant enzymes suggest a role for oxidative stress in alveolar epithelial cell (AEC) apoptosis. Increased Smad3 phosphorylation and expression of transforming growth factor-β/Smad3 targets Cdkn1a (encoding p21) and Gadd45a suggest that interactions among the apoptotic arm of the UPR, oxidative stress, and transforming growth factor-β/Smad signaling pathways contribute to Grp78 KO-induced AEC apoptosis and developmental arrest. Chemical chaperone Tauroursodeoxycholic acid reduced UPR activation and apoptosis in cGrp78(f/f) lungs cultured ex vivo, confirming a role for ER stress in observed AEC abnormalities. These results demonstrate a key role for GRP78 in AEC survival and gene expression during lung development through modulation of ER stress, and suggest the UPR as a potential therapeutic target in BPD.

  6. Health technology assessment review: Computerized glucose regulation in the intensive care unit--how to create artificial control.

    Hoekstra, Miriam; Vogelzang, Mathijs; Verbitskiy, Evgeny; Nijsten, Maarten W N

    2009-01-01

    Current care guidelines recommend glucose control (GC) in critically ill patients. To achieve GC, many ICUs have implemented a (nurse-based) protocol on paper. However, such protocols are often complex, time-consuming, and can cause iatrogenic hypoglycemia. Computerized glucose regulation protocols may improve patient safety, efficiency, and nurse compliance. Such computerized clinical decision support systems (Cuss) use more complex logic to provide an insulin infusion rate based on previous blood glucose levels and other parameters. A computerized CDSS for glucose control has the potential to reduce overall workload, reduce the chance of human cognitive failure, and improve glucose control. Several computer-assisted glucose regulation programs have been published recently. In order of increasing complexity, the three main types of algorithms used are computerized flowcharts, Proportional-Integral-Derivative (PID), and Model Predictive Control (MPC). PID is essentially a closed-loop feedback system, whereas MPC models the behavior of glucose and insulin in ICU patients. Although the best approach has not yet been determined, it should be noted that PID controllers are generally thought to be more robust than MPC systems. The computerized Cuss that are most likely to emerge are those that are fully a part of the routine workflow, use patient-specific characteristics and apply variable sampling intervals.

  7. Reverse Genetics of Escherichia coli Glycerol Kinase Allosteric Regulation and Glucose Control of Glycerol Utilization In Vivo

    Holtman, C. Kay; Pawlyk, Aaron C.; Meadow, Norman D.; Pettigrew, Donald W.

    2001-01-01

    Reverse genetics is used to evaluate the roles in vivo of allosteric regulation of Escherichia coli glycerol kinase by the glucose-specific phosphocarrier of the phosphoenolpyruvate:glycose phosphotransferase system, IIAGlc (formerly known as IIIglc), and by fructose 1,6-bisphosphate. Roles have been postulated for these allosteric effectors in glucose control of both glycerol utilization and expression of the glpK gene. Genetics methods based on homologous recombination are used to place glp...

  8. A PI-fuzzy logic controller for the regulation of blood glucose level in diabetic patients.

    Ibbini, M

    2006-01-01

    This manuscript investigates different fuzzy logic controllers for the regulation of blood glucose level in diabetic patients. While fuzzy logic control is still intuitive and at a very early stage, it has already been implemented in many industrial plants and reported results are very promising. A fuzzy logic control (FLC) scheme was recently proposed for maintaining blood glucose level in diabetics within acceptable limits, and was shown to be more effective with better transient characteristics than conventional techniques. In fact, FLC is based on human expertise and on desired output characteristics, and hence does not require precise mathematical models. This observation makes fuzzy rule-based technique very suitable for biomedical systems where models are, in general, either very complicated or over-simplistic. Another attractive feature of fuzzy techniques is their insensitivity to system parameter variations, as numerical values of physiological parameters are often not precise and usually vary from patient to another. PI and PID controllers are very popular and are efficiently used in many industrial plants. Fuzzy PI and PID controllers behave in a similar fashion to those classical controllers with the obvious advantage that the controller parameters are time dependant on the range of the control variables and consequently, result in a better performance. In this manuscript, a fuzzy PI controller is designed using a simplified design scheme and then subjected to simulations of the two common diabetes disturbances--sudden glucose meal and system parameter variations. The performance of the proposed fuzzy PI controller is compared to that of the conventional PID and optimal techniques and is shown to be superior. Moreover, the proposed fuzzy PI controller is shown to be more effective than the previously proposed FLC, especially with respect to the overshoot and settling time.

  9. Calcium release channel RyR2 regulates insulin release and glucose homeostasis.

    Santulli, Gaetano; Pagano, Gennaro; Sardu, Celestino; Xie, Wenjun; Reiken, Steven; D'Ascia, Salvatore Luca; Cannone, Michele; Marziliano, Nicola; Trimarco, Bruno; Guise, Theresa A; Lacampagne, Alain; Marks, Andrew R

    2015-05-01

    The type 2 ryanodine receptor (RyR2) is a Ca2+ release channel on the endoplasmic reticulum (ER) of several types of cells, including cardiomyocytes and pancreatic β cells. In cardiomyocytes, RyR2-dependent Ca2+ release is critical for excitation-contraction coupling; however, a functional role for RyR2 in β cell insulin secretion and diabetes mellitus remains controversial. Here, we took advantage of rare RyR2 mutations that were identified in patients with a genetic form of exercise-induced sudden death (catecholaminergic polymorphic ventricular tachycardia [CPVT]). As these mutations result in a "leaky" RyR2 channel, we exploited them to assess RyR2 channel function in β cell dynamics. We discovered that CPVT patients with mutant leaky RyR2 present with glucose intolerance, which was heretofore unappreciated. In mice, transgenic expression of CPVT-associated RyR2 resulted in impaired glucose homeostasis, and an in-depth evaluation of pancreatic islets and β cells from these animals revealed intracellular Ca2+ leak via oxidized and nitrosylated RyR2 channels, activated ER stress response, mitochondrial dysfunction, and decreased fuel-stimulated insulin release. Additionally, we verified the effects of the pharmacological inhibition of intracellular Ca2+ leak in CPVT-associated RyR2-expressing mice, in human islets from diabetic patients, and in an established murine model of type 2 diabetes mellitus. Taken together, our data indicate that RyR2 channels play a crucial role in the regulation of insulin secretion and glucose homeostasis.

  10. Topology mapping of insulin-regulated glucose transporter GLUT4 using computational biology.

    Chakraborty, Chiranjib; Bandyopadhyay, Sanghamitra; Maulik, Ujjwal; Agoramoorthy, Govindasamy

    2013-01-01

    The type 2 diabetes is increasing rapidly around the globe. The primary cause for this is insulin resistance due to the disruption of the insulin signal transduction mechanism. Insulin signal transduction stimulates glucose transport through the glucose transporter GLUT4, by promoting the exocytosis process. Understanding the structural topology of GLUT4 mechanism will increase our understanding of the dynamic activities about glucose transport and its regulation in the membrane environment. However, little is known about the topology of GLUT4. In this article, we have determined the amino acid composition, disulfide topology, structure conformation pattern of GLUT4. The amino acid composition portrays that leucine composition is the highest contributing to 15.5% among all other amino acids. Three cysteine residues such as Cys223, Cys361, and Cys363 were observed and the last two were associated with one disulfide bond formation. We have generated surface cavities to know the clefts/pockets on the surface of this protein that showed few irregular cavities placed mostly in the transmembrane-helical part. Besides, topology mapping of 12 transmembrane-helixes was done to predict N- and O-glycosylation sites and to show the highly glycosylated GLUT4 that includes both N- and O-glycosylation sites. Furthermore, hydrophobic segment and molecular charge distribution were analyzed. This article shows that bioinformatics tools can provide a rapid methodology to predict the topology of GLUT4. It also provides insights into the structural details and structural functioning relationships in the human GLUT4. The results can be of great help to advance future drug development research using GLUT4 as a target protein.

  11. (p)ppGpp, a Small Nucleotide Regulator, Directs the Metabolic Fate of Glucose in Vibrio cholerae.

    Oh, Young Taek; Lee, Kang-Mu; Bari, Wasimul; Raskin, David M; Yoon, Sang Sun

    2015-05-22

    When V. cholerae encounters nutritional stress, it activates (p)ppGpp-mediated stringent response. The genes relA and relV are involved in the production of (p)ppGpp, whereas the spoT gene encodes an enzyme that hydrolyzes it. Herein, we show that the bacterial capability to produce (p)ppGpp plays an essential role in glucose metabolism. The V. cholerae mutants defective in (p)ppGpp production (i.e. ΔrelAΔrelV and ΔrelAΔrelVΔspoT mutants) lost their viability because of uncontrolled production of organic acids, when grown with extra glucose. In contrast, the ΔrelAΔspoT mutant, a (p)ppGpp overproducer strain, exhibited better growth in the presence of the same glucose concentration. An RNA sequencing analysis demonstrated that transcriptions of genes consisting of an operon for acetoin biosynthesis were markedly elevated in N16961, a seventh pandemic O1 strain, but not in its (p)ppGpp(0) mutant during glucose-stimulated growth. Transposon insertion in acetoin biosynthesis gene cluster resulted in glucose-induced loss of viability of the ΔrelAΔspoT mutant, further suggesting the crucial role of acetoin production in balanced growth under glucose-rich environments. Additional deletion of the aphA gene, encoding a negative regulator for acetoin production, failed to rescue the (p)ppGpp(0) mutant from the defective glucose-mediated growth, suggesting that (p)ppGpp-mediated acetoin production occurs independent of the presence of AphA. Overall, our results reveal that (p)ppGpp, in addition to its well known role as a stringent response mediator, positively regulates acetoin production that contributes to the successful glucose metabolism and consequently the proliferation of V. cholerae cells under a glucose-rich environment, a condition that may mimic the human intestine.

  12. Role of FGF19 induced FGFR4 activation in the regulation of glucose homeostasis.

    Wu, Xinle; Li, Yang

    2009-12-09

    FGF19, FGF21, and FGF23 form a unique subfamily of fibroblast growth factors. Because they contain intra-molecular disulfide bonds and show reduced affinity toward heparan sulfate located in the extracellular space, it is thought that, in contrast to other FGFs, they function as endocrine hormones. FGF23 and its co-receptor alphaKlotho are involved in the control of aging, but it is not known if the same holds true for FGF19, which can also signal through alphaKlotho. However, considerable evidence supports a role for FGF19 in controlling various aspects of metabolism. We have recently fully characterized FGF19/FGFR/co-factor interactions and signaling, and in the current manuscript discuss the contribution of the FGF19/FGFR4 axis to bile acid and glucose regulation.

  13. Molecular and immunological characterisation of the glucose regulated protein 78 of Leishmania donovani

    Jensen, A T; Curtis, J; Montgomery, J

    2001-01-01

    To identify novel potential Leishmania vaccine antigens, antibodies from patients with visceral leishmaniasis (VL) were used to isolate clones from a cDNA expression library of L. donovani amastigotes. Glucose Regulated Protein (GRP78), a member of the 70 kDa heat-shock protein family was identif......To identify novel potential Leishmania vaccine antigens, antibodies from patients with visceral leishmaniasis (VL) were used to isolate clones from a cDNA expression library of L. donovani amastigotes. Glucose Regulated Protein (GRP78), a member of the 70 kDa heat-shock protein family...

  14. High activity enables life on a high-sugar diet: blood glucose regulation in nectar-feeding bats.

    Kelm, Detlev H; Simon, Ralph; Kuhlow, Doreen; Voigt, Christian C; Ristow, Michael

    2011-12-01

    High blood glucose levels caused by excessive sugar consumption are detrimental to mammalian health and life expectancy. Despite consuming vast quantities of sugar-rich floral nectar, nectar-feeding bats are long-lived, provoking the question of how they regulate blood glucose. We investigated blood glucose levels in nectar-feeding bats (Glossophaga soricina) in experiments in which we varied the amount of dietary sugar or flight time. Blood glucose levels increased with the quantity of glucose ingested and exceeded 25 mmol l(-1) blood in resting bats, which is among the highest values ever recorded in mammals fed sugar quantities similar to their natural diet. During normal feeding, blood glucose values decreased with increasing flight time, but only fell to expected values when bats spent 75 per cent of their time airborne. Either nectar-feeding bats have evolved mechanisms to avoid negative health effects of hyperglycaemia, or high activity is key to balancing blood glucose levels during foraging. We suggest that the coevolutionary specialization of bats towards a nectar diet was supported by the high activity and elevated metabolic rates of these bats. High activity may have conferred benefits to the bats in terms of behavioural interactions and foraging success, and is simultaneously likely to have increased their efficiency as plant pollinators.

  15. Integrative Genomics Outlines a Biphasic Glucose Response and a ChREBP-RORγ Axis Regulating Proliferation in β Cells

    Schmidt, Søren Fisker; Madsen, Jesper Grud Skat; Frafjord, Kari Østerli

    2016-01-01

    activity in response to glucose in the INS-1E pancreatic β cell line. Our data outline a biphasic response with a first transcriptional wave during which metabolic genes are activated, and a second wave where cell-cycle genes are activated and β cell identity genes are repressed. The glucose......Glucose is an important inducer of insulin secretion, but it also stimulates long-term adaptive changes in gene expression that can either promote or antagonize the proliferative potential and function of β cells. Here, we have generated time-resolved profiles of enhancer and transcriptional...... regulators of the second wave. These include RORγ, the activity of which is important for glucose-induced proliferation of both INS-1E and primary rat β cells....

  16. Dapagliflozin a glucose-regulating drug with diuretic properties in subjects with type 2 diabetes

    Heerspink, H. J. Lambers; de Zeeuw, D.; Wie, L.; Leslie, B.; List, J.

    2013-01-01

    Aims: Sodium-glucose co-transporter 2 (SGLT2) reabsorbs glucose and sodium in the renal proximal tubule. Dapagliflozin, an SGLT2 inhibitor, targets hyperglycaemia in type 2 diabetes by increasing renal glucose excretion. To investigate whether the parallel occurring sodium loss would have diuretic-l

  17. Lycium barbarum L. Polysaccharide (LBP Reduces Glucose Uptake via Down-Regulation of SGLT-1 in Caco2 Cell

    Huizhen Cai

    2017-02-01

    Full Text Available Lycium barbarum L. polysaccharide (LBP is prepared from Lycium barbarum L. (L. barbarum, which is a traditional Chinese medicine. LPB has been shown to have hypoglycemic effects. In order to gain some mechanistic insights on the hypoglycemic effects of LBP, we investigated the uptake of LBP and its effect on glucose absorption in the human intestinal epithelial cell line Caco2 cell. The uptake of LBP through Caco2 cell monolayer was time-dependent and was inhibited by phloridzin, a competitive inhibitor of SGLT-1. LPB decreased the absorption of glucose in Caco2 cell, and down-regulated the expression of SGLT-1. These results suggest that LBP might be transported across the human intestinal epithelium through SGLT-1 and it inhibits glucose uptake via down-regulating SGLT-1.

  18. The mammalian AMP-activated protein kinase complex mediates glucose regulation of gene expression in the yeast Saccharomyces cerevisiae.

    Ye, Tian; Bendrioua, Loubna; Carmena, David; García-Salcedo, Raúl; Dahl, Peter; Carling, David; Hohmann, Stefan

    2014-06-01

    The AMP-activated protein kinase (AMPK) controls energy homeostasis in eukaryotic cells. Here we expressed hetero-trimeric mammalian AMPK complexes in a Saccharomyces cerevisiae mutant lacking all five genes encoding yeast AMPK/SNF1 components. Certain mammalian complexes complemented the growth defect of the yeast mutant on non-fermentable carbon sources. Phosphorylation of the AMPK α1-subunit was glucose-regulated, albeit not by the Glc7-Reg1/2 phosphatase, which performs this function on yeast AMPK/SNF1. AMPK could take over SNF1 function in glucose derepression. While indirectly acting anti-diabetic drugs had no effect on AMPK in yeast, compound 991 stimulated α1-subunit phosphorylation. Our results demonstrate a remarkable functional conservation of AMPK and that glucose regulation of AMPK may not be mediated by regulatory features of a specific phosphatase.

  19. Two-Component Signal Transduction System SaeRS Positively Regulates Staphylococcus epidermidis Glucose Metabolism

    Qiang Lou

    2014-01-01

    Full Text Available Staphylococcus epidermidis, which is a causative pathogen of nosocomial infection, expresses its virulent traits such as biofilm and autolysis regulated by two-component signal transduction system SaeRS. In this study, we performed a proteomic analysis of differences in expression between the S. epidermidis 1457 wild-type and saeRS mutant to identify candidates regulated by saeRS using two-dimensional gel electrophoresis (2-DE combined with matrix-assisted laser desorption/lonization mass spectrometry (MALDI-TOF-MS. Of 55 identified proteins that significantly differed in expression between the two strains, 15 were upregulated and 40 were downregulated. The downregulated proteins included enzymes related to glycolysis and TCA cycle, suggesting that glucose is not properly utilized in S. epidermidis when saeRS was deleted. The study will be helpful for treatment of S. epidermidis infection from the viewpoint of metabolic modulation dependent on two-component signal transduction system SaeRS.

  20. RNAi silenced Dd-grp94 (Dictyostelium discoideum glucose-regulated protein 94 kDa) cell lines in Dictyostelium exhibit marked reduction in growth rate and delay in development.

    Baviskar, Sandhya N; Shields, Malcolm S

    2010-01-01

    Glucose-regulated 94 kDa protein (Grp94) is a resident of the endoplasmic reticulum (ER) of multicellular eukaryotes. It is a constitutively expressed protein that is overexpressed in certain abnormal conditions of the cell such as depletion of glucose and calcium, and low oxygen and pH. The protein is also implicated in diseased conditions like cancer and Alzheimer's disease. In this study, the consequences of downregulation of Grp94 were investigated at both unicellular and multicellular stages of Dictyostelium discoideum. Previous studies have shown the expression of Dd-Grp94 (Dictyostelium discoideum glucose-regulated 94 kDa protein) in wild-type cells varies during development, and overexpression of Dd-Grp94 leads to abnormal cell shape and inhibition of development (i.e., formation of fruiting bodies). Grp94 is a known calcium binding protein and an efficient calcium buffer. Therefore, in the present study we hypothesized that downregulation of Dd-Grp94 protein would affect Dictyostelium cell structure, growth, and development. We found that Dd-grp94 RNAi recombinants exhibited reduced growth rate, cell size, and a subtle change in cell motility compared to the parental cells. The recombinants also exhibited a delay in development and small fruiting bodies. These results establish that Dd-grp94 plays a crucial role in determining normal cell structure, growth and differentiation.

  1. Tctex1d2 Is a Negative Regulator of GLUT4 Translocation and Glucose Uptake.

    Shimoda, Yoko; Okada, Shuichi; Yamada, Eijiro; Pessin, Jeffrey E; Yamada, Masanobu

    2015-10-01

    Tctex1d2 (Tctex1 domain containing 2) is an open reading frame that encodes for a functionally unknown protein that contains a Tctex1 domain found in dynein light chain family members. Examination of gene expression during adipogenesis demonstrated a marked increase in Tctex1d2 protein expression that was essentially undetectable in preadipocytes and markedly induced during 3T3-L1 adipocyte differentiation. Tctex1d2 overexpression significantly inhibited insulin-stimulated glucose transporter 4 (GLUT4) translocation and 2-deoxyglucose uptake. In contrast, Tctex1d2 knockdown significantly increased insulin-stimulated GLUT4 translocation and 2-deoxyglucose uptake. However, acute insulin stimulation (up to 30 min) in 3T3-L1 adipocytes with overexpression or knockdown of Tctex1d2 had no effect on Akt phosphorylation, a critical signal transduction target required for GLUT4 translocation. Although overexpression of Tctex1d2 had no significant effect on GLUT4 internalization, Tctex1d2 was found to associate with syntaxin 4 in an insulin-dependent manner and inhibit Doc2b binding to syntaxin 4. In addition, glucose-dependent insulinotropic polypeptide rescued the Tctex1d2 inhibition of insulin-stimulated GLUT4 translocation by suppressing the Tctex1d2-syntaxin 4 interaction and increasing Doc2b-Synatxin4 interactions. Taking these results together, we hypothesized that Tctex1d2 is a novel syntaxin 4 binding protein that functions as a negative regulator of GLUT4 plasma membrane translocation through inhibition of the Doc2b-syntaxin 4 interaction.

  2. Age-related differences in glucose abnormalities in women with ST-elevation myocardial infarction submitted to percutaneous coronary intervention: a single-center experience.

    Lazzeri, Chiara; Gensini, Gian Franco; D'Alfonso, Maria Grazia; Chiostri, Marco; Attanà, Paola; Valente, Serafina

    2015-05-01

    No datum is so far available on the relation between age and the acute glucose response to stress in women with ST-elevation myocardial infarction (STEMI) treated with percutaneous coronary intervention (PCI).We evaluated the age-related differences in the acute glucose response in 373 STEMI women submitted to PCI. The oldest women, when compared to the other age subgroups, showed the higher admission and peak glycemia (P acute glucose response to myocardial injury since older women showed the higher admission glucose values and the poorer in-hospital glucose control, in the lack of differences of insulin-resistance incidence. Glucose values were independent predictors of in-hospital mortality, but were not related to long-term survival.

  3. Drosophila adiponectin receptor in insulin producing cells regulates glucose and lipid metabolism by controlling insulin secretion.

    Su-Jin Kwak

    Full Text Available Adipokines secreted from adipose tissue are key regulators of metabolism in animals. Adiponectin, one of the adipokines, modulates pancreatic beta cell function to maintain energy homeostasis. Recently, significant conservation between Drosophila melanogaster and mammalian metabolism has been discovered. Drosophila insulin like peptides (Dilps regulate energy metabolism similarly to mammalian insulin. However, in Drosophila, the regulatory mechanism of insulin producing cells (IPCs by adipokine signaling is largely unknown. Here, we describe the discovery of the Drosophila adiponectin receptor and its function in IPCs. Drosophila adiponectin receptor (dAdipoR has high homology with the human adiponectin receptor 1. The dAdipoR antibody staining revealed that dAdipoR was expressed in IPCs of larval and adult brains. IPC- specific dAdipoR inhibition (Dilp2>dAdipoR-Ri showed the increased sugar level in the hemolymph and the elevated triglyceride level in whole body. Dilps mRNA levels in the Dilp2>dAdipoR-Ri flies were similar with those of controls. However, in the Dilp2>dAdipoR-Ri flies, Dilp2 protein was accumulated in IPCs, the level of circulating Dilp2 was decreased, and insulin signaling was reduced in the fat body. In ex vivo fly brain culture with the human adiponectin, Dilp2 was secreted from IPCs. These results indicate that adiponectin receptor in insulin producing cells regulates insulin secretion and controls glucose and lipid metabolism in Drosophila melanogaster. This study demonstrates a new adipokine signaling in Drosophila and provides insights for the mammalian adiponectin receptor function in pancreatic beta cells, which could be useful for therapeutic application.

  4. Involvement of AMPK in regulating the degradation of MAD2B under high glucose in neuronal cells.

    Meng, Xianfang; Chu, Guangpin; Ye, Chen; Tang, Hui; Qiu, Ping; Hu, Yue; Li, Man; Zhang, Chun

    2016-12-13

    Although our recent study has demonstrated that mitotic spindle assembly checkpoint protein (MAD2B) mediates high glucose-induced neuronal apoptosis, the mechanisms for MAD2B degradation under hyperglycaemia have not yet been elucidated. In this study, we first found that the activation of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) was decreased in neurons, accompanied with the increased expression of MAD2B. Mechanistically, we demonstrated that activation of AMPK with its activators such as AICAR and metformin decreased the expression of MAD2B, indicating a role of AMPK in regulating the expression of MAD2B. Moreover, activation of AMPK prevented neuronal cells from high glucose-induced injury as demonstrated by the reduced expression of cyclin B1 and percentage of apoptosis as detected by TUNEL. We further found that when total protein synthesis was suppressed by chlorhexidine, the degradation of MAD2B was slower in high glucose-treated neurons and was mainly dependent on the ubiquitin-proteasome system. Finally, it was indicated that high glucose inhibited the ubiquitination of MAD2B, which could be reversed by activation of AMPK. Collectively, this study demonstrates that AMPK acts as a key regulator of MAD2B expression, suggesting that activation of AMPK signalling might be crucial for the treatment of high glucose-induced neuronal injury.

  5. Activin B regulates islet composition and islet mass but not whole body glucose homeostasis or insulin sensitivity

    Bonomi, Lara; Brown, Melissa; Ungerleider, Nathan; Muse, Meghan; Matzuk, Martin M.

    2012-01-01

    Based on the phenotype of the activin-like kinase-7 (ALK7)-null mouse, activins A and B have been proposed to play distinct roles in regulating pancreatic islet function and glucose homeostasis, with activin A acting to enhance islet function and insulin release while activin B antagonizes these actions. We therefore hypothesized that islets from activin B-null (BBKO) mice would have enhanced glucose-stimulated insulin secretion. In addition, we hypothesized that this enhanced islet function would translate into increased whole body glucose tolerance. We tested these hypotheses by analyzing glucose homeostasis, insulin secretion, and islet function in BBKO mice. No differences were observed in fasting glucose or insulin levels, glucose tolerance, or insulin sensitivity compared with weight-matched young or older males. Similarly, there were no significant differences in insulin secretion comparing islets from WT or BBKO males at either age. However, BBKO islets were more sensitive to activin A, myostatin (MSTN), and follistatin (FST) treatments, so that activin A and FST inhibited and MSTN enhanced glucose stimulated insulin secretion. While mean islet area and the distribution of islet areas were not different between the genotypes, islet mass, islet number, and the proportion of α-cells/islet were significantly reduced in BBKO islets. These results indicate that activin B does not antagonize activin A to influence whole body glucose homeostasis or β-cell function but does influence islet mass and proportion of α-cells/islet. Therefore, loss of activin B signaling alone does not account for the ALK7-null phenotype, but activin B may have important roles in modulating islet mass, islet number, and the cellular composition of islets. PMID:22739106

  6. Impact of L-FABP and glucose on polyunsaturated fatty acid induction of PPARα-regulated β-oxidative enzymes.

    Petrescu, Anca D; Huang, Huan; Martin, Gregory G; McIntosh, Avery L; Storey, Stephen M; Landrock, Danilo; Kier, Ann B; Schroeder, Friedhelm

    2013-02-01

    Liver fatty acid binding protein (L-FABP) is the major soluble protein that binds very-long-chain n-3 polyunsaturated fatty acids (n-3 PUFAs) in hepatocytes. However, nothing is known about L-FABP's role in n-3 PUFA-mediated peroxisome proliferator activated receptor-α (PPARα) transcription of proteins involved in long-chain fatty acid (LCFA) β-oxidation. This issue was addressed in cultured primary hepatocytes from wild-type, L-FABP-null, and PPARα-null mice with these major findings: 1) PUFA-mediated increase in the expression of PPARα-regulated LCFA β-oxidative enzymes, LCFA/LCFA-CoA binding proteins (L-FABP, ACBP), and PPARα itself was L-FABP dependent; 2) PPARα transcription, robustly potentiated by high glucose but not maltose, a sugar not taken up, correlated with higher protein levels of these LCFA β-oxidative enzymes and with increased LCFA β-oxidation; and 3) high glucose altered the potency of n-3 relative to n-6 PUFA. This was not due to a direct effect of glucose on PPARα transcriptional activity nor indirectly through de novo fatty acid synthesis from glucose. Synergism was also not due to glucose impacting other signaling pathways, since it was observed only in hepatocytes expressing both L-FABP and PPARα. Ablation of L-FABP or PPARα as well as treatment with MK886 (PPARα inhibitor) abolished/reduced PUFA-mediated PPARα transcription of these genes, especially at high glucose. Finally, the PUFA-enhanced L-FABP distribution into nuclei with high glucose augmentation of the L-FABP/PPARα interaction reveals not only the importance of L-FABP for PUFA induction of PPARα target genes in fatty acid β-oxidation but also the significance of a high glucose enhancement effect in diabetes.

  7. Involvement of atypical protein kinase C in the regulation of cardiac glucose and long-chain fatty acid uptake

    Daphna D.J. Habets

    2012-09-01

    Full Text Available Aim: The signaling pathways involved in the regulation of cardiac GLUT4 translocation/glucose uptake and CD36 translocation/ long-chain fatty acid uptake are not fully understood. We compared in heart/muscle-specific PKC-λ knockout mice the roles of atypical PKCs (PKC-ζ and PKC-λ in regulating cardiac glucose and fatty acid uptake. Results: Neither insulin-stimulated nor AMPK-mediated glucose and fatty acid uptake were inhibited upon genetic PKC-λ ablation in cardiomyocytes. In contrast, myristoylated PKC-ζ pseudosubstrate inhibited both insulin-stimulated and AMPK-mediated glucose and fatty acid uptake by >80% in both wild-type and PKC-λ-knockout cardiomyocytes. In PKC-λ knockout cardiomyocytes, PKC-ζ is the sole remaining atypical PKC isoform, and its expression level is not different from wild-type cardiomyocytes, in which it contributes to 29% and 17% of total atypical PKC expression and phosphorylation, respectively. Conclusion: Taken together, atypical PKCs are necessary for insulin-stimulated and AMPK-mediated glucose uptake into the heart, as well as for insulin-stimulated and AMPK-mediated fatty acid uptake. However, the residual PKC-ζ activity in PKC-λ-knockout cardiomyocytes is sufficient to allow optimal stimulation of glucose and fatty acid uptake, indicating that atypical PKCs are necessary but not rate-limiting in the regulation of cardiac substrate uptake and that PKC-λ and PKC-ζ have interchangeable functions in these processes.

  8. Metformin-induced regulation of the intestinal D-glucose transporters.

    Sakar, Yassine; Meddah, Bouchra; El Abbes Faouzi, Moulay; Cherrah, Yahia; Bado, André; Ducroc, Robert

    2010-01-01

    International audience; Metformin is an orally administered drug that lowers blood glucose and improves insulin sensitivity in patients with non insulin-dependent diabetes. Although the antihyperglycemic effect of metformin has been extensively studied, its cellular mechanism(s) of action (including the effect on enterocyte) remains to be defined. This study was designed to examine the effect of metformin on glucose transporters in enterocyte. Na(+)-dependent glucose transporter-1 (SGLT-1) ac...

  9. A RAS oncogene imparts growth factor independence to myeloid cells that abnormally regulate protein kinase C: a nonautocrine transformation pathway.

    Boswell, H S; Nahreini, T S; Burgess, G S; Srivastava, A; Gabig, T G; Inhorn, L; Srour, E F; Harrington, M A

    1990-06-01

    The factor-dependent cell line FDC-P1 has been utilized as a model of interleukin 3 (IL-3)-dependent myeloid cell proliferation. However, it has been recently observed that active phorbol esters (e.g., phorbol 12-myristate 13-acetate) may entirely replace IL-3 to promote its proliferation. These observations reveal abnormal regulation of protein kinase C (pkC) (absence of downregulation or overexpression). This property allowed a test of the hypothesis that the T24 RAS (codon 12) oncogene acts by constitutive and persistent pkC activation, driving proliferation. FDC-P1 cells were transfected by electroporation with the T24 RAS-containing vector pAL 8, or with a control vector pSVX Zip Neo, and neomycin-resistant clones were selected. Multiple RAS-transfectant clones were categorized for their growth factor requirement and incorporation of the 6.6-kb human mutant H-RAS genome. IL-3-independent clones had incorporated multiple (more than two) copies of the entire 6.6-kb RAS genome. The incorporation of multiple 6.6-kb RAS genomes was correlated with high-level p21 RAS expression. No evidence for autostimulatory growth factor production by clones containing the RAS oncogene was observed. Thus, acquisition of growth factor independence in myeloid cells by abundant expression of a RAS oncogene is linked, in part, to abnormal regulation of pkC, which acts as a collaborating oncogene.

  10. Ultrastructural abnormalities in CA1 hippocampus caused by deletion of the actin regulator WAVE-1.

    Diána Hazai

    Full Text Available By conveying signals from the small GTPase family of proteins to the Arp2/3 complex, proteins of the WAVE family facilitate actin remodeling. The WAVE-1 isoform is expressed at high levels in brain, where it plays a role in normal synaptic processing, and is implicated in hippocampus-dependent memory retention. We used electron microscopy to determine whether synaptic structure is modified in the hippocampus of WAVE-1 knockout mice, focusing on the neuropil of CA1 stratum radiatum. Mice lacking WAVE-1 exhibited alterations in the morphology of both axon terminals and dendritic spines; the relationship between the synaptic partners was also modified. The abnormal synaptic morphology we observed suggests that signaling through WAVE-1 plays a critical role in establishing normal synaptic architecture in the rodent hippocampus.

  11. Oxygen-glucose deprivation regulates BACE1 expression through induction of autophagy in Neuro-2a/APP695 cells

    Rong-fu Chen

    2015-01-01

    Full Text Available Our previous findings have demonstrated that autophagy regulation can alleviate the decline of learning and memory by eliminating deposition of extracellular beta-amyloid peptide (Aβ in the brain after stroke, but the exact mechanism is unclear. It is presumed that the regulation of beta-site APP-cleaving enzyme 1 (BACE1, the rate-limiting enzyme in metabolism of Aβ, would be a key site. Neuro-2a/amyloid precursor protein 695 (APP695 cell models of cerebral ischemia were established by oxygen-glucose deprivation to investigate the effects of Rapamycin (an autophagy inducer or 3-methyladenine (an autophagy inhibitor on the expression of BACE1. Either oxygen-glucose deprivation or Rapamycin down-regulated the expression of BACE1 while 3-methyladenine up-regulated BACE1 expression. These results confirm that oxygen-glucose deprivation down-regulates BACE1 expression in Neuro-2a/APP695 cells through the introduction of autophagy.

  12. Oxygen-glucose deprivation regulates BACE1 expression through induction of autophagy in Neuro-2a/APP695 cells

    Rong-fu Chen; Xiao-jiang Sun; Ting Zhang; Yin-yi Sun; Ya-meng Sun; Wen-qi Chen; Nan Shi; Fang Shen; Yan Zhang; Kang-yong Liu

    2015-01-01

    Our previous ifndings have demonstrated that autophagy regulation can alleviate the decline of learning and memory by eliminating deposition of extracellular beta-amyloid peptide (Aβ) in the brain after stroke, but the exact mechanism is unclear. It is presumed that the regulation of beta-site APP-cleaving enzyme 1 (BACE1), the rate-limiting enzyme in metabolism of Aβ, would be a key site. Neuro-2a/amyloid precursor protein 695 (APP695) cell models of cerebral isch-emia were established by oxygen-glucose deprivation to investigate the effects of Rapamycin (an autophagy inducer) or 3-methyladenine (an autophagy inhibitor) on the expression of BACE1. Either oxygen-glucose deprivation or Rapamycin down-regulated the expression of BACE1 while 3-methyladenine up-regulated BACE1 expression. These results confirm that oxygen-glucose deprivation down-regulates BACE1 expression in Neuro-2a/APP695 cells through the introduc-tion of autophagy.

  13. Yeast glucose pathways converge on the transcriptional regulation of trehalose biosynthesis

    Apweiler Eva

    2012-06-01

    Full Text Available Abstract Background Cellular glucose availability is crucial for the functioning of most biological processes. Our understanding of the glucose regulatory system has been greatly advanced by studying the model organism Saccharomyces cerevisiae, but many aspects of this system remain elusive. To understand the organisation of the glucose regulatory system, we analysed 91 deletion mutants of the different glucose signalling and metabolic pathways in Saccharomyces cerevisiae using DNA microarrays. Results In general, the mutations do not induce pathway-specific transcriptional responses. Instead, one main transcriptional response is discerned, which varies in direction to mimic either a high or a low glucose response. Detailed analysis uncovers established and new relationships within and between individual pathways and their members. In contrast to signalling components, metabolic components of the glucose regulatory system are transcriptionally more frequently affected. A new network approach is applied that exposes the hierarchical organisation of the glucose regulatory system. Conclusions The tight interconnection between the different pathways of the glucose regulatory system is reflected by the main transcriptional response observed. Tps2 and Tsl1, two enzymes involved in the biosynthesis of the storage carbohydrate trehalose, are predicted to be the most downstream transcriptional components. Epistasis analysis of tps2Δ double mutants supports this prediction. Although based on transcriptional changes only, these results suggest that all changes in perceived glucose levels ultimately lead to a shift in trehalose biosynthesis.

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

    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.

  15. 妊娠期糖代谢异常对妊娠结局影响%Influence of abnormal glucose tolerance during pregnancy on pregnanty outcome

    王娇; 许榕仙; 张雪芹; 李健

    2012-01-01

    Objective To investigate the impact of gestational diabetes mellitus (GDM) and gestational impaired glucose tolerance (GIGT) on pregnant women and newborns. Methods Totally 250 pregnant women hospitalized for their deliveries and diagnosed with GDM( 105) or GIGT( 145) were recruited in the study. And 234 pregnant women witti normal blood glucose level were taken as control group at the same time. The pregnancy outcomes of the three groups were recorded and analyzed. Results There were significant differences among the three groups in the incidences of hepatitis B virus (HBV) positive (P - 0. 009) , caesarean birth (P = 0. 000), gestational hypertension (P = 0. 002), intrahepatic cholestasis of pregnancy (P = 0. 004), preterm delivery (P = 0.027 ) , small-for-date infant (P = 0. 011), neonatal hypoglycemia (P = 0. 007), neonatal pneumonia (P = 0. 001), and neonate hospitalization (P = 0. 000) among the three groups. Compared with those of the control group, there were significantly increased risks for HBV positive (P =0. 041) , caesarean birth ( P = 0. 000) .gestational hypertension ( P =0.001) , intrahepatic cholestasis of pregnancy (P = 0.009),preterm delivery(/5=0. 012) ,small-for-date infant(P =0. 019) .neonatal hypoglycemia (P = 0, 03) .neonatal pneumonia( P = 0. 000) , and neonatal intensive care unit (NICU) admission (P = 0. 000) in the GDM group. The pregnant women in GIGT group showed higher risks of HBV positive ( P = 0. 041) , caesarean birth ( P = 0. 000) , gestational hypertension (P = 0. 021) , intrahepatic cholestasis of pregnancy ( P - 0. 021) , preterm delivery (P = 0. 048 ) , neonatal hypoglycemia( P = 0. 021), neonatal pneumonia ( P = 0. 004), and NICU admission (P = 0. 000). Conclusion GDM and GIGT could cause undesirable pregnancy outcomes. The perinatal screening for gestational abnormal glucose metabolism and standardized treatment for GDM and GIGT should be strengthened to improve pregnanty outcomes a-mong the wonen.%目的 研究妊娠期

  16. ANALYSIS OF THE PREVALENCE RATE AND RISK FACTOR OF ABNORMAL GLUCOSE METABOLISM IN CADRE MEMBERS%副厅级以上干部人群糖代谢异常患病情况及危险因素分析

    杨英; 曾莉; 吴琴琴; 张帆; 秦恳; 邹天富; 黄燕; 王佑娟

    2011-01-01

    [Objective]To realize the prevalence rate and analyse the risk factor of abnormal glucose metabolism in cadre members in Sichuan province to provide scientific evidence to set up the preventive strategies.[Methods]Information were collected in the cadre menbers checked in our hospital and medical examination including height, weight, blood pressure, oral glucose tolerance test (OGTT) and biochemical test, etc.Abnormal glucose metabolism was based on the diagnosis criteria in 1999.The relationships between risk factors and IGR were analyzed by unconditional multivariate logistic regression.[Results](1) The detection rate of total abnormal glucose metabolism was 33.2%, with 7.3% of DM.The detection rate of IGR was 25.8%.The detection rate of I-IFG, I-IGT, IFG/IGT was 1.9%, 20.3%, 3.6%, respectively, (2) Compared with the NGT group, the IGR group had higher body mass index (BMI) , waist-to-hip ratio (WHR), triglyceride (TG) , systolic blood pressure (SBP), serum creatinine (Cr) , lower high density lipoprotein with statistical significance (P < 0.01 or P < 0.05).(3) Age, BMI, WHR, TG were risk factors of abnormal glucose metabolism (P< 0.01 or P< 0.05).[Conclusion]The abnormality rare of glucose metabolism in cadre menbers in Sichuan province is high.Age, BMI, WHR, TG are main risk factors of abnormal glucose metabolism.%[目的]了解四川省干部人群糖代谢异常的患病情况并分析其危险因素,为制定适宜的干预措施提供依据.[方法]选用2009年在某院健康体检的干部人群,分别进行身高体重血压测定、糖耐量试验(OGTT)及生化指标检查等.糖代谢异常的诊断依据WHO1999年糖尿病的诊断标准.运用多因素非条件Logistic回归分析,探讨影响糖代谢异常发生的危险因素.[结果](1)糖代谢异常总检出率为33.2%,其中DM的检出率7.3%,糖调节受损(IGR,糖尿病前期)总的检出率为25.8%,IGR各亚组的检出率分别为:I-IFG1.9%、I-IGT20.3%及IFG/IGT3

  17. High glucose induced oxidative stress and apoptosis in cardiac microvascular endothelial cells are regulated by FoxO3a.

    Chaoming Peng

    Full Text Available AIM: Cardiac microvascular endothelial cells (CMECs dysfunction contributes to cardiovascular complications in diabetes, whereas, the underlying mechanism is not fully clarified. FoxO transcription factors are involved in apoptosis and reactive oxygen species (ROS production. Therefore, the present study was designed to elucidate the potential role of FoxO3a on the CMECs injury induced by high glucose. MATERIALS AND METHODS: CMECs were isolated from hearts of adult rats and cultured in normal or high glucose medium for 6 h, 12 h and 24 h respectively. To down-regulate FoxO3a expression, CMECs were transfected with FoxO3a siRNA. ROS accumulation and apoptosis in CMECs were assessed by dihydroethidine (DHE staining and TUNEL assay respectively. Moreover, the expressions of Akt, FoxO3a, Bim and BclxL in CMECs were assessed by Western blotting assay. RESULTS: ROS accumulation in CMECs was significantly increased after high glucose incubation for 6 to 24 h. Meanwhile, high glucose also increased apoptosis in CMECs, correlated with decreased the phosphorylation expressions of Akt and FoxO3a. Moreover, high glucose incubation increased the expression of Bim, whereas increased anti-apoptotic protein BclxL. Furthermore, siRNA target FoxO3a silencing enhanced the ROS accumulation, whereas suppressed apoptosis in CMECs. FoxO3a silencing also abolished the disturbance of Bcl-2 proteins induced by high glucose in CMECs. CONCLUSION: Our data provide evidence that high glucose induced FoxO3a activation which suppressed ROS accumulation, and in parallel, resulted in apoptosis of CMECs.

  18. Glucose and angiotensin II-derived endothelial extracellular vesicles regulate endothelial dysfunction via ERK1/2 activation.

    Taguchi, Kumiko; Hida, Mari; Narimatsu, Haruka; Matsumoto, Takayuki; Kobayashi, Tsuneo

    2017-02-01

    In various diseases, including diabetes, extracellular vesicles (EVs) have been detected in circulation and tissues. EVs are small membrane vesicles released from various cell types under varying conditions. Recently, endothelial cell-derived EVs (EEVs) were identified as a marker of endothelial dysfunction in diabetes, but the ensuing mechanisms remain poorly understood. In this study, we dissected the ensuing pathways with respect to nitric oxide (NO) production under the condition of type 2 diabetes. Human umbilical vein endothelial cells (HUVECs) were stimulated with glucose alone and with glucose in combination with angiotensin II (Ang II) for 48 h. In supernatants from glucose + Ang II-stimulated HUVECs, release of EEVs was assessed using Western blotting with an anti-CD144 antibody. EEV release was significantly increased after stimulation of HUVECs, and high glucose + Ang II-derived EEVs impaired ACh-induced vascular relaxation responses and NO production in mice aortic rings. Furthermore, high glucose + Ang II-derived EEVs induced ERK1/2 signalling and decreased endothelial NO synthase (eNOS) protein expression in mice aortas. Furthermore, in the presence of the MEK/ERK1/2 inhibitor PD98059, high glucose plus Ang II treatment stimulated EEVs in HUVECs and those EEVs prevented the impairments of ACh-induced relaxation and NO production in mice aortas. These data strongly indicate that high glucose and Ang II directly affect endothelial cells and the production of EEVs; the resultant EEVs aggravate endothelial dysfunction by regulating eNOS protein levels and ERK1/2 signalling in mice aortas.

  19. 妊娠期糖代谢异常162例母儿预后分析%Analysis on the outcomes of 162 maternal and fetal with abnormal glucose metabolism during pregnancy

    徐亚萍

    2011-01-01

    Objective: To investigate the effect of abnormal glucose metabolism during pregnancy on maternal and fetal outcomes.Methods: 162 patients were diagnosed definitely in our hospital from June 2003 to August 2007.They were divided into Gestational Diabetes Mellitus (GDM) group (58 cases) and gestational impaired glucose tolerance (GIGT) group (104 cases).150 pregnant women of normal blood glucose were taken as normal glucose tolerance (GNGT) group, maternal and fetal outcomes were compared in three groups.Results: The incidences of postpartum hemorrhage, cesarean section, pregnancy - induced hypertension, polyhydramnios, fatal macrosomia, premature delivery, neonatal hypoglycemia were higher in GDM group than in GNGT group (P < 0.05 ).The incidences of cesarean section, polyhydramnios, fatal acrosomia were higher in the GIGT group than in GNGT group (P <0.05).Conclusion: Abnormal glucose metabolism during pregnancy can produce adverse effect on mothers and neonates.It is very important to positive treatment the pregnant women of abnormal glucose metabolism during pregnancy.%目的:探讨妊娠期糖代谢异常对母儿预后的影响.方法:2003年6月~2007年8月在大同市第一人民医院诊断为妊娠期糖代谢异常的孕妇162例,其中妊娠期糖尿病(GDM)组58例,妊娠期糖耐量减低(GIGT)组104例,另选择150例血糖值正常孕妇作为血糖正常(GNGT)组,比较3组的母儿预后.结果:GDM组孕妇产后即时出血、剖宫产、妊娠期高血压疾病、羊水过多、巨大儿、早产儿和新生儿低血糖的发生率均显著高于GNGT组(P<0.05);GIGT组剖宫产、羊水过多、巨大儿的发生率显著高于GNGT组(P<0.05).结论:妊娠期糖代谢异常对孕产妇和围生儿的预后有不良影响,应对妊娠期糖代谢异常的孕产妇进行积极干预.

  20. Chronic stress, inflammation, and glucose regulation in U.S. Hispanics from the HCHS/SOL Sociocultural Ancillary Study.

    McCurley, Jessica L; Mills, Paul J; Roesch, Scott C; Carnethon, Mercedes; Giacinto, Rebeca E; Isasi, Carmen R; Teng, Yanping; Sotres-Alvarez, Daniela; Llabre, Maria M; Penedo, Frank J; Schneiderman, Neil; Gallo, Linda C

    2015-08-01

    Diabetes prevalence is rising rapidly, and diabetes disproportionately affects Hispanics and other underserved groups. Chronic stress may contribute to diabetes risk, but few studies have examined this relationship in U.S. Hispanics. We examined associations of chronic stress with fasting glucose, glucose tolerance, and glycosylated hemoglobin (HbA1c) in Hispanics without diabetes, and also assessed indirect effects of stress through inflammation (CRP). Participants were 3,923 men and women, aged 18-74, without diabetes, from the four U.S. field centers (Bronx, NY; Chicago, IL; Miami, FL; San Diego, CA) of the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) Sociocultural Ancillary study. Participants completed a measure of chronic life stress and a physical exam with oral glucose tolerance test. In a multivariate regression analysis with adjustment for demographic and health covariates, higher chronic stress was related to higher fasting glucose (standardized regression coefficient: β = .09, p effect of stress through inflammation. Findings suggest that higher chronic stress is associated with poorer glucose regulation in Hispanics, prior to the onset of a clinical diabetes diagnosis.

  1. Dibenzoylmethane exerts metabolic activity through regulation of AMP-activated protein kinase (AMPK-mediated glucose uptake and adipogenesis pathways.

    Nami Kim

    Full Text Available Dibenzoylmethane (DBM has been shown to exert a variety of beneficial effects on human health. However, the mechanism of action is poorly understood. In this study, DBM increased phosphorylation of AMP-activated protein kinase (AMPK and stimulated glucose uptake in a skeletal muscle cell line. Both knockdown of AMPK with siRNA and inhibition with AMPK inhibitor blocked DBM-induced glucose uptake. DBM increased the concentration of intracellular calcium and glucose uptake due to DBM was abolished by STO-609 (a calcium/calmodulin-dependent protein kinase inhibitor. DBM stimulated phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK, which was blocked by pretreatment with compound C, an AMPK inhibitor. The expression of glucose transporter type 4 (GLUT4 was increased by DBM. The translocation of GLUT4 to the plasma membrane was also increased by DBM in AMPK dependently. In addition, DBM suppressed weight gain and prevented fat accumulation in the liver and abdomen in mice fed a high-fat diet. In pre-adipocyte cells, DBM decreased the activity of acetyl-CoA carboxylase (ACC, the rate-limiting enzyme of fatty acid synthesis. Expression of the adipogenic gene, fatty acid synthase (FAS, was suppressed by DBM in an AMPK-dependent manner. These results showed that the beneficial metabolic effects of DBM might be due to regulation of glucose uptake via AMPK in skeletal muscle and inhibition of adipogenesis in pre-adipocytes.

  2. Performance Analysis of Fuzzy-PID Controller for Blood Glucose Regulation in Type-1 Diabetic Patients.

    Yadav, Jyoti; Rani, Asha; Singh, Vijander

    2016-12-01

    This paper presents Fuzzy-PID (FPID) control scheme for a blood glucose control of type 1 diabetic subjects. A new metaheuristic Cuckoo Search Algorithm (CSA) is utilized to optimize the gains of FPID controller. CSA provides fast convergence and is capable of handling global optimization of continuous nonlinear systems. The proposed controller is an amalgamation of fuzzy logic and optimization which may provide an efficient solution for complex problems like blood glucose control. The task is to maintain normal glucose levels in the shortest possible time with minimum insulin dose. The glucose control is achieved by tuning the PID (Proportional Integral Derivative) and FPID controller with the help of Genetic Algorithm and CSA for comparative analysis. The designed controllers are tested on Bergman minimal model to control the blood glucose level in the facets of parameter uncertainties, meal disturbances and sensor noise. The results reveal that the performance of CSA-FPID controller is superior as compared to other designed controllers.

  3. 丙型肝炎病毒感染致糖代谢异常的相关机制研究进展%Progress in mechanisms of abnormal glucose metabolism in patients with hepatitis C virus infection

    康姚洁(综述); 王煊(审校)

    2014-01-01

    丙型肝炎病毒感染者糖代谢异常的发病率有不同程度的升高。除了肝源性糖尿病共有的发病机制外,胰岛β细胞功能的减低和胰岛素抵抗(IR)在丙型肝炎病毒感染者糖代谢异常的发病机制中起着重要作用。但IR可能更为重要,而肝脂肪变性、肿瘤坏死因子-α过表达、脂联素水平下降、细胞因子信号抑制因子合成以及铁代谢异常等都可能参与了IR的形成。%The morbidity of abnormal glucose metabolism in patients with hepatitis C infection increases gradually. In addition to the common pathogenesis similar to hepatogenous diabetes,malfunciton in pancreaticβ-cell and insulin resistance (IR) play important roles in the pathogenesis of abnormal glucose metabolism in pa-tients with hepatitis C virus infection. IR may be more important,and hepatic steatosis, tumor necrosis factor-αoverexpression,decreased adiponectin, abnormality in synthesis of cytokine signaling inhibitory factors and in iron metabolism may all be involved in IR.

  4. 多囊卵巢综合征患者糖代谢异常发生率及其特点%Characteristics and prevalence of abnormal glucose metabolism in patients with polycystic ovary syndrome

    倪仁敏; 钟俊敏; 陈晓莉; 李琳; 李予; 陈亚肖; 刘雯; 杨冬梓

    2009-01-01

    目的 探讨多囊卵巢综合征患者糖代谢异常特点及其发生率.方法 回顾性分析2006年6月1日至2009年2月1日广州中山大学孙逸仙纪念医院妇产科收治的初诊多囊卵巢综合征患者654例(青春期101例,成人553例),以120名年龄匹配的健康志愿者为对照组(青春期40名,成人80名).病例和对照组均行口服葡萄糖耐量试验和胰岛素释放试验,比较病例组和对照组、成人多囊卵巢综合征与青春期多囊卵巢综合征、不同体重指数亚组中糖代谢异常的特点及其发生率.结果 多囊卵巢综合征患者糖代谢异常的发生率为24.5%(160/654),显著高于对照组的3.3%(4/120)(χ2=27.11,P7.0 mmol/L,9例(69.2%)通过口服葡萄糖耐量试验筛查发现.多囊卵巢综合征组糖代谢异常的发生率随体重指数升高而升高(χ2=53.71,P<0.0001).结论 多囊卵巢综合征患者为糖代谢异常的高危人群,其糖代谢异常以糖耐量受损为主,空腹血糖受损次之.多囊卵巢综合征患者(尤其是肥胖者)应行口服葡萄糖耐最试验,以早期发现其糖代谢异常.%Objective To evaluate the characteristics and prevalence of abnormal glucose metabolism in polycystic ovary syndrome (PCOS) patients. Methods A retrospective case-control study was performed in 654 PCOS patients (101 were in adolescence, 553 were adults) and 120 healthy controls (40 were in adolescence, 80 were adults). Oral glucose tolerance test (OGTT), insulin releasing test (IRT), and other biochemical testing were underwent in all patients and controls. The characteristics and prevalence of abnormal glucose metabolism were analyzed and compared. Results The prevalence of abnormal glucose metabolism, including impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and diabetes mellitus (DM), was 24.5% in PCOS patients, which was significantly higher than that in the controls (χ2 = 27.11, P < 0.0001). The prevalence of abnormal glucose metabolism in

  5. The insulin-like growth factor I receptor regulates glucose transport by astrocytes.

    Hernandez-Garzón, Edwin; Fernandez, Ana M; Perez-Alvarez, Alberto; Genis, Laura; Bascuñana, Pablo; Fernandez de la Rosa, Ruben; Delgado, Mercedes; Angel Pozo, Miguel; Moreno, Estefania; McCormick, Peter J; Santi, Andrea; Trueba-Saiz, Angel; Garcia-Caceres, Cristina; Tschöp, Matthias H; Araque, Alfonso; Martin, Eduardo D; Torres Aleman, Ignacio

    2016-11-01

    Previous findings indicate that reducing brain insulin-like growth factor I receptor (IGF-IR) activity promotes ample neuroprotection. We now examined a possible action of IGF-IR on brain glucose transport to explain its wide protective activity, as energy availability is crucial for healthy tissue function. Using (18) FGlucose PET we found that shRNA interference of IGF-IR in mouse somatosensory cortex significantly increased glucose uptake upon sensory stimulation. In vivo microscopy using astrocyte specific staining showed that after IGF-IR shRNA injection in somatosensory cortex, astrocytes displayed greater increases in glucose uptake as compared to astrocytes in the scramble-injected side. Further, mice with the IGF-IR knock down in astrocytes showed increased glucose uptake in somatosensory cortex upon sensory stimulation. Analysis of underlying mechanisms indicated that IGF-IR interacts with glucose transporter 1 (GLUT1), the main facilitative glucose transporter in astrocytes, through a mechanism involving interactions with the scaffolding protein GIPC and the multicargo transporter LRP1 to retain GLUT1 inside the cell. These findings identify IGF-IR as a key modulator of brain glucose metabolism through its inhibitory action on astrocytic GLUT1 activity. GLIA 2016;64:1962-1971.

  6. Regulation of myosin light chain kinase during insulin-stimulated glucose uptake in 3T3-L1 adipocytes.

    Shelly Woody

    Full Text Available Myosin II (MyoII is required for insulin-responsive glucose transporter 4 (GLUT4-mediated glucose uptake in 3T3-L1 adipocytes. Our previous studies have shown that insulin signaling stimulates phosphorylation of the regulatory light chain (RLC of MyoIIA via myosin light chain kinase (MLCK. The experiments described here delineate upstream regulators of MLCK during insulin-stimulated glucose uptake. Since 3T3-L1 adipocytes express two MyoII isoforms, we wanted to determine which isoform was required for insulin-stimulated glucose uptake. Using a siRNA approach, we demonstrate that a 60% decrease in MyoIIA protein expression resulted in a 40% inhibition of insulin-stimulated glucose uptake. We also show that insulin signaling stimulates the phosphorylation of MLCK. We further show that MLCK can be activated by calcium as well as signaling pathways. We demonstrate that adipocytes treated with the calcium chelating agent, 1,2-b (iso-aminophenoxy ethane-N,N,N',N'-tetra acetic acid, (BAPTA (in the presence of insulin impaired the insulin-induced phosphorylation of MLCK by 52% and the RLC of MyoIIA by 45% as well as impairing the recruitment of MyoIIA to the plasma membrane when compared to cells treated with insulin alone. We further show that the calcium ionophore, A23187 alone stimulated the phosphorylation of MLCK and the RLC associated with MyoIIA to the same extent as insulin. To identify signaling pathways that might regulate MLCK, we examined ERK and CaMKII. Inhibition of ERK2 impaired phosphorylation of MLCK and insulin-stimulated glucose uptake. In contrast, while inhibition of CaMKII did inhibit phosphorylation of the RLC associated with MyoIIA, inhibition of CAMKIIδ did not impair MLCK phosphorylation or translocation to the plasma membrane or glucose uptake. Collectively, our results are the first to delineate a role for calcium and ERK in the activation of MLCK and thus MyoIIA during insulin-stimulated glucose uptake in 3T3-L1 adipocytes.

  7. Up-regulation of sucrose synthase and UDP-glucose pyrophosphorylase impacts plant growth and metabolism.

    Coleman, Heather D; Ellis, Dave D; Gilbert, Margarita; Mansfield, Shawn D

    2006-01-01

    The effects of the overexpression of sucrose synthase (SuSy) and UDP-glucose pyrophosphorylase (UGPase) on plant growth and metabolism were evaluated in tobacco (Nicotiana tabacum cv. Xanthi). T(1) transgenic plants expressing either gene under the control of a tandem repeat cauliflower mosaic virus 35S promoter (2x35S) or a xylem-localized 4CL promoter (4-coumarate:CoA ligase; 4CL) were generated, and reciprocally crossed to generate plants expressing both genes. Transcript levels, enzyme activity, growth parameters, fibre properties and carbohydrate content of stem tissue were quantified. The expression profiles of both genes confirmed the expression pattern of the promoters: 2x35S expressed more strongly in leaves, while 4CL expression was highest in stem tissue. In-depth plant characterization revealed that the single-transgene lines showed significant increases in the height growth compared with corresponding control lines. The double-transgene plants demonstrated an additive effect, proving to be even taller than the single-transgene parents. Several of these lines had associated increases in soluble sugar content. Although partitioning of storage carbohydrates into starch or cellulose was not observed, the increased height growth and increases in soluble carbohydrates suggest a role for SuSy as a marker in sink strength and lend credit to the function of UGPase in a similar role. The up-regulation of these two genes, although not increasing the percentage cellulose content, was effective in increasing the total biomass, and thus the overall cellulose yield, from a given plant.

  8. Autophagic flux regulates microglial phenotype according to the time of oxygen-glucose deprivation/reperfusion.

    Xia, Cong-Yuan; Zhang, Shuai; Chu, Shi-Feng; Wang, Zhen-Zhen; Song, Xiu-Yun; Zuo, Wei; Gao, Yan; Yang, Peng-Fei; Chen, Nai-Hong

    2016-10-01

    Microglial phenotype alternation is a potential novel pathogenic mechanism for cerebral ischemia. Cerebral ischemia induced autophagy aggravates inflammation and neural injury. However, the effect of autophagy in the modulation of microglial phenotype is still unknown. In this study, we investigated the role of autophagic flux in the alternation of microglial phenotype following oxygen glucose deprivation/reperfusion (OGD/R) in BV-2 cells. Inhibition of autophagic flux by NH4Cl exposure significantly increased the level of microtubule-associated protein 1 light chain 3 (LC3)-II and p62 in control and OGD/R (12h, 24h and 48h) groups, but did not change their expression in OGD/R 72h group, indicating that autophagic flux was inhibited at OGD/R 72h. Once autophagic flux was inhibited at OGD/R 72h or at OGD/R 24h (with NH4Cl), BV-2 cells mainly showed M1 phenotype with increased tumor necrosis factor alpha (TNF-α), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and decreased M2 markers including interleukin-10 (IL-10), Arginase 1 (Arg-1), and brain derived neurotrophic factor (BDNF). Further study indicated that inhibition of autophagic flux activated NF-κB pathway and decreased the activity of cAMP-response element binding protein (CREB), which contributed to the alternation of microglial phenotype. Therefore, inhibition of autophagic flux regulated the alternation of microglial phenotype by modulating the balance between NF-κB and CREB.

  9. Transcriptome profiling of brown adipose tissue during cold exposure reveals extensive regulation of glucose metabolism

    Hao, Qin; Yadav, Rachita; Basse, Astrid L.

    2015-01-01

    exposure, we propose a model for the intermediary glucose metabolism in activated BAT: 1) fluxes through glycolysis and the pentose phosphate pathway are induced, the latter providing reducing equivalents for de novo fatty acid synthesis; 2) glycerol synthesis from glucose is increased, facilitating...... metabolism, and the pentose phosphate pathway was observed in BAT from cold-exposed animals. In addition, glycerol-3-phosphate dehydrogenase 1 expression was induced in BAT from cold-challenged mice, suggesting increased synthesis of glycerol from glucose. Similarly, expression of lactate dehydrogenases...

  10. Abnormal regulation for progesterone production in placenta with prenatal cocaine exposure in rats.

    Wu, L; Yan, J; Qu, S C; Feng, Y Q; Jiang, X L

    2012-12-01

    Cocaine abuse in pregnant women is currently a significant public hygiene problem and is tightly associated with elevated risk for preterm delivery. Placental steroidogenesis especially progesterone production was essential for success and maintenance of pregnancy in humans and rodents. In the present study, we determined the impact of prenatal cocaine exposure on pathways of placental progesterone synthesis in rats. Pregnant rats were treated cocaine twice daily (15 mg/kg/day) during the third trimester, and the maternal and fetal plasma progesterone and pregnenolone concentrations were detected. We also examined both the protein and mRNA expression of some key enzymes and regulators for progesterone production in placenta. Results showed that, after maternal cocaine use during pregnancy, progesterone and pregnenolone concentrations in both maternal and fetal rats were significantly decreased. Although prenatal cocaine exposure had no effects on placental 3β-hydroxysteroid dehydrogenase type 1 (3βHSD1) expression, protein and mRNA expression of the cholesterol side-chain cleavage enzyme (P450scc/CYP11a) in placenta was significantly inhibited. Moreover, protein and mRNA expressions of MLN64 that regulating cholesterol transport and activating protein 2γ (AP2γ/Tfap2c) that controlling P450scc/CYP11a gene expression in placenta were both decreased following maternal cocaine use in pregnancy. Collectively, this study suggested that prenatal cocaine exposure could insult the placental progesterone production in rats possibly associated with the high risk for preterm delivery.

  11. Analysis of gestational diabetes in pregnant women with different blood glucose abnormalities and pregnancy Outcome%妊娠期糖尿病孕妇不同血糖指标异常与妊娠结局分析

    许丽

    2015-01-01

    目的 观察并研究妊娠期糖尿病(GDM)孕妇各项血糖指标异常对妊娠结局的影响.方法 选取400例产前检查并选择在院分娩的产妇为本次研究对象,通过75 g葡萄糖耐量实验检测方法将其均分为对照组和实验组,即正常血糖组(服糖后1/2 h、空腹血糖处于正常状态)和妊娠期糖尿病组(GDM),其中实验组(妊娠期糖尿病组)分为实验组A(仅空腹血糖异常)、实验组B(服糖后1/2 h、空腹血糖均表现异常)和实验组C(服糖后任意时间点和空腹血糖值均表现异常);同时根据葡萄糖耐量实验结果将实验组患者划分为GDM1(1项血糖指数异常)、GDM2(2项血糖指数异常)、GDM3(3项血糖指数异常),通过对照研究方法评估不同类型GDM产妇妊娠结局.结果 与对照组相比,实验组整体早产率、剖宫产率以及大于胎龄儿(LGA)发生率更高,组间差异显著(P<0.05);实验组中,实验组B患者中LGA、巨大儿发生率超出对照组和实验组C,组间差异显著(P<0.05);GDM1、GDM2、GDM3组剖宫产率、LGA和巨大儿发生率高于对照组,组间差异显著(P<0.05).结论 在妊娠期糖尿病患者中,空腹血糖异常且伴有血糖指数不同时间点内异常(不低于1项)者明显出现妊娠结局不良的情况,临床应根据此种情况针对产妇实施密切观察和有效干预,以控制不良妊娠结局.此外,空腹血糖指数低于4.4 mmol/L的孕妇通常不会发生妊娠期糖尿病或出现不良妊娠结局,不建议临床采用葡萄糖耐量实验对此类孕妇进行检测.%Objective To observe and study the effect of glucose abnormalities on pregnancy outcome in pregnant women with gestational diabetes(GDM).Methods Four hundred cases of prenatal care and childbirth were selected for the study object,through 75 g glucose tolerance test method to detect both into control group and experimental group,namely normal glucose group (oral glucose after 1/2 h,fasting blood glucose in

  12. Roles of Chlorogenic Acid on Regulating Glucose and Lipids Metabolism: A Review

    Shengxi Meng

    2013-01-01

    Full Text Available Intracellular glucose and lipid metabolic homeostasis is vital for maintaining basic life activities of a cell or an organism. Glucose and lipid metabolic disorders are closely related with the occurrence and progression of diabetes, obesity, hepatic steatosis, cardiovascular disease, and cancer. Chlorogenic acid (CGA, one of the most abundant polyphenol compounds in the human diet, is a group of phenolic secondary metabolites produced by certain plant species and is an important component of coffee. Accumulating evidence has demonstrated that CGA exerts many biological properties, including antibacterial, antioxidant, and anticarcinogenic activities. Recently, the roles and applications of CGA, particularly in relation to glucose and lipid metabolism, have been highlighted. This review addresses current studies investigating the roles of CGA in glucose and lipid metabolism.

  13. Glucose Regulation of Pre-steady State Kinetics of ATP Hydrolysis by Na,K-ATPase

    Mohammad Mahfuzul HAQUE; Nikhat MANZOOR; Mohammad AMIN; Mohammad Ejaz HUSSAIN; Luqman Ahmad KHAN

    2007-01-01

    The effect of glucose and 2-deoxy-D-glucose on pre-steady state kinetics of ATP hydrolysis by Na,K-ATPase has been investigated by following pH transients in a stopped-flow spectrophotometer. A typical pre-steady state signal showed an initial decrease then subsequent increase in acidity. Under optimal Na+ (120 mM) and K+ (30 mM) concentrations, magnitudes of both H+ release and H+ absorption were found to be approximately 1.0/ATPase molecule. The presence of 1 mM glucose significantly decreased H+ absorption at high Na+ concentrations, whereas it was ineffective at low Na+. H+ release was decreased significantly in the presence of 1 mM glucose at Na+ concentrations ranging from 30 mM to 120 mM. Similar to the control,K+ did not show any effect on either H+ release or H+ absorption at all tested combinations of Na+ and K+ concentrations. Pre-steady state H+ signal obtained in the presence of 2-deoxy-D-glucose did not vary significantly as compared with glucose. Delayed addition of K+ (by 30 ms) to the mixture (enzyme+120 mM Na++ATP+glucose) showed that only small fractions of population absorb H+ in the absence of K+. No H+ absorption was observed in the absence of Na+. Delayed mixing of Na+ or K+ did not have any effect on H+ release. Effect of 2-deoxy-D-glucose on H+ absorption and release was almost the same as that of glucose at all combinations of Na+ and K+ concentrations. Results obtained have been discussed in terms of an extended kinetic scheme which shows that, in the presence of either glucose or 2-deoxy-D-glucose, significantly fewer enzyme molecules reache the E~P(3Na+) stage and that K+ plays an important role in the conversion of E1.ADP.P(3Na+) to H+.E1~(3Na+) complex.

  14. Metformin Protects Neurons against Oxygen-Glucose Deprivation/Reoxygenation -Induced Injury by Down-Regulating MAD2B

    Xianfang Meng

    2016-11-01

    Full Text Available Background/Aims: Metformin, the common medication for type II diabetes, has protective effects on cerebral ischemia. However, the molecular mechanisms are far from clear. Mitotic arrest deficient 2-like protein 2 (MAD2B, an inhibitor of the anaphase-promoting complex (APC, is widely expressed in hippocampal and cortical neurons and plays an important role in mediating high glucose-induced neurotoxicity. The present study investigated whether metformin modifies the expression of MAD2B and to exert its neuroprotective effects in primary cultured cortical neurons during oxygen-glucose deprivation/reoxygenation (OGD/R, a widely used in vitro model of ischemia/reperfusion. Methods: Primary cortical neurons were cultured, deprived of oxygen-glucose for 1 h, and then recovered with oxygen-glucose for 12 h and 24 h. Cell viability was measured by detecting the levels of lactate dehydrogenase (LDH in culture medium. The levels of MAD2B, cyclin B and p-histone 3 were measured by Western blot. Results: Cell viability of neurons was reduced under oxygen-glucose deprivation/reoxygenation (OGD/R. The expression of MAD2B was increased under OGD/R. The levels of cyclin B1, which is a substrate of APC, were also increased. Moreover, OGD/R up-regulated the phosphorylation levels of histone 3, which is the induction of aberrant re-entry of post-mitotic neurons. However, pretreatment of neurons with metformin alleviated OGD/R-induced injury. Metformin further decreased the expression of MAD2B, cyclin B1 and phosphorylation levels of histone 3. Conclusion: Metformin exerts its neuroprotective effect through regulating the expression of MAD2B in neurons under OGD/R.

  15. Up-regulation of mRNA ventricular PRNP prion protein gene expression in air pollution highly exposed young urbanites: endoplasmic reticulum stress, glucose regulated protein 78, and nanosized particles.

    Villarreal-Calderon, Rodolfo; Franco-Lira, Maricela; González-Maciel, Angélica; Reynoso-Robles, Rafael; Harritt, Lou; Pérez-Guillé, Beatriz; Ferreira-Azevedo, Lara; Drecktrah, Dan; Zhu, Hongtu; Sun, Qiang; Torres-Jardón, Ricardo; Aragón-Flores, Mariana; Calderón-Garcidueñas, Ana; Diaz, Philippe; Calderón-Garcidueñas, Lilian

    2013-11-28

    Mexico City Metropolitan Area children and young adults exposed to high concentrations of air pollutants including fine and ultrafine particulate matter (PM) vs. clean air controls, exhibit myocardial inflammation and inflammasome activation with a differential right and left ventricular expression of key inflammatory genes and inflammasomes. We investigated the mRNA expression levels of the prion protein gene PRNP, which plays an important role in the protection against oxidative stress and metal toxicity, and the glucose regulated protein 78, a key protein in endoplasmic reticulum (ER) stress signaling, in ventricular autopsy samples from 30 children and young adults age 19.97 ± 6.8 years with a lifetime of low (n:4) vs. high (n:26) air pollution exposures. Light microscopy and transmission electron microscopy studies were carried out in human ventricles, and electron microscopy studies were also done in 5 young, highly exposed Mexico City dogs. There was significant left ventricular PRNP and bi-ventricular GRP78 mRNA up-regulation in Mexico City young urbanites vs. controls. PRNP up-regulation in the left ventricle was significantly different from the right, p ventricular PRNP and GRP78 correlation (p = 0.0005). Marked abnormalities in capillary endothelial cells, numerous nanosized particles in myocardial ER and in abnormal mitochondria characterized the highly exposed ventricles. Early and sustained cardiac ER stress could result in detrimental irreversible consequences in urban children, and while highly complex systems maintain myocardial homeostasis, failure to compensate for chronic myocardial inflammation, oxidative and ER stress, and particles damaging myocardial organelles may prime the development of pathophysiological cardiovascular states in young urbanites. Nanosized PM could play a key cardiac myocyte toxicity role.

  16. Up-Regulation of mRNA Ventricular PRNP Prion Protein Gene Expression in Air Pollution Highly Exposed Young Urbanites: Endoplasmic Reticulum Stress, Glucose Regulated Protein 78, and Nanosized Particles

    Villarreal-Calderon, Rodolfo; Franco-Lira, Maricela; González-Maciel, Angélica; Reynoso-Robles, Rafael; Harritt, Lou; Pérez-Guillé, Beatriz; Ferreira-Azevedo, Lara; Drecktrah, Dan; Zhu, Hongtu; Sun, Qiang; Torres-Jardón, Ricardo; Aragón-Flores, Mariana; Calderón-Garcidueñas, Ana; Diaz, Philippe; Calderón-Garcidueñas, Lilian

    2013-01-01

    Mexico City Metropolitan Area children and young adults exposed to high concentrations of air pollutants including fine and ultrafine particulate matter (PM) vs. clean air controls, exhibit myocardial inflammation and inflammasome activation with a differential right and left ventricular expression of key inflammatory genes and inflammasomes. We investigated the mRNA expression levels of the prion protein gene PRNP, which plays an important role in the protection against oxidative stress and metal toxicity, and the glucose regulated protein 78, a key protein in endoplasmic reticulum (ER) stress signaling, in ventricular autopsy samples from 30 children and young adults age 19.97 ± 6.8 years with a lifetime of low (n:4) vs. high (n:26) air pollution exposures. Light microscopy and transmission electron microscopy studies were carried out in human ventricles, and electron microscopy studies were also done in 5 young, highly exposed Mexico City dogs. There was significant left ventricular PRNP and bi-ventricular GRP78 mRNA up-regulation in Mexico City young urbanites vs. controls. PRNP up-regulation in the left ventricle was significantly different from the right, p < 0.0001, and there was a strong left ventricular PRNP and GRP78 correlation (p = 0.0005). Marked abnormalities in capillary endothelial cells, numerous nanosized particles in myocardial ER and in abnormal mitochondria characterized the highly exposed ventricles. Early and sustained cardiac ER stress could result in detrimental irreversible consequences in urban children, and while highly complex systems maintain myocardial homeostasis, failure to compensate for chronic myocardial inflammation, oxidative and ER stress, and particles damaging myocardial organelles may prime the development of pathophysiological cardiovascular states in young urbanites. Nanosized PM could play a key cardiac myocyte toxicity role. PMID:24287918

  17. The Study of Abnormal Metabalism in Essential Hypertention out Patient with Normol Fasting Blood Glucose%空腹血糖正常的门诊高血压患者代谢异常研究

    王俊利; 费丽萍; 牛青英; 李艳芳

    2015-01-01

    Objective:To investigate the factors that influence glucose tolerance in essential hypertention,identify the clinical characteristics of abnormal metabalism.Methods:436 outpatients with essential hypertention,with no history of diabites mellitus and normol fasting blood glucose were recruited.All eligible patients received oral glucose tolerance test. We analyzed the relationships between impaired glucose tolerance and other variables including age,gender,body mass index, blood pressure,uric acid,lipid levels,and carotid atherosclerosis plague.Results:Among 436 patients,the number of patients with impaired glucose tolerance was 127 (29.1%),the number of newly diagnosed diabites DM was 41 (9.5%).A positive correlation exists between glucose tolerance and other variables including age,gender,lowdensity cholesterol,uric acid and carotid atherosclerosis plague.Conclusion:High prevalence of abnormal glucose tolerance was discoved in essential hypertention patients with normol fasting blood glucose.Oral glucose tolerance test should be actively engaged in those patients to detect impaired glucose toleranc early.And it is helpful to postpone progression of diabites and reduce risk of cardelvassculer and cerebrovassculer disease.%目的::研究空腹血糖正常的门诊原发性高血压患者糖代谢异常临床特征,揭示糖耐量异常与血脂、尿酸及颈动脉粥样硬化的情况。方法:选择确诊有原发性高血压而无糖尿病的患者436例,入选患者口服葡萄糖耐量实验测定,分析年龄、性别、体重指数、血脂水平、颈动脉粥样硬化等参数与糖耐量异常的关系。结果:436例患者中检出糖耐量减低患者127例,占29.1%,糖尿病患者41例,占9.5%,糖耐量异常与性别、年龄、血尿酸水平、低密度脂蛋白、颈动脉粥样硬化呈正相关。结论:空腹血糖正常的门诊高血压患者合并糖耐量异常比例较高,常伴有血脂

  18. Degree of abnormality is associated with rate of change in measures of beta-amyloid, glucose metabolism and cognition in an autopsy-verified Alzheimer's disease case.

    Almkvist, Ove; Kadir, Ahmadul; Nordberg, Agneta

    2015-01-01

    The degree of abnormality and rate of change in cognitive functions, positron emission tomography Pittsburg compound B (PET PIB), and fluorodeoxyglucose (FDG) measures were studied for 8 years in an autopsy-confirmed Alzheimer's disease (AD) patient, who died 61 years old (Mini-Mental State Examination (MMSE) score 7). At first encounter with medical care, the patient was very mildly demented (MMSE score 27). She had four cognitive assessments and two examinations with PET PIB and FDG in 23 bilateral brain regions. The onset of cognitive decline was retrospectively estimated to have started in the early forties. The degree of impairment was inversely related to the rate of decline. A similar relationship was seen between the rate of change and the level of abnormality in both PIB and FDG. To conclude, rate of change in cognition, PIB, and FDG was associated with the degree of abnormality.

  19. Metabolic regulation of lateral hypothalamic glucose-inhibited orexin neurons may influence midbrain reward neurocircuitry.

    Sheng, Zhenyu; Santiago, Ammy M; Thomas, Mark P; Routh, Vanessa H

    2014-09-01

    Lateral hypothalamic area (LHA) orexin neurons modulate reward-based feeding by activating ventral tegmental area (VTA) dopamine (DA) neurons. We hypothesize that signals of peripheral energy status influence reward-based feeding by modulating the glucose sensitivity of LHA orexin glucose-inhibited (GI) neurons. This hypothesis was tested using electrophysiological recordings of LHA orexin-GI neurons in brain slices from 4 to 6week old male mice whose orexin neurons express green fluorescent protein (GFP) or putative VTA-DA neurons from C57Bl/6 mice. Low glucose directly activated ~60% of LHA orexin-GFP neurons in both whole cell and cell attached recordings. Leptin indirectly reduced and ghrelin directly enhanced the activation of LHA orexin-GI neurons by glucose decreases from 2.5 to 0.1mM by 53±12% (n=16, PFasting increased activation of LHA orexin-GI neurons by decreased glucose, as would be predicted by these hormonal effects. We also evaluated putative VTA-DA neurons in a novel horizontal slice preparation containing the LHA and VTA. Decreased glucose increased the frequency of spontaneous excitatory post-synaptic currents (sEPSCs; 125 ± 40%, n=9, P<0.05) and action potentials (n=9; P<0.05) in 45% (9/20) of VTA DA neurons. sEPSCs were completely blocked by AMPA and NMDA glutamate receptor antagonists (CNQX 20 μM, n=4; APV 20μM, n=4; respectively), demonstrating that these sEPSCs were mediated by glutamatergic transmission onto VTA DA neurons. Orexin-1 but not 2 receptor antagonism with SB334867 (10μM; n=9) and TCS-OX2-29 (2μM; n=5), respectively, blocks the effects of decreased glucose on VTA DA neurons. Thus, decreased glucose increases orexin-dependent excitatory glutamate neurotransmission onto VTA DA neurons. These data suggest that the glucose sensitivity of LHA orexin-GI neurons links metabolic state and reward-based feeding.

  20. Danthron activates AMP-activated protein kinase and regulates lipid and glucose metabolism in vitro

    Rong ZHOU; Ling WANG; Xing XU; Jing CHEN; Li-hong HU; Li-li CHEN; Xu SHEN

    2013-01-01

    Aim:To discover the active compound on AMP-activated protein kinase (AMPK) activation and investigate the effects of the active compound 1,8-dihydroxyanthraquinone (danthron) from the traditional Chinese medicine rhubarb on AMPK-mediated lipid and glucose metabolism in vitro.Methods:HepG2 and C2C12 cells were used.Cell viability was determined using MTT assay.Real-time PCR was performed to measure the gene expression.Western blotting assay was applied to investigate the protein phosphorylation level.Enzymatic assay kits were used to detect the total cholesterol (TC),triglyceride (TG) and glucose contents.Results:Danthron (0.1,1,and 10 μmol/L) dose-dependently promoted the phosphorylation of AMPK and acetyl-CoA carboxylase (ACC)in both HepG2 and C2C12 cells.Meanwhile,danthron treatment significantly reduced the lipid synthesis related sterol regulatory element-binding protein 1c (SREBP1c) and fatty acid synthetase (FAS) gene expressions,and the TC and TG levels.In addition,danthron treatment efficiently increased glucose consumption.The actions of danthron on lipid and glucose metabolism were abolished or reversed by co-treatment with the AMPK inhibitor compound C.Conclusion:Danthron effectively reduces intracellular lipid contents and enhanced glucose consumption in vitro via activation of AMPK signaling pathway.

  1. Autoreactivity to Glucose Regulated Protein 78 Links Emphysema and Osteoporosis in Smokers

    Zhang, Yingze; Xue, Jianmin; Fuhrman, Carl R.; Tan, Jiangning; Burger, Mathew; Kass, Daniel J.; Csizmadia, Eva; Otterbein, Leo; Chandra, Divay; Bhargava, Arpit; Pilewski, Joseph M.; Roodman, G. David; Sciurba, Frank C.; Duncan, Steven R.

    2014-01-01

    Rationale Emphysema and osteoporosis are epidemiologically associated diseases of cigarette smokers. The causal mechanism(s) linking these illnesses is unknown. We hypothesized autoimmune responses may be involved in both disorders. Objectives To discover an antigen-specific autoimmune response associated with both emphysema and osteoporosis among smokers. Methods Replicate nonbiased discovery assays indicated that autoimmunity to glucose regulated protein 78 (GRP78), an endoplasmic reticulum chaperone and cell surface signaling receptor, is present in many smokers. Subject assessments included spirometry, chest CT scans, dual x-ray absorptiometry, and immunoblots for anti-GRP78 IgG. Anti-GRP78 autoantibodies were isolated from patient plasma by affinity chromatography, leukocyte functions assessed by flow cytometry, and soluble metabolites and mediators measured by immunoassays. Measurements and Main Results Circulating anti-GRP78 IgG autoantibodies were detected in plasma specimens from 86 (32%) of the 265 smoking subjects. Anti-GRP78 autoantibodies were singularly prevalent among subjects with radiographic emphysema (OR 3.1, 95%CI 1.7–5.7, p = 0.003). Anti-GRP78 autoantibodies were also associated with osteoporosis (OR 4.7, 95%CI 1.7–13.3, p = 0.002), and increased circulating bone metabolites (p = 0.006). Among emphysematous subjects, GRP78 protein was an autoantigen of CD4 T-cells, stimulating lymphocyte proliferation (p = 0.0002) and IFN-gamma production (p = 0.03). Patient-derived anti-GRP78 autoantibodies had avidities for osteoclasts and macrophages, and increased macrophage NFkB phosphorylation (p = 0.005) and productions of IL-8, CCL-2, and MMP9 (p = 0.005, 0.007, 0.03, respectively). Conclusions Humoral and cellular GRP78 autoimmune responses in smokers have numerous biologically-relevant pro-inflammatory and other deleterious actions, and are associated with emphysema and osteoporosis. These findings may have relevance

  2. Autoreactivity to glucose regulated protein 78 links emphysema and osteoporosis in smokers.

    Jessica Bon

    Full Text Available RATIONALE: Emphysema and osteoporosis are epidemiologically associated diseases of cigarette smokers. The causal mechanism(s linking these illnesses is unknown. We hypothesized autoimmune responses may be involved in both disorders. OBJECTIVES: To discover an antigen-specific autoimmune response associated with both emphysema and osteoporosis among smokers. METHODS: Replicate nonbiased discovery assays indicated that autoimmunity to glucose regulated protein 78 (GRP78, an endoplasmic reticulum chaperone and cell surface signaling receptor, is present in many smokers. Subject assessments included spirometry, chest CT scans, dual x-ray absorptiometry, and immunoblots for anti-GRP78 IgG. Anti-GRP78 autoantibodies were isolated from patient plasma by affinity chromatography, leukocyte functions assessed by flow cytometry, and soluble metabolites and mediators measured by immunoassays. MEASUREMENTS AND MAIN RESULTS: Circulating anti-GRP78 IgG autoantibodies were detected in plasma specimens from 86 (32% of the 265 smoking subjects. Anti-GRP78 autoantibodies were singularly prevalent among subjects with radiographic emphysema (OR 3.1, 95%CI 1.7-5.7, p = 0.003. Anti-GRP78 autoantibodies were also associated with osteoporosis (OR 4.7, 95%CI 1.7-13.3, p = 0.002, and increased circulating bone metabolites (p = 0.006. Among emphysematous subjects, GRP78 protein was an autoantigen of CD4 T-cells, stimulating lymphocyte proliferation (p = 0.0002 and IFN-gamma production (p = 0.03. Patient-derived anti-GRP78 autoantibodies had avidities for osteoclasts and macrophages, and increased macrophage NFkB phosphorylation (p = 0.005 and productions of IL-8, CCL-2, and MMP9 (p = 0.005, 0.007, 0.03, respectively. CONCLUSIONS: Humoral and cellular GRP78 autoimmune responses in smokers have numerous biologically-relevant pro-inflammatory and other deleterious actions, and are associated with emphysema and osteoporosis. These findings may have

  3. Hypothyroidism in Noninterferon Treated-HCV Infected Individuals Is Associated with Abnormalities in the Regulation of Th17 Cells

    Luis A. Salazar

    2010-01-01

    Full Text Available HCV-Ag-specific TH17 cells secrete IL17, a cytokine involved in autoimmune diseases and regulated by IL10 and TGF-b. 5–12% of patients with chronic HCV infection have hypothyroidism. We evaluated the role of these cytokines in this patients by determining serum concentration of TsH, T3, free T4, IL2, IL10, IL12, IL17, TGF-b, anti-TG, TPO, CCP, GBM, and cardiolipin antibodies in 87 chronically noninterferon treated HCV-infected patients. 20 patients (group A had elevated TsH values (>5 μUI/ml whereas the remaining 67 (group B had normal values. The percentage of anti-TPO, TG, GBM, and cardiolipin antibodies in group A patients (33%, 41%, 5% and 5%, resp. as well as IL17, IL2 and TGF-b concentrations (25±23 pg/ml, 643±572 pg/ml, and 618±221 pg/ml, resp. were significantly higher than group B. Abnormal Th17 regulation mediated by IL-2 and low TGF-b concentrations is associated with hypothyroidism in chronically-infected HCV patients.

  4. Regulation of MDA-MB-231 cell proliferation by GSK-3β involves epigenetic modifications under high glucose conditions.

    Gupta, Chanchal; Kaur, Jasmine; Tikoo, Kulbhushan

    2014-05-15

    Hyperglycemia is a critical risk factor for development and progression of breast cancer. We have recently reported that high glucose induces phosphorylation of histone H3 at Ser 10 as well as de-phosphorylation of GSK-3β at Ser 9 in MDA-MB-231 cells. Here, we elucidate the mechanism underlying hyperglycemia-induced proliferation in MDA-MB-231 breast cancer cells. We provide evidence that hyperglycemia led to increased DNA methylation and DNMT1 expression in MDA-MB-231 cells. High glucose condition led to significant increase in the expression of PCNA, cyclin D1 and decrease in the expression of PTPN 12, p21 and PTEN. It also induced hypermethylation of DNA at the promoter region of PTPN 12, whereas hypomethylation at Vimentin and Snail. Silencing of GSK-3β by siRNA prevented histone H3 phosphorylation and reduced DNMT1 expression. We show that chromatin obtained after immunoprecipitation with phospho-histone H3 was hypermethylated under high glucose condition, which indicates a cross-talk between DNA methylation and histone H3 phosphorylation. ChIP-qPCR analysis revealed up-regulation of DNMT1 and metastatic genes viz. Vimentin, Snail and MMP-7 by phospho-histone H3, which were down-regulated upon GSK-3β silencing. To the best of our knowledge, this is the first report which shows that interplay between GSK-3β activation, histone H3 phosphorylation and DNA methylation directs proliferation of breast cancer cells.

  5. Withdrawal of dietary phytoestrogens in adult male rats affects hypothalamic regulation of food intake, induces obesity and alters glucose metabolism.

    Andreoli, María Florencia; Stoker, Cora; Rossetti, María Florencia; Alzamendi, Ana; Castrogiovanni, Daniel; Luque, Enrique H; Ramos, Jorge Guillermo

    2015-02-05

    The absence of phytoestrogens in the diet during pregnancy has been reported to result in obesity later in adulthood. We investigated whether phytoestrogen withdrawal in adult life could alter the hypothalamic signals that regulate food intake and affect body weight and glucose homeostasis. Male Wistar rats fed from conception to adulthood with a high phytoestrogen diet were submitted to phytoestrogen withdrawal by feeding a low phytoestrogen diet, or a high phytoestrogen-high fat diet. Withdrawal of dietary phytoestrogens increased body weight, adiposity and energy intake through an orexigenic hypothalamic response characterized by upregulation of AGRP and downregulation of POMC. This was associated with elevated leptin and T4, reduced TSH, testosterone and estradiol, and diminished hypothalamic ERα expression, concomitant with alterations in glucose tolerance. Removing dietary phytoestrogens caused manifestations of obesity and diabetes that were more pronounced than those induced by the high phytoestrogen-high fat diet intake.

  6. Cholinergic Abnormalities, Endosomal Alterations and Up-Regulation of Nerve Growth Factor Signaling in Niemann-Pick Type C Disease

    Cabeza Carolina

    2012-03-01

    dysfunction through the abnormal up-regulation of survival pathways, which causes the perturbation of signaling cascades and anomalous phosphorylation of the cytoskeleton.

  7. Regulation of MDA-MB-231 cell proliferation by GSK-3β involves epigenetic modifications under high glucose conditions

    Gupta, Chanchal; Kaur, Jasmine; Tikoo, Kulbhushan, E-mail: tikoo.k@gmail.com

    2014-05-15

    Hyperglycemia is a critical risk factor for development and progression of breast cancer. We have recently reported that high glucose induces phosphorylation of histone H3 at Ser 10 as well as de-phosphorylation of GSK-3β at Ser 9 in MDA-MB-231 cells. Here, we elucidate the mechanism underlying hyperglycemia-induced proliferation in MDA-MB-231 breast cancer cells. We provide evidence that hyperglycemia led to increased DNA methylation and DNMT1 expression in MDA-MB-231 cells. High glucose condition led to significant increase in the expression of PCNA, cyclin D1 and decrease in the expression of PTPN 12, p21 and PTEN. It also induced hypermethylation of DNA at the promoter region of PTPN 12, whereas hypomethylation at Vimentin and Snail. Silencing of GSK-3β by siRNA prevented histone H3 phosphorylation and reduced DNMT1 expression. We show that chromatin obtained after immunoprecipitation with phospho-histone H3 was hypermethylated under high glucose condition, which indicates a cross-talk between DNA methylation and histone H3 phosphorylation. ChIP-qPCR analysis revealed up-regulation of DNMT1 and metastatic genes viz. Vimentin, Snail and MMP-7 by phospho-histone H3, which were down-regulated upon GSK-3β silencing. To the best of our knowledge, this is the first report which shows that interplay between GSK-3β activation, histone H3 phosphorylation and DNA methylation directs proliferation of breast cancer cells. - Highlights: • High glucose induces phosphorylation of histone H3 and dephosphorylation of GSK-3β. • Moreover, hyperglycemia also leads to increased DNA methylation in MDA-MB-231 cells. • Inhibition of GSK-3β prevented histone H3 phosphorylation and reduced DNMT1 levels. • Interplay exists between GSK-3β, histone H3 phosphorylation and DNA methylation.

  8. Exercise and Type 2 Diabetes: Molecular Mechanisms Regulating Glucose Uptake in Skeletal Muscle

    Stanford, Kristin I.; Goodyear, Laurie J.

    2014-01-01

    Exercise is a well-established tool to prevent and combat type 2 diabetes. Exercise improves whole body metabolic health in people with type 2 diabetes, and adaptations to skeletal muscle are essential for this improvement. An acute bout of exercise increases skeletal muscle glucose uptake, while chronic exercise training improves mitochondrial…

  9. TUSC5 regulates insulin-mediated adipose tissue glucose uptake by modulation of GLUT4 recycling

    Nigel Beaton

    2015-11-01

    Conclusions: Collectively, these findings establish TUSC5 as an adipose tissue-specific protein that enables proper protein recycling, linking the ubiquitous vesicle traffic machinery with tissue-specific insulin-mediated glucose uptake into adipose tissue and the maintenance of a healthy metabolic phenotype in mice and humans.

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

    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.

  11. Regulation of myosin IIA and filamentous actin during insulin-stimulated glucose uptake in 3T3-L1 adipocytes

    Stall, Richard; Ramos, Joseph; Kent Fulcher, F.; Patel, Yashomati M., E-mail: ympatel@uncg.edu

    2014-03-10

    Insulin stimulated glucose uptake requires the colocalization of myosin IIA (MyoIIA) and the insulin-responsive glucose transporter 4 (GLUT4) at the plasma membrane for proper GLUT4 fusion. MyoIIA facilitates filamentous actin (F-actin) reorganization in various cell types. In adipocytes F-actin reorganization is required for insulin-stimulated glucose uptake. What is not known is whether MyoIIA interacts with F-actin to regulate insulin-induced GLUT4 fusion at the plasma membrane. To elucidate the relationship between MyoIIA and F-actin, we examined the colocalization of MyoIIA and F-actin at the plasma membrane upon insulin stimulation as well as the regulation of this interaction. Our findings demonstrated that MyoIIA and F-actin colocalized at the site of GLUT4 fusion with the plasma membrane upon insulin stimulation. Furthermore, inhibition of MyoII with blebbistatin impaired F-actin localization at the plasma membrane. Next we examined the regulatory role of calcium in MyoIIA-F-actin colocalization. Reduced calcium or calmodulin levels decreased colocalization of MyoIIA and F-actin at the plasma membrane. While calcium alone can translocate MyoIIA it did not stimulate F-actin accumulation at the plasma membrane. Taken together, we established that while MyoIIA activity is required for F-actin localization at the plasma membrane, it alone is insufficient to localize F-actin to the plasma membrane. - Highlights: • Insulin induces colocalization of MyoIIA and F-actin at the cortex in adipocytes. • MyoIIA is necessary but not sufficient to localize F-actin at the cell cortex. • MyoIIA-F-actin colocalization is regulated by calcium and calmodulin.

  12. Rac1 governs exercise-stimulated glucose uptake in skeletal muscle through regulation of GLUT4 translocation in mice

    Sylow, Lykke; Laurent, Ida; Kleinert, Maximilian

    2016-01-01

    % in gastrocnemius and tibialis anterior muscles, respectively, in muscle-specific inducible Rac1 knockout (mKO) mice compared to wildtype littermates. By developing an assay to quantify endogenous GLUT4 translocation, we observed that GLUT4 content at the sarcolemma in response to exercise was reduced in Rac1 m......KO muscle. Our findings implicate Rac1 as a regulatory element critical for controlling glucose uptake during exercise via regulation of GLUT4 translocation. This article is protected by copyright. All rights reserved....

  13. Oleic acid and glucose regulate glucagon-like peptide 1 receptor expression in a rat pancreatic ductal cell line

    Zhang, Leshuai W.; McMahon Tobin, Grainne A.; Rouse, Rodney L., E-mail: rodney.rouse@fda.hhs.gov

    2012-10-15

    The glucagon-like peptide 1 receptor (GLP1R) plays a critical role in glucose metabolism and has become an important target for a growing class of drugs designed to treat type 2 diabetes. In vitro studies were designed to investigate the effect of the GLP1R agonist, exenatide (Ex4), in “on-target” RIN-5mF (islet) cells as well as in “off-target” AR42J (acinar) and DSL-6A/C1 (ductal) cells in a diabetic environment. Ex4 increased islet cell proliferation but did not affect acinar cells or ductal cells at relevant concentrations. A high caloric, high fat diet is a risk factor for impaired glucose tolerance and type-2 diabetes. An in vitro Oleic acid (OA) model was used to investigate the effect of Ex4 in a high calorie, high fat environment. At 0.1 and 0.4 mM, OA mildly decreased the proliferation of all pancreatic cell types. Ex4 did not potentiate the inhibitory effect of OA on cell proliferation. Akt phosphorylation in response to Ex4 was diminished in OA-treated ductal cells. GLP1R protein detected by western blot was time and concentration dependently decreased after glucose stimulation in OA-treated ductal cells. In ductal cells, OA treatment altered the intracellular localization of GLP1R and its co-localization with early endosome and recycling endosomes. Chloroquine (lysosomal inhibitor), N-acetyl-L-cysteine (reactive oxygen species scavenger) and wortmannin (a phosphatidylinositol-3-kinase inhibitor), fully or partially, rescued GLP1R protein in OA-pretreated, glucose-stimulated ductal cells. The impact of altered regulation on phenotype/function is presently unknown. However, these data suggest that GLP1R regulation in ductal cells can be altered by a high fat, high calorie environment. -- Highlights: ► Exenatide did not inhibit islet, acinar or ductal cell proliferation. ► GLP1R protein decreased after glucose stimulation in oleic acid-treated ductal cells. ► Oleic acid treatment altered localization of GLP1R with early and recycling

  14. Characterization of the biocontrol activity of pseudomonas fluorescens strain X reveals novel genes regulated by glucose.

    Gerasimos F Kremmydas

    Full Text Available Pseudomonas fluorescens strain X, a bacterial isolate from the rhizosphere of bean seedlings, has the ability to suppress damping-off caused by the oomycete Pythium ultimum. To determine the genes controlling the biocontrol activity of strain X, transposon mutagenesis, sequencing and complementation was performed. Results indicate that, biocontrol ability of this isolate is attributed to gcd gene encoding glucose dehydrogenase, genes encoding its co-enzyme pyrroloquinoline quinone (PQQ, and two genes (sup5 and sup6 which seem to be organized in a putative operon. This operon (named supX consists of five genes, one of which encodes a non-ribosomal peptide synthase. A unique binding site for a GntR-type transcriptional factor is localized upstream of the supX putative operon. Synteny comparison of the genes in supX revealed that they are common in the genus Pseudomonas, but with a low degree of similarity. supX shows high similarity only to the mangotoxin operon of Ps. syringae pv. syringae UMAF0158. Quantitative real-time PCR analysis indicated that transcription of supX is strongly reduced in the gcd and PQQ-minus mutants of Ps. fluorescens strain X. On the contrary, transcription of supX in the wild type is enhanced by glucose and transcription levels that appear to be higher during the stationary phase. Gcd, which uses PQQ as a cofactor, catalyses the oxidation of glucose to gluconic acid, which controls the activity of the GntR family of transcriptional factors. The genes in the supX putative operon have not been implicated before in the biocontrol of plant pathogens by pseudomonads. They are involved in the biosynthesis of an antimicrobial compound by Ps. fluorescens strain X and their transcription is controlled by glucose, possibly through the activity of a GntR-type transcriptional factor binding upstream of this putative operon.

  15. Characterization of the biocontrol activity of pseudomonas fluorescens strain X reveals novel genes regulated by glucose.

    Kremmydas, Gerasimos F; Tampakaki, Anastasia P; Georgakopoulos, Dimitrios G

    2013-01-01

    Pseudomonas fluorescens strain X, a bacterial isolate from the rhizosphere of bean seedlings, has the ability to suppress damping-off caused by the oomycete Pythium ultimum. To determine the genes controlling the biocontrol activity of strain X, transposon mutagenesis, sequencing and complementation was performed. Results indicate that, biocontrol ability of this isolate is attributed to gcd gene encoding glucose dehydrogenase, genes encoding its co-enzyme pyrroloquinoline quinone (PQQ), and two genes (sup5 and sup6) which seem to be organized in a putative operon. This operon (named supX) consists of five genes, one of which encodes a non-ribosomal peptide synthase. A unique binding site for a GntR-type transcriptional factor is localized upstream of the supX putative operon. Synteny comparison of the genes in supX revealed that they are common in the genus Pseudomonas, but with a low degree of similarity. supX shows high similarity only to the mangotoxin operon of Ps. syringae pv. syringae UMAF0158. Quantitative real-time PCR analysis indicated that transcription of supX is strongly reduced in the gcd and PQQ-minus mutants of Ps. fluorescens strain X. On the contrary, transcription of supX in the wild type is enhanced by glucose and transcription levels that appear to be higher during the stationary phase. Gcd, which uses PQQ as a cofactor, catalyses the oxidation of glucose to gluconic acid, which controls the activity of the GntR family of transcriptional factors. The genes in the supX putative operon have not been implicated before in the biocontrol of plant pathogens by pseudomonads. They are involved in the biosynthesis of an antimicrobial compound by Ps. fluorescens strain X and their transcription is controlled by glucose, possibly through the activity of a GntR-type transcriptional factor binding upstream of this putative operon.

  16. "Glucose and ethanol-dependent transcriptional regulation of the astaxanthin biosynthesis pathway in Xanthophyllomyces dendrorhous"

    Cifuentes Víctor; Baeza Marcelo; Alcaíno Jennifer; Lozano Carla; Wozniak Aniela; Niklitschek Mauricio; Marcoleta Andrés

    2011-01-01

    Abstract Background The yeast Xanthophyllomyces dendrorhous is one of the most promising and economically attractive natural sources of astaxanthin. The biosynthesis of this valuable carotenoid is a complex process for which the regulatory mechanisms remain mostly unknown. Several studies have shown a strong correlation between the carbon source present in the medium and the amount of pigments synthesized. Carotenoid production is especially low when high glucose concentrations are used in th...

  17. Injectable Self-Healing Glucose-Responsive Hydrogels with pH-Regulated Mechanical Properties.

    Yesilyurt, Volkan; Webber, Matthew J; Appel, Eric A; Godwin, Colin; Langer, Robert; Anderson, Daniel G

    2016-01-01

    Dynamically restructuring pH-responsive hydrogels are synthesized, employing dynamic covalent chemistry between phenylboronic acid and cis-diol modified poly(ethylene glycol) macromonomers. These gels display shear-thinning behavior, followed by a rapid structural recovery (self-healing). Size-dependent in vitro controlled and glucose-responsive release of proteins from the hydrogel network, as well as the biocompatibility of the gels, are evaluated both in vitro and in vivo.

  18. Endoproteolytic cleavage of TUG protein regulates GLUT4 glucose transporter translocation.

    Bogan, Jonathan S; Rubin, Bradley R; Yu, Chenfei; Löffler, Michael G; Orme, Charisse M; Belman, Jonathan P; McNally, Leah J; Hao, Mingming; Cresswell, James A

    2012-07-06

    To promote glucose uptake into fat and muscle cells, insulin causes the translocation of GLUT4 glucose transporters from intracellular vesicles to the cell surface. Previous data support a model in which TUG traps GLUT4-containing vesicles and tethers them intracellularly in unstimulated cells and in which insulin mobilizes this pool of vesicles by releasing this tether. Here we show that TUG undergoes site-specific endoproteolytic cleavage, which separates a GLUT4-binding, N-terminal region of TUG from a C-terminal region previously suggested to bind an intracellular anchor. Cleavage is accelerated by insulin stimulation in 3T3-L1 adipocytes and is highly dependent upon adipocyte differentiation. The N-terminal TUG cleavage product has properties of a novel 18-kDa ubiquitin-like modifier, which we call TUGUL. The C-terminal product is observed at the expected size of 42 kDa and also as a 54-kDa form that is released from membranes into the cytosol. In transfected cells, intact TUG links GLUT4 to PIST and also binds Golgin-160 through its C-terminal region. PIST is an effector of TC10α, a GTPase previously shown to transmit an insulin signal required for GLUT4 translocation, and we show using RNAi that TC10α is required for TUG proteolytic processing. Finally, we demonstrate that a cleavage-resistant form of TUG does not support highly insulin-responsive GLUT4 translocation or glucose uptake in 3T3-L1 adipocytes. Together with previous results, these data support a model whereby insulin stimulates TUG cleavage to liberate GLUT4 storage vesicles from the Golgi matrix, which promotes GLUT4 translocation to the cell surface and enhances glucose uptake.

  19. 出生体重与成年期肥胖指标联合效应对糖代谢异常的影响%Joint effect of birth weight and obesity measures on abnormal glucose metabolism at adulthood

    席波; 程红; 陈芳芳; 赵小元; 米杰

    2016-01-01

    Objective To investigate the joint effect of birth weight and each of obesity measures (body mass index (BMI) and waist circumference (WC)) on abnormal glucose metabolism (including diabetes) at adulthood. Methods Using the historical cohort study design and the convenience sampling method, 1 921 infants who were born in Beijing Union Medical College Hospital from June 1948 to December 1954 were selected to do the follow-up in 1995 and 2001 respectively. Through Beijing Household Registration and Management System, they were invited to participate in this study. A total of 972 subjects (627 were followed up in 1995 and 345 were followed up in 2001) with complete information on genders, age, birth weight, family history of diabetes, BMI, WC, fasting plasma glucose (FPG) and 2-hour plasma glucose (2 h PG) met the study inclusion criteria at the follow-up visits. In the data analysis, they were divided into low, normal, and high birth weight, respectively. The ANOVA and Chi-squared tests were used to compare the differences in their characteristics by birth weight group. In addition, multiple binary Logistic regression model was used to investigate the single effect of birth weight, BMI, and waist circumference on abnormal glucose metabolism at adulthood. Stratification analysis was used to investigate the joint effect of birth weight and each of obesity measures (BMI and WC) on abnormal glucose metabolism. Results There were 972 subjects (males:50.7%, mean age:(46.0±2.2) years) included in the final data analysis. The 2 h PG in low birth weight group was (7.6±3.2) mmol/L , which was higher than that in normal birth weight group (6.9± 2.1) mmol/L and high birth weight group (6.4±1.3) mmol/L (F=3.88, P=0.021). After adjustment for genders, age, body length, gestation age, family history of diabetes, physical activity, smoking and alcohol consumption, and duration of follow-up, subjects with overweight and obesity at adulthood had 2.73 (95%confidence interval (CI

  20. Dairy product intake in relation to glucose regulation indices and risk of type 2 diabetes

    Struijk, E A; Heraclides, A; Witte, Daniel Rinse;

    2013-01-01

    BACKGROUND AND AIM: A high intake of dairy has been linked to lower risk of type 2 diabetes (T2D). The relationship between dairy intake and glucose metabolism is still not well understood. The aim of this study was to investigate the relation between the intake of total dairy and dairy subgroups...... and milk products, cheese and fermented dairy. Fasting plasma glucose (FPG), 2-h plasma glucose (2hPG), HbA(1c), insulin resistance (HOMA2-IR) and beta-cell function (HOMA2-B) were considered at 5-year follow-up. In the maximally-adjusted model (demographics, lifestyle factors, dietary factors and waist......), cheese intake was inversely associated with 2hPG (β = -0.048, 95% CI -0.095; -0.001). Fermented dairy intake was inversely associated with FPG (β = -0.028, 95% CI -0.048; -0.008) and HbA(1c) (β = -0.016, 95% CI -0.030; -0.001). Total dairy intake and the dairy subgroups were not related to HOMA...

  1. Apigenin and naringenin regulate glucose and lipid metabolism, and ameliorate vascular dysfunction in type 2 diabetic rats.

    Ren, Bei; Qin, Weiwei; Wu, Feihua; Wang, Shanshan; Pan, Cheng; Wang, Liying; Zeng, Biao; Ma, Shiping; Liang, Jingyu

    2016-02-15

    Vascular endothelial dysfunction is regarded as the initial step of vascular complications in diabetes mellitus. This study investigated the amelioration of apigenin and naringenin in type 2 diabetic (T2D) rats induced by high-fat diet and streptozotocin and explored the underlying mechanism. Apigenin or naringenin was intragastrically administered at 50 or 100mg/kg once a day for 6 weeks. Biochemical parameters including blood glucose, glycated serum protein, serum lipid, insulin, superoxide dismutase (SOD), malonaldehyde and intercellular adhesion molecule-1 (ICAM-1) were measured. Vascular reactivity in isolated thoracic aortic rings was examined. Pathological features of the thoracic aorta were further observed through optical microscopy and transmission electron microscopy. Lastly, we evaluated their effects on insulin resistance of palmitic acid (PA)-induced endothelial cells. Compared with diabetic control group, apigenin and naringenin significantly decreased the levels of blood glucose, serum lipid, malonaldehyde, ICAM-1 and insulin resistance index, increased SOD activity and improved impaired glucose tolerance. Apigenin and naringenin restored phenylephrine-mediated contractions and acetylcholine or insulin-induced relaxations in aortic tissues. Furthermore, pathological damage in the thoracic aorta of apigenin and naringenin groups was more remissive than diabetic control group. In vitro, apigenin and naringenin inhibited NF-κB activation and ICAM-1 mRNA expression in PA-treated endothelial cells and improved nitric oxide production in the presence of insulin. In conclusion, both apigenin and naringenin can ameliorate glucose and lipid metabolism, as well as endothelial dysfunction in T2D rats at least in part by down-regulating oxidative stress and inflammation. In general, apigenin showed greater potency than naringenin equivalent.

  2. Post-translational inhibitory regulation of acid invertase induced by fructose and glucose in developing apple fruit

    张大鹏; 王永章

    2002-01-01

    Acid invertase (EC 3.2.1.26) is one of the key enzymes involved in the carbohydrate sink-organ development and the sink strength modulation in crops. The experiment conducted with 'Starkrimson' apple (Malus domestica Borkh) fruit showed that, during the fruit development, the activity of acid invertase gradually declined concomitantly with the progressive accumulation of fructose, glucose and sucrose, while Western blotting assay of acid invertase detected a 30 ku peptide of which the immuno-signal intensity increased during the fruit development. The immuno-localization via immunogold electron microscopy showed that, on the one hand, acid invertase was mainly located on the flesh cell wall with numbers of the immunosignals present in the vacuole at the late stage of fruit development; and on the other hand, the amount of acid invertase increased during fruit development, which was consistent with the results of Western blotting. The in vivo pre-incubation of fruit discs with soluble sugars showed that the activity of extractible acid invertase was inhibited by fructose or glucose, while Western blotting did not detect any changes in apparent quantity of the enzyme nor other peptides than 30 ku one. So it is considered that fructose and glucose induced the post-translational or translocational inhibitory regulation of acid invertase in developing apple fruit. The mechanism of the post-translational inhibition was shown different from both the two previously reported ones that proposed either the inhibition by hexose products in the in vitro chemical reaction equilibrium system or the inhibition by the proteinaceous inhibitors. It was hypothesized that fructose and glucose might induce acid invertase inhibition by modulating the expression of some inhibition-related genes or some structural modification of acid invertase.

  3. MicroRNA-29a is up-regulated in beta-cells by glucose and decreases glucose-stimulated insulin secretion

    Bagge, Annika; Clausen, Trine R; Larsen, Sylvester;

    2012-01-01

    Chronically elevated levels of glucose impair pancreatic beta-cell function while inducing beta-cell proliferation. MicroRNA-29a (miR-29a) levels are increased in several tissues in diabetic animals and mediate decreased insulin-stimulated glucose-transport of adipocytes. The aim was to investiga...

  4. Efficacy and safety of 131Ⅰ in treating hyperthyroidism combined with abnormal glucose metabolism%131Ⅰ治疗甲亢合并糖代谢异常的有效性和安全性

    劳丹华; 叶学和; 黄庆娟; 梁深; 谭宗连

    2011-01-01

    Objective To evaluate the efficacy and safety of 131Ⅰ in treating hyperthyroidism combined with abnormal glucose metabolism. Methods 108 patients with hyperthyroidism combined with abnormal glucose metabolism were divided into 131 Ⅰ group of 55 cases and antithyroid drug(ATD) group of 53 cases as contrast group. Compared the curative effect of hyperthyroidism, blood sugar,glycosylated hemoglobin(HbAlc), β-cell function and adverse reaction between the two groups. Results The total efficiency of hyperthyroidism in 131 Ⅰ group was obviously higher than that of the contrast group (P=0. 008). The hyperthyroidism recurrence rate of 131 Ⅰ group was evidently much lower than the contrast group (P=0. 001). The occurring rate of hypothyroidism in 131 Ⅰ group was evidently higher than the contrast group (P=0. 031). After treatment, fasting plasma glucose(FPG), two hour plasma glucose after breakfast (2hPG), bAlc and HOMA-IR in the 131Ⅰ group were evidently under than those in the contrast group (P <0.05). HOMA-IS was distinctly higher than that in the contrast group (P<0. 05). There was no other adverse reaction in 131 Ⅰ group, while diabetic ketoacidosis, hypoglycemia and other adverse reaction in the contrast group. Conclusion 131 Ⅰ has a good curative effect in treating hyperthyroidism combined with abnormal glucose metabolism,with little adverse reaction.%目的 评价131Ⅰ治疗甲状腺功能亢进症(甲亢)合并糖代谢异常的疗效及安全性.方法 108例甲亢合并糖代谢异常患者分为131Ⅰ治疗组55例和抗甲状腺药物(ATD)对照组53例,比较两组甲亢的疗效、血糖、糖化血红蛋白(HbA1c)、胰岛β细胞功能及不良反应.结果 治疗组甲亢总有效率显著高于对照组(P=0.008),复发率显著低于对照组(P=0.001),甲状腺功能减退症(甲减)发生率高于对照组(P=0.031),治疗后治疗组的空腹血糖(FPG)、餐后2 h血糖(2hPG)、HbA1c及胰岛素抵抗指数显著低于对照组(P<0

  5. Spleen tyrosine kinase mediates high glucose-induced transforming growth factor-{beta}1 up-regulation in proximal tubular epithelial cells

    Yang, Won Seok; Chang, Jai Won [Division of Nephrology, Department of Internal Medicine, Asan Medical Center, College of Medicine, University of Ulsan, Seoul (Korea, Republic of); Han, Nam Jeong [Department of Cell Biology, Asan Institute for Life Sciences, Seoul (Korea, Republic of); Lee, Sang Koo [Division of Nephrology, Department of Internal Medicine, Asan Medical Center, College of Medicine, University of Ulsan, Seoul (Korea, Republic of); Park, Su-Kil, E-mail: skpark@amc.seoul.kr [Division of Nephrology, Department of Internal Medicine, Asan Medical Center, College of Medicine, University of Ulsan, Seoul (Korea, Republic of)

    2012-09-10

    The role of spleen tyrosine kinase (Syk) in high glucose-induced intracellular signal transduction has yet to be elucidated. We investigated whether Syk is implicated in high glucose-induced transforming growth factor-{beta}1 (TGF-{beta}1) up-regulation in cultured human proximal tubular epithelial cells (HK-2 cell). High glucose increased TGF-{beta}1 gene expression through Syk, extracellular signal-regulated kinase (ERK), AP-1 and NF-{kappa}B. High glucose-induced AP-1 DNA binding activity was decreased by Syk inhibitors and U0126 (an ERK inhibitor). Syk inhibitors suppressed high glucose-induced ERK activation, whereas U0126 had no effect on Syk activation. High glucose-induced NF-{kappa}B DNA binding activity was also decreased by Syk inhibitors. High glucose increased nuclear translocation of p65 without serine phosphorylation of I{kappa}B{alpha} and without degradation of I{kappa}B{alpha}, but with an increase in tyrosine phosphorylation of I{kappa}B{alpha} that may account for the activation of NF-{kappa}B. Both Syk inhibitors and Syk-siRNA attenuated high glucose-induced I{kappa}B{alpha} tyrosine phosphorylation and p65 nuclear translocation. Depletion of p21-activated kinase 2 (Pak2) by transfection of Pak2-siRNA abolished high glucose-induced Syk activation. In summary, high glucose-induced TGF-{beta}1 gene transcription occurred through Pak2, Syk and subsequent ERK/AP-1 and NF-{kappa}B pathways. This suggests that Syk might be implicated in the diabetic kidney disease.

  6. Up-regulation of HIF-1α and VEGF Expression by Elevated Glucose Concentration and Hypoxia in Cultured Human Retinal Pigment Epithelial Cells

    XIAO Qing; ZENG Shuiqing; LING Shiqi; LV Mingliang

    2006-01-01

    In order to explore the effect of high glucose concentration and high glucose concentration with hypoxia on the production of hypoxia-inducible factor-1 α (HIF-1α) and vascular endothelial growth factor (VEGF), human RPE cells were cultured in 5.56 mmol/L glucose (control group), 5.56 mmol/L glucose with 150 μ mol/L CoCl2 (hypoxic group), 25 mmol/L glucose (high glucose group)and 25 mmol/L glucose with 150 μ mol/L CoCl2 (combination group). RT-PCR was used to detect the expression of HIF-1α and VEGF mRNAs. Western blot analysis was used to measure the levels of HIF-1α and VEGF proteins. Although the small amount of HIF-1α protein was able to be detected in high glucose group but not in control group, there was no significant difference between the expression of HIF-1α mRNA of RPE cells in high glucose group and that of RPE cells in control group.As compared with RPE cells in control group, the mRNA expression and the protein synthesis of VEGF in high glucose group were up-regulated. As compared with RPE cells in hypoxic group, the expression of HIF-1α mRNA of RPE cells in combination group was not different, but the protein synthesis of HIF-1 α, the mRNA expression and the protein synthesis of VEGF were more obviously up-regulated. In conclusion, high concentration glucose mainly influence the protein synthesis of HIF-1α of RPE cell, and HIF-1α protein is able to be accumulated in high concentration glucose.Under hypoxia, the HIF-1α protein induced by high concentration glucose is more stable, and the expression of VEGF is obviously increased. It is suggested that high concentration glucose may play a role in retinal neovascularization, especially at ischemia stage of diabetic retinopathy.

  7. Mechanisms of expression and translocation of major fission yeast glucose transporters regulated by CaMKK/phosphatases, nuclear shuttling, and TOR.

    Saitoh, Shigeaki; Mori, Ayaka; Uehara, Lisa; Masuda, Fumie; Soejima, Saeko; Yanagida, Mitsuhiro

    2015-01-15

    Hexose transporters are required for cellular glucose uptake; thus they play a pivotal role in glucose homeostasis in multicellular organisms. Using fission yeast, we explored hexose transporter regulation in response to extracellular glucose concentrations. The high-affinity transporter Ght5 is regulated with regard to transcription and localization, much like the human GLUT transporters, which are implicated in diabetes. When restricted to a glucose concentration equivalent to that of human blood, the fission yeast transcriptional regulator Scr1, which represses Ght5 transcription in the presence of high glucose, is displaced from the nucleus. Its displacement is dependent on Ca(2+)/calmodulin-dependent kinase kinase, Ssp1, and Sds23 inhibition of PP2A/PP6-like protein phosphatases. Newly synthesized Ght5 locates preferentially at the cell tips with the aid of the target of rapamycin (TOR) complex 2 signaling. These results clarify the evolutionarily conserved molecular mechanisms underlying glucose homeostasis, which are essential for preventing hyperglycemia in humans.

  8. Investigation and analysis of risk factors of abnormal glucose metabolism in pregnant women%妊娠期糖代谢异常相关因素调查分析

    吴红媛; 刘春燕

    2014-01-01

    目的:探讨妊娠期糖代谢异常发病的高危因素,为制定有效干预措施提供科学依据。方法采用前瞻性对照研究方法,收集2011年4至9月在珠海市妇幼保健院产科门诊行产前检查诊断的糖代谢异常孕妇(研究组)共108例,其中妊娠期糖尿病(GDM)75例、妊娠糖耐量异常(GIGT)33例;收集同期糖代谢正常孕妇91例(对照组),对两组孕妇的临床资料进行单因素及多因素回归分析,探讨各因素对妊娠期糖代谢异常发病的影响。结果一般情况分析显示,糖代谢异常孕妇年龄、孕前身体质量指数( BMI)、孕期体重增长、孕次及产次均大于正常孕妇( t 值分别为-6.567、-4.818、-1.929、-3.231、-3.270,均P<0.05);糖代谢异常孕妇高中以下文化程度的比例较对照组高,差异有统计学意义(χ2=5.642,P<0.05)。单因素分析发现,孕次、产次、文化程度、年龄≥30岁、孕前BMI≥24kg/m2、糖尿病家族史、不良孕产史、高脂血症、反复发生霉菌性阴道炎( VCC)、孕期大量甜食、孕期大量水果、孕期锻炼等因素与糖代谢异常的发生相关。多因素Logistic回归分析表明,孕期大量甜食、孕期大量水果、糖尿病家族史、孕前BMI≥24kg/m2、VCC、年龄≥30岁、孕期锻炼7个因素进入主效应模型,其中孕期锻炼为保护性因素,其他为危险因素。结论不合理饮食、糖尿病家族史、孕前超重、年龄≥30岁、反复发生霉菌性阴道炎为影响妊娠期糖代谢异常发生的高危因素,孕期锻炼为保护性因素。对存在高危因素的妇女在产前检查时应加强监护和指导。%Objective To explore the risk factors of abnormal glucose metabolism during pregnancy , so as to provide evidence for effective intervention .Methods A prospective case-control study was performed among 108 women with abnormal glucose metabolism

  9. Pancreatic Transdifferentiation and Glucose-Regulated Production of Human Insulin in the H4IIE Rat Liver Cell Line

    Binhai Ren

    2016-04-01

    Full Text Available Due to the limitations of current treatment regimes, gene therapy is a promising strategy being explored to correct blood glucose concentrations in diabetic patients. In the current study, we used a retroviral vector to deliver either the human insulin gene alone, the rat NeuroD1 gene alone, or the human insulin gene and rat NeuroD1 genes together, to the rat liver cell line, H4IIE, to determine if storage of insulin and pancreatic transdifferentiation occurred. Stable clones were selected and expanded into cell lines: H4IIEins (insulin gene alone, H4IIE/ND (NeuroD1 gene alone, and H4IIEins/ND (insulin and NeuroD1 genes. The H4IIEins cells did not store insulin; however, H4IIE/ND and H4IIEins/ND cells stored 65.5 ± 5.6 and 1475.4 ± 171.8 pmol/insulin/5 × 106 cells, respectively. Additionally, several β cell transcription factors and pancreatic hormones were expressed in both H4IIE/ND and H4IIEins/ND cells. Electron microscopy revealed insulin storage vesicles in the H4IIE/ND and H4IIEins/ND cell lines. Regulated secretion of insulin to glucose (0–20 mmol/L was seen in the H4IIEins/ND cell line. The H4IIEins/ND cells were transplanted into diabetic immunoincompetent mice, resulting in normalization of blood glucose. This data shows that the expression of NeuroD1 and insulin in liver cells may be a useful strategy for inducing islet neogenesis and reversing diabetes.

  10. The effects of high-intensity interval training on glucose regulation and insulin resistance: a meta-analysis.

    Jelleyman, C; Yates, T; O'Donovan, G; Gray, L J; King, J A; Khunti, K; Davies, M J

    2015-11-01

    The aim of this meta-analysis was to quantify the effects of high-intensity interval training (HIIT) on markers of glucose regulation and insulin resistance compared with control conditions (CON) or continuous training (CT). Databases were searched for HIIT interventions based upon the inclusion criteria: training ≥2 weeks, adult participants and outcome measurements that included insulin resistance, fasting glucose, HbA1c or fasting insulin. Dual interventions and participants with type 1 diabetes were excluded. Fifty studies were included. There was a reduction in insulin resistance following HIIT compared with both CON and CT (HIIT vs. CON: standardized mean difference [SMD] = -0.49, confidence intervals [CIs] -0.87 to -0.12, P = 0.009; CT: SMD = -0.35, -0.68 to -0.02, P = 0.036). Compared with CON, HbA1c decreased by 0.19% (-0.36 to -0.03, P = 0.021) and body weight decreased by 1.3 kg (-1.9 to -0.7, P < 0.001). There were no statistically significant differences between groups in other outcomes overall. However, participants at risk of or with type 2 diabetes experienced reductions in fasting glucose (-0.92 mmol L(-1), -1.22 to -0.62, P < 0.001) compared with CON. HIIT appears effective at improving metabolic health, particularly in those at risk of or with type 2 diabetes. Larger randomized controlled trials of longer duration than those included in this meta-analysis are required to confirm these results.

  11. Abnormal brain glucose metabolism and depressive mood in patients with pre-dialytic chronic kidney disease: SPM analysis of F-18 FDG positron emission tomography

    Jun, Sung Min; Song, Sang Heon; Kim, Seong Jang; Kim, Ji Hoon; Kwak, Ihm Soo; Kim, In Ju; Kim, Yong Ki [Pusan National University Hospital, Pusan (Korea, Republic of)

    2007-07-01

    The aim of this study was to investigate the relationship between depressive mood and pre-dialytic CKD, to localize and quantify depressive mood -related lesions in pre-dialytic CKD patients through statistical parametric mapping (SPM) analysis of brain positron emission tomography (PET), and to examine the usefulness of brain PET for early detection and proper treatment of depressive mood. Twenty one patients with stage 5 CKD and 22 healthy volunteers were analyzed by depressive mood assessment and statistical parametric mapping (SPM) analysis of 18F-FDG PET. Depressive mood assessment was done by Beck Depression Inventory (BDI) and Hamilton Depression Rating Scale (HDRS). The largest clusters were areas including precentral gyrus, prefrontal cortex, and anterior cingulated cortex of left hemisphere. Other clusters were left transverse temporal gyrus, left superior temporal gyrus, right prefrontal cortex, right dorsolateral prefrontal cortex (BA 46, 44), right inferior frontal gyrus, right inferior parietal lobule, left angular gyrus. In addition, correlation was found between hypometabolized areas and HDRS scores of CKD patients in right prefrontal cortex (BA 11) and right anterior cingulated gyrus (BA 24). In conclusion, this study demonstrated specific depressive mood-related abnormal metabolic lesion. Interestingly, in CKD patients with severe depressive mood, cerebral metabolism was similar to that of MDD.

  12. Down-regulation of UDP-glucose dehydrogenase affects glycosaminoglycans synthesis and motility in HCT-8 colorectal carcinoma cells

    Wang, Tsung-Pao; Pan, Yun-Ru; Fu, Chien-Yu; Chang, Hwan-You, E-mail: hychang@life.nthu.edu.tw

    2010-10-15

    UDP-glucose dehydrogenase (UGDH) catalyzes oxidation of UDP-glucose to yield UDP-glucuronic acid, a precursor of hyaluronic acid (HA) and other glycosaminoglycans (GAGs) in extracellular matrix. Although association of extracellular matrix with cell proliferation and migration has been well documented, the importance of UGDH in these behaviors is not clear. Using UGDH-specific small interference RNA to treat HCT-8 colorectal carcinoma cells, a decrease in both mRNA and protein levels of UGDH, as well as the cellular UDP-glucuronic acid and GAG production was observed. Treatment of HCT-8 cells with either UGDH-specific siRNA or HA synthesis inhibitor 4-methylumbelliferone effectively delayed cell aggregation into multicellular spheroids and impaired cell motility in both three-dimensional collagen gel and transwell migration assays. The reduction in cell aggregation and migration rates could be restored by addition of exogenous HA. These results indicate that UGDH can regulate cell motility through the production of GAG. The enzyme may be a potential target for therapeutic intervention of colorectal cancers.

  13. AMP-activated protein kinase acts as a negative regulator of high glucose-induced RANKL expression in human periodontal ligament cells

    FENG Yuan; LIU Jia-qiang; LIU Hong-chen

    2012-01-01

    Background It is well known that the function of periodontal ligament cells may be affected by high glucose levels.This study investigated the direct effect of high glucose on the expression of receptor activator of nuclear factor-kappa B ligand (RANKL) in human PDL (hPDL) cells.In addition,we examined whether this effect was mediated via AMPK activation.Methods We examined the expression of osteoprotegerin in hPDL cells cultured at different concentrations of glucose using real-time polymerase chain reaction (PCR),and Western blotting analysis.AMPK phosphorylation in hPDL cells was studied using immunoprecipitate kinase assay and Western blotting.The effect of AMPK activation on RANKL expression in hPDL cells was investigated by real-time PCR and Western blotting.Results High glucose levels caused an increase in RANKL mRNA and protein expression in hPDL cells.Moreover,the amount of p-AMPK and AMPK activity was lower in hPDL cells exposed to high glucose levels than in cells exposed to normal glucose levels.Suppression of AMPK by Compound C augmented RANKL expression,and AMPK activation by metformin significantly decreased RANKL expression in hPDL cells.Additionally,metformin down-regulated RANKL expression in hPDL cells exposed to high glucose via AMPK activation.Conclusion High glucose-induced up-regulation of RANKL could be due to decreased AMPK activity,and AMPK activation may be involved in regulating of RANKL expression in hPDL cells.

  14. UDP-glucose pyrophosphorylase influences polysaccharide synthesis, cell wall components, and hyphal branching in Ganoderma lucidum via regulation of the balance between glucose-1-phosphate and UDP-glucose.

    Li, Mengjiao; Chen, Tianxi; Gao, Tan; Miao, Zhigang; Jiang, Ailiang; Shi, Liang; Ren, Ang; Zhao, Mingwen

    2015-09-01

    UDP-glucose pyrophosphorylase (UGP) is a key enzyme involved in carbohydrate metabolism, but there are few studies on the functions of this enzyme in fungi. The ugp gene of Ganoderma lucidum was cloned, and enzyme kinetic parameters of the UGP recombinant protein were determined in vitro, revealing that this protein was functional and catalyzed the reversible conversion between Glc-1-P and UDP-Glc. ugp silencing by RNA interference resulted in changes in the levels of the intermediate metabolites Glc-1-P and UDP-Glc. The compounds and structure of the cell wall in the silenced strains were also altered compared with those in the wild-type strains. Moreover, the number of hyphal branches was also changed in the silenced strains. To verify the role of UGP in hyphal branching, a ugp-overexpressing strain was constructed. The results showed that the number of hyphal branches was influenced by UGP. The mechanism underlying hyphal branching was further investigated by adding exogenous Glc-1-P. Our results showed that hyphal branching was regulated by a change in the cytosolic Ca(2+) concentration, which was affected by the level of the intermediate metabolite Glc-1-P, in G. lucidum. Our findings indicate the existence of an interaction between carbon metabolism and Ca(2+) signaling in this fungus.

  15. Abnormal glucose tolerance and insulin resistance in polycystic ovary syndrome amongst the Taiwanese population- not correlated with insulin receptor substrate-1 Gly972Arg/Ala513Pro polymorphism

    Liang Shu-Fen

    2006-04-01

    Full Text Available Abstract Background Insulin resistance and glucose dysmetabolism in polycystic ovary syndrome (PCOS are related with the polymorphisms in the genes encoding the insulin receptor substrate (IRS proteins, especially Gly972Arg/Ala513Pro polymorphism being reported to be associated with type-2 diabetes and PCOS. We intended to assess the prevalence of abnormal glucose tolerance (AGT and insulin resistance in Taiwanese PCOS women. We also tried to assess whether the particular identity of Gly972Arg/Ala513Pro polymorphic alleles of the IRS-1 gene mutation can be used as an appropriate diagnostic indicator for PCOS. Methods We designed a prospective clinical study. Forty-seven Taiwanese Hoklo and Hakka women, diagnosed with PCOS were enrolled in this study as were forty-five healthy Hoklo and Hakka women as the control group. Insulin resistance was evaluated with fasting insulin, fasting glucose/insulin ratio, and homeostasis model assessment index for insulin resistance (HOMAIR. The genomic DNA of the subjects was amplified by PCR and digested by restriction fragmented length polymorphism (RFLP with Bst N1 used for codon 972 and Dra III for codon 513. Results AGT was found in 46.8% of these PCOS patients and was significantly related to high insulin resistance rather than the low insulin resistance. Those patients with either insulin resistance or AGT comprised the majority of PCOS affected patients (AGT + fasting insulin ≥17: 83%, AGT + glucose/insulin ratio ≥6.5: 85.1%, AGT + HOMAIR ≥ 2: 87.2%, and AGT + HOMAIR ≥ 3.8: 72.3%. None of the tested samples revealed any polymorphism due to the absence of any Dra III recognition site or any Bst N1 recognition site in the amplified PCR fragment digested by restriction fragmented length polymorphism. Conclusion There is significantly high prevalence of AGT and insulin resistance in PCOS women, but Gly972Arg and Ala513Pro polymorphic alleles of IRS-1 are rare and are not associated with the elevated

  16. Short-term regulation of the hypothalamic melanocortinergic system under fasting and defined glucose-refeeding conditions in rats: a laser capture microdissection (LMD)-based study.

    Landmann, Emelie M; Schellong, Karen; Melchior, Kerstin; Rodekamp, Elke; Ziska, Thomas; Harder, Thomas; Plagemann, Andreas

    2012-04-25

    It is well established that under fasting conditions the expression of the orexigenic neuropeptide agouti-related peptide (AGRP) is up-regulated in the hypothalamic arcuate nucleus (ARC), while inconsistent data exist regarding fasting regulation of the anorexigenic neurohormone proopiomelanocortin (POMC). Inconsistencies might have methodological reasons, especially concerning neuromorphological and/or experimental (nutritional) specificity. We analyzed the expression of both neuropeptides in ARC neurons, using lasercapture microdissection (LMD) and real-time PCR in 12h fasted vs. fed Wistar rats as well as after a standardized glucose load, i.e., under clinically relevant conditions in terms of diagnosing glucose intolerance in the human. Under fasting conditions, clear up-regulation of AGRP was observed, with increasing magnitude in ARC single neurons (SNP) as compared to ARC cell layers (+125% vs. +23%, resp.), closely correlated to hypoinsulinemia and hypoleptinemia. Surprisingly, in the fasting state POMC was not found to be down-regulated, neither in ARC cell layers nor in ARC single neurons (+9% vs. +6%). However, glucose-refeeding under diagnostically relevant conditions led to strong neuronal up-regulation of POMC expression in ARC SNP (+128%), and AGRP down-regulation (-50%). In conclusion, experimentally, topographically, and analytically specific and standardized conditions confirmed AGRP in ARC neurons as being neuronally up- and down-regulated, resp., depending on the general nutritional state, while POMC was found to be (up-) regulated only after peripheral glucose load. Findings suggest that POMC in ARC neurons acts glucose-mediated as an "anti-orexigenic" neurohormone, specifically responding to hyperglycemia.

  17. PGC-1α integrates glucose metabolism and angiogenesis in multiple myeloma cells by regulating VEGF and GLUT-4.

    Cao, Dedong; Zhou, Hao; Zhao, Jikai; Jin, Lu; Yu, Wen; Yan, Han; Hu, Yu; Guo, Tao

    2014-03-01

    Human peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) is a key coactivator in the regulation of gene transcriptional activity in normal tissues. However, it is not clear whether it is involved in the angiogenesis and metabolism of multiple myeloma (MM). The aim of the present study was to investigate the role of PGC-1α in MM. Small interfering RNA (siRNA) was used to inhibit PGC-1α expression in RPMI-8226 cells. An endothelial cell migration assay was performed using transwell chambers and the expression of PGC-1α, estrogen-related receptor-α (ERR-α), vascular endothelial growth factor (VEGF) and glucose transporter-4 (GLUT-4) was tested by reverse transcription-polymerase chain reaction (RT-PCR). The protein expression of PGC-1α, ERR-α and GLUT-4 was assayed by western blot analysis. Lastly, RPMI-8226 cell proliferation was evaluated using CCK-8 assay. VEGF and GLUT-4 mRNA levels were decreased in cells treated with siRNA targeting PGC-1α, as was the level of GLUT-4 protein. Endothelial cell migration was significantly reduced when these cells were cultured with culture medium from RPMI-8226 cells treated with siPGC-1α. The proliferation rates at 24 and 48 h were suppressed by PGC-1α inhibition. Our results showed that inhibition of PGC-1α suppresses cell proliferation probably by downregulation of VEGF and GLUT-4. The present study suggests that PGC-1α integrates angiogenesis and glucose metabolism in myeloma through regulation of VEGF and GLUT-4.

  18. 不同糖代谢状态血管内皮功能变化及相关影响因素分析%Changes and influencing factors of vascular endothelial function in different abnormal glucose metabolism

    王蕾蕾; 张丽娜; 郭立新

    2015-01-01

    Objective To evaluate the vascular endothelial function and explore the related influencing factors in patients with abnormal glucose metabolism by use of ultrasound technology. Methods A total of 109 participants selected from endocrinology outpatients of Beijing Hospital from October 2011 to June 2013 were enrolled in this study. Oral glucose tolerance test(OGTT) was carried out, including fasting plasma glucose(FPG) and postprandial glucose(PPG), fasting and 2 hours after glucose load testing insulin, C-peptide, glycated hemoglobin A1c(HbA1c), glycated albumin(GA), lipids, liver and kidney function, blood uric acid,flow-mediated endothelium-dependent vasodilation (FMEDD), serum nitric oxide (NO), endothelin-1(ET-1), serum malondialdehyde(MDA) and superoxide dismutase(SOD).With the receiver operating characteristic (ROC)curve, the best critical points of fasting and glucose loading vascular endothelial function were obtained. Results (1)The critical points of FMEDD in the state of abnormal glucose metabolism: fasting FMEDD was 13.37%, Youden index was 0.467, and the area under the curve was 0.786 (95%CI:0.697⁃0.876);FMEDD of OGTT 2 h was 10.67%,Youden index was 0.458, and the area under the curve was 0.774(95% CI:0.687⁃0.861). (2)Body mass index(BMI), FPG, HbA1c, GA, triglyceride (TG), MDA in the patients withabnormal fasting FMEDD were significantly higher than those in the normalgroup(t=-3.013,-4.567,-3.487,-4.611,-2.309,-2.909, all P<0.05); and the homeostasis model assessment⁃β(HOMA⁃β), NO, SOD were significantly lower than those in the normal group(t=2.765,2.472, 5.937, all P<0.05). PPG, HbA1c, GA in the patients with abnormal FMEDD after glucose load were significantly higher than those in the normal group(t=-4.907,-4.236,-3.896, all P<0.05);and the HOMA⁃β, NO, SOD were all significantly lower than those in the normal group(t=2.704,4.675,4.633, all P<0.05).(3) FPG,HbA1c,GA were negatively correlated with fasting FMEDD(r=-0

  19. Histidine phosphocarrier protein regulates pyruvate kinase A activity in response to glucose in Vibrio vulnificus.

    Kim, Hey-Min; Park, Young-Ha; Yoon, Chang-Kyu; Seok, Yeong-Jae

    2015-04-01

    The bacterial phosphoenolpyruvate:sugar phosphotransferase system (PTS) consists of two general energy-coupling proteins [enzyme I and histidine phosphocarrier protein (HPr)] and several sugar-specific enzyme IIs. Although, in addition to the phosphorylation-coupled transport of sugars, various regulatory roles of PTS components have been identified in Escherichia coli, much less is known about the PTS in the opportunistic human pathogen Vibrio vulnificus. In this study, we have identified pyruvate kinase A (PykA) as a binding partner of HPr in V. vulnificus. The interaction between HPr and PykA was strictly dependent on the presence of inorganic phosphate, and only dephosphorylated HPr interacted with PykA. Experiments involving domain swapping between the PykAs of V. vulnificus and E. coli revealed the requirement for the C-terminal domain of V. vulnificus PykA for a specific interaction with V. vulnificus HPr. Dephosphorylated HPr decreased the Km of PykA for phosphoenolpyruvate by approximately fourfold without affecting Vmax . Taken together, these findings indicate that the V. vulnificus PTS catalyzing the first step of glycolysis stimulates the final step of glycolysis in the presence of glucose through the direct interaction of dephospho-HPr with the C-terminal domain of PykA.

  20. Methanolic extract of Momordica cymbalaria enhances glucose uptake in L6 myotubes in vitro by up-regulating PPAR-γ and GLUT-4.

    Kumar, Puttanarasaiah Mahesh; Venkataranganna, Marikunte V; Manjunath, Kirangadur; Viswanatha, Gollapalle L; Ashok, Godavarthi

    2014-12-01

    The present study was undertaken to evaluate the influence of the methanolic fruit extract of Momordica cymbalaria (MFMC) on PPARγ (Peroxisome Proliferator Activated Receptor gamma) and GLUT-4 (Glucose transporter-4) with respect to glucose transport. Various concentrations of MFMC ranging from 62.5 to 500 μg·mL(-1) were evaluated for glucose uptake activity in vitro using L6 myotubes, rosiglitazone was used as a reference standard. The MFMC showed significant and dose-dependent increase in glucose uptake at the tested concentrations, further, the glucose uptake activity of MFMC (500 μg·mL(-1)) was comparable with rosigilitazone. Furthermore, MFMC has shown up-regulation of GLUT-4 and PPARγ gene expressions in L6 myotubes. In addition, the MFMC when incubated along with cycloheximide (CHX), which is a protein synthesis inhibitor, has shown complete blockade of glucose uptake. This indicates that new protein synthesis is required for increased GLUT-4 translocation. In conclusion, these findings suggest that MFMC is enhancing the glucose uptake significantly and dose dependently through the enhanced expression of PPARγ and GLUT-4 in vitro.

  1. The RabGAP TBC1D1 plays a central role in exercise-regulated glucose metabolism in skeletal muscle

    Stöckli, Jacqueline; Meoli, Christopher C; Hoffman, Nolan J

    2015-01-01

    Insulin and exercise stimulate glucose uptake into skeletal muscle via different pathways. Both stimuli converge on the translocation of the glucose transporter GLUT4 from intracellular vesicles to the cell surface. Two Rab guanosine triphosphatases-activating proteins (GAPs) have been implicated...... weight, insulin action, and exercise. TBC1D1(-/-) mice showed normal glucose and insulin tolerance, with no difference in body weight compared with wild-type littermates. GLUT4 protein levels were reduced by ∼40% in white TBC1D1(-/-) muscle, and TBC1D1(-/-) mice showed impaired exercise endurance...... together with impaired exercise-mediated 2-deoxyglucose uptake into white but not red muscles. These findings indicate that the RabGAP TBC1D1 plays a key role in regulating GLUT4 protein levels and in exercise-mediated glucose uptake in nonoxidative muscle fibers....

  2. Glucose-Regulated Phosphorylation of the PUF Protein Puf3 Regulates the Translational Fate of Its Bound mRNAs and Association with RNA Granules

    Chien-Der Lee

    2015-06-01

    Full Text Available PUF proteins are post-transcriptional regulators that bind to the 3′ UTRs of mRNA transcripts. Herein, we show how a yeast PUF protein, Puf3p, responds to glucose availability to switch the fate of its bound transcripts that encode proteins required for mitochondrial biogenesis. Upon glucose depletion, Puf3p becomes heavily phosphorylated within its N-terminal region of low complexity, associates with polysomes, and promotes translation of its target mRNAs. Such nutrient-responsive phosphorylation toggles the activity of Puf3p to promote either degradation or translation of these mRNAs according to the needs of the cell. Moreover, activation of translation of pre-existing mRNAs might enable rapid adjustment to environmental changes without the need for de novo transcription. Strikingly, a Puf3p phosphomutant no longer promotes translation but becomes trapped in intracellular foci in an mRNA-dependent manner. Our findings suggest that the inability to properly resolve Puf3p-containing RNA-protein granules via a phosphorylation-based mechanism might be toxic to a cell.

  3. Ontogenetic profile and thyroid hormone regulation of type-1 and type-8 glucose transporters in rat Sertoli cells.

    Carosa, Eleonora; Radico, Carla; Giansante, Nadia; Rossi, Simona; D'Adamo, Fabio; Di Stasi, Savino M; Lenzi, Andrea; Jannini, Emmanuele A

    2005-04-01

    The glucose transporters (GLUTs) gene encode glycoproteins responsible for facilitating transfer of glucose across plasma membrane. In testis, different members of this family are present. In particular the main GLUT mRNA expression within the adult testis is the type 8, while type 1 is more expressed in prepubertal testis. Thyroid hormone, which receptors and function have been characterized in the testis, plays a crucial role in the cellular energetic metabolism. In fact, in the immature Sertoli cells, GLUT1 is up regulated by l-triiodothyronine (T(3)). The aim of this paper is to investigate the expression profile of GLUT1 and GLUT8 in the testis during development and in adulthood and analyse the role of T(3) on their expression. To analyse the expression of GLUT8 and GLUT1 we performed Northern blot and RT-PCR experiments in the whole testis and in Sertoli cells from rats of different ages. Treatments in vivo and in vitro with T(3) were used to study the effect of thyroid hormones on GLUT1 and GLUT8 expression. The activity of the rat GLUT1 promoter and its regulation by T(3) was studied with transient transfections in gonadal and non-gonadal cell lines and in primary Sertoli cell cultures. GLUT8 is expressed at a low level in the prepubertal testis and Sertoli cells and does not appear to be under T(3) control. GLUT1 is the predominant form in immature Sertoli cells. The effect of T(3) on its mRNA accumulation was quantified and confirmed by RT-PCR (control: 0.65 +/- 0.17; T(3): 1.23 +/- 0.04, arbitrary units, p regulate GLUT1 promoter in any cell line tested. This is confirmed by the evidence that, upon extensive analysis, the rat GLUT1 promoter and the first intron sequence do not shows any thyroid responsive elements. Our data demonstrate that GLUT1 and GLUT8 are both expressed in prepubertal testis, but only GLUT1 is regulated by T(3). In addition, we found that the effect of T(3) cannot be attributed to its action on GLUT1 promoter.

  4. Glucose-6-Phosphate Dehydrogenase Regulation in Anoxia Tolerance of the Freshwater Crayfish Orconectes virilis

    Benjamin Lant

    2011-01-01

    Full Text Available Glucose-6-phosphate dehydrogenase (G6PDH, the enzyme which catalyzes the rate determining step of the pentose phosphate pathway (PPP, controls the production of nucleotide precursor molecules (R5P and powerful reducing molecules (NADPH that support multiple biosynthetic functions, including antioxidant defense. G6PDH from hepatopancreas of the freshwater crayfish (Orconectes virilis showed distinct kinetic changes in response to 20 h anoxic exposure. Km values for both substrates decreased significantly in anoxic crayfish; Km NADP+ dropped from 0.015±0.008 mM to 0.012±0.008 mM, and Km G6P decreased from 0.13±0.02 mM to 0.08±0.007 mM. Two lines of evidence indicate that the mechanism involved is reversible phosphorylation. In vitro incubations that stimulated protein kinase or protein phosphatase action mimicked the effects on anoxia on Km values, whereas DEAE-Sephadex chromatography showed the presence of two enzyme forms (low- and high-phosphate whose proportions changed during anoxia. Incubation studies implicated protein kinase A and G in mediating the anoxia-responsive changes in G6PDH kinetic properties. In addition, the amount of G6PDH protein (measured by immunoblotting increased by ∼60% in anoxic hepatopancreas. Anoxia-induced phosphorylation of G6PDH could contribute to modifying carbon flow through the PPP under anoxic conditions, potentially maintaining NADPH supply for antioxidant defense during prolonged anoxia-induced hypometabolism.

  5. SH2B1 regulation of energy balance, body weight, and glucose metabolism

    Liangyou; Rui

    2014-01-01

    The Src homology 2B(SH2B)family members(SH2B1,SH2B2 and SH2B3)are adaptor signaling proteins containing characteristic SH2 and PH domains.SH2B1(also called SH2-B and PSM)and SH2B2(also called APS)are able to form homo-or hetero-dimers via their N-terminal dimerization domains.Their C-terminal SH2 domains bind to tyrosyl phosphorylated proteins,including Janus kinase 2(JAK2),TrkA,insulin receptors,insulin-like growth factor-1 receptors,insulin receptor substrate-1(IRS1),and IRS2.SH2B1 enhances leptin signaling by both stimulating JAK2 activity and assembling a JAK2/IRS1/2 signaling complex.SH2B1 promotes insulin signaling by both enhancing insulin receptor catalytic activity and protecting against dephosphorylation of IRS proteins.Accordingly,genetic deletion of SH2B1 results in severe leptin resistance,insulin resistance,hyperphagia,obesity,and type 2 diabetes in mice.Neuronspecific overexpression of SH2B1βtransgenes protects against diet-induced obesity and insulin resistance.SH2B1 in pancreaticβcells promotesβcell expansion and insulin secretion to counteract insulin resistance in obesity.Moreover,numerous SH2B1 mutations are genetically linked to leptin resistance,insulin resistance,obesity,and type 2 diabetes in humans.Unlike SH2B1,SH2B2 and SH2B3 are not required for the maintenance of normal energy and glucose homeostasis.The metabolic function of the SH2B family is conserved from insects to humans.

  6. 农村高血压患者血糖与血脂参数改变的调查%Investigation on abnormality of glucose and lipid metabolism in patients with hypertension in rural area

    鲁永华; 诸葛毅; 徐军

    2012-01-01

    Objective:To observe the abnormality of glucose and lipid metabolism in patients with hypertension in rural population in mountain area of Kaihua county and to provide a reference for the prevention and treatment of cardiovascular disease. Methods:298 cases of patients with hypertension in rural population in mountain area of Kaihua county as objective group and 291 cases of healthy people as control group were investigated with total cholesterol, triglyceride,high density lipoprotein cholesterol, low density lipoprotein cholesterol and fasting plasma glucose. The comparative study was done. Results:There were 84 cases of patients with hyperlipidemia in objective group and 21 cases with hyperlipidemia in control group, x =44.2,P<0.01. There was a low positive correlation( r = 0. 117, P < 0. 05 ) between diastolic pressure and total cholesterol of plasma in patients with hypertension. Conclusion:The fact showed that abnormality of glucose and lipid metabolism in patients with hypertension in rural population in mountain area of Kaihua county was present. Glucose, lipid parameters contributed to the clinical observation of disease in patients with hypertension. Health education should be carried out and rural population should be encouraged to cultivate a healthy mode of life. The measures to adjust the blood lipid levels should be carried out.%目的:调查开化山区高血压患者的血糖与血脂代谢异常,为心血管疾病的防治提供参考依据.方法:298例高血压患者为观察组,291例健康人为对照组,测定空腹血糖、总胆固醇、甘油三酯、高密度脂蛋白胆固醇、低密度脂蛋白胆固醇,比较分析.结果:高血压观察组检出高血脂84例,对照组检出高血脂21例,x2=44.2,P<0.01.高血压组舒张压与血总胆固醇之间呈低度显著正相关(r为0.117,P<0.05).结论:开化山区高血压患者存在血糖、血脂参数的异常改变,测定血糖、血脂参数有助于临床观察高血压患者

  7. Establishment and Evaluation of Rat Model of Metabolic Syndrome with Abnormal Glucose Metabolism%糖代谢异常的代谢综合征大鼠模型的建立及评价

    姜楠; 石岩; 蒲纪; 张文顺; 张冰冰; 马贤德

    2011-01-01

    Objective:To establish and to evaluate rat model of metabolic syndrome (MS) with abnormal glucose metablism. Method: Wistar male rats were fed with a diet of high fat, salt and sugar for 12 weeks.Afterwards, body weight, blood pressure, blood glucose, triglycerides, high density lipoprotein and insulin level were determined. According to the MS diagnostic criteria established by Chinese Diabetes Society (CDS) and statistical theory, the model was evaluated. Result: In the first 8 weeks, rats were significantly increased body weight and systolic blood pressure; in the first 12 weeks, fasting blood glucose, triglycerides, insulin level were significantly elevated, high-density lipoprotein significantly reduced. Based on the evaluation criteria, a success rate of 80% for the model was found. Conclusion: We successfully established the rat model of MS with abnormal glucose metabolism, and also the preliminary evaluation criteria for the model.%目的:建立糖代谢异常的代谢综合征大鼠模型及其评价标准.方法:采用高脂高盐高糖饮食配合饮用蔗糖水喂养Wistar雄性大鼠12周,喂养结束后检测其体重、血压、血糖、甘油三酯、高密度脂蛋白及胰岛素水平.根据中华医学会糖尿病学分会关于代谢综合征(MS)的诊断标准和统计学原理建立模型评价标准.结果:第8周开始,高脂高糖高盐膳食组大鼠体重(367±17)g和收缩压(130.67±4.31)mmHg与普通膳食对照组比较显著升高(P<0.01);第12周时,大鼠空腹血糖(10.51±0.89)mmol·L-1、甘油三酯(1.63±0.23)mmol·L-1、胰岛素水平(1.97±1.07)mmol·L-1显著升高(P<0.01或P<0.05),高密度脂蛋白(0.54±0.07)mmol·L-1显著降低(P<0.01).根据评价标准,模型成功率达到80%.结论:实验成功建立了糖代谢异常的MS大鼠模型,并初步建立了该模型的评价标准.

  8. Involvement of capsaicin-sensitive nerves in regulation of insulin secretion and glucose tolerance in conscious mice

    Karlsson, Sven; Scheurink, Anton J.W.; Steffens, Anton B.; Ahrén, Bo

    1994-01-01

    The impact of sensory nerves in glucose-stimulated insulin secretion and glucose tolerance was investigated in conscious mice treated neonatally with either capsaicin (Cap) or vehicle (Veh). At 10-12 wk after Cap, both the early (1 min) insulin secretory response to intravenous glucose (2.8 mmol/kg)

  9. 2-Deoxy glucose regulate MMP-9 in a SIRT-1 dependent and NFkB independent mechanism.

    Edatt, Lincy; Haritha, K; Sruthi, T V; Aswini, P; Sameer Kumar, V B

    2016-12-01

    MMP9 is a member of the family of zinc-containing endopeptidases which degrade various components of the extracellular matrix, thereby regulating matrix remodeling. Since matrix remodeling plays an important role during growth and progression of cancer and considering the fact that, tumor cells switch to aerobic glycolysis as its major energy source, this study was designed to analyze if partial inhibition of glycolysis (the major energy pathway during hypoxia) can be used as a means to control matrix remodeling in terms of MMP9 activity and expression. For this, human epithelial carcinoma cells were treated with glycolytic inhibitor, 2-deoxy glucose (2DG) at sub-lethal concentrations followed by analysis of the expression and activity of MMP2 and MMP9. The experimental findings demonstrate that exposure of cancer cells to glycolytic inhibitor at concentration that does not induce ER stress, downregulates the activity and expression of MMP9 without affecting the expression levels and activity of MMP2. Further mechanistic analysis revealed that the regulation of MMP9 was mediated in a SIRT-1 dependent mechanism and did not alter the NFkB signaling pathway. The overall results presented here, therefore suggest that the use of glycolytic inhibitor, 2DG at concentration that do not affect cell viability or induce ER stress can be an effective strategy to control matrix remodeling.

  10. FGF19 regulates cell proliferation, glucose and bile acid metabolism via FGFR4-dependent and independent pathways.

    Ai-Luen Wu

    Full Text Available Fibroblast growth factor 19 (FGF19 is a hormone-like protein that regulates carbohydrate, lipid and bile acid metabolism. At supra-physiological doses, FGF19 also increases hepatocyte proliferation and induces hepatocellular carcinogenesis in mice. Much of FGF19 activity is attributed to the activation of the liver enriched FGF Receptor 4 (FGFR4, although FGF19 can activate other FGFRs in vitro in the presence of the coreceptor βKlotho (KLB. In this report, we investigate the role of FGFR4 in mediating FGF19 activity by using Fgfr4 deficient mice as well as a variant of FGF19 protein (FGF19v which is specifically impaired in activating FGFR4. Our results demonstrate that FGFR4 activation mediates the induction of hepatocyte proliferation and the suppression of bile acid biosynthesis by FGF19, but is not essential for FGF19 to improve glucose and lipid metabolism in high fat diet fed mice as well as in leptin-deficient ob/ob mice. Thus, FGF19 acts through multiple receptor pathways to elicit pleiotropic effects in regulating nutrient metabolism and cell proliferation.

  11. FGF19 regulates cell proliferation, glucose and bile acid metabolism via FGFR4-dependent and independent pathways.

    Wu, Ai-Luen; Coulter, Sally; Liddle, Christopher; Wong, Anne; Eastham-Anderson, Jeffrey; French, Dorothy M; Peterson, Andrew S; Sonoda, Junichiro

    2011-03-18

    Fibroblast growth factor 19 (FGF19) is a hormone-like protein that regulates carbohydrate, lipid and bile acid metabolism. At supra-physiological doses, FGF19 also increases hepatocyte proliferation and induces hepatocellular carcinogenesis in mice. Much of FGF19 activity is attributed to the activation of the liver enriched FGF Receptor 4 (FGFR4), although FGF19 can activate other FGFRs in vitro in the presence of the coreceptor βKlotho (KLB). In this report, we investigate the role of FGFR4 in mediating FGF19 activity by using Fgfr4 deficient mice as well as a variant of FGF19 protein (FGF19v) which is specifically impaired in activating FGFR4. Our results demonstrate that FGFR4 activation mediates the induction of hepatocyte proliferation and the suppression of bile acid biosynthesis by FGF19, but is not essential for FGF19 to improve glucose and lipid metabolism in high fat diet fed mice as well as in leptin-deficient ob/ob mice. Thus, FGF19 acts through multiple receptor pathways to elicit pleiotropic effects in regulating nutrient metabolism and cell proliferation.

  12. Up-regulation of heme oxygenase-1 by isoflurane preconditioning during tolerance against neuronal injury induced by oxygen glucose deprivation

    Qifang Li; Yesen Zhu; Hong Jiang; Hui Xu; Heping Liu

    2008-01-01

    Heme oxygenase (HO) is the rate-limiting enzyme in the degradation of heme to produce bile pigments and carbon monoxide. The HO-1 isozyme is induced by a variety of factors such as heat, heme, ischemia, and hydrogen peroxide. In recent years, mounting findings have suggested that HO-1 has a neuroprotective activity against ischemic injury. The neuroprotective role of isoflurane, a commonly used anesthetic, has been well documented, but little is known about the underlying mechanisms involved. Recently, isoflurane has been shown to up-regulate HO-1 in the liver. In this study,we show that isoflurane preconditioning promotes the survival of cultured ischemic hippocampal neurons by increasing the number of surviving neurons and their viability. Further study by reverse transcription-polymerase chain reaction and Western blot analysis showed that isoflurane preconditioning significantly increases HO-1 expression in oxygen glucose deprivation (OGD)-induced neuronal injury. Furthermore,inhibition of HO activity by tin protoporphyrin partially abolishes isoflurane preconditioning's protective effect as measured by lactate dehydrogenase release in OGD neurons.These findings indicated that the neuroprotective role of isoflurane preconditioning against OGD-induced injury might be associated with its role in up-regulating HO-1 in ischemic neurons.

  13. Up-regulation of heme oxygenase-1 by isoflurane preconditioning during tolerance against neuronal injury induced by oxygen glucose deprivation.

    Li, Qifang; Zhu, Yesen; Jiang, Hong; Xu, Hui; Liu, Heping

    2008-09-01

    Heme oxygenase (HO) is the rate-limiting enzyme in the degradation of heme to produce bile pigments and carbon monoxide. The HO-1 isozyme is induced by a variety of factors such as heat, heme, ischemia, and hydrogen peroxide. In recent years, mounting findings have suggested that HO-1 has a neuroprotective activity against ischemic injury. The neuroprotective role of isoflurane, a commonly used anesthetic, has been well documented, but little is known about the underlying mechanisms involved. Recently, isoflurane has been shown to up-regulate HO-1 in the liver. In this study, we show that isoflurane preconditioning promotes the survival of cultured ischemic hippocampal neurons by increasing the number of surviving neurons and their viability. Further study by reverse transcription-polymerase chain reaction and Western blot analysis showed that isoflurane preconditioning significantly increases HO-1 expression in oxygen glucose deprivation (OGD)-induced neuronal injury. Furthermore, inhibition of HO activity by tin protoporphyrin partially abolishes isoflurane preconditioning's protective effect as measured by lactate dehydrogenase release in OGD neurons. These findings indicated that the neuroprotective role of isoflurane preconditioning against OGD-induced injury might be associated with its role in up-regulating HO-1 in ischemic neurons.

  14. Testosterone Protects Mitochondrial Function and Regulates Neuroglobin Expression in Astrocytic Cells Exposed to Glucose Deprivation

    Toro-Urrego, Nicolas; Garcia-Segura, Luis M.; Echeverria, Valentina; Barreto, George E.

    2016-01-01

    Testosterone is a hormone that has been shown to confer neuroprotection from different insults affecting the central nervous system (CNS). Testosterone induces this protection by different mechanisms that include the activation of anti-apoptotic pathways that are directly implicated in neuronal survival. However, little attention has been devoted to its actions on glial cells. In the present study, we have assessed whether testosterone exerts protection in a human astrocyte cell model, the T98G cells. Our results indicate that testosterone improves cell survival and mitochondrial membrane potential and reduces nuclear fragmentation and reactive oxygen species (ROS) generation. These effects were accompanied by a positive regulation of neuroglobin, an oxygen-binding and sensor protein, which may serve as a regulator of ROS and nitrogen reactive species (NOS), and these protective effects of testosterone may be at least in part mediated by estradiol and DHT. In conclusion, these findings suggest that astroglia may mediate some of the protective actions of testosterone in the brain upon pathological conditions. PMID:27445795

  15. Effect of cocoa and green tea on biomarkers of glucose regulation, oxidative stress, inflammation and hemostasis in obese adults at risk for insulin resistance

    Flavanols may provide protection against insulin resistance, but little is known about the amounts and types of flavanols that may be efficacious. This study was designed to determine whether cocoa flavanols, over a range of intakes, improve biomarkers of glucose regulation, inflammation and hemost...

  16. 糖脂代谢异常对肝硬化患者疾病进展的影响%Impact of abnormal glucose and lipid metabolism on the progression of disease in patients with cirrhosis

    岑光力; 岑柏春

    2015-01-01

    ,triglycerides (TG) in patients with different Child-Pugh score had no statistically significant difference,P =0.558,0.169.The level of serum albumin (ALB) of patients with DM in cirrhosis was significantly lower than those without DM,P =0.009.The patients with DM in liver cirrhosis had higher incidence of complications such as ascites,gastro esophageal variceal bleeding(GEVB) or hepatic encephalopathy than those without DM,P =0.000.Conclusion The patients with cirrhosis had higher incidence of abnormal glucose metabolism,and DM lead to progression of liver disease in turn.

  17. Influence of pH Regulation Mode in Glucose Fermentation on Product Selection and Process Stability

    Zuhaida Mohd-Zaki

    2016-01-01

    Full Text Available Mixed culture anaerobic fermentation generates a wide range of products from simple sugars, and is potentially an effective process for producing renewable commodity chemicals. However it is difficult to predict product spectrum, and to control the process. One of the key control handles is pH, but the response is commonly dependent on culture history. In this work, we assess the impact of pH regulation mode on the product spectrum. Two regulation modes were applied: in the first, pH was adjusted from 4.5 to 8.5 in progressive steps of 0.5 and in the second, covered the same pH range, but the pH was reset to 5.5 before each change. Acetate, butyrate, and ethanol were produced throughout all pH ranges, but there was a shift from butyrate at pH < 6.5 to ethanol at pH > 6.5, as well as a strong and consistent shift from hydrogen to formate as pH increased. Microbial analysis indicated that progressive pH resulted in dominance by Klebsiella, while reset pH resulted in a bias towards Clostridium spp., particularly at low pH, with higher variance in community between different pH levels. Reset pH was more responsive to changes in pH, and analysis of Gibbs free energy indicated that the reset pH experiments operated closer to thermodynamic equilibrium, particularly with respect to the formate/hydrogen balance. This may indicate that periodically resetting pH conforms better to thermodynamic expectations.

  18. Abnormal insulin levels and vertigo.

    Proctor, C A

    1981-10-01

    Fifty patients with unexplained vertigo (36) or lightheadedness (14) are evaluated, all of whom had abnormal ENGs and normal audiograms. Five hour insulin glucose tolerance tests were performance on all patients, with insulin levels being obtained fasting and at one-half, one, two, and three hours. The results of this investigation were remarkable. Borderline or abnormal insulin levels were discovered in 82% of patients; 90% were found to have either an abnormal glucose tolerance test or at least borderline insulin levels. The response to treatment in these dizzy patients was also startling, with appropriate low carbohydrate diets improving the patient's symptoms in 90% of cases. It is, therefore, apparent that the earliest identification of carbohydrate imbalance with an insulin glucose tolerance test is extremely important in the work-up of the dizzy patients.

  19. Impacts of Abnormal Glucose Metabolism on Chronic Ischemic Leukoaraiosis%糖代谢异常对慢性缺血性脑白质疏松的影响

    王君梅; 李静; 金桂花; 田沈

    2014-01-01

    目的:探究糖代谢异常对慢性缺血性脑白质疏松(LA)的影响。方法回顾性分析2013年6月~12月中国医科大学附属第四医院神经内科收治的258例缺血性脑血管疾病患者的临床资料。根据病史及化验结果将糖代谢情况分为正常糖代谢、2型糖尿病以及前驱期糖尿病,依据头MRI结果对LA严重程度进行分级,分析比较不同糖代谢情况以及不同血糖化验指标(包括FPG、2hPG及HbA1c)对慢性缺血性脑白质疏松及其严重程度的影响。结果单因素分析显示,慢性缺血性脑白质疏松的相关危险因素有年龄、高血压病史、糖尿病病史、糖代谢异常、甘油三酯、2hPG(OR>1,P<0.05)。Logistic回归分析显示脑白质疏松与年龄、高血压病史、2hPG相关(P<0.05)。Spearman秩相关检验显示LA严重程度分级与年龄大小、高血压病史时长、2hPG水平呈正相关,与HDL、apoA、腔梗病史呈负相关(P<0.05,r=0.402、0.227、0.135、-0.154、-0.147、-0.312)。结论年龄、高血压病史、糖尿病病史、糖代谢异常、2hPG、甘油三酯是脑白质疏松的危险因素;年龄越大、高血压病史时间越长、2hPG越高、HDL及apoA越低,脑白质疏松越严重;而FPG、HbA1c、前驱期糖尿病、糖尿病及其时长与脑白质疏松的严重程度无相关性。%Objective To explore the impacts of abnormal glucose metabolism on chronic ischemic leukoaraiosis (LA).Methods The clinical data of 258 patients with ischemic cerebrovascular disease were analyzed who were cured in the Fourth Affi liated Hospital of China Medical University from Jun to December in 2013. According to the medical history and laboratory reports, these patients were divided into normal glucose metabolism group, type 2 diabetes group and pre-diabetes group. Based on the results of head MRI, the severity of leukoaraiosis was graded. Then we compared and analyzed the impacts of

  20. Regulation of gene expression by glucose in pancreatic beta -cells (MIN6) via insulin secretion and activation of phosphatidylinositol 3'-kinase.

    da Silva Xavier, G; Varadi, A; Ainscow, E K; Rutter, G A

    2000-11-17

    Increases in glucose concentration control the transcription of the preproinsulin (PPI) gene and several other genes in the pancreatic islet beta-cell. Although recent data have demonstrated that secreted insulin may regulate the PPI gene (Leibiger, I. B., Leibiger, B., Moede, T., and Berggren, P. O. (1998) Mol. Cell 1, 933-938), the role of insulin in the control of other beta-cell genes is unexplored. To study the importance of insulin secretion in the regulation of the PPI and liver-type pyruvate kinase (L-PK) genes by glucose, we have used intranuclear microinjection of promoter-luciferase constructs into MIN6 beta-cells and photon-counting imaging. The activity of each promoter was increased either by 30 (versus 3) mm glucose or by 1-20 nm insulin. These effects of insulin were not due to enhanced glucose metabolism since culture with the hormone had no impact on the stimulation of increases in intracellular ATP concentration caused by 30 mm glucose. Furthermore, the islet-specific glucokinase promoter and cellular glucokinase immunoreactivity were unaffected by 30 mm glucose or 20 nm insulin. Inhibition of insulin secretion with the Ca(2+) channel blocker verapamil, the ATP-sensitive K(+) channel opener diazoxide, or the alpha(2)-adrenergic agonist clonidine blocked the effects of glucose on L-PK gene transcription. Similarly, 30 mm glucose failed to induce the promoter after inhibition of phosphatidylinositol 3'-kinase activity with LY294002 and the expression of dominant negative-acting phosphatidylinositol 3'-kinase (Deltap85) or the phosphoinositide 3'-phosphatase PTEN (phosphatase and tensin homologue). LY294002 also diminished the activation of the L-PK gene caused by inhibition of 5'-AMP-activated protein kinase with anti-5'-AMP-activated protein kinase alpha2 antibodies. Conversely, stimulation of insulin secretion with 13 mm KCl or 10 microm tolbutamide strongly activated the PPI and L-PK promoters. These data indicate that, in MIN6 beta

  1. Meiotic abnormalities

    NONE

    1993-12-31

    Chapter 19, describes meiotic abnormalities. These include nondisjunction of autosomes and sex chromosomes, genetic and environmental causes of nondisjunction, misdivision of the centromere, chromosomally abnormal human sperm, male infertility, parental age, and origin of diploid gametes. 57 refs., 2 figs., 1 tab.

  2. Effects of the Non-Nutritive Sweeteners on Glucose Metabolism and Appetite Regulating Hormones: Systematic Review of Observational Prospective Studies and Clinical Trials

    Romo-Romo, Alonso; Aguilar-Salinas, Carlos A.; Brito-Córdova, Griselda X.; Gómez Díaz, Rita A.; Vilchis Valentín, David

    2016-01-01

    Background The effects of non-nutritive sweeteners (NNS) on glucose metabolism and appetite regulating hormones are not clear. There is an ongoing debate concerning NNS use and deleterious changes in metabolism. Objectives The aim of this review is to analyze the scientific available evidence regarding the effects of NNS on glucose metabolism and appetite regulating hormones. Data Sources and Study Eligibility Criteria We identified human observational studies evaluating the relation between NNS consumption and obesity, diabetes, and metabolic syndrome, in addition to clinical trials evaluating the effects of NNS in glucose metabolism and appetite regulating hormones. Results Fourteen observational studies evaluating the association between NNS consumption and the development of metabolic diseases and twenty-eight clinical trials studying the effects of NNS on metabolism were included. Finally, two meta-analyses evaluating the association between the consumption of NNS-containing beverages and the development of type 2 diabetes were identified. Conclusions Some observational studies suggest an association between NNS consumption and development of metabolic diseases; however, adiposity is a confounder frequently found in observational studies. The effects of the NNS on glucose metabolism are not clear. The results of the identified clinical trials are contradictory and are not comparable because of the major existing differences between them. Studies evaluating specific NNS, with an adequate sample size, including a homogeneous study group, identifying significant comorbidities, with an appropriate control group, with an appropriate exposure time, and considering adjustment for confounder variables such as adiposity are needed. PMID:27537496

  3. Meiotic prophase abnormalities and metaphase cell death in MLH1-deficient mouse spermatocytes: insights into regulation of spermatogenic progress.

    Eaker, Shannon; Cobb, John; Pyle, April; Handel, Mary Ann

    2002-09-01

    The MLH1 protein is required for normal meiosis in mice and its absence leads to failure in maintenance of pairing between bivalent chromosomes, abnormal meiotic division, and ensuing sterility in both sexes. In this study, we investigated whether failure to develop foci of MLH1 protein on chromosomes in prophase would lead to elimination of prophase spermatocytes, and, if not, whether univalent chromosomes could align normally on the meiotic spindle and whether metaphase spermatocytes would be delayed and/or eliminated. In spite of the absence of MLH1 foci, no apoptosis of spermatocytes in prophase was detected. In fact, chromosomes of pachytene spermatocytes from Mlh1(-/-) mice were competent to condense metaphase chromosomes, both in vivo and in vitro. Most condensed chromosomes were univalents with spatially distinct FISH signals. Typical metaphase events, such as synaptonemal complex breakdown and the phosphorylation of Ser10 on histone H3, occurred in Mlh1(-/-) spermatocytes, suggesting that there is no inhibition of onset of meiotic metaphase in the face of massive chromosomal abnormalities. However, the condensed univalent chromosomes did not align correctly onto the spindle apparatus in the majority of Mlh1(-/-) spermatocytes. Most meiotic metaphase spermatocytes were characterized with bipolar spindles, but chromosomes radiated away from the microtubule-organizing centers in a prometaphase-like pattern rather than achieving a bipolar orientation. Apoptosis was not observed until after the onset of meiotic metaphase. Thus, spermatocytes are not eliminated in direct response to the initial meiotic defect, but are eliminated later. Taken together, these observations suggest that a spindle assembly checkpoint, rather than a recombination or chiasmata checkpoint, may be activated in response to meiotic errors, thereby ensuring elimination of chromosomally abnormal gamete precursors.

  4. Regulation of glucose transport in the NIH 3T3 L1 preadipocyte cell line by TCDD.

    1994-01-01

    This study examined the changes in cellular glucose uptake induced by 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) as measured by quantification of intracellular radioactivity in the NIH 3T3 L1 preadipocyte cell line after a 30-minute incubation with the non-metabolizable radioactive analogue of glucose, 3-O-methyl-D-[1-3H] glucose. Treatment of differentiated NIH 3T3 L1 cells with TCDD produced a time- and dose-dependent decrease in the cellular uptake of glucose. Treatment of cells for 3 hr w...

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

    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.

  6. Investment Choice and Perceived Mating Intentions Regulated by External Resource Cues and Internal Fluctuation in Blood Glucose Levels

    Li-Lin eRao

    2015-01-01

    Full Text Available We examined resource allocation priorities in the framework of an updated Maslow hierarchy of fundamental human needs. In Experiment 1, the participants in the food abundance priming condition viewing photos of high-calorie food allocated more money to savings than to spending. However, the participants preferred spending to savings under the condition of mating availability priming with romantic photographs. In Experiment 2, before and after drinking either water or a sugary beverage, fasting participants rated photos of a conversation between a man and a woman. Water drinking lowered the rating scores of mating intentions as well as blood glucose (BG levels. The sugary drink buffered this decline in sexual perceptivity. Overall, the change in BG levels was positively associated with changes in the ratings of mating intentions but was not associated with other likelihood ratings. These results suggest that both external cues of food and mating resources and internal BG fluctuation regulate the cognitive priority of physiological needs versus mate acquisition and retention.

  7. Identification and functional characterization of a glucose regulated protein 94 gene in Litopenaeus vannamei and its responsiveness in WSSV infection.

    Bi, Hai-Tao; Yuan, Feng-Hua; Yuan, Kai; Weng, Shao-Ping; He, Jian-Guo; Chen, Yi-Hong

    2016-05-01

    In the current study, a cDNA of glucose regulated protein 94 (LvGRP94) was cloned from Litopenaeus vannamei. Subcellular localization assay revealed that LvGRP94 expressed in endoplasmic reticulum (ER). And results of reported gene assays demonstrated that the promoter of LvGRP94 was activated by L. vannamei leucine zipper domain transcription factor X-box binding protein 1 (LvXBP1) or heat shock treatment. Furthermore, LvGRP94 was found to highly express in hemocytes as well as in epidermis by real-time RT-PCR. In addition, it was shown that LvGRP94 inhibited by LvXBP1 knocked-down in the hemocytes, was induced by white spot syndrome virus (WSSV) infection, or unfolded protein response (UPR) pathway activation. Importantly, decreasing LvGRP94 reduced the cumulative mortality of WSSV-infected shrimps and WSSV copies in shrimp muscle. These results suggested that LvGRP94 might involve in shrimp UPR pathway as well as WSSV infection.

  8. Expression and significance of heat shock protein 70 and glucose-regulated protein 94 in human esophageal carcinoma

    Xiao-Ping Wang; Guo-Zhen Liu; Ai-Li Song; Rui-Fen Chen; Hai-Yan Li; Yu Liu

    2005-01-01

    AIM: To investigate the expression and significance of heat shock protein 70 (HSP70) and glucose-regulated protein 94 (grp94) in human esophageal carcinoma and adjacent normal tissues.METHODS: The expression of HSP70 and grp94 in 78human esophageal cancer and adjacent normal tissues was studied by immunohistochemistry and pathology photograph analysis.RESULTS: Both esophageal cancer and adjacent normal tissues could express HSP70 and grp94. Of the 78 cases of esophageal carcinoma, 95.0%(72/78) showed positive HSP70, mainly stained in nuclei, while grp94 was mainly stained in cell plasma, and the positive rate was 71.8%(56/78).There was a significant difference in the expression of HSP70 and grp94 between esophageal cancer and adjacent normal tissues (P<0.01). Compared with adjacent normal tissues, there was a significant difference between differential types and HSP70 expression (P<0.01).CONCLUSION: HSP70 and grp94 express differently in cell plasma and nuclei. The expression intensity of HSP70is related to the differentiation of esophageal carcinoma.

  9. Development of a lifestyle intervention using the MRC framework for diabetes prevention in people with impaired glucose regulation

    Troughton, Jacqui; Chatterjee, Sudesna; Hill, Siân E.; Daly, Heather; Martin Stacey, Lorraine; Stone, Margaret A.; Patel, Naina; Khunti, Kamlesh; Yates, Thomas; Gray, Laura J.; Davies, Melanie J.

    2016-01-01

    Background We report development of a group-based lifestyle intervention, Let's Prevent, using the UK Medical Research Council (MRC) framework, and delivered by structured education to prevent type 2 diabetes mellitus (T2DM) in people with impaired glucose regulation (IGR) in a UK multi-ethnic population. Methods Diabetes Education and Self-Management for Ongoing and Newly Diagnosed (DESMOND) is the first national T2DM programme that meets National Institute for Health and Care Excellence criteria and formed the basis for Let's Prevent. An iterative cycle of initial development, piloting, collecting and collating qualitative and quantitative data, and reflection and modification, was used to inform and refine lifestyle intervention until it was fit for evaluation in a definitive randomized controlled trial (RCT). The programme encouraged IGR self-management using simple, non-technical language and visual aids. Results Qualitative and quantitative data suggested that intervention resulted in beneficial short-term behaviour change such as healthier eating patterns, improved health beliefs and greater participant motivation and empowerment. We also demonstrated that recruitment strategy and data collection methods were feasible for RCT implementation. Conclusions Let's Prevent was developed following successful application of MRC framework criteria and the subsequent RCT will determine whether it is feasible, reliable and transferable from research into a real-world NHS primary healthcare setting. Trial Registration ISRCTN80605705. PMID:26311822

  10. A clinical analysis of abnormal gestational glucose metabolism and pregnancy outcome of the woman%妊娠期糖代谢异常与妊娠结局的临床分析

    米阳; 闫坤; 黄谱; 苟文丽

    2009-01-01

    Objective To investigate relationship between abnormal gestational glucose metabolism and pregnancy outcome of the woman. Methods 1 636 pregnant women who received antenatal examination in Shannxi Provincial Maternal and Child Health Hospital in a period from January to June, 2008 were screened at their 24~28 weeks of gestation with 50g glucose challenge test (GCT). Those pregnant women with abnormal GCT results further received oral 75g glucose tolerance test (OGTT). According to OGTT results, the pregnant women were divided into 2 groups: GDM group (n=69) and gestational impaired glucose tolerance group (GIGT group, n=124). 300 pregnant women with normal glucose metabolism were as controls. All of them were followed up untill delivery and the perinatal outcomes in the 3groups were compared. Results The incidence of GDM was 4.21% and that of GIGT was 7.58%. The incidences of hypertensive disorder complicating pregnancy, polyhydramnios, premature rupture of membrane and premature delivery in GDM group were higher than those in the control group (χ2=4.660,11.530,5.193,4.661 respectively,all P<0.05).In GIGT group ,the incidences of polyhydramnios and premature rupture of membrane were significantly higher than those in the control group(χ2=12.450,6.325,respectively,both P<0.05). Conclusion The pregnant women with GDM or GIGT have significantly high incidences of obstetric complications and rate of cesarean section. So, screening of GDM should be strengthened and early diagnosis, early treatment, gestational supervision and guidance should be carried out in order to reduce incidence rates of maternal and infantile complications.%目的 探讨妊娠期糖代谢异常与妊娠结局的关系.方法 选取2008年1~6月在陕西省妇幼保健院进行产前检查的1 636名孕妇,于24~28周进行50g葡萄糖筛查试验,异常者行75g糖耐量试验,按糖代谢异常情况分为妊娠期糖尿病组(69例)和妊娠期糖耐量受损组(124例);

  11. Regulation of glucose metabolism via hepatic forkhead transcription factor 1 (FoxO1) by Morinda citrifolia (noni) in high-fat diet-induced obese mice.

    Nerurkar, Pratibha V; Nishioka, Adrienne; Eck, Philip O; Johns, Lisa M; Volper, Esther; Nerurkar, Vivek R

    2012-07-01

    Renewed interest in alternative medicine among diabetic individuals prompted us to investigate anti-diabetic effects of Morinda citrifolia (noni) in high-fat diet (HFD)-fed mice. Type 2 diabetes is associated with increased glucose production due to the inability of insulin to suppress hepatic gluconeogenesis and promote glycolysis. Insulin inhibits gluconeogenesis by modulating transcription factors such as forkhead box O (FoxO1). Based on microarray analysis data, we tested the hypothesis that fermented noni fruit juice (fNJ) improves glucose metabolism via FoxO1 phosphorylation. C57BL/6 male mice were fed a HFD and fNJ for 12 weeks. Body weights and food intake were monitored daily. FoxO1 expression was analysed by real-time PCR and Western blotting. Specificity of fNJ-associated FoxO1 regulation of gluconeogenesis was confirmed by small interfering RNA (siRNA) studies using human hepatoma cells, HepG2. Supplementation with fNJ inhibited weight gain and improved glucose and insulin tolerance and fasting glucose in HFD-fed mice. Hypoglycaemic properties of fNJ were associated with the inhibition of hepatic FoxO1 mRNA expression, with a concomitant increase in FoxO1 phosphorylation and nuclear expulsion of the proteins. Gluconeogenic genes, phosphoenolpyruvate C kinase (PEPCK) and glucose-6-phosphatase (G6P), were significantly inhibited in mice fed a HFD+fNJ. HepG2 cells demonstrated more than 80 % inhibition of PEPCK and G6P mRNA expression in cells treated with FoxO1 siRNA and fNJ. These data suggest that fNJ improves glucose metabolism via FoxO1 regulation in HFD-fed mice.

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

    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.

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

    Mithieux, G

    2013-03-01

    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.

  14. 有载调压分接开关运行与异常状态分析%Operation and the Abnormal State of Load Voltage Regulation Tap

    员学军

    2011-01-01

    本文介绍了CV型有载调压分接开关的动作原理、电压变化过程,对有载调压分接开关异常情况进行了汇总分析,强调了加强状态检修与维护的要点,并提出了一些有价值的建议.%This paper introduces the action principle of CV-type load voltage regulation tap, the change process of voltage, summarizes the abnormal situations of load voltage regulation tap, emphasizes the main points of the state repair and maintenance, and made some valuable suggestions.

  15. The expression of insulin and insulin receptor mRNAs is regulated by nutritional state and glucose in rainbow trout (Oncorhynchus mykiss).

    Caruso, Michael A; Sheridan, Mark A

    2012-01-15

    Many species of fish, including rainbow trout, possess multiple INS- and IR-encoding mRNAs. In this study, rainbow trout (Oncorhynchus mykiss) were used as a model to study the regulation of INS (INS1, INS2) and IR (IR1, IR2, IR3, and IR4) mRNA expression by nutritional state and glucose. In the nutritional state study, fish were either fed continuously, fasted (4 or 6 weeks), or fasted 4 weeks, then refed for 2 weeks. Nutritional state regulated INS and IR mRNA expression in a subtype- and tissue-specific manner. A 4-week fast reduced INS1 expression in endocrine pancreas (Brockmann body) and of INS1 and INS2 in brain, whereas a 6-week fast reduced the expression of both INS1 and INS2 in pancreas but only of INS1 in brain. Refeeding only restored INS2 levels in pancreas. In adipose tissue, by contrast, a 4-week fast increased INS1 expression, and a 6-week fast increased the expression of both INS1 and INS2. Nutritional state also modulated the pattern of IR mRNA expression. Fasting for 4 weeks resulted in no significant change in IR expression. Prolonged fasting (6 weeks) increased the expression of IR4 mRNA in the pancreas, adipose tissue, cardiac muscle, and gill; however, fasting decreased expression of IR3 mRNA in liver. Refeeding restored fasting-associated increases in IR4 expression in pancreas, adipose tissue, cardiac muscle, and gill, but had no effect on the fasting-associated decrease in IR3 expression in liver. Glucose differentially regulated the expression of INS and IR mRNAs in Brockmann bodies and liver pieces incubated in vitro, respectively. Low glucose (1 mM) reduced pancreatic expression of both INS1 and INS2 mRNAs compared to levels observed at 4 or 10 mM glucose. In the liver, IR1 and IR2 mRNA expression was insensitive to glucose concentration, whereas expression of IR3 and IR4 was attenuated at 1 and 10 mM compared to 4 mM glucose. These findings indicate that the pattern of INS and IR expression in selected tissues is regulated by

  16. Regulation of high glucose-induced apoptosis of brain pericytes by mitochondrial CA VA: A specific target for prevention of diabetic cerebrovascular pathology.

    Price, Tulin O; Sheibani, Nader; Shah, Gul N

    2017-04-01

    Events responsible for cerebrovascular disease in diabetes are not fully understood. Pericyte loss is an early event that leads to endothelial cell death, microaneurysms, and cognitive impairment. A biochemical mechanism underlying pericyte loss is rapid respiration (oxidative metabolism of glucose). This escalation in respiration results from free influx of glucose into insulin-insensitive tissues in the face of high glucose levels in the blood. Rapid respiration generates superoxide, the precursor to all reactive oxygen species (ROS), and results in pericyte death. Respiration is regulated by carbonic anhydrases (CAs) VA and VB, the two isozymes expressed in mitochondria, and their pharmacologic inhibition with topiramate reduces respiration, ROS, and pericyte death. Topiramate inhibits both isozymes; therefore, in the earlier studies, their individual roles were not discerned. In a recent genetic study, we showed that mitochondrial CA VA plays a significant role in regulation of reactive oxygen species and pericyte death. The role of CA VB was not addressed. In this report, genetic knockdown and overexpression studies confirm that mitochondrial CA VA regulates respiration in pericytes, whereas mitochondrial CA VB does not contribute significantly. Identification of mitochondrial CA VA as a sole regulator of respiration provides a specific target to develop new drugs with fewer side effects that may be better tolerated and can protect the brain from diabetic injury. Since similar events occur in the capillary beds of other insulin-insensitive tissues such as the eye and kidney, these drugs may also slow the onset and progression of diabetic disease in these tissues.

  17. The proapoptotic function of Noxa in human leukemia cells is regulated by the kinase Cdk5 and by glucose.

    Lowman, Xazmin H; McDonnell, Maureen A; Kosloske, Ashley; Odumade, Oludare A; Jenness, Christopher; Karim, Christine B; Jemmerson, Ronald; Kelekar, Ameeta

    2010-12-10

    The BH3-only protein, Noxa, is induced in response to apoptotic stimuli, such as DNA damage, hypoxia, and proteasome inhibition in most human cells. Noxa is constitutively expressed in proliferating cells of hematopoietic lineage and required for apoptosis in response to glucose stress. We show that Noxa is phosphorylated on a serine residue (S(13)) in the presence of glucose. Phosphorylation promotes its cytosolic sequestration and suppresses its apoptotic function. We identify Cdk5 as the Noxa kinase and show that Cdk5 knockdown or expression of a Noxa S(13) to A mutant increases sensitivity to glucose starvation, confirming that the phosphorylation is protective. Both glucose deprivation and Cdk5 inhibition promote apoptosis by dephosphorylating Noxa. Paradoxically, Noxa stimulates glucose consumption and may enhance glucose turnover via the pentose phosphate pathway rather than through glycolysis. We propose that Noxa plays both growth-promoting and proapoptotic roles in hematopoietic cancers with phospho-S(13) as the glucose-sensitive toggle switch controlling these opposing functions.

  18. AMPK and PKA interaction in the regulation of survival of liver cancer cells subjected to glucose starvation

    Ferretti, Anabela C.; Tonucci, Facundo M.; Hidalgo, Florencia; Almada, Evangelina; Larocca, Maria C.; Favre, Cristián

    2016-01-01

    The signaling pathways that govern survival response in hepatic cancer cells subjected to nutritional restriction have not been clarified yet. In this study we showed that liver cancer cells undergoing glucose deprivation both arrested in G0/G1 and died mainly by apoptosis. Treatment with the AMPK activator AICAR phenocopied the effect of glucose deprivation on cell survival, whereas AMPK silencing in HepG2/C3A, HuH-7 or SK-Hep-1 cells blocked the cell cycle arrest and the increase in apoptotic death induced by glucose starvation. Both AMPK and PKA were promptly activated after glucose withdrawal. PKA signaling had a dual role during glucose starvation: whereas it elicited an early decreased in cell viability, it later improved this parameter. We detected AMPK phosphorylation (AMPKα(Ser173)) by PKA, which was increased in glucose starved cells and was associated with diminution of AMPK activation. To better explore this inhibitory effect, we constructed a hepatocarcinoma derived cell line which stably expressed an AMPK mutant lacking that PKA phosphorylation site: AMPKα1(S173C). Expression of this mutant significantly decreased viability in cells undergoing glucose starvation. Furthermore, after 36 h of glucose deprivation, the index of AMPKα1(S173C) apoptotic cells doubled the apoptotic index observed in control cells. Two main remarks arise: 1. AMPK is the central signaling kinase in the scenario of cell cycle arrest and death induced by glucose starvation in hepatic cancer cells; 2. PKA phosphorylation of Ser173 comes out as a strong control point that limits the antitumor effects of AMPK in this situation. PMID:26894973

  19. A broader role for AmyR in Aspergillus niger: regulation of the utilisation of D-glucose or D-galactose containing oligo- and polysaccharides.

    vanKuyk, Patricia A; Benen, Jaques A E; Wösten, Han A B; Visser, Jaap; de Vries, Ronald P

    2012-01-01

    AmyR is commonly considered a regulator of starch degradation whose activity is induced by the presence of maltose, the disaccharide building block of starch. In this study, we demonstrate that the role of AmyR extends beyond starch degradation. Enzyme activity assays, genes expression analysis and growth profiling on D-glucose- and D-galactose-containing oligo- and polysaccharides showed that AmyR regulates the expression of some of the Aspergillus niger genes encoding α- and β-glucosidases, α- and β- galactosidases, as well as genes encoding α-amlyases and glucoamylases. In addition, we provide evidence that D-glucose or a metabolic product thereof may be the inducer of the AmyR system in A. niger and not maltose, as is commonly assumed.

  20. Correlation between clinicopathology and expression of heat shock protein 70 and glucose-regulated protein 94 in human colonic adenocarcinoma

    Xiao-Ping Wang; Fan-Rong Qiu; Guo-Zhen Liu; Rui-Fen Chen

    2005-01-01

    AIM: To investigate the correlation between dinicopathology and expression of heat shock protein 70 (HSP70) and glucose-regulated protein 94 (grp94) in human colonic carcinoma.METHODS: The expression of HSP70 and grp94 was studied in 80 human colonic cancers with or without metastasis as well as in their adjacent mucous membrane by way of immunohistochemistry and pathology photograph analysis.RESULTS: The expression of HSP70 and grp94 was significantly higher in cancer than that in adjacent mucous membrane (92.5%, 85.0% vs 56.3%, 42.5%, P<0.01).HSP70 and grp94 expressed higher in moderately- and poorly-differentiated colonic cancers than that in their adjacent tissues (93.7%, 87.5%; 100%, 90% vs 56.3%,42.5%; P<0.01). Dukes C and D stages of colonic cancers showed higher positive rates than Dukes A and B stage groups (97.1%, 91.2%; 100%, 90.9%; vs 80%, 70%;78.6%, 71.4%; P<0.05). There were definite differences in HSP70 and grp94 expression between metastasis groups and non-metastasis groups (100% vs75%, 100%vs 50%, P<0.05).CONCLUSION: The HSP70 and grp94 expression rates in colonic cancer groups are significantly higher than that in their adjacent mucous membrane. The HSP70 and grp94expression in poorly-differentiated colonic cancers with metastasis is significantly higher than well-differentiated cancers without metastasis. The overexpression of HSP70and grp94 can be used as diagnostic or prognostic markers for colonic cancer.

  1. Evidence of prognostic relevant expression profiles of heat-shock proteins and glucose-regulated proteins in oesophageal adenocarcinomas.

    Julia Slotta-Huspenina

    Full Text Available A high percentage of oesophageal adenocarcinomas show an aggressive clinical behaviour with a significant resistance to chemotherapy. Heat-shock proteins (HSPs and glucose-regulated proteins (GRPs are molecular chaperones that play an important role in tumour biology. Recently, novel therapeutic approaches targeting HSP90/GRP94 have been introduced for treating cancer. We performed a comprehensive investigation of HSP and GRP expression including HSP27, phosphorylated (p-HSP27((Ser15, p-HSP27((Ser78, p-HSP27((Ser82, HSP60, HSP70, HSP90, GRP78 and GRP94 in 92 primary resected oesophageal adenocarcinomas by using reverse phase protein arrays (RPPA, immunohistochemistry (IHC and real-time quantitative RT-PCR (qPCR. Results were correlated with pathologic features and survival. HSP/GRP protein and mRNA expression was detected in all tumours at various levels. Unsupervised hierarchical clustering showed two distinct groups of tumours with specific protein expression patterns: The hallmark of the first group was a high expression of p-HSP27((Ser15, Ser78, Ser82 and low expression of GRP78, GRP94 and HSP60. The second group showed the inverse pattern with low p-HSP27 and high GRP78, GRP94 and HSP60 expression. The clinical outcome for patients from the first group was significantly improved compared to patients from the second group, both in univariate analysis (p = 0.015 and multivariate analysis (p = 0.029. Interestingly, these two groups could not be distinguished by immunohistochemistry or qPCR analysis. In summary, two distinct and prognostic relevant HSP/GRP protein expression patterns in adenocarcinomas of the oesophagus were detected by RPPA. Our approach may be helpful for identifying candidates for specific HSP/GRP-targeted therapies.

  2. Evidence of prognostic relevant expression profiles of heat-shock proteins and glucose-regulated proteins in oesophageal adenocarcinomas.

    Slotta-Huspenina, Julia; Berg, Daniela; Bauer, Karina; Wolff, Claudia; Malinowsky, Katharina; Bauer, Lukas; Drecoll, Enken; Bettstetter, Marcus; Feith, Marcus; Walch, Axel; Höfler, Heinz; Becker, Karl-Friedrich; Langer, Rupert

    2012-01-01

    A high percentage of oesophageal adenocarcinomas show an aggressive clinical behaviour with a significant resistance to chemotherapy. Heat-shock proteins (HSPs) and glucose-regulated proteins (GRPs) are molecular chaperones that play an important role in tumour biology. Recently, novel therapeutic approaches targeting HSP90/GRP94 have been introduced for treating cancer. We performed a comprehensive investigation of HSP and GRP expression including HSP27, phosphorylated (p)-HSP27((Ser15)), p-HSP27((Ser78)), p-HSP27((Ser82)), HSP60, HSP70, HSP90, GRP78 and GRP94 in 92 primary resected oesophageal adenocarcinomas by using reverse phase protein arrays (RPPA), immunohistochemistry (IHC) and real-time quantitative RT-PCR (qPCR). Results were correlated with pathologic features and survival. HSP/GRP protein and mRNA expression was detected in all tumours at various levels. Unsupervised hierarchical clustering showed two distinct groups of tumours with specific protein expression patterns: The hallmark of the first group was a high expression of p-HSP27((Ser15, Ser78, Ser82)) and low expression of GRP78, GRP94 and HSP60. The second group showed the inverse pattern with low p-HSP27 and high GRP78, GRP94 and HSP60 expression. The clinical outcome for patients from the first group was significantly improved compared to patients from the second group, both in univariate analysis (p = 0.015) and multivariate analysis (p = 0.029). Interestingly, these two groups could not be distinguished by immunohistochemistry or qPCR analysis. In summary, two distinct and prognostic relevant HSP/GRP protein expression patterns in adenocarcinomas of the oesophagus were detected by RPPA. Our approach may be helpful for identifying candidates for specific HSP/GRP-targeted therapies.

  3. Cell surface area regulation in neurons in hippocampal slice cultures is resistant to oxygen-glucose deprivation

    Natalya Shulyakova

    2010-09-01

    Full Text Available Natalya Shulyakova1,2, Jamie Fong2, Diana Diec2, Adrian Nahirny1,2, Linda R Mills1,21Department of Physiology, University of Toronto, Toronto, ON, Canada, M5T 2S8; 2Toronto Western Hospital Research Institute, University Health Network, 11-430, 399 Bathurst St, Toronto, ON, Canada, M5T 2S8Background: Neurons swell in response to a variety of insults. The capacity to recover, ie, to shrink, is critical for neuronal function and survival. Studies on dissociated neurons have shown that during swelling and shrinking, neurons reorganize their plasma membrane; as neurons swell, in response to hypo-osmotic media, the bilayer area increases. Upon restoration of normo-osmotic media, neurons shrink, forming transient invaginations of the plasma membrane known as vacuole-like dilations (VLDs, to accommodate the decrease in the bilayer.Methods: Here we used confocal microscopy to monitor neuronal swelling and shrinking in the three-dimensional (3D environment of post-natal rat hippocampal slice cultures. To label neurons, we used biolistic transfection, to introduce enhanced green fluorescent protein (eGFP targeted to the cytoplasm; and a membrane targeted GFP (lckGFP, targeted to the plasma membrane.Results: Neurons in slice cultures swelled and shrank in response to hypo-osmotic to normo-osmotic media changes. Oxygen-glucose deprivation (OGD caused sustained neuronal swelling; after reperfusion, some neurons recovered but in others, VLD recovery was stalled. OGD did not impair neuronal capacity to recover from a subsequent osmotic challenge.Conclusion: These results suggest cell surface area regulation (SAR is an intrinsic property of neurons, and that neuronal capacity for SAR may play an important role in the brain’s response to ischemic insults.Keywords: neurons, swelling, ischemia, cell surface area, hippocampal slice culture

  4. Effects of Intragastric Balloon on Body Mass Index, Lipid Profile and Blood Glucose Regulation: A Prospective Study

    Hasan Erdem

    2016-03-01

    Full Text Available Objective: Obesity remains an increasing public health and socioeconomic problem. Life style changes including healthy diet and physical activity are the first-line therapy for successful weight loss. The intragastric balloon has been considered as an effective and reversible, non-sur­gical method for weight loss. In this study, we aimed to investigate the effects of Intragastric balloon on weight loss, lipid profiles and blood glucose regulation in obese patients Methods: 75 consecutive Intragastric balloon patients (55 Female, 20 Male with a mean age of 35.2±9.6 years were included in this study. The study was conducted prospectively and an air-filled intragastric balloon was introduced in ambulatory settings. In this study, patients’ pre-intervention body mass index, peripheral blood pa­rameters such as HbA1c, lipid profiles were recorded and compared with post-intervention values. Results: The median intervention time for intragastric balloon application was 13 min (8-19. After follow-up period of median 186 days (180-211, BMI was reduced significantly, 41.6±6.7 vs. 34.9±6.4 kg/m2 (p0.05. On the other hand, only pre and post-intervention HbA1c level was to be statistically significant (p=0.001 Conclusion: There was significant change in BMI and HbA1c level with the intervention of intragastric balloon after follow-up period. For long-term benefit of balloon, further studies are needed.

  5. The clinical value of Mood glucose and insulin detection in early period of pregnancy on predicting abnormal glucose metabolism%妊娠初期检测血糖和胰岛素预测糖代谢异常的临床意义

    陈丽萍

    2012-01-01

    Objective To investigate the correlation of fasting plasma glucose (FPG) in early period of pregnancy and abnormal glucose metabolism during gestation period.Methods Two hundred and seventy-seven women with single pregnancy and non-propregnant diabetes mellitus were selected.FPG,fasting insulin,insulin resistance index were detected in early period of pregnancy ( <19 weeks).One hundred g oral glucose tolerant test (OGTT) was taken during 24-36 weeks.According to OGTT,patients were divided into gestational impaired glucose tolerance (GIGT) group (24 cases),gestational diabetes mellitus(GDM) group(23 cases),OGTT 1 h higher blood glucose (HG-1) group (26 cases) and normal group (204 cases).Results FPG,fasting insulin and insulin resistance index of GDM group and HG-1 group were obviously higher than those of normal group [( 4.58 ± 0.36 ),( 4.58 ± 0.38) mmol/L vs.( 4.20 ±0.33) mmol/L,(9.4 ± 1.1),(9.3 ±2.1) U/L vs.(7.0 ± 2.1) U/L,2.0 ± 0.4,2.0 ± 0.3 vs.1.3 ± 0.4,P< 0.05].FPG of GIGT group [(4.45 ±0.36) mmol/L] was higher than that of normal group (P <0.05).After controlled age,body mass index,family history of type-2 diabetes mellitus and sport exercises,the relative risk degree of blood glucose metabolism had correlation with FPG,fasting insulin and insulin resistance index in early period of pregnancy (P < 0.05).Conclusion FPG,fasting insulin and insulin resistance index in early period of pregnancy can predict abnormal glucose metabolism.%目的 探讨妊娠初期空腹血糖(FPG)与妊娠期糖代谢异常的相关性.方法 单胎非孕前糖尿病孕妇277例,在妊娠初期(<19周)检测FPG、空腹血胰岛素、胰岛素抵抗指数.在妊娠24 ~ 36周行100 g口服葡萄糖耐量试验(OGTT),按OGTT结果进行分组,妊娠期糖耐量受损(GIGT)组24例,妊娠期糖尿病(GDM)组23例,OGTT1 h高血糖(HG-1)组26例,正常组204例.结果 GDM组和HG-1组FPG、空腹血胰岛素、胰岛素抵抗指数均明显高于正常组[(4.58±0

  6. Hydrophobic motif site-phosphorylated protein kinase CβII between mTORC2 and Akt regulates high glucose-induced mesangial cell hypertrophy.

    Das, Falguni; Ghosh-Choudhury, Nandini; Mariappan, Meenalakshmi M; Kasinath, Balakuntalam S; Choudhury, Goutam Ghosh

    2016-04-01

    PKCβII controls the pathologic features of diabetic nephropathy, including glomerular mesangial cell hypertrophy. PKCβII contains the COOH-terminal hydrophobic motif site Ser-660. Whether this hydrophobic motif phosphorylation contributes to high glucose-induced mesangial cell hypertrophy has not been determined. Here we show that, in mesangial cells, high glucose increased phosphorylation of PKCβII at Ser-660 in a phosphatidylinositol 3-kinase (PI3-kinase)-dependent manner. Using siRNAs to downregulate PKCβII, dominant negative PKCβII, and PKCβII hydrophobic motif phosphorylation-deficient mutant, we found that PKCβII regulates activation of mechanistic target of rapamycin complex 1 (mTORC1) and mesangial cell hypertrophy by high glucose. PKCβII via its phosphorylation at Ser-660 regulated phosphorylation of Akt at both catalytic loop and hydrophobic motif sites, resulting in phosphorylation and inactivation of its substrate PRAS40. Specific inhibition of mTORC2 increased mTORC1 activity and induced mesangial cell hypertrophy. In contrast, inhibition of mTORC2 decreased the phosphorylation of PKCβII and Akt, leading to inhibition of PRAS40 phosphorylation and mTORC1 activity and prevented mesangial cell hypertrophy in response to high glucose; expression of constitutively active Akt or mTORC1 restored mesangial cell hypertrophy. Moreover, constitutively active PKCβII reversed the inhibition of high glucose-stimulated Akt phosphorylation and mesangial cell hypertrophy induced by suppression of mTORC2. Finally, using renal cortexes from type 1 diabetic mice, we found that increased phosphorylation of PKCβII at Ser-660 was associated with enhanced Akt phosphorylation and mTORC1 activation. Collectively, our findings identify a signaling route connecting PI3-kinase to mTORC2 to phosphorylate PKCβII at the hydrophobic motif site necessary for Akt phosphorylation and mTORC1 activation, leading to mesangial cell hypertrophy.

  7. Jicama (Pachyrhizus erosus) extract increases insulin sensitivity and regulates hepatic glucose in C57BL/Ksj-db/db mice

    Park, Chan Joo; Lee, Hyun-Ah; Han, Ji-Sook

    2015-01-01

    This study investigated the effect of jicama extract on hyperglycemia and insulin sensitivity in an animal model of type 2 diabetes. Male C57BL/Ksj-db/db mice were divided into groups subsequently fed a regular diet (controls), or diet supplemented with jicama extract, and rosiglitazone. After 6 weeks, blood levels of glucose and glycosylated hemoglobin were significantly lower in animals administered the jicama extract than the control group. Additionally, glucose and insulin tolerance tests...

  8. Glucose-sensitive gel rheology of dextran-concanavalin A mixtures suitable for self-regulating insulin delivery.

    Taylor, M Joan; Tanna, Sangeeta; Sahota, Tarsem S

    2010-01-01

    Aqueous concentrated plain mixtures of dextran and concanavalin A (con A) were examined for their rheological response to glucose for comparison with previously studied partially photopolymerized acrylic derivatives. Non-destructive oscillatory tests were undertaken within the linear viscoelastic range to examine the relationship between the rheometry and the stoichiometry of the interactive materials and to examine rheological parameters as affected by molecular weight, component ratio, temperature and glucose concentrations between 0 and 1% w/w. These simple formulations were studied at 1 and 10 Hz at 0.5% strain at both 20 and 37 degrees C. A second simplified rheological test was undertaken to demonstrate gel-sol reversibility and to produce a measure of equilibria created between these gels and glucose solutions with which they are in contact. This mimics the conditions in which the gel acts as a responsive gateway in the insulin delivery device. It proved that the gels equilibrate with glucose solutions, rather than indiscriminately removing glucose. This is important in terms of producing a delivery device that can respond in a reversible, glucose concentration-dependent manner. The method used for this is capable of relative values only but provides information not obtainable from conventional rheometry.

  9. Deletion of Rab GAP AS160 modifies glucose uptake and GLUT4 translocation in primary skeletal muscles and adipocytes and impairs glucose homeostasis.

    Lansey, Melissa N; Walker, Natalie N; Hargett, Stefan R; Stevens, Joseph R; Keller, Susanna R

    2012-11-15

    Tight control of glucose uptake in skeletal muscles and adipocytes is crucial to glucose homeostasis and is mediated by regulating glucose transporter GLUT4 subcellular distribution. In cultured cells, Rab GAP AS160 controls GLUT4 intracellular retention and release to the cell surface and consequently regulates glucose uptake into cells. To determine AS160 function in GLUT4 trafficking in primary skeletal muscles and adipocytes and investigate its role in glucose homeostasis, we characterized AS160 knockout (AS160(-/-)) mice. We observed increased and normal basal glucose uptake in isolated AS160(-/-) adipocytes and soleus, respectively, while insulin-stimulated glucose uptake was impaired and GLUT4 expression decreased in both. No such abnormalities were found in isolated AS160(-/-) extensor digitorum longus muscles. In plasma membranes isolated from AS160(-/-) adipose tissue and gastrocnemius/quadriceps, relative GLUT4 levels were increased under basal conditions and remained the same after insulin treatment. Concomitantly, relative levels of cell surface-exposed GLUT4, determined with a glucose transporter photoaffinity label, were increased in AS160(-/-) adipocytes and normal in AS160(-/-) soleus under basal conditions. Insulin augmented cell surface-exposed GLUT4 in both. These observations suggest that AS160 is essential for GLUT4 intracellular retention and regulation of glucose uptake in adipocytes and skeletal muscles in which it is normally expressed. In vivo studies revealed impaired insulin tolerance in the presence of normal (male) and impaired (female) glucose tolerance. Concurrently, insulin-elicited increases in glucose disposal were abolished in all AS160(-/-) skeletal muscles and liver but not in AS160(-/-) adipose tissues. This suggests AS160 as a target for differential manipulation of glucose homeostasis.

  10. Leukocyte abnormalities.

    Gabig, T G

    1980-07-01

    Certain qualitative abnormalities in neutrophils and blood monocytes are associated with frequent, severe, and recurrent bacterial infections leading to fatal sepsis, while other qualitative defects demonstrated in vitro may have few or no clinical sequelae. These qualitative defects are discussed in terms of the specific functions of locomotion, phagocytosis, degranulation, and bacterial killing.

  11. Improvement of cloned [alpha]-amylase gene expression in fed-batch culture of recombinant Saccharomyces cerevisiae by regulating both glucose and ethanol concentrations using a fuzzy controller

    Shiba, Sumihisa; Nishida, Yoshio; Park, Y.S.; Iijima, Shinji; Kobayashi, Takeshi (Nagoya Univ. (Japan). Dept. of Biotechnology)

    1994-11-05

    The effect of ethanol concentration on cloned gene expression in recombinant Saccharomyces cerevisiae strain 20B-12 containing one of two plasmids, pNA3 and pNA7, was investigated in batch cultures. Plasmids pNA3 and pNA7 contain the [alpha]-amylase gene under the control of the SUC2 or PGK promoter, respectively. When the ethanol concentration was controlled at 2 to 5 g/L, the gene expressions were two times higher than those at 20 g/L ethanol. To increase the gene expression by maintaining both the ethanol and glucose concentrations at low levels, a fuzzy controller was developed. The concentrations of glucose and ethanol were controlled simultaneously at 0.15 and 2 g/L, respectively, in the production phase using the fuzzy controller in fed-batch culture. The synthesis of [alpha]-amylase was induced by the low glucose concentration and maintained at a high level of activity by regulating the ethanol concentration at 2 g/L. The secretory [alpha]-amylase activities of cells harboring plasmids pNA3 and pNA7 in fed-batch culture were 175 and 392 U/mL, and their maximal specific activities 7.7 and 12.4 U/mg dry cells, respectively. These values are two to three times higher in activity and three to four times higher in specific activity than those obtained when glucose only was controlled.

  12. Rosemary (Rosmarinus officinalis L.) extract regulates glucose and lipid metabolism by activating AMPK and PPAR pathways in HepG2 cells.

    Tu, Zheng; Moss-Pierce, Tijuana; Ford, Paul; Jiang, T Alan

    2013-03-20

    An epidemic of metabolic disorders such as obesity and diabetes is rising dramatically. Using natural products as potential preventive and therapeutic interventions for these disorders has drawn worldwide attention. Rosemary has been shown to lower blood glucose and cholesterol levels and mitigate weight gain in several in vivo studies. However, the mechanisms are essentially unknown. We investigated the effects of rosemary extract on metabolism and demonstrated that rosemary extract significantly increased glucose consumption in HepG2 cells. The phosphorylation of AMP-activated protein kinase (AMPK) and its substrate, acetyl-CoA carboxylase (ACC), was increased by rosemary extract. Rosemary extract also transcriptionally regulated the genes involved in metabolism, including SIRT1, PPARγ coactivator 1α (PGC1α), glucose-6-phosphatase (G6Pase), ACC, and low-density lipoprotein receptor (LDLR). Furthermore, the PPARγ-specific antagonist GW9662 diminished rosemary's effects on glucose consumption. Overall, our study suggested that rosemary potentially increases liver glycolysis and fatty acid oxidation by activating AMPK and PPAR pathways.

  13. Minocycline Promotes Neurite Outgrowth of PC12 Cells Exposed to Oxygen-Glucose Deprivation and Reoxygenation Through Regulation of MLCP/MLC Signaling Pathways.

    Tao, Tao; Feng, Jin-Zhou; Xu, Guang-Hui; Fu, Jie; Li, Xiao-Gang; Qin, Xin-Yue

    2017-04-01

    Minocycline, a semi-synthetic second-generation derivative of tetracycline, has been reported to exert neuroprotective effects both in animal models and in clinic trials of neurological diseases. In the present study, we first investigated the protective effects of minocycline on oxygen-glucose deprivation and reoxygenation-induced impairment of neurite outgrowth and its potential mechanism in the neuronal cell line, PC12 cells. We found that minocycline significantly increased cell viability, promoted neurite outgrowth and enhanced the expression of growth-associated protein-43 (GAP-43) in PC12 cells exposed to oxygen-glucose deprivation/reoxygenation injury. In addition, immunoblots revealed that minocycline reversed the overexpression of phosphorylated myosin light chain (MLC) and the suppression of activated extracellular signal-regulated kinase 1/2 (ERK1/2) caused by oxygen-glucose deprivation/reoxygenation injury. Moreover, the minocycline-induced neurite outgrowth was significantly blocked by Calyculin A (1 nM), an inhibitor of myosin light chain phosphatase (MLCP), but not by an ERK1/2 inhibitor (U0126; 10 μM). These findings suggested that minocycline activated the MLCP/MLC signaling pathway in PC12 cells after oxygen-glucose deprivation/reoxygenation injury, which resulted in the promotion of neurite outgrowth.

  14. MicroRNA-34a regulates high glucose-induced apoptosis in H9c2 cardiomyocytes.

    Zhao, Fang; Li, Bo; Wei, Yin-zhi; Zhou, Bin; Wang, Han; Chen, Ming; Gan, Xue-dong; Wang, Zhao-hui; Xiong, Shi-xi

    2013-12-01

    Hyperglycemia is an important initiator of cardiovascular disease, contributing to the development of cardiomyocyte death and diabetic complications. The purpose of the present study was to investigate whether high glucose state could induce apoptosis of rat cardiomyocyte cell line H9c2 through microRNA-mediated Bcl-2 signaling pathway. The expression of miR-34a and Bcl-2 mRNA was detected by using real-time PCR. Western blotting was used to examine the changes in apoptosis-associated protein Bcl-2. Apoptosis of H9c2 cells was tested by using flow cytometry. The results showed that the expression of miR-34a was significantly elevated and that of Bcl-2 was strongly reduced, and apoptosis of cardiomyocytes was apparently increased in the high-glucose-treated H9c2 cells as compared with normal-glucose-treated controls. In addition, we identified Bcl-2 gene was the target of miR-34a. miR-34a mimics reduced the expression of Bcl-2 and increased glucose-induced apoptosis, but miR-34a inhibitor acted as the opposite mediator. Our data demonstrate that miR-34a contributes to high glucose-induced decreases in Bcl-2 expression and subsequent cardiomyocyte apoptosis.

  15. Regulation of glucose utilization and lipogenesis in adipose tissue of diabetic and fat fed animals: Effects of insulin and manganese

    Najma Z Baquer; M Sinclair; S Kunjara; Umesh C S Yadav; P McLean

    2003-03-01

    In order to evaluate the modulatory effects of manganese, high fat diet fed and alloxan diabetic rats were taken and the changes in the glucose oxidation, glycerol release and effects of manganese on these parameters were measured from adipose tissue. An insulin-mimetic effect of manganese was observed in the adipose tissue in the controls and an additive effect of insulin and manganese on glucose oxidation was seen when Mn2+ was added in vitro. The flux of glucose through the pentose phosphate pathway and glycolysis was significantly decreased in high fat fed animals. Although the in vitro addition of Mn2+ was additive with insulin when 14CO2 was measured from control animals, it was found neither in young diabetic animals (6–8 weeks old) nor in the old (16 weeks old). Both insulin and manganese caused an increased oxidation of carbon-1 of glucose and an increase of its incorporation into 14C-lipids in the young control animals; the additive effect of insulin and manganese suggests separate site of action. This effect was decreased in fat fed animals, diabetic animals and old animals. Manganese alone was found to decrease glycerol in both the control and diabetic adipose tissue in in vitro incubations. The results of the effects of glucose oxidation, lipogenesis, and glycerol release in adipose tissue of control and diabetic animals of different ages are presented together with the effect of manganese on adipose tissue from high fat milk diet fed animals.

  16. Glucose-6-phosphate dehydrogenase regulation in the hepatopancreas of the anoxia-tolerant marine mollusc, Littorina littorea.

    Lama, Judeh L; Bell, Ryan A V; Storey, Kenneth B

    2013-01-01

    Glucose-6-phosphate dehydrogenase (G6PDH) gates flux through the pentose phosphate pathway and is key to cellular antioxidant defense due to its role in producing NADPH. Good antioxidant defenses are crucial for anoxia-tolerant organisms that experience wide variations in oxygen availability. The marine mollusc, Littorina littorea, is an intertidal snail that experiences daily bouts of anoxia/hypoxia with the tide cycle and shows multiple metabolic and enzymatic adaptations that support anaerobiosis. This study investigated the kinetic, physical and regulatory properties of G6PDH from hepatopancreas of L. littorea to determine if the enzyme is differentially regulated in response to anoxia, thereby providing altered pentose phosphate pathway functionality under oxygen stress conditions. Several kinetic properties of G6PDH differed significantly between aerobic and 24 h anoxic conditions; compared with the aerobic state, anoxic G6PDH (assayed at pH 8) showed a 38% decrease in K m G6P and enhanced inhibition by urea, whereas in pH 6 assays K m NADP and maximal activity changed significantly between the two states. The mechanism underlying anoxia-responsive changes in enzyme properties proved to be a change in the phosphorylation state of G6PDH. This was documented with immunoblotting using an anti-phosphoserine antibody, in vitro incubations that stimulated endogenous protein kinases versus protein phosphatases and significantly changed K m G6P, and phosphorylation of the enzyme with (32)P-ATP. All these data indicated that the aerobic and anoxic forms of G6PDH were the high and low phosphate forms, respectively, and that phosphorylation state was modulated in response to selected endogenous protein kinases (PKA or PKG) and protein phosphatases (PP1 or PP2C). Anoxia-induced changes in the phosphorylation state of G6PDH may facilitate sustained or increased production of NADPH to enhance antioxidant defense during long term anaerobiosis and/or during the transition

  17. Glucose-6-phosphate dehydrogenase regulation in the hepatopancreas of the anoxia-tolerant marine mollusc, Littorina littorea

    Judeh L. Lama

    2013-02-01

    Full Text Available Glucose-6-phosphate dehydrogenase (G6PDH gates flux through the pentose phosphate pathway and is key to cellular antioxidant defense due to its role in producing NADPH. Good antioxidant defenses are crucial for anoxia-tolerant organisms that experience wide variations in oxygen availability. The marine mollusc, Littorina littorea, is an intertidal snail that experiences daily bouts of anoxia/hypoxia with the tide cycle and shows multiple metabolic and enzymatic adaptations that support anaerobiosis. This study investigated the kinetic, physical and regulatory properties of G6PDH from hepatopancreas of L. littorea to determine if the enzyme is differentially regulated in response to anoxia, thereby providing altered pentose phosphate pathway functionality under oxygen stress conditions. Several kinetic properties of G6PDH differed significantly between aerobic and 24 h anoxic conditions; compared with the aerobic state, anoxic G6PDH (assayed at pH 8 showed a 38% decrease in Km G6P and enhanced inhibition by urea, whereas in pH 6 assays Km NADP and maximal activity changed significantly between the two states. The mechanism underlying anoxia-responsive changes in enzyme properties proved to be a change in the phosphorylation state of G6PDH. This was documented with immunoblotting using an anti-phosphoserine antibody, in vitro incubations that stimulated endogenous protein kinases versus protein phosphatases and significantly changed Km G6P, and phosphorylation of the enzyme with 32P-ATP. All these data indicated that the aerobic and anoxic forms of G6PDH were the high and low phosphate forms, respectively, and that phosphorylation state was modulated in response to selected endogenous protein kinases (PKA or PKG and protein phosphatases (PP1 or PP2C. Anoxia-induced changes in the phosphorylation state of G6PDH may facilitate sustained or increased production of NADPH to enhance antioxidant defense during long term anaerobiosis and/or during the

  18. Characterization of a FGF19 variant with altered receptor specificity revealed a central role for FGFR1c in the regulation of glucose metabolism.

    Hongfei Ge

    Full Text Available Diabetes and associated metabolic conditions have reached pandemic proportions worldwide, and there is a clear unmet medical need for new therapies that are both effective and safe. FGF19 and FGF21 are distinctive members of the FGF family that function as endocrine hormones. Both have potent effects on normalizing glucose, lipid, and energy homeostasis, and therefore, represent attractive potential next generation therapies for combating the growing epidemics of type 2 diabetes and obesity. The mechanism responsible for these impressive metabolic effects remains unknown. While both FGF19 and FGF21 can activate FGFRs 1c, 2c, and 3c in the presence of co-receptor βKlotho in vitro, which receptor is responsible for the metabolic activities observed in vivo remains unknown. Here we have generated a variant of FGF19, FGF19-7, that has altered receptor specificity with a strong bias toward FGFR1c. We show that FGF19-7 is equally efficacious as wild type FGF19 in regulating glucose, lipid, and energy metabolism in both diet-induced obesity and leptin-deficient mouse models. These results are the first direct demonstration of the central role of the βKlotho/FGFR1c receptor complex in glucose and lipid regulation, and also strongly suggest that activation of this receptor complex alone might be sufficient to achieve all the metabolic functions of endocrine FGF molecules.

  19. Characterization of a FGF19 variant with altered receptor specificity revealed a central role for FGFR1c in the regulation of glucose metabolism.

    Ge, Hongfei; Baribault, Helene; Vonderfecht, Steven; Lemon, Bryan; Weiszmann, Jennifer; Gardner, Jonitha; Lee, Ki Jeong; Gupte, Jamila; Mookherjee, Paramita; Wang, Minghan; Sheng, Jackie; Wu, Xinle; Li, Yang

    2012-01-01

    Diabetes and associated metabolic conditions have reached pandemic proportions worldwide, and there is a clear unmet medical need for new therapies that are both effective and safe. FGF19 and FGF21 are distinctive members of the FGF family that function as endocrine hormones. Both have potent effects on normalizing glucose, lipid, and energy homeostasis, and therefore, represent attractive potential next generation therapies for combating the growing epidemics of type 2 diabetes and obesity. The mechanism responsible for these impressive metabolic effects remains unknown. While both FGF19 and FGF21 can activate FGFRs 1c, 2c, and 3c in the presence of co-receptor βKlotho in vitro, which receptor is responsible for the metabolic activities observed in vivo remains unknown. Here we have generated a variant of FGF19, FGF19-7, that has altered receptor specificity with a strong bias toward FGFR1c. We show that FGF19-7 is equally efficacious as wild type FGF19 in regulating glucose, lipid, and energy metabolism in both diet-induced obesity and leptin-deficient mouse models. These results are the first direct demonstration of the central role of the βKlotho/FGFR1c receptor complex in glucose and lipid regulation, and also strongly suggest that activation of this receptor complex alone might be sufficient to achieve all the metabolic functions of endocrine FGF molecules.

  20. Genetics of Glucose regulation in Gestation and Growth (Gen3G): a prospective prebirth cohort of mother–child pairs in Sherbrooke, Canada

    Guillemette, Laetitia; Allard, Catherine; Lacroix, Marilyn; Patenaude, Julie; Battista, Marie-Claude; Doyon, Myriam; Moreau, Julie; Ménard, Julie; Bouchard, Luigi; Ardilouze, Jean-Luc; Perron, Patrice; Hivert, Marie-France

    2016-01-01

    Purpose We initiated the Genetics of Glucose regulation in Gestation and Growth (Gen3G) prospective cohort to increase our understanding of biological, environmental and genetic determinants of glucose regulation during pregnancy and their impact on fetal development. Participants Between January 2010 and June 2013, we invited pregnant women aged ≥18 years old who visited the blood sampling in pregnancy clinic in Sherbrooke for their first trimester clinical blood samples: 1034 women accepted to participate in our cohort study. Findings to date At first and second trimester, we collected demographics and lifestyle questionnaires, anthropometry measures (including fat and lean mass estimated using bioimpedance), blood pressure, and blood samples. At second trimester, women completed a full 75 g oral glucose tolerance test and we collected additional blood samples. At delivery, we collected cord blood and placenta samples; obstetrical and neonatal clinical data were abstracted from electronic medical records. We also collected buffy coats and extracted DNA from maternal and/or offspring samples (placenta and blood cells) to pursue genetic and epigenetic hypotheses. So far, we have found that low adiponectin and low vitamin D maternal levels in first trimester predict higher risk of developing gestational diabetes. Future plans We are now in the phase of prospective follow-up of mothers and offspring 3 and 5 years postdelivery to investigate the consequences of maternal dysglycaemia during pregnancy on offspring adiposity and metabolic profile. Trial registration number NCT01623934. PMID:26842272

  1. Keratin 8/18 regulation of glucose metabolism in normal versus cancerous hepatic cells through differential modulation of hexokinase status and insulin signaling

    Mathew, Jasmin; Loranger, Anne; Gilbert, Stéphane [Centre de recherche en cancérologie de l' Université Laval and Centre de recherche du CHUQ (L' Hôtel-Dieu de Québec), 9 McMahon, Québec, Qc, Canada G1R 2J6 (Canada); Faure, Robert [Département de Pédiatrie, Université Laval and Centre de recherche du CHUQ (Centre Mère-Enfant), Québec, Qc, Canada G1V 4G2 (Canada); Marceau, Normand, E-mail: normand.marceau@crhdq.ulaval.ca [Centre de recherche en cancérologie de l' Université Laval and Centre de recherche du CHUQ (L' Hôtel-Dieu de Québec), 9 McMahon, Québec, Qc, Canada G1R 2J6 (Canada)

    2013-02-15

    As differentiated cells, hepatocytes primarily metabolize glucose for ATP production through oxidative phosphorylation of glycolytic pyruvate, whereas proliferative hepatocellular carcinoma (HCC) cells undergo a metabolic shift to aerobic glycolysis despite oxygen availability. Keratins, the intermediate filament (IF) proteins of epithelial cells, are expressed as pairs in a lineage/differentiation manner. Hepatocyte and HCC (hepatoma) cell IFs are made solely of keratins 8/18 (K8/K18), thus providing models of choice to address K8/K18 IF functions in normal and cancerous epithelial cells. Here, we demonstrate distinctive increases in glucose uptake, glucose-6-phosphate formation, lactate release, and glycogen formation in K8/K18 IF-lacking hepatocytes and/or hepatoma cells versus their respective IF-containing counterparts. We also show that the K8/K18-dependent glucose uptake/G6P formation is linked to alterations in hexokinase I/II/IV content and localization at mitochondria, with little effect on GLUT1 status. In addition, we find that the insulin-stimulated glycogen formation in normal hepatocytes involves the main PI-3 kinase-dependent signaling pathway and that the K8/K18 IF loss makes them more efficient glycogen producers. In comparison, the higher insulin-dependent glycogen formation in K8/K18 IF-lacking hepatoma cells is associated with a signaling occurring through a mTOR-dependent pathway, along with an augmentation in cell proliferative activity. Together, the results uncover a key K8/K18 regulation of glucose metabolism in normal and cancerous hepatic cells through differential modulations of mitochondrial HK status and insulin-mediated signaling.

  2. The role of β-cell GLP-1 signaling in glucose regulation and response to diabetes drugs

    Smith, Eric P.; An, Zhibo; Wagner, Constance; Lewis, Alfor G.; Cohen, Eric B.; Li, Bailing; Mahbod, Parinaz; Sandoval, Darleen; Perez-Tilve, Diego; Tamarina, Natalia; Philipson, Louis H; Stoffers, Doris A.; Seeley, Randy J; D’Alessio, David A.

    2014-01-01

    Glucagon-like peptide-1 (GLP-1), an insulinotropic peptide released from the intestine after eating, is essential for normal glucose tolerance (GT). To determine whether this effect is mediated directly by GLP-1 receptors (GLP1R) on islet β-cells, we developed mice with β-cell specific knockdown of Glp1r. β-cell Glp1r knockdown mice had impaired GT after intraperitoneal (IP) glucose, and did not secrete insulin in response to IP or intravenous GLP-1. However, they had normal GT after oral glu...

  3. Insulin Resistance is Accompanied by Increased Fasting Glucagon and Delayed Glucagon Suppression in Individuals With Normal and Impaired Glucose Regulation

    Faerch, Kristine; Vistisen, Dorte; Pacini, Giovanni

    2016-01-01

    Hyperinsulinemia is an adaptive mechanism that enables the maintenance of normoglycemia in the presence of insulin resistance. We assessed whether glucagon is also involved in the adaptation to insulin resistance. A total of 1,437 individuals underwent an oral glucose tolerance test with measurem......Hyperinsulinemia is an adaptive mechanism that enables the maintenance of normoglycemia in the presence of insulin resistance. We assessed whether glucagon is also involved in the adaptation to insulin resistance. A total of 1,437 individuals underwent an oral glucose tolerance test...

  4. Regulation of glucose transport and c-fos and egr-1 expression in cells with mutated or endogenous growth hormone receptors

    Gong, T W; Meyer, D J; Liao, J;

    1998-01-01

    To identify mechanisms by which GH receptors (GHR) mediate downstream events representative of growth and metabolic responses to GH, stimulation by GH of c-fos and egr-1 expression and glucose transport activity were examined in Chinese hamster ovary (CHO) cells expressing mutated GHR. In CHO cells......, whereas P11 inhibits the GH-dependent tyrosyl phosphorylation of only some proteins, including extracellular signal regulated kinases ERK1 and -2, but not JAK2. Taken together, these results implicate association of GHR with JAK2 and GH-stimulated tyrosyl phosphorylation of an additional cellular protein...... in GH-stimulated glucose transport and c-fos and egr-1 expression. These studies also indicate that, in contrast to spi-2.1, the N-terminal half of the cytoplasmic domain of GHR is sufficient to mediate stimulation of c-fos and egr-1 expression and Elk-1 activation, supporting multiple mechanisms for GH...

  5. Nerve growth factor blocks the glucose-induced down-regulation of caveolin-1 expression in Schwann cells via p75 neurotrophin receptor signaling.

    Tan, Wenbin; Rouen, Shefali; Barkus, Kristin M; Dremina, Yelena S; Hui, Dongwei; Christianson, Julie A; Wright, Douglas E; Yoon, Sung Ok; Dobrowsky, Rick T

    2003-06-20

    Altered neurotrophism in diabetic peripheral neuropathy (DPN) is associated in part with substantial degenerative changes in Schwann cells (SCs) and an increased expression of the p75 neurotrophin receptor (p75NTR). Caveolin-1 (Cav-1) is highly expressed in adult SCs, and changes in its expression can regulate signaling through Erb B2, a co-receptor that mediates the effects of neuregulins in promoting SC growth and differentiation. We examined the hypothesis that hyperglycemia-induced changes in Cav-1 expression and p75NTR signaling may contribute to altered neurotrophism in DPN by modulating SC responses to neuregulins. In an animal model of type 1 diabetes, hyperglycemia induced a progressive decrease of Cav-1 in SCs of sciatic nerve that was reversed by insulin therapy. Treatment of primary neonatal SCs with 20-30 mm d-glucose, but not l-glucose, was sufficient to inhibit transcription from the Cav-1 promoter and decrease Cav-1 mRNA and protein expression. Hyperglycemia prolonged the kinetics of Erb B2 phosphorylation and significantly enhanced the mitogenic response of SCs to neuregulin1-beta1, and this effect was mimicked by the forced down-regulation of Cav-1. Intriguingly, nerve growth factor antagonized the enhanced mitogenic response of SCs to neuregulin1-beta1 and inhibited the glucose-induced down-regulation of Cav-1 transcription, mRNA, and protein expression through p75NTR-dependent activation of JNK. Our data suggest that Cav-1 down-regulation may contribute to altered neurotrophism in DPN by enhancing the response of SCs to neuregulins and that p75NTR-mediated JNK activation may provide a mechanism for the neurotrophic modulation of hyperglycemic stress.

  6. [Abnormal expression of genes that regulate retinoid metabolism and signaling in non-small-cell lung cancer].

    Kuznetsova, E S; Zinovieva, O L; Oparina, N Yu; Prokofjeva, M M; Spirin, P V; Favorskaya, I A; Zborovskaya, I B; Lisitsyn, N A; Prassolov, V S; Mashkova, T D

    2016-01-01

    Retinoids are signaling molecules that control a wide variety of cellular processes and possess antitumor activity. This work presents a comprehensive description of changes in the expression of 23 genes that regulate retinoid metabolism and signaling in non-small-cell lung cancer tumors compared to adjacent normal tissues obtained using RT-PCR. Even at early stages of malignant transformation, a significant decrease in ADH1B, ADH3, RDHL, and RALDH1 mRNA levels was observed in 82, 79, 73, and 64% of tumor specimens, respectively, and a considerable increase in AKR1B10 mRNA content was observed in 80% of tumors. Dramatic changes in the levels of these mRNAs can impair the synthesis of all-trans retinoic acid, a key natural regulatory retinoid. Apart from that, it was found that mRNA levels of nuclear retinoid receptor genes RXRγ, RARα, RXRα, and gene RDH11 were significantly decreased in 80, 67, 57, and 66% of tumor specimens, respectively. Thus, neoplastic transformation of lung tissue cells is accompanied with deregulated expression of key genes of retinoid metabolism and function.

  7. Anti-diabetic effects of rice hull smoke extract on glucose-regulating mechanism in type 2 diabetic mice

    The aim of this study is to determine the protective effect of a liquid rice hull smoke extract (RHSE) against type 2 diabetes induced by a high fat diet administered to mice. Dietary administration of 0.5% or 1% RHSE for 7 weeks results in significantly reduced blood glucose and triglyceride and to...

  8. Jicama (Pachyrhizus erosus) extract increases insulin sensitivity and regulates hepatic glucose in C57BL/Ksj-db/db mice.

    Park, Chan Joo; Lee, Hyun-Ah; Han, Ji-Sook

    2016-01-01

    This study investigated the effect of jicama extract on hyperglycemia and insulin sensitivity in an animal model of type 2 diabetes. Male C57BL/Ksj-db/db mice were divided into groups subsequently fed a regular diet (controls), or diet supplemented with jicama extract, and rosiglitazone. After 6 weeks, blood levels of glucose and glycosylated hemoglobin were significantly lower in animals administered the jicama extract than the control group. Additionally, glucose and insulin tolerance tests showed that jicama extract increased insulin sensitivity. The homeostatic index of insulin resistance was lower in the jicama extract-treated group than in the diabetic control group. Administration of jicama extract significantly enhanced the expressions of the phosphorylated AMP-activated protein kinase and Akt substrate of 160 kDa, and plasma membrane glucose transporter type 4 in skeletal muscle. Jicama extract administration also decreased the expressions of glucose 6-phosphatase and phosphoenol pyruvate carboxykinase in the liver. Jicama extract may increases insulin sensitivity and inhibites the gluconeogenesis in the liver.

  9. Behavioral Self-Regulation in Adolescents with Type 1 Diabetes: Negative Affectivity and Blood Glucose Symptom Perception.

    Wiebe, Deborah J.; And Others

    1994-01-01

    Adolescents who were more internally focused were more able to discern which symptoms actually covaried with blood glucose (BG) fluctuations; those with higher trait anxiety tended to misattribute non-diabetes-related symptoms to BG levels. Interactions suggested those who both attend to internal physical sensations and experience-heightened…

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

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

    2015-01-01

    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...... glucose and lipid homeostasis, in part through recruitment and metabolic activation of brown and beige adipocytes....

  11. High glucose upregulates BACE1-mediated Aβ production through ROS-dependent HIF-1α and LXRα/ABCA1-regulated lipid raft reorganization in SK-N-MC cells.

    Lee, Hyun Jik; Ryu, Jung Min; Jung, Young Hyun; Lee, Sei-Jung; Kim, Jeong Yeon; Lee, Sang Hun; Hwang, In Koo; Seong, Je Kyung; Han, Ho Jae

    2016-11-10

    There is an accumulation of evidence indicating that the risk of Alzheimer's disease is associated with diabetes mellitus, an indicator of high glucose concentrations in blood plasma. This study investigated the effect of high glucose on BACE1 expression and amyloidogenesis in vivo, and we present details of the mechanism associated with those effects. Our results, using ZLC and ZDF rat models, showed that ZDF rats have high levels of amyloid-beta (Aβ), phosphorylated tau, BACE1, and APP-C99. In vitro result with mouse hippocampal neuron and SK-N-MC, high glucose stimulated Aβ secretion and apoptosis in a dose-dependent manner. In addition, high glucose increased BACE1 and APP-C99 expressions, which were reversed by a reactive oxygen species (ROS) scavenger. Indeed, high glucose increased intracellular ROS levels and HIF-1α expression, associated with regulation of BACE1 and Liver X Receptor α (LXRα). In addition, high glucose induced ATP-binding cassette transporter A1 (ABCA1) down-regulation, was associated with LXR-induced lipid raft reorganization and BACE1 localization on the lipid raft. Furthermore, silencing of BACE1 expression was shown to regulate Aβ secretion and apoptosis of SK-N-MC. In conclusion, high glucose upregulates BACE1 expression and activity through HIF-1α and LXRα/ABCA1-regulated lipid raft reorganization, leading to Aβ production and apoptosis of SK-N-MC.

  12. Cystic fibrosis transmembrane conductance regulator (CFTR) gene abnormalities in Indian males with congenital bilateral absence of vas deferens & renal anomalies

    Gajbhiye, Rahul; Kadam, Kaushiki; Khole, Aalok; Gaikwad, Avinash; Kadam, Seema; Shah, Rupin; Kumaraswamy, Rangaswamy; Khole, Vrinda

    2016-01-01

    Background & objectives: The role of cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in congenital bilateral absence of vas deferens and unilateral renal agenesis (CBAVD-URA) has been controversial. Here, we report the cases of five Indian males with CBAVD-URA. The objective was to evaluate the presence or absence of CFTR gene mutations and variants in CBAVD-URA. The female partners of these males were also screened for cystic fibrosis (CF) carrier status. Methods: Direct DNA sequencing of CFTR gene was carried out in five Indian infertile males having CBAVD-URA. Female partners (n=5) and healthy controls (n=32) were also screened. Results: Three potential regulatory CFTR gene variants (c.1540A>G, c.2694T>G and c.4521G>A) were detected along with IVS8-5T mutation in three infertile males with CBAVD-URA. Five novel CFTR gene variants (c.621+91A>G, c.2752+106A>T, c.2751+85_88delTA, c.3120+529InsC and c.4375-69C>T), four potential regulatory CFTR gene variants (M470V, T854T, P1290P, Q1463Q) and seven previously reported CFTR gene variants (c.196+12T>C, c.875+40A>G, c.3041-71G>C, c.3271+42A>T, c.3272-93T>C, c.3500-140A>C and c.3601-65C>A) were detected in infertile men having CBAVD and renal anomalies Interpretation & conclusions: Based on our findings, we speculate that CBAVD-URA may also be attributed to CFTR gene mutations and can be considered as CFTR-related disorder (CFTR-RD). The CFTR gene mutation screening may be offered to CBAVD-URA men and their female partners undergoing ICSI. Further studies need to be done in a large sample to confirm the findings. PMID:27488005

  13. Glucose Sensing

    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...

  14. 肝脏G蛋白偶联受体与糖代谢调节%Liver GPCRs and regulations of glucose metabolism

    薛妮娜; 王晓娟; 王莉莉

    2011-01-01

    肝脏是调节机体能量平衡尤其是糖、脂代谢的主要器官.在前糖尿病状态,患者表现为高胰岛素血症以及包括肝脏在内的外周组织的胰岛素抵抗,但不表现为空腹血糖升高.随着病程的发展,患者自身代偿能力逐渐衰退,出现肝脏糖代谢紊乱,糖原分解和糖异生增强,空腹血糖水平增高,最终发生糖尿病.研究表明,一些G蛋白偶联受体(GPCRs)参与了肝脏糖异生、糖原分解等代谢途径的调节,在肝糖代谢中发挥着重要作用.该文综述了参与肝糖代谢调节作用的GPCRs,以及靶向GPCRs改善胰岛素抵抗、治疗2型糖尿病的研究进展.%Liver, a key organ in energy balance, plays an important role in regulating glucose and lipid metabolism.In pre-diabetic status, patients show hyperinsulinemia and insulin resistance in peripheral tissue ,including the liver, but do not show for the fasting hyperglycemia.As the disease progresses, the liver glucose metabolism disorder appears, excessive glycogenolysis and gluconeogenesis arise, Which results in hyperglycemia.Several G protein-coupled receptors ( GPCRs ) expressed in liver tissues are known to be involved in the regulation of glycogenolysis and gluconeogenesis.Here,the progresses of the GPCRs involved in regulation in glucose metabolism and the targeting GPCRs for insuline resistance and the diabetes have been reviewed.

  15. HCdc14A is involved in cell cycle regulation of human brain vascular endothelial cells following injury induced by high glucose, free fatty acids and hypoxia.

    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.

  16. Sweet taste receptor expression in ruminant intestine and its activation by artificial sweeteners to regulate glucose absorption.

    Moran, A W; Al-Rammahi, M; Zhang, C; Bravo, D; Calsamiglia, S; Shirazi-Beechey, S P

    2014-01-01

    Absorption of glucose from the lumen of the intestine into enterocytes is accomplished by sodium-glucose co-transporter 1 (SGLT1). In the majority of mammalian species, expression (this includes activity) of SGLT1 is upregulated in response to increased dietary monosaccharides. This regulatory pathway is initiated by sensing of luminal sugar by the gut-expressed sweet taste receptor. The objectives of our studies were to determine (1) if the ruminant intestine expresses the sweet taste receptor, which consists of two subunits [taste 1 receptor 2 (T1R2) and 3 (T1R3)], and other key signaling molecules required for SGLT1 upregulation in nonruminant intestines, and (2) whether T1R2-T1R3 sensing of artificial sweeteners induces release of glucagon-like peptide-2 (GLP-2) and enhances SGLT1 expression. We found that the small intestine of sheep and cattle express T1R2, T1R3, G-protein gustducin, and GLP-2 in enteroendocrine L-cells. Maintaining 110-d-old ruminating calves for 60d on a diet containing a starter concentrate and the artificial sweetener Sucram (consisting of saccharin and neohesperidin dihydrochalcone; Pancosma SA, Geneva, Switzerland) enhances (1) Na(+)-dependent d-glucose uptake by over 3-fold, (2) villus height and crypt depth by 1.4- and 1.2-fold, and (3) maltase- and alkaline phosphatase-specific activity by 1.5-fold compared to calves maintained on the same diet without Sucram. No statistically significant differences were observed for rates of intestinal glucose uptake, villus height, crypt depth, or enzyme activities between 50-d-old milk-fed calves and calves maintained on the same diet containing Sucram. When adult cows were kept on a diet containing 80:20 ryegrass hay-to-concentrate supplemented with Sucram, more than a 7-fold increase in SGLT1 protein abundance was noted. Collectively, the data indicate that inclusion of this artificial sweetener enhances SGLT1 expression and mucosal growth in ruminant animals. Exposure of ruminant sheep

  17. The Prevalence and Associated Risk Factors of Impaired Glucose Regulation in Chinese Adults: A Population-Based Cross-Sectional Study

    Dong Zhao

    2015-01-01

    Full Text Available The goal of this study was to determine the prevalence and associated risk factors of impaired glucose regulation (IGR in the population of Tongzhou, China, and to provide scientific basis for preventive interventions. In the study, the overall age-standardized prevalence of IGR (16.0% in Tongzhou residents was higher than that in the national population (15.0%. There was no significant geographic difference in prevalence of IGR between urban and rural males. Older age, elevated blood pressure, high serum lipids, overweight, and central obesity were significantly associated with increased risk of IGR.

  18. Hepatic and Extrahepatic Insulin Clearance Are Differentially Regulated: Results From a Novel Model-Based Analysis of Intravenous Glucose Tolerance Data.

    Polidori, David C; Bergman, Richard N; Chung, Stephanie T; Sumner, Anne E

    2016-06-01

    Insulin clearance is a highly variable and important factor that affects circulating insulin concentrations. We developed a novel model-based method to estimate both hepatic and extrahepatic insulin clearance using plasma insulin and C-peptide profiles obtained from the insulin-modified frequently sampled intravenous glucose tolerance test. Data from 100 African immigrants without diabetes (mean age 38 years, body weight 81.7 kg, fasting plasma glucose concentration 83 mg/dL, and fasting insulin concentration 37 pmol/L) were used. Endogenous insulin secretion (calculated by C-peptide deconvolution) and insulin infusion rates were used as inputs to a new two-compartment model of insulin kinetics and hepatic and extrahepatic clearance parameters were estimated. Good agreement between modeled and measured plasma insulin profiles was observed (mean normalized root mean square error 6.8%), and considerable intersubject variability in parameters of insulin clearance among individuals was identified (the mean [interquartile range] for hepatic extraction was 25.8% [32.7%], and for extrahepatic insulin clearance was 20.7 mL/kg/min [11.7 mL/kg/min]). Parameters of insulin clearance were correlated with measures of insulin sensitivity and acute insulin response to glucose. The method described appears promising for future research aimed at characterizing variability in insulin clearance and the mechanisms involved in the regulation of insulin clearance.

  19. Design of FPGA-based Digital PID Controller Using Xilinx SysGen® For Regulating Blood Glucose Level of Type-I Diabetic Patients

    Arezou Geramipour

    2013-04-01

    Full Text Available This paper emphasizes on a method for designing digital PID controller based on Field Programmable Gate Array (FPGA device for regulating blood glucose level of type-I diabetic patients. The controller is tuned using Bergman Minimal model as a diabetic patient model in MATLAB and Simulink environment. The PID parameters are tuned using a genetic algorithm (GA. Because the speed of control systems has influence on their performance and stability, Field Programmable Gate Array (FPGA device is considered. A Simulink to FPGA flow is applied to the structure of PID controller with Xilinx blocks in Simulink. The results of blood glucose of two diabetic patient models using different quantization in bits are simulated. The results show that unsuitable number of bits cause hypoglycemia and increasing the peak of blood glucose in diabetic patients. System Generator and Integrated Software Environment (ISE are used for creating Bitstream file that can be downloaded into FPGA device. The results show that implementation of PID controller on FPGA using System Generator is compact and high speed and causes the designer can evaluate and implement different designs simply.

  20. Statins suppress glucose-induced plasminogen activator inhibitor-1 expression by regulating RhoA and nuclear factor-κB activities in cardiac microvascular endothelial cells.

    Ni, Xiao-Qing; Zhu, Jian-Hua; Yao, Ning-Hua; Qian, Juan; Yang, Xiang-Jun

    2013-01-01

    The aim of this study was to investigate the possible proinflammatory signaling pathways involved in statin inhibition of glucose-induced plasminogen activator inhibitor-1 (PAI-1) expression in cardiac microvascular endothelial cells (CMECs). Primary rat CMECs were grown in the presence of 5.7 or 23 mmol/L glucose. PAI-1 mRNA and protein expression levels were measured by realtime polymerase chain reaction, Western blotting and enzyme-linked immunosorbent assay, respectively. A pull-down assay was performed to determine RhoA activity. IκBα protein expression was measured by Western blotting, nuclear factor (NF)-κB activation was detected by electrophoretic mobility shift assay and its transcription activity was determined by a dual luciferase reporter gene assay. PAI-1 mRNA and protein expression levels were both increased with high glucose concentrations, but they were significantly suppressed by simvastatin and atorvastatin treatment (P statins (P statins may occur partly by regulating the RhoA/ROCK-NF-κB pathway. The multifunctional roles of statins may be particularly beneficial for patients with metabolic syndrome.

  1. Lactate and glucose concomitant consumption as a self-regulated pH detoxification mechanism in HEK293 cell cultures.

    Liste-Calleja, Leticia; Lecina, Martí; Lopez-Repullo, Jonatan; Albiol, Joan; Solà, Carles; Cairó, Jordi Joan

    2015-12-01

    One of the most important limitations of mammalian cell-based processes is the secretion and accumulation of lactate as a by-product of their metabolism. Among the cell lines commonly used in industrial bioprocesses, HEK293 has been gaining importance over the last years. Up recently, HEK293 cells were known to consume lactate in late stages of cell culture usually when glucose and/or glutamine were depleted from media. Remarkably, in both scenarios, no significant cell growth was reported. However, we have observed a different metabolic behavior regarding lactate production and consumption in HEK293 cultures. HEK293 cells were able to co-metabolize glucose and lactate simultaneously, even in exponentially growing cell cultures. Our deep study of the effects of environmental conditions on lactate metabolism revealed that pH was the key to trigger the metabolic shift from lactate production to lactate and glucose concomitant consumption. Remarkably, this shift could be triggered at will when pH was set at 6.8. Even more interesting was the fact that lowering pH to 6.6 and supplementing media with exogenous lactate resulted in co-consumption of glucose and lactate from the beginning of cell culture, without affecting cell growth or protein productivity. On the contrary, cell growth was clearly hampered at this low pH if extracellular lactate was lacking. From our results, we hypothesize that HEK293 cells metabolize extracellular lactate as a strategy for pH detoxification, by means of co-transporting extracellular protons together with lactate into the cytosol. This novel hypothesis for unraveling lactate metabolism in HEK293 cells could open a door to re-direct genetic engineering strategies in order to obtain more efficient cell lines and also to further develop animal cell technology applications.

  2. The Roots of Atractylodes macrocephala Koidzumi Enhanced Glucose and Lipid Metabolism in C2C12 Myotubes via Mitochondrial Regulation

    Mi Young Song

    2015-01-01

    Full Text Available The root of Atractylodes macrocephala Koidzumi (Atractylodis Rhizoma Alba, ARA is a Traditional Korean Medicine and has been commonly used for weight control. Mitochondrial dysfunction appears to be a key contributor to insulin resistance, and therefore mitochondrial targeting drugs represent an important potential strategy for the treatment of insulin resistance and obesity. In this study, the authors investigated the regulatory effects of ARA on mitochondrial function with respect to the stimulation of glucose and lipid metabolism in C2C12 myotubes. After differentiating C2C12 myotubes, cells were treated with or without different concentrations (0.2, 0.5, and 1.0 mg/mL of ARA extract. ARA extract significantly increased the expression of peroxisome proliferator-activated receptor coactivator 1 alpha (PGC1α and the downregulations of its targets, nuclear respiratory factor-1 (NRF-1, transcription factor A (TFAM, and total ATP content in C2C12 myotubes. ARA extract also increased the expressions of PGC1α activator and of the metabolic sensors, AMP-activated protein kinase (AMPK, and acetyl-CoA carboxylase and sirtuin (SIRT 1. Furthermore, it significantly increased glucose uptake by enhancing glucose consumption and subsequently decreased FFA contents and increased carnitine palmitoyltransferase (CPT 1b expression. Our study indicates that ARA has a potential for stimulating mitochondrial function and energy metabolism in muscle.

  3. A role for cytosolic isocitrate dehydrogenase as a negative regulator of glucose signaling for insulin secretion in pancreatic ß-cells.

    Guay, Claudiane; Joly, Erik; Pepin, Emilie; Barbeau, Annie; Hentsch, Lisa; Pineda, Marco; Madiraju, S R Murthy; Brunengraber, Henri; Prentki, Marc

    2013-01-01

    Cytosolic NADPH may act as one of the signals that couple glucose metabolism to insulin secretion in the pancreatic ß-cell. NADPH levels in the cytoplasm are largely controlled by the cytosolic isoforms of malic enzyme and isocitrate dehydrogenase (IDHc). Some studies have provided evidence for a role of malic enzyme in glucose-induced insulin secretion (GIIS) via pyruvate cycling, but the role of IDHc in ß-cell signaling is unsettled. IDHc is an established component of the isocitrate/α-ketoglutarate shuttle that transfers reducing equivalents (NADPH) from the mitochondrion to the cytosol. This shuttle is energy consuming since it is coupled to nicotinamide nucleotide transhydrogenase that uses the mitochondrial proton gradient to produce mitochondrial NADPH and NAD(+) from NADP(+) and NADH. To determine whether flux through IDHc is positively or negatively linked to GIIS, we performed RNAi knockdown experiments in ß-cells. Reduced IDHc expression in INS 832/13 cells and isolated rat islet ß-cells resulted in enhanced GIIS. This effect was mediated at least in part via the KATP-independent amplification arm of GIIS. IDHc knockdown in INS 832/13 cells did not alter glucose oxidation but it reduced fatty acid oxidation and increased lipogenesis from glucose. Metabolome profiling in INS 832/13 cells showed that IDHc knockdown increased isocitrate and NADP(+) levels. It also increased the cellular contents of several metabolites linked to GIIS, in particular some Krebs cycle intermediates, acetyl-CoA, glutamate, cAMP and ATP. The results identify IDHc as a component of the emerging pathways that negatively regulate GIIS.

  4. 糖耐量异常对急性脑梗死患者血浆Hcy和血清hs-CRP水平的影响%The Influence of Abnormal Glucose Tolerance on the Levels of Plasma Homocysteine and Serum High-sensitivity C-reactive Protein in Patients with Acute Cerebral Infarction(ACI)

    赵红东; 陆敏; 唐冰

    2012-01-01

    Objective To observe the influence of abnormal glucose tolerance on the levels of homocysteine and high-sensitivity C-reactive protein in patients with acute cerebral infarction( AGI). Methods 756 patients with AGI were divided into normal glucose tolerance group (NGT, 33 leases) , abnormal glucose tolerance group(IGT,142cases) ,and diabetes mellitus group (DM,283 scase) ac-cording to the result of oral glucose tolerance test( OGTT). The serum levels of Hcy and hs-GRP were measured in 24 hours after ad-mission. Result The both levels of Hey and hs-GRP in IGT group(19.17 9.35juno]/L,20.46 10.56μmol/L) and DM group (8.0 2.9 mg/L,7.7 2.3 mg/L) were higher than the NGT group with no difference between each other. Conclusion The levels of Hey and hs-GRP in patients with AGI and abnormal glucose tolerance rise significantly,which indicate the presence of chronic low-grade inflammation and atherosclerosis in the stage of abnormal glucose tolerance. The results showed abnormal glucose tolerance is the risk factor of atherosclerosis as diabetes mellitus,and the OGTT test is valuable in screening risk factors of AGI and stroke prevention.%目的:观察糖耐量异常对急性脑梗死(acute cerebral infarction,ACI)患者的同型半胱氨酸(Hcy)、超敏C反应蛋白(hs-CRP)水平的影响.方法:756例ACI患者按葡萄糖耐量试验(OGTT)结果分为糖耐量正常组(NGT,331例)、单纯性糖耐量异常组(IGT,142例)、2型糖尿病组(DM2,283例).在入院24h之内测定血清Hcy、hs-CRP水平并进行组间比较.结果:IGT组及DM2组的Hcy水平(19.17±9.35)μmol/L、(20.46±10.56)μmol/L以及hs-CRP水平(8.0±2.9)mg/L、(7.7±2.3)mg/L明显高于NGT组(16.17±7.35)μmol/L、(3.5±1.2)mg/L.IGT组及DM2组两组之间的Hcy、hs-CRP水平差异均无统计学意义(P>0.05、P>0.05).结论:单纯性糖耐量异常的ACI患者血清Hcy、hs-CRP水平明显升高,表明在糖耐量异常阶段,已经出现了慢性低水平炎症和动脉粥样硬化的发生.提

  5. Antitumor and chemosensitizing action of dichloroacetate implicates modulation of tumor microenvironment: A role of reorganized glucose metabolism, cell survival regulation and macrophage differentiation

    Kumar, Ajay; Kant, Shiva; Singh, Sukh Mahendra, E-mail: sukhmahendrasingh@yahoo.com

    2013-11-15

    Targeting of tumor metabolism is emerging as a novel therapeutic strategy against cancer. Dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase (PDK), has been shown to exert a potent tumoricidal action against a variety of tumor cells. The main mode of its antineoplastic action implicates a shift of glycolysis to oxidative metabolism of glucose, leading to generation of cytotoxic reactive oxygen intermediates. However, the effect of DCA on tumor microenvironment, which in turn regulates tumor cell survival; remains speculative to a large extent. It is also unclear if DCA can exert any modulatory effect on the process of hematopoiesis, which is in a compromised state in tumor-bearing hosts undergoing chemotherapy. In view of these lacunas, the present study was undertaken to investigate the so far unexplored aspects with respect to the molecular mechanisms of DCA-dependent tumor growth retardation and chemosensitization. BALB/c mice were transplanted with Dalton's lymphoma (DL) cells, a T cell lymphoma of spontaneous origin, followed by administration of DCA with or without cisplatin. DCA-dependent tumor regression and chemosensitization to cisplatin was found to be associated with altered repertoire of key cell survival regulatory molecules, modulated glucose metabolism, accompanying reconstituted tumor microenvironment with respect to pH homeostasis, cytokine balance and alternatively activated TAM. Moreover, DCA administration also led to an alteration in the MDR phenotype of tumor cells and myelopoietic differentiation of macrophages. The findings of this study shed a new light with respect to some of the novel mechanisms underlying the antitumor action of DCA and thus may have immense clinical applications. - Highlights: • DCA modulates tumor progression and chemoresistance. • DCA alters molecules regulating cell survival, glucose metabolism and MDR. • DCA reconstitutes biophysical and cellular composition of tumor microenvironment.

  6. Thiazolidinediones mimic glucose starvation in facilitating Sp1 degradation through the up-regulation of beta-transducin repeat-containing protein.

    Wei, Shuo; Chuang, Hsiao-Ching; Tsai, Wan-Chi; Yang, Hsiao-Ching; Ho, Shiuh-Rong; Paterson, Andrew J; Kulp, Samuel K; Chen, Ching-Shih

    2009-07-01

    This study investigated the mechanism by which the transcription factor Sp1 is degraded in prostate cancer cells. We recently developed a thiazolidinedione derivative, (Z)-5-(4-hydroxy-3-trifluoromethylbenzylidene)-3-(1-methylcyclohexyl)-thiazolidine-2,4-dione (OSU-CG12), that induces Sp1 degradation in a manner paralleling that of glucose starvation. Based on our finding that thiazolidinediones suppress beta-catenin and cyclin D1 by up-regulating the E3 ligase SCF(beta-TrCP), we hypothesized that beta-transducin repeat-containing protein (beta-TrCP) targets Sp1 for proteasomal degradation in response to glucose starvation or OSU-CG12. Here we show that either treatment of LNCaP cells increased specific binding of Sp1 with beta-TrCP. This direct binding was confirmed by in vitro pull-down analysis with bacterially expressed beta-TrCP. Although ectopic expression of beta-TrCP enhanced the ability of OSU-CG12 to facilitate Sp1 degradation, suppression of endogenous beta-TrCP function by a dominant-negative mutant or small interfering RNA-mediated knockdown blocked OSU-CG12-facilitated Sp1 ubiquitination and/or degradation. Sp1 contains a C-terminal conventional DSG destruction box ((727)DSGAGS(732)) that mediates beta-TrCP recognition and encompasses a glycogen synthase kinase 3beta (GSK3beta) phosphorylation motif (SXXXS). Pharmacological and molecular genetic approaches and mutational analyses indicate that extracellular signal-regulated kinase-mediated phosphorylation of Thr739 and GSK3beta-mediated phosphorylation of Ser728 and Ser732 were critical for Sp1 degradation. The ability of OSU-CG12 to mimic glucose starvation to activate beta-TrCP-mediated Sp1 degradation has translational potential to foster novel strategies for cancer therapy.

  7. Association between the melatonin receptor 1B gene polymorphism on the risk of type 2 diabetes, impaired glucose regulation: a meta-analysis.

    Qing Xia

    Full Text Available BACKGROUND: Melatonin receptor 1B (MTNR1B belongs to the seven-transmembrane G protein-coupled receptor superfamily involved in insulin secretion, which has attracted considerable attention as a candidate gene for type 2 diabetes (T2D since it was first identified as a loci associated with fasting plasma glucose level through genome wide association approach. The relationship between MTNR1B and T2D has been reported in various ethnic groups. The aim of this study was to consolidate and summarize published data on the potential of MTNR1B polymorphisms in T2D risk prediction. METHODS: PubMed, EMBASE, ISI web of science and the CNKI databases were systematically searched to identify relevant studies. Odds ratios (ORs and 95% confidence intervals (95% CIs were calculated. Heterogeneity and publication bias were also tested. RESULTS: A total of 23 studies involving 172,963 subjects for two common polymorphisms (rs10830963, rs1387153 on MTNR1B were included. An overall random effects per-allele OR of 1.05 (95% CI: 1.02-1.08; P<10(-4 and 1.04 (95% CI: 0.98-1.10; P = 0.20 were found for the two variants respectively. Similar results were also observed using dominant or recessive genetic model. There was strong evidence of heterogeneity, which largely disappeared after stratification by ethnicity. Significant results were found in Caucasians when stratified by ethnicity; while no significant associations were observed in East Asians and South Asians. Besides, we found that the rs10830963 polymorphism is a risk factor associated with increased impaired glucose regulation susceptibility. CONCLUSIONS: This meta-analysis demonstrated that the rs10830963 polymorphism is a risk factor for developing impaired glucose regulation and T2D.

  8. Specific N-glycans of Hepatocellular Carcinoma Cell Surface and the Abnormal Increase of Core-α-1, 6-fucosylated Triantennary Glycan via N-acetylglucosaminyltransferases-IVa Regulation.

    Nie, Huan; Liu, Xia; Zhang, Yubao; Li, Tingting; Zhan, Chao; Huo, Wenjuan; He, Anshun; Yao, Yuanfei; Jin, Yu; Qu, Youpeng; Sun, Xue-Long; Li, Yu

    2015-11-05

    Glycosylation alterations of cell surface proteins are often observed during the progression of malignancies. The specific cell surface N-glycans were profiled in hepatocellular carcinoma (HCC) with clinical tissues (88 tumor and adjacent normal tissues) and the corresponding serum samples of HCC patients. The level of core-α-1,6-fucosylated triantennary glycan (NA3Fb) increased both on the cell surface and in the serum samples of HCC patients (p IVa (GnT-IVa), which was related to the synthesis of the NA3Fb, was substantially increased in HCC tissues. Knockdown of GnT-IVa leads to a decreased level of NA3Fb and decreased ability of invasion and migration in HCC cells. NA3Fb can be regarded as a specific cell surface N-glycan of HCC. The high expression of GnT-IVa is the cause of the abnormal increase of NA3Fb on the HCC cell surface, which regulates cell migration. This study demonstrated the specific N-glycans of the cell surface and the mechanisms of altered glycoform related with HCC. These findings lead to better understanding of the function of glycan and glycosyltransferase in the tumorigenesis, progression and metastasis of HCC.

  9. Short-Term Regulation of Lipocalin-2 but not RBP-4 During Oral Lipid Tolerance Test and Oral Glucose Tolerance Test.

    Schmid, A; Leszczak, S; Ober, I; Schäffler, A; Karrasch, T

    2016-02-01

    The postprandial regulation of lipocalin-2 and retinol binding protein-4 (RBP-4) by oral uptake of lipids and carbohydrates in healthy individuals has not yet been investigated. The regulation of lipocalin-2 and RBP-4 in 2 large cohorts of healthy volunteers during oral lipid tolerance test (OLTT; n=100) and oral glucose tolerance test (OGTT; n=100) was analyzed. One hundred healthy volunteers underwent OLTT and OGTT in an outpatient setting. Venous blood was drawn after 0, 2, 4, and 6 h in OLTT and after 0, 1, and 2 h in OGTT. In order to dissect carbohydrate-induced from lipid-induced effects, a novel OLTT solution completely free of carbohydrates and protein was applied. Subjects were characterized by anthropometric and laboratory parameters. Serum concentrations of lipocalin-2 and RBP-4 were measured by enzyme-linked immunosorbent assay (ELISA). Whereas RBP-4 levels remained unchanged during OGTT, lipocalin-2 concentrations significantly decreased during OGTT. During OLTT, RBP-4 levels were not influenced, whereas lipocalin-2 levels decreased significantly and stepwise. Fasting concentrations of RBP-4 were negatively correlated with BMI and waist-hip ratio, whereas lipocalin-2 levels were positively associated with BMI and waist-hip ratio. Female users of hormonal contraception had higher RBP-4 levels than females not on contraceptives. There is no significant short-term regulation of RBP-4 by orally ingested lipids or carbohydrates. Lipocalin-2 is downregulated after lipid and carbohydrate ingestion and this kind of regulation was not predicted by age, sex, triglycerides, glucose, or insulin levels.

  10. Adenine nucleotides and intracellular Ca2+ regulate a voltage-dependent and glucose-sensitive potassium channel in neurosecretory cells.

    Onetti, C G; Lara, J; García, E

    1996-05-01

    Effects of membrane potential, intracellular Ca2+ and adenine nucleotides on glucose-sensitive channels from X organ (XO) neurons of the crayfish were studied in excised inside-out patches. Glucose- sensitive channels were selective to K+ ions; the unitary conductance was 112 pS in symmetrical K+, and the K+ permeability (PK) was 1.3 x 10(-13) cm x s(-1). An inward rectification was observed when intracellular K+ was reduced. Using a quasi-physiological K+ gradient, a non-linear K+ current/voltage relationship was found showing an outward rectification and a slope conductance of 51 pS. The open-state probability (Po) increased with membrane depolarization as a result of an enhancement of the mean open time and a shortening of the longer period of closures. In quasi-physio- logical K+ concentrations, the channel was activated from a threshold of about -60 mV, and the activation midpoint was -2 mV. Po decreased noticeably at 50 microM internal adenosine 5'-triphosphate (ATP), and single-channel activity was totally abolished at 1 mM ATP. Hill analysis shows that this inhibition was the result of simultaneous binding of two ATP molecules to the channel, and the half-blocking concentration of ATP was 174 microM. Internal application of 5'-adenylylimidodiphosphate (AMP-PNP) as well as glibenclamide also decreased Po. By contrast, the application of internal ADP (0.1 to 2 mM) activated this channel. An optimal range of internal free Ca2+ ions (0.1 to 10 microM) was required for the activation of this channel. The glucose--sensitive K+ channel of XO neurons could be considered as a subtype of ATP-sensitive K+ channel, contributing substantially to macroscopic outward current.

  11. “P2X7 Receptor Activation Regulates Microglial Cell Death During Oxygen-Glucose Deprivation”

    Eyo, Ukpong B.; Miner, Sam A.; Ahlers, Katelin E.; Wu, Long-Jun; Dailey, Michael E.

    2013-01-01

    Brain-resident microglia may promote tissue repair following stroke but, like other cells, they are vulnerable to ischemia. Here we identify mechanisms involved in microglial ischemic vulnerability. Using time-lapse imaging of cultured BV2 microglia, we show that simulated ischemia (oxygen-glucose deprivation; OGD) induces BV2 microglial cell death. Removal of extracellular Ca2+ or application of Brilliant Blue G (BBG), a potent P2X7 receptor (P2X7R) antagonist, protected BV2 microglia from d...

  12. Identification of 9 uterine genes that are regulated during mouse pregnancy and exhibit abnormal levels in the cyclooxygenase-1 knockout mouse

    Soper Jessica

    2007-07-01

    Full Text Available Abstract Background Preterm birth is the leading cause of all infant mortality. In 2004, 12.5% of all births were preterm. In order to understand preterm labor, we must first understand normal labor. Since many of the myometrial changes that occur during pregnancy are similar in mice and humans and mouse gestation is short, we have studied the uterine genes that change in the mouse during pregnancy. Here, we used microarray analysis to identify uterine genes in the gravid mouse that are differentially regulated in the cyclooxygenase-1 knockout mouse model of delayed parturition. Methods Gestational d18.0 uteri (n = 4 were collected from pregnant wild-type and cyclooxygenase-1 knockout mice. Part of the uterus was used for frozen sections and RNA was isolated from the remainder. Microarray analysis was performed at the Indiana University School of Medicine Genomic Core and analyzed using the Microarray Data Portal. Northern analysis was performed to confirm microarray data and the genes localized in the gravid uterus by in situ hybridization. Results We identified 277 genes that are abnormally expressed in the gravid d18.0 cyclooxygenase-1 knockout mouse. Nine of these genes are also regulated in the normal murine uterus during the last half of gestation. Many of these genes are involved in the immune response, consistent with an important role of the immune system in parturition. Expression of 4 of these genes; arginase I, IgJ, Tnfrsf9 and troponin; was confirmed by Northern analysis to be mis-regulated during pregnancy in the knockout mouse. In situ hybridization of these genes demonstrated a similar location in the gravid wild-type and Cox-1 knockout mouse uteri. Conclusion To our knowledge, this is the first work to demonstrate the uterine location of these 4 genes in the mouse during late pregnancy. There are several putative transcription factor binding sites that are shared by many of the 9 genes identified here including; estrogen and

  13. A muscle-specific knockout implicates nuclear receptor coactivator MED1 in the regulation of glucose and energy metabolism.

    Chen, Wei; Zhang, Xiaoting; Birsoy, Kivanc; Roeder, Robert G

    2010-06-01

    As conventional transcriptional factors that are activated in diverse signaling pathways, nuclear receptors play important roles in many physiological processes that include energy homeostasis. The MED1 subunit of the Mediator coactivator complex plays a broad role in nuclear receptor-mediated transcription by anchoring the Mediator complex to diverse promoter-bound nuclear receptors. Given the significant role of skeletal muscle, in part through the action of nuclear receptors, in glucose and fatty acid metabolism, we generated skeletal muscle-specific Med1 knockout mice. Importantly, these mice show enhanced insulin sensitivity and improved glucose tolerance as well as resistance to high-fat diet-induced obesity. Furthermore, the white muscle of these mice exhibits increased mitochondrial density and expression of genes specific to type I and type IIA fibers, indicating a fast-to-slow fiber switch, as well as markedly increased expression of the brown adipose tissue-specific UCP-1 and Cidea genes that are involved in respiratory uncoupling. These dramatic results implicate MED1 as a powerful suppressor in skeletal muscle of genetic programs implicated in energy expenditure and raise the significant possibility of therapeutical approaches for metabolic syndromes and muscle diseases through modulation of MED1-nuclear receptor interactions.

  14. Adipose tissue mTORC2 regulates ChREBP-driven de novo lipogenesis and hepatic glucose metabolism

    Tang, Yuefeng; Wallace, Martina; Sanchez-Gurmaches, Joan; Hsiao, Wen-Yu; Li, Huawei; Lee, Peter L.; Vernia, Santiago; Metallo, Christian M.; Guertin, David A.

    2016-01-01

    Adipose tissue de novo lipogenesis (DNL) positively influences insulin sensitivity, is reduced in obesity, and predicts insulin resistance. Therefore, elucidating mechanisms controlling adipose tissue DNL could lead to therapies for type 2 diabetes. Here, we report that mechanistic target of rapamycin complex 2 (mTORC2) functions in white adipose tissue (WAT) to control expression of the lipogenic transcription factor ChREBPβ. Conditionally deleting the essential mTORC2 subunit Rictor in mature adipocytes decreases ChREBPβ expression, which reduces DNL in WAT, and impairs hepatic insulin sensitivity. Mechanistically, Rictor/mTORC2 promotes ChREBPβ expression in part by controlling glucose uptake, but without impairing pan-AKT signalling. High-fat diet also rapidly decreases adipose tissue ChREBPβ expression and insulin sensitivity in wild-type mice, and does not further exacerbate insulin resistance in adipose tissue Rictor knockout mice, implicating adipose tissue DNL as an early target in diet-induced insulin resistance. These data suggest mTORC2 functions in WAT as part of an extra-hepatic nutrient-sensing mechanism to control glucose homeostasis. PMID:27098609

  15. NDRG2 is a novel p53-associated regulator of apoptosis in C6-originated astrocytes exposed to oxygen-glucose deprivation.

    Yan Li

    Full Text Available N-myc downstream-regulated gene 2 (NDRG2 has been documented to be a pro-differentiative and anti-proliferative gene in cancer research. Our previous study found a significant NDRG2 up-regulation in reactive astrocytes of penumbra after transient focal cerebral ischemia, which was parallel to the enhancement of TUNEL-positive signals. However, it is still uncertain whether NDRG2 participates in cellular apoptosis induced by ischemia-reperfusion injury in brain. In this study, we investigated the role of NDRG2 in cellular apoptosis induced by oxygen-glucose deprivation (OGD in IL-6-differentiated C6 glioma cells. The results showed that NDRG2 was up-regulated and translocated from the cytoplasm to the nucleus after OGD exposure. NDRG2 over-expression exhibited an anti-proliferative effect and increased the Bax/Bcl-2 ratio after OGD exposure, while NDRG2 silencing promoted the cellular proliferation and attenuated the up-regulation of Bax/Bcl-2 ratio. The pro-apoptotic effect of p53 was verified by the results in which p53 silencing greatly reduced the percentage of OGD-induced apoptotic cells. p53 silencing also reduced the OGD-induced NDRG2 up-regulation. However, over-expression of p53 did not further improve the NDRG2 up-regulation. In conclusion, NDRG2 is a p53-associated regulator of apoptosis in C6-originated astrocytes after OGD exposure. These findings bring insight to the roles of NDRG2 in ischemic-hypoxic injury and provide potential targets for future clinical therapies on stroke.

  16. Effects of abnormal glucose metabolism during pregnancy on fetal body mass and incidence of neonatal complications%妊娠期糖代谢异常对胎儿体质量及新生儿并发症发生率的影响

    李女好; 林碧绿; 曾胤; 庄泽吟

    2014-01-01

    Objective To investigate the effects of abnormal glucose tolerance during pregnancy on the incidence of fetal body mass and neonatal complications.Methods Oral 50g glucose challenge test (GCT)was done in 2502 cases of pregnant women,156 cases of abnormal 75g oral glucose tolerance retest (OGTT),diagnosed with gestational diabetes mellitus (GDM) in 86 cases,gestational impaired glucose tolerance (GIGT) in 70 cases,and 300 cases of the control group,then we compared the incidence of fetal students body mass,neonatal complications.Results Fetal body mass of GIGT and GDM groups was large for gestational age and fetal macrosomia,significantly higher than that of the control group,the appropriate for gestational age at birth rate was significantly lower than that of the control group,there was statistical significant difference (P < 0.01); small for gestational age infants birth rate was also higher than that of the control group (P < 0.05); GIGT and GDM groups of pregnant women neonatal hypoglycemia,hyperbilirubinemia and in birth injury incidence was significantly higher than that in the control group,there was significant difference (P < 0.01); concurrent premature,asphyxia morbidity were igher than those of the control group,there was statistical significant difference (P < 0.05).Conclusion In clinical practice it is very necessary to detect glucose metabolism with anomaly detection and diagnosis system for all pregnant women,normal glucose metabolism treatment should be standardized and monitored; neonates delivered by all pregnant women with abnormal glucose metabolism should be given timely monitoring of blood glucose,complications and timely intervention.%目的 探讨妊娠期糖耐量异常对胎儿体质量及新生儿并发症发生率的影响.方法 对2502例孕妇进行口服50 g葡萄糖筛查试验(GCT),对156例异常者再行75 g葡萄糖耐量试验(OGTT),确诊妊娠期糖尿病(GDM) 86例,妊娠糖耐量受损(GIGT) 70例,与对照组300

  17. 合并糖代谢异常的冠心病患者血浆脂联素水平变化及其临床意义%Plasma level of adiponectin in coronary heart disease patients combined with abnormal glucose metabolism

    夏珂; 郭兰燕; 赵震宇; Ali Sheikh Md Sayed; 李非; 杨天伦

    2012-01-01

    Objective: To examine the plasma adiponectin concentration in coronary heart disease (CHD)patients combined with abnormal glucose metabolism, and to explore the clinical significance ofadiponectin.Methods: Eighty-seven hospitalized CHD patients confirmed by coronary angiography fromAugust 2009 to April 2010 at Xiangya Hospital were enrolled and divided into 3 groups according to their glucose metabolic state: 31 patients were selected as a simple CHD group, 28 were selected as a CHD combined with impaired glucose tolerance group (CHD+IGT group), and the other 28 as a CHD combined with diabetes mellitus group (CHD+DM group). The 31 healthy subjects who got health checkup at the same time were enrolled as a normal control group (NC group). Plasma adiponectin was measured by enzyme linked immunosorbent assay. The height, weight, waistline and blood pressure of all the subjects were checked, and the fasting blood glucose (FBG), insulin, lipids, high-sensitivity C-reactive protein (hs-CRP), free fatty acids (FFA), the liver function and the renal function were checked as well. The body mass index and the homeostasis model were assessed for insulin resistance.Results: 1) Plasma adiponectin in the CHD group, the CHD+IGT group, and the CHD+DM group was all lower than that in the NC group (P<0.05); 2) Compared with the CHD group, the plasma adiponectin in the CHD+DM group was the lowest, followed by the CHD+IGT group, and there was significant difference in the 3 groups (P<0.05); 3) Plasma adiponectin level was positively related with the high density lipoprotein cholesterol-C (HDL-C) (r=0.483, P<0.01), while it was negatively related with the hs-CRP and Gensini score (r=-0.489, P<0.05; r=-0.252, P<0.05). Conclusion: Plasma adiponectin concentration is reduced in the CHD patients, and significantly reduced in CHD patients combined with abnormal glucose metabolism. Plasma adiponectin concentration decreases significantly with the severity of abnormal glucose metabolism. CHD

  18. Abnormal functional connectivity with mood regulating circuit in unmedicated individual with major depression: a resting-state functional magnetic resonance study

    PENG Dai-hui; SHEN Ting; ZHANG Jie; HUANG Jia; LIU Jun; LIU Shu-yong; JIANG Kai-da; XU Yi-feng; FANG Yi-ru

    2012-01-01

    Background Reports on mood regulating circuit (MRC) indicated different activities between depressed patients and healthy controls.The functional networks based on MRC have not been described in major depression disorder (MDD).Both the anterior cingulate cortex (ACC) and thalamus are all the key regions of MRC.This study was to investigate the two functional networks related to ACC and thalamus in MDD.Methods Sixteen patients with MDD on first episode which never got any medication and sixteen matched health controls were scanned by 3.0 T functional magnetic resonance imaging (fMRI) during resting-state.The pregenual anterior cingulate cortex (pgACC) was used as seed region to construct the functional network by cortex section.The thalamus was used as seed region to construct the functional network by limbic section.Paired-t tests between-groups were performed for the seed-target correlations based on the individual fisher z-transformed correlation maps by SPM2.Results Depressed subjects exhibited significantly great functional connectivity (FC) between pgACC and the parahippocampus gyrus in one cluster (size 923) including left parahippocampus gyrus (-21,-49,7),left parietal lobe (-3,-46,52) and left frontal lobe (-27,-46,28).The one cluster (size 962) of increased FC on thalamus network overlapped the precuneus near to right parietal lobe (9,-52,46) and right cingulate gyrus (15,-43,43) in health controls.Conclusions Abnormal functional networks exist in earlier manifestation of MDD related to MRC by both cortex and limbic sections.The increased functional connectivity of pgACC and decreased functional connectivity of thalamus is mainly involved in bias mood processing and cognition.

  19. Diverse mechanisms of post-transcriptional repression by the small RNA regulator of glucose-phosphate stress.

    Bobrovskyy, Maksym; Vanderpool, Carin K

    2016-01-01

    The Escherichia coli small RNA SgrS controls a metabolic stress response that occurs upon accumulation of certain glycolytic intermediates. SgrS base pairs with and represses translation of ptsG and manXYZ mRNAs, which encode sugar transporters, and activates translation of yigL mRNA, encoding a sugar phosphatase. This study defines four new genes as direct targets of E. coli SgrS. These new targets, asd, adiY, folE and purR, encode transcription factors or enzymes of diverse metabolic pathways, including aspartate semialdehyde dehydrogenase, arginine decarboxylase gene activator, GTP cyclohydrolase I and a repressor of purine biosynthesis, respectively. SgrS represses translation of each of the four target mRNAs via distinct mechanisms. SgrS binding sites overlapping the Shine-Dalgarno sequences of adiY and folE mRNAs suggest that SgrS pairing with these targets directly occludes ribosome binding and prevents translation initiation. SgrS binding within the purR coding sequence recruits the RNA chaperone Hfq to directly repress purR translation. Two separate SgrS binding sites were found on asd mRNA, and both are required for full translational repression. Ectopic overexpression of asd, adiY and folE is specifically detrimental to cells experiencing glucose-phosphate stress, suggesting that SgrS-dependent repression of the metabolic functions encoded by these targets promotes recovery from glucose-phosphate stress.

  20. Resveratrol inhibits high glucose induced collagen upregulation in cardiac fibroblasts through regulating TGF-β1-Smad3 signaling pathway.

    Liu, Junhui; Zhuo, Xiaozhen; Liu, Weimin; Wan, Zhaofei; Liang, Xiao; Gao, Shanshan; Yuan, Zuyi; Wu, Yue

    2015-02-05

    Cardiac fibrosis is a common pathological process presented in a variety of diseases, including hypertension and diabetes. Cardiac fibroblasts (CFs) have been identified as the most important participants in the development of cardiac fibrosis. Exposure of cultured CFs to high glucose (HG) or angiotensin II (Ang II) resulted in increased collagen synthesis. Resveratrol (Res) is a natural polyphenol exhibiting anti-fibrosis effects in a number of different organs fibrosis process, whether Res can prevent HG and Ang II induced fibrosis response in CFs remains unclear. The aim of this work was to evaluate the effects of Res in HG and Ang II induced fibrosis response in CFs. We cultured rat CFs in either normal glucose (5.6 mM) or HG (25 mM) media in the presence of Res or not and the changes in collagens synthesis and TGF-β1 production were assessed by Real-time PCR, Western blotting, and enzyme linked immunosorbent assay (ELISA). Furthermore, normal and diabetic mice (induced by single dose of streptozotocin (100 mg/kg) via tail vein) receiving Res (10 mg/kg) were used to explore the effects of Res on cardiac fibrosis in vivo. Masson staining and immunohistochemistry were performed to visualize cardiac collagen deposition. Results indicate that CFs exposed to HG condition shows enhanced proliferation rate. Furthermore, in the presence of HG or Ang II, CFs exhibited increased collagens synthesis and TGF-β1 production. And these effects were abolished by Res intervention. In vivo results show that diabetic mice exhibit increased collagen deposition in the cardiac compared with the normal mice. And this change was prevented by the treatment of Res. These results suggest that Res possesses a potential antifibrogenic effect in hypertension and diabetes-related cardiac fibrosis. Moreover, the action mechanism is probably associated with its ability to reduce TGF-β1 content in CFs.

  1. 妊娠期孕妇糖代谢异常对外阴阴道假丝酵母菌感染及妊娠结局的影响%The influence of gestational abnormal glucose metabolism on vulvovaginal candidiasis infection and pregnan-cy outcome

    董海玲

    2015-01-01

    Objective To investigate the effect of abnormal glucose metabolism on vulvovaginal candidiasis infection and pregnancy outcome in pregnant women.Methods One thousand and fifty-six pregnant women were col-lected who did prenatal examination and termly deliveried in the department of obstetrics and gynecology of our hospi-tal from Jun 2011 to Jun 2013.According to the glucose screening test results, they were divided into glucose normal group(n=624), GCT abnormal group(n=326)and gestational diabetes mellitus(GDM) group(n=106).The oc-currence of the vulvovaginal candidiasis(VVC) infection and pregnancy outcome of the three groups were observed during pregnancy.Results The occurrence rates of VVC of GCT abnormal group and GDM group had no significant differences(P>0.05), but they were significantly higher than those of glucose normal group(P0.05).Conclusion Abnormal glucose metabolism during pregnancy may increase occurrence risk of VVC, which affects the outcome of pregnancy and in-creases the risk of cesarean section and premature rupture of membranes and intrauterine fetal distress, thus it should be payed more attention to the changes of blood glucose level.Glycated hemoglobin level in pregnant women should be monitored.%目的:探讨妊娠期孕妇糖代谢异常对外阴阴道假丝酵母菌感染及妊娠结局的影响。方法收集行产前检查并足月分娩的初次孕产妇1056例,根据葡萄糖筛查试验( GCT )结果将孕妇分为血糖正常组624例,GCT异常组326例,妊娠期糖尿病( GDM)组106例。观察三组在妊娠期间外阴阴道假丝酵母菌病(VVC)的发生情况及妊娠结局情况。结果 GDM组、GCT异常组VVC发生率差异无统计学意义(P>0.05),但均明显高于血糖正常组(P<0.05);三组VVC复发率差异无统计学意义(P>0.05)。 GCT异常组、GDM组的胎膜早破、胎儿宫内窘迫发生率、剖宫产率、足月低体重儿率

  2. Glucagon-Like Peptide-1 Secreting Cell Function as well as Production of Inflammatory Reactive Oxygen Species Is Differently Regulated by Glycated Serum and High Levels of Glucose

    Alessandra Puddu

    2014-01-01

    Full Text Available Glucagon-like peptide-1 (GLP-1, an intestinal hormone contributing to glucose homeostasis, is synthesized by proglucagon and secreted from intestinal neuroendocrine cells in response to nutrients. GLP-1 secretion is impaired in type 2 diabetes patients. Here, we aimed at investigating whether diabetic toxic products (glycated serum (GS or high levels of glucose (HG may affect viability, function, and insulin sensitivity of the GLP-1 secreting cell line GLUTag. Cells were cultured for 5 days in presence or absence of different dilutions of GS or HG. GS and HG (alone or in combination increased reactive oxygen species (ROS production and upregulated proglucagon mRNA expression as compared to control medium. Only HG increased total production and release of active GLP-1, while GS alone abrogated secretion of active GLP-1. HG-mediated effects were associated with the increased cell content of the prohormone convertase 1/3 (PC 1/3, while GS alone downregulated this enzyme. HG upregulated Glucokinase (GK and downregulated SYNTHAXIN-1. GS abrogated SYNTHAXIN-1 and SNAP-25. Finally, high doses of GS alone or in combination with HG reduced insulin-mediated IRS-1 phosphorylation. In conclusion, we showed that GS and HG might regulate different pathways of GLP-1 production in diabetes, directly altering the function of neuroendocrine cells secreting this hormone.

  3. Glucagon-like peptide 1 interacts with ghrelin and leptin to regulate glucose metabolism and food intake through vagal afferent neuron signaling.

    Ronveaux, Charlotte C; Tomé, Daniel; Raybould, Helen E

    2015-04-01

    Emerging evidence has suggested a possible physiologic role for peripheral glucagon-like peptide 1 (GLP-1) in regulating glucose metabolism and food intake. The likely site of action of GLP-1 is on vagal afferent neurons (VANs). The vagal afferent pathway is the major neural pathway by which information about ingested nutrients reaches the central nervous system and influences feeding behavior. Peripheral GLP-1 acts on VANs to inhibit food intake. The mechanism of the GLP-1 receptor (GLP-1R) is unlike other gut-derived receptors; GLP-1Rs change their cellular localization according to feeding status rather than their protein concentrations. It is possible that several gut peptides are involved in mediating GLP-1R translocation. The mechanism of peripheral GLP-1R translocation still needs to be elucidated. We review data supporting the role of peripheral GLP-1 acting on VANs in influencing glucose homeostasis and feeding behavior. We highlight evidence demonstrating that GLP-1 interacts with ghrelin and leptin to induce satiation. Our aim was to understand the mechanism of peripheral GLP-1 in the development of noninvasive antiobesity treatments.

  4. S-Allyl cysteine improves nonalcoholic fatty liver disease in type 2 diabetes Otsuka Long-Evans Tokushima Fatty rats via regulation of hepatic lipogenesis and glucose metabolism.

    Takemura, Shigekazu; Minamiyama, Yukiko; Kodai, Shintaro; Shinkawa, Hiroji; Tsukioka, Takuma; Okada, Shigeru; Azuma, Hideki; Kubo, Shoji

    2013-09-01

    It is important to prevent and improve diabetes mellitus and its complications in a safe and low-cost manner. S-Allyl cysteine, an aged garlic extract with antioxidant activity, was investigated to determine whether S-allyl cysteine can improve type 2 diabetes in Otsuka Long-Evans Tokushima Fatty rats with nonalcoholic fatty liver disease. Male Otsuka Long-Evans Tokushima Fatty rats and age-matched Long-Evans Tokushima Otsuka rats were used and were divided into two groups at 29 weeks of age. S-Allyl cysteine (0.45% diet) was administered to rats for 13 weeks. Rats were killed at 43 weeks of age, and detailed analyses were performed. S-Allyl cysteine improved hemoglobinA1c, blood glucose, triglyceride, and low-density lipoprotein cholesterol levels. Furthermore, S-allyl cysteine normalized plasma insulin levels. S-Allyl cysteine activated the mRNA and protein expression of both peroxisome proliferator-activated receptor α and γ, as well as inhibiting pyruvate dehydrogenase kinase 4 in Otsuka Long-Evans Tokushima Fatty rat liver. Sterol regulatory element-binding protein 1c and forkhead box O1 proteins were normalized by S-allyl cysteine in Otsuka Long-Evans Tokushima Fatty rat liver. In conclusions, these findings support the hypothesis that S-allyl cysteine has diabetic and nonalcoholic fatty liver disease therapeutic potential as a potent regulating agent against lipogenesis and glucose metabolism.

  5. 糖筛查试验异常而糖耐量试验正常孕妇的妊娠结局分析%Analysis on pregnancy outcomes of abnormal glucose screening test and normal glucose tolerance test in pregnant women

    李瑞凇

    2015-01-01

    Objective To explore the impact of abnormal glucose challenge test (GCT ) and normal oral glu‐cose tolerance test (OGTT ) on the maternal and neonatal perinatal period in pregnant women ,and to observe and an‐alyze their outcomes to provide the objective basis for pregnancy health care .Methods 220 pregnant women with ab‐normal GCT and normal OGTT in our hospital from January 2012 to January 2014 were selected as the observation group .Contemporaneous 240 normal pregnant women were selected as the control group .The pregnancy outcomes and neonatal status and Apgar scores were observed in the two groups .Results The vaginal delivery rate of the ob‐servation group was 61 .82% (136/220) ,which was lower than that of the control group ,the cesarean section rate of the observation group was 36 .36% (80/220) ,which was higher than that of the control group (P< 0 .05) .The post‐partum hemorrhage ,polyhydramnios ,puerperal infection and premature rupture of membranes in the observation group accounted for 9 .55% (21/220) ,which was higher than that of the control group (P< 0 .05) .The macrosomia , premature delivery and neonatal hyperbilirubinemia of the observation group were 15 .45% (34/220) ,5 .00% (11/220) and 5 .45% (12/220) respectively ,which were higher than those of the control group (P < 0 .05) ;the average neonatal body weight mass of the observation group was (3 186 .35 ± 31 .20)g ,which was higher than that of the con‐trol group ,the neonatal Apgar score of the observation group of was (9 .21 ± 0 .13) ,which was lower than that of the control group (P< 0 .05) .Conclusion The abnormal GCT and normal OGTT in pregnant women can significantly affect the perinatal health ,has lower natural labor rate and higher complications ,moreover the number of premature newborns and macrosomia is significantly increased ,easier to develop the complications of hyperbilirubinemia ,etc ., which affect the health and life safety of regnant women and perinatal period

  6. Glucose uptake regulation in E. coli by the small RNA SgrS: comparative analysis of E. coli K-12 (JM109 and MG1655 and E. coli B (BL21

    Ng Weng-Ian

    2010-09-01

    Full Text Available Abstract Background The effect of high glucose concentration on the transcription levels of the small RNA SgrS and the messenger RNA ptsG, (encoding the glucose transporter IICBGlc, was studied in both E. coli K-12 (MG1655 and JM109 and E. coli B (BL21. It is known that the transcription level of sgrS increases when E. coli K-12 (MG1655 and JM109 is exposed to the non-metabolized glucose alpha methyl glucoside (αMG or when the bacteria with a defective glycolysis pathway is grown in presence of glucose. The increased level of sRNA SgrS reduces the level of the ptsG mRNA and consequently lowers the level of the glucose transporter IICBGlc. The suggested trigger for this action is the accumulation of the corresponding phospho-sugars. Results In the course of the described work, it was found that E. coli B (BL21 and E. coli K-12 (JM109 and MG1655 responded similarly to αMG: both strains increased SgrS transcription and reduced ptsG transcription. However, the two strains reacted differently to high glucose concentration (40 g/L. E. coli B (BL21 reacted by increasing sgrS transcription and reducing ptsG transcription while E. coli K-12 (JM109 and MG1655 did not respond to the high glucose concentration, and, therefore, transcription of sgrS was not detected and ptsG mRNA level was not affected. Conclusions The results suggest that E. coli B (BL21 tolerates high glucose concentration not only by its more efficient central carbon metabolism, but also by controlling the glucose transport into the cells regulated by the sRNA SgrS, which may suggest a way to control glucose consumption and increase its efficient utilization.

  7. Gestational Diabetes Mellitus (GDM) on Maternal and Neonatal Outcomes of Pregnant Women with Different Blood Glucose Abnormalities%妊娠期糖尿病(GDM)孕妇不同血糖指标异常的母婴结局研究

    冯艳红

    2016-01-01

    Objective To study the effect of gestational diabetes mellitus (GDM) pregnant women with different glycemic in-dex of abnormal pregnancy outcome. Methods Admitted to our hospital with 300 cases of pregnancy with gestational dia-betes mellitus pregnant women and 150 cases of normal pregnant women as the observation object, the admitted time for June 5, 2012 to 2015, the normal pregnant women as control group, the 300 cases of pregnancy with gestational diabetes, according to the degree of blood glucose control points for normal glycemic index group (158 cases) and abnormal blood glu-cose index group (142 cases), three groups of clinical data were retrospectively analyzed to observe the differences between the three groups of pregnant women, maternal and neonatal outcomes. Results Control group and blood sugar index normal group of pregnant women pregnancy differences between outcome was not significant (P > 0.05); control group and blood sugar index group of abnormal pregnant women, maternal and neonatal outcomes between the difference is significant (P0.05);对照组与血糖指标异常组孕妇母婴结局之间的差异有统计学意义(P<0.05);且血糖指标异常组与血糖指标正常组之间对比的母婴结局,差异具有统计学意义(P<0.05)。结论妊娠期糖尿病孕妇不同血糖指标对母婴结局的影响较大,临床中应注意控制孕妇的血糖水平,达到改善母婴结局的效果。

  8. Interleukin-22 restored mitochondrial damage and impaired glucose-stimulated insulin secretion through down-regulation of uncoupling protein-2 in INS-1 cells.

    Hu, Minling; Lin, Hanxiao; Yang, Li; Cheng, Yanzhen; Zhang, Hua

    2017-01-07

    Defective glucose-stimulated insulin secretion (GSIS) induced by chronic exposure to fatty acids is a hallmark of type 2 diabetes (T2D). Interleukin-22 (IL-22) has been shown to exert beneficial effects on insulin secretion and to protect pancreatic β-cells from stress. Moreover, uncoupling protein-2 (UCP-2) plays a central role in the regulation of GSIS and β-cell dysfunction, whereas the role of UCP-2 in IL-22-enhanced glycemic control under conditions of lipotoxicity remains unclear. In this present study, we investigated the effects of IL-22 on rat insulin-secreting cells (INS-1 cells) and the mechanisms that underlie IL-22 and lipotoxicity-impaired GSIS in vitro. Chronic palmitate (PA) treatment impaired insulin secretion and activated UCP-2 expression in INS-1 cells. Furthermore, in INS-1 cells, both reduced mitochondrial membrane potential (ΔΨm) and impaired GSIS induced by PA treatment were effectively reversed by an inhibitor of UCP-2 (genipin). Additionally, compared with the PA-treated group, INS-1 cells treated with IL-22 down-regulated UCP-2 expression, increased mitochondrial membrane potential, and restored GSIS. Together, our findings indicate that chronic exposure to PA could activate UCP-2, resulting in mitochondrial damage and impaired GSIS in INS-1 cells. We also suggest that IL-22 plays a protective role in this process via the down-regulation of UCP-2.

  9. Glucose, amino acids and fatty acids directly regulate ghrelin and NUCB2/nesfatin-1 in the intestine and hepatopancreas of goldfish (Carassius auratus) in vitro.

    Bertucci, Juan Ignacio; Blanco, Ayelén Melisa; Canosa, Luis Fabián; Unniappan, Suraj

    2017-04-01

    Ghrelin and nesfatin-1 are two peptidyl hormones primarily involved in food intake regulation. We previously reported that the amount of dietary carbohydrates, protein and lipids modulates the expression of these peptides in goldfish in vivo. In the present work, we aimed to characterize the effects of single nutrients on ghrelin and nesfatin-1 in the intestine and hepatopancreas. First, immunolocalization of ghrelin and NUCB2/nesfatin-1 in goldfish hepatopancreas cells was studied by immunohistochemistry. Second, the effects of 2 and 4hour-long exposures of cultured intestine and hepatopancreas sections to glucose, l-tryptophan, oleic acid, linolenic acid (LNA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on ghrelin and nesfatin-1 gene and protein expression were studied. Co-localization of ghrelin and NUCB2/nesfatin-1 in the cytoplasm of goldfish hepatocytes was found. Exposure to glucose led to an upregulation of preproghrelin and a downregulation of nucb2/nesfatin-1 in the intestine. l-Tryptophan mainly decreased the expression of both peptides in the intestine and hepatopancreas. Fatty acids, in general, downregulated NUCB2/nesfatin-1 in the intestine, but only the longer and highly unsaturated fatty acids inhibited preproghrelin. EPA exposure led to a decrease in preproghrelin, and an increase in nucb2/nesfatin-1 expression in hepatopancreas after 2h. These results show that macronutrients exert a dose- and time-dependent, direct regulation of ghrelin and nesfatin-1 in the intestine and hepatopancreas, and suggest a role for these hormones in the digestive process and nutrient metabolism.

  10. The separate roles of PQQ and apo-enzyme syntheses in the regulation of glucose dehydrogenase activity in Klebsiella pneumoniae NCTC 418.

    Hommes, R W; Herman, P T; Postma, P W; Tempest, D W; Neijssel, O M

    1989-01-01

    No holoenzyme pyrroloquinoline quinone (PQQ)-dependent glucose dehydrogenase and only very low apoenzyme levels could be detected in cells of Klebsiella pneumoniae, growing anaerobically, or carrying out a fumarate or nitrate respiration. Low glucose dehydrogenase activity in some aerobic glucose-excess cultures of K. pneumoniae (ammonia or sulphate limitation) was increased significantly by addition of PQQ, whereas in cells already possessing a high glucose dehydrogenase activity (phosphate or potassium limitation) extra PQQ had almost no effect. These observations indicate that the glucose dehydrogenase activity in K. pneumoniae is modulated by both PQQ synthesis and synthesis of the glucose dehydrogenase apo-enzyme.

  11. Glucose-dependent insulinotropic polypeptide

    Christensen, Mikkel Bring

    2016-01-01

    The hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are secreted by enteroendocrine cells in the intestinal mucosa in response to nutrient ingestion. They are called incretin hormones because of their ability to enhance insulin secretion. However...... the blood glucose levels. In Study 3, we also used stable glucose isotopes to estimate the endogenous glucose production and assessed symptoms and cognitive function during hypoglycaemia. The results from the three studies indicate that GIP has effects on insulin and glucagon responses highly dependent upon...... glucose to prevent hypoglycaemia. In conclusion, the studies position GIP as a bifunctional blood glucose stabilising hormone that glucose-dependently regulates insulin and glucagon responses in humans....

  12. Gallic Acid Decreases Inflammatory Cytokine Secretion Through Histone Acetyltransferase/Histone Deacetylase Regulation in High Glucose-Induced Human Monocytes.

    Lee, Wooje; Lee, Sang Yeol; Son, Young-Jin; Yun, Jung-Mi

    2015-07-01

    Hyperglycemia contributes to diabetes and several diabetes-related complications. Gallic acid is a polyhydroxy phenolic compound found in various natural products. In this study, we investigated the effects and mechanism of gallic acid on proinflammatory cytokine secretion in high glucose-induced human monocytes (THP-1 cells). THP-1 cells were cultured under normoglycemic or hyperglycemic conditions, in the absence or presence of gallic acid. Hyperglycemic conditions significantly induced histone acetylation, nuclear factor-κB (NF-κB) activation, and proinflammatory cytokine release from THP-1 cells, whereas gallic acid suppressed NF-κB activity and cytokine release. It also significantly reduced CREB-binding protein/p300 (CBP/p300, a NF-κB coactivator) gene expression, acetylation levels, and CBP/p300 histone acetyltransferase (HAT) activity. In addition, histone deacetylase 2 (HDAC2) expression was significantly induced. These results suggest that gallic acid inhibits hyperglycemic-induced cytokine production in monocytes through epigenetic changes involving NF-κB. Therefore, gallic acid may have potential for the treatment and prevention of diabetes and its complications.

  13. Oxidative stress in mouse sperm impairs embryo development, fetal growth and alters adiposity and glucose regulation in female offspring.

    Michelle Lane

    Full Text Available Paternal health cues are able to program the health of the next generation however the mechanism for this transmission is unknown. Reactive oxygen species (ROS are increased in many paternal pathologies, some of which program offspring health, and are known to induce DNA damage and alter the methylation pattern of chromatin. We therefore investigated whether a chemically induced increase of ROS in sperm impairs embryo, pregnancy and offspring health. Mouse sperm was exposed to 1500 µM of hydrogen peroxide (H2O2, which induced oxidative damage, however did not affect sperm motility or the ability to bind and fertilize an oocyte. Sperm treated with H2O2 delayed on-time development of subsequent embryos, decreased the ratio of inner cell mass cells (ICM in the resulting blastocyst and reduced implantation rates. Crown-rump length at day 18 of gestation was also reduced in offspring produced by H2O2 treated sperm. Female offspring from H2O2 treated sperm were smaller, became glucose intolerant and accumulated increased levels of adipose tissue compared to control female offspring. Interestingly male offspring phenotype was less severe with increases in fat depots only seen at 4 weeks of age, which was restored to that of control offspring later in life, demonstrating sex-specific impacts on offspring. This study implicates elevated sperm ROS concentrations, which are common to many paternal health pathologies, as a mediator of programming offspring for metabolic syndrome and obesity.

  14. The transcription factor Snf1p is involved in a Tup1p-independent manner in the glucose regulation of the major methanol metabolism genes of Hansenula polymorpha

    Marcos A. Oliveira

    2003-12-01

    Full Text Available Hansenula polymorpha is a methylotrophic yeast widely employed in biotechnology as a ''protein factory''. Most promoters used for heterologous protein expression, like MOX (methanol oxidase and DAS (di-hydroxy acetone synthase, are involved in the peroxisomal methanol metabolism (C1 metabolism and are under strong glucose repression. Interestingly, the MOX promoter is subjected to glucose regulation also in Saccharomyces cerevisiae, a non-methylotrophic yeast in which this phenomenon is well studied. In this species, the transcription factor Tup1p plays an essential role in glucose repression of several genes. This effect is counteracted by the activator Snf1p when glucose is exhausted from medium. Therefore, to test whether this regulatory circuit has been conserved in H. polymorpha, HpTUP1 and HpSNF1 were partially cloned and disrupted. Deletion of HpTUP1 did not affect glucose repression of the major C1 metabolism genes (MOX, DAS. Thus, though conserved, HpTUP1 does not seem to take part in a general glucose repression in H. polymorpha. In contrast, the deletion of HpSNF1 led to significant decreases in the activation of these genes in the absence of glucose. Therefore, the effect of HpSNF1 in transcriptional activation may be through an HpTUP1- independent circuit.

  15. Gluconeogenesis is Not Regulated by Either Glucose or Insulin in Extremely Low Birth Weight Infants Receiving Total Parenteral Nutrition

    Chacko, Shaji K.; Ordonez, Jorge; Sauer, Pieter J. J.; Sunehag, Agneta L.

    2011-01-01

    Objective To determine potential factors regulating gluconeogenesis (GNG) in extremely low birth weight infants receiving total parenteral nutrition. Study design Seven infants (birth weight, 0.824 +/- 0.068 kg; gestational age, 25.4 +/- 0.5 weeks; postnatal age, 3.3 +/- 0.2 days) were studied for 1

  16. BMP4 Cross-talks With Estrogen/ERα Signaling to Regulate Adiposity and Glucose Metabolism in Females

    Shu-wen Qian

    2016-09-01

    Full Text Available Similar to estrogens, bone morphogenetic protein 4 (BMP4 promotes the accumulation of more metabolically active subcutaneous fat and reduction of visceral fat. However, whether there is a cross-talk between BMP4 and estrogen signaling remained unknown. Herein, we found that BMP4 deficiency in white adipose tissue (WAT increased the estrogen receptor α (ERα level and its signaling, which prevented adult female mice from developing high fat diet (HFD-induced obesity and insulin resistance; estrogens depletion up regulated BMP4 expression to overcome overt adiposity and impaired insulin sensitivity with aging, and failure of BMP4 regulation due to genetic knockout led to more fat gain in aged female mice. This mutual regulation between BMP4 and estrogen/ERα signaling may also happen in adipose tissue of women, since the BMP4 level significantly increased after menopause, and was inversely correlated with body mass index (BMI. These findings suggest a counterbalance between BMP4 and estrogen/ERα signaling in the regulation of adiposity and relative metabolism in females.

  17. Sodium-glucose cotransport

    Poulsen, Søren Brandt; Fenton, Robert A.; Rieg, Timo

    2017-01-01

    Purpose of review Sodium-glucose cotransporters (SGLTs) are important mediators of glucose uptake across apical cell membranes. SGLT1 mediates almost all sodium-dependent glucose uptake in the small intestine, while in the kidney SGLT2, and to a lesser extent SGLT1, account for more than 90% and nearly 3%, respectively, of glucose reabsorption from the glomerular ultrafiltrate. Although the recent availability of SGLT2 inhibitors for the treatment of diabetes mellitus has increased the number of clinical studies, this review has a focus on mechanisms contributing to the cellular regulation of SGLTs. Recent findings Studies have focused on the regulation of SGLT expression under different physiological/pathophysiological conditions, for example diet, age or diabetes mellitus. Several studies provide evidence of SGLT regulation via cyclic adenosine monophosphate/protein kinase A, protein kinase C, glucagon-like peptide 2, insulin, leptin, signal transducer and activator of transcription-3 (STAT3), phosphoinositide-3 kinase (PI3K)/Akt, mitogen-activated protein kinases (MAPKs), nuclear factor-kappaB (NF-kappaB), with-no-K[Lys] kinases/STE20/SPS1-related proline/alanine-rich kinase (Wnk/SPAK) and regulatory solute carrier protein 1 (RS1) pathways. Summary SGLT inhibitors are important drugs for glycemic control in diabetes mellitus. Although the contribution of SGLT1 for absorption of glucose from the intestine as well as SGLT2/SGLT1 for renal glucose reabsorption has been comprehensively defined, this review provides an up-to-date outline for the mechanistic regulation of SGLT1/SGLT2. PMID:26125647

  18. 铬镁离子对糖代谢异常患者的影响及研究进展%Research progress and advances in chromium magnesium ion effect on patients with abnormal glucose metabolism

    周蒙蒙; 王会玲; 姚民秀

    2015-01-01

    血清镁离子及三价铬离子均是体内重要的阳性离子,2型糖尿病患者普遍存在血清铬及镁离子浓度的降低;铬镁离子可促进葡萄糖的利用,增加机体对胰岛素的敏感性,改善胰岛素抵抗,预防或延缓2型糖尿病的发生。铬镁离子可调节细胞内信号转导,降低血糖,保护组织器官,铬镁离子对脂质代谢也具有改善作用。下面就铬镁离子对糖尿病及糖耐量异常患者的影响做一综述。%Serum magnesium ion and trivalent chromium ion are important cations in body, magnesium ion and chromium ion are general deficiencies in type 2 diabetes mellitus. They can promote glucose metabolism, improve insulin sensitivity and beneficial to insulin resistance, prevent normal persons to diabetes. Magnesium ion and chromium ion can adjust the information transmission of intracellular, decrease the glucose, protect the tissues and organs. They are beneficial to the lipid metabolism. Here we made a review about the impact of chromium ion and magnesium ion in patients with diabetes and impaired glucose tolerance.

  19. Prevalence of Type 2 Diabetes and Impaired Glucose Regulation with Associated Cardiometabolic Risk Factors and Depression in an Urbanizing Rural Community in Bangladesh: A Population-Based Cross-Sectional Study

    Bishwajit Bhowmik

    2012-12-01

    Full Text Available BackgroundTo determine the prevalence of type 2 diabetes (T2DM and impaired glucose regulation (impaired fasting glucose [IFG] and impaired glucose tolerance [IGT] in an urbanizing rural population of Bangladesh and associated cardiometabolic risk indicators and depression.MethodsA total of 2,293 subjects aged ≥20 years in an urbanizing rural Bangladeshi community were investigated. Socio-demographic and anthropometric details, blood pressure, fasting plasma glucose (FPG, 2 hours after 75 g plasma glucose (2hPG, glycosylated hemoglobin, fasting serum insulin and lipid profiles were studied. Presence of depressive symptoms using Montogomery-Asberg Depression Rating Scale was also assessed.ResultsThe prevalence of IFG, IGT, IFG+IGT, and T2DM were 3.4%, 4.0%, 1.2%, and 7.9%, respectively. The prevalence of T2DM and impaired glucose regulation differed between males and females, but, both increased with age in both sexes. FPG and 2hPG had positive correlation. Employing logistic regression, it was found that increased age, waist to hip ratio, systolic blood pressure, total cholesterol, triglycerides, and depression were independent risk indicators for diabetes. Both insulin resistance and β-cell deficiency were significantly related for causation of diabetes. Among the study population, 26.2% had general obesity, 39.8% central obesity, 15.5% hypertension, 28.7% dyslipidemia, 17.6% family history of diabetes, and 15.3% had depression. Physical inactivity and smoking habits were significantly higher in male.ConclusionRising prevalence of diabetes and impaired glucose regulation in this urbanizing rural population exist as a significant but hidden public health problem. Depression and other cardiometabolic risk indicators including obesity, hypertension, and dyslipdemia were also prevalent in this population.

  20. The Nkx6.1 homeodomain transcription factor suppresses glucagon expression and regulates glucose-stimulated insulin secretion in islet beta cells

    Schisler, Jonathan C; Jensen, Per Bo; Harper, David Alexander Taylor;

    2005-01-01

    We have previously described rat insulinoma INS-1-derived cell lines with robust or poor glucose-stimulated insulin secretion (GSIS). In the current study, we have further resolved these lines into three classes: class 1, glucose-unresponsive/glucagon-expressing; class 2, glucose-unresponsive/glu...

  1. Effect of Metformin Intervention on Blood Sugar of Patients with Breast Cancer Chemotherapy with Abnormal Glucose Metabolism%二甲双胍干预对乳腺癌化疗伴糖代谢异常患者血糖的影响

    翟媛媛

    2016-01-01

    目的 研究二甲双胍干预对乳腺癌化疗伴糖代谢异常患者血糖的影响.方法 整群选择2012年2月—2014年8月来该院行乳腺癌化疗,伴糖代谢紊乱的60例患者作为研究对象,随机分为两组. 对照组给予AC-T化疗方案,同时给予患者饮食控制和运动治疗,观察组在对照组基础上加用二甲双胍,观察两组血糖控制情况. 结果 观察组化疗结束时和化疗结束后3个月正常血糖患者例数显著多于对照组,差异具有统计学意义(P0.05). 结论 二甲双胍对于控制乳腺癌化疗伴糖代谢紊乱患者血糖水平效果显著,且具有潜在抗肿瘤作用,值得进一步研究.%Objective To research the effect of metformin intervention on blood sugar of patients with breast cancer chemotherapy with abnormal glucose metabolism. Methods 60 cases of patients with breast cancer chemotherapy with ab-normal glucose metabolism in our hospital from February 2012 to August 2014 were selected as the research object and randomly divided into two groups, the control group received AC-T chemotherapy plan, and were treated with diet control and exercise, the observation group were given additional metformin on the basis of the control group, the blood sugar con-trol conditions of the two groups were observed. Results The case number of patients with normal blood sugar at the end of chemotherapy and in 3 months after chemotherapy in the observation group was obviously more than that in the control group, and the difference was statistically significant (P0.05). Conclusion Metformin for controlling the blood sugar levels of patients with breast cancer chemotherapy with abnormal glucose metabolism has an obvious effect and has a potential anti-tumor effect, which is further research.

  2. Transcription factor Ets-1 inhibits glucose-stimulated insulin secretion of pancreatic β-cells partly through up-regulation of COX-2 gene expression.

    Zhang, Xiong-Fei; Zhu, Yi; Liang, Wen-Biao; Zhang, Jing-Jing

    2014-08-01

    Increased cyclooxygenase-2 (COX-2) expression is associated with pancreatic β-cell dysfunction. We previously demonstrated that the transcription factor Ets-1 significantly up-regulated COX-2 gene promoter activity. In this report, we used the pancreatic β-cell line INS-1 and isolated rat islets to investigate whether Ets-1 could induce β-cell dysfunction through up-regulating COX-2 gene expression. We investigated the effects of ETS-1 overexpression and the effects of ETS-1 RNA interference on endogenous COX-2 expression in INS-1 cells. We used site-directed mutagenesis and a dual luciferase reporter assay to study putative Ets-1 binding sites in the COX-2 promoter. The effect of ETS-1 1 overexpression on the insulin secretion function of INS-1 cells and rat islets and the potential reversal of these effects by a COX-2 inhibitor were determined in a glucose-stimulated insulin secretion (GSIS) assay. ETS-1 overexpression significantly induces endogenous COX-2 expression, but ETS-1 RNA interference has no effect on basal COX-2 expression in INS-1 cells. Ets-1 protein significantly increases COX-2 promoter activity through the binding site located in the -195/-186 region of the COX-2 promoter. ETS-1 overexpression significantly inhibited the GSIS function of INS-1 cells and islet cells and COX-2 inhibitor treatment partly reversed this effect. These findings indicated that ETS-1 overexpression induces β-cell dysfunction partly through up-regulation of COX-2 gene expression. Moreover, Ets-1, the transcriptional regulator of COX-2 expression, may be a potential target for the prevention of β-cell dysfunction mediated by COX-2.

  3. Pregnant outcomes and neonatal anthropometry in women with abnormal glucose challenge test and normal oral glucose tolerance test during pregnancy%单纯葡萄糖筛查试验异常对妊娠结局和新生儿体质指标的影响

    陈海天; 王子莲; 胡明晶; 李铭岚; 祝文晶; 刘斌

    2009-01-01

    Objective To evaluate the influences of abnormal glucose challenge test (GCT) on pregnancy outcomes and neonatal anthropometric data in women with normal oral glucose tolerance test (OGTT).Methods Totally 214 women who delivered in the First Affiliated Hospital of Sun Yat-sen University from November 2006 to December 2007 were enrolled.50 g GCT was performed at 24-28 weeks of gestation and 75 g OGTT would be followed if GCT≥7.8 mmol/L.Those patients,whose OGTT results below the following criteria (5.3 mmoL/L,10.0 mmol/L,8.6 mmol/L,7.8 mmol/L),were classified as normal OGTT.Altogether,116 of the 214 women with abnormal GCT and normal OGTT were collected as the study group and the rest 98 women with normal GCT as the control group.The pregnant outcomes of the two groups were analyzed.The neonatal anthropometry,including birth weight,body length,head circumference and shoulder circumference,were recorded.Other neonatal anthropometric data,such as upper arm circumference,tricep skinfold thickness and hypodermic fat thickness of abdomen were measured by a tape measure within 24 hours after birth.Results (1) Pregnant outcomes:No significant difference was found in the rate of assisted vaginal delivery,polyhydramnios,premature rupture of membranes and fetal distress between the study and control group[10.3% (12/116) vs 4% (4/98),5.2% (6/116) vs 10% (10/98),13.8% (16/116) vs 17% (17/98),20.7% (24/116) vs 13% (13/98),P >0.05,respectively],but the rate of cesarean section,spontaneous vaginal delivery and large for gestational age babies in the study group were different from those of the control[72.4% (84/116) vs 51% (51/98),17.2%(20/116) vs 45% (44/98),25.9% (30/116) vs 6% (6/98),P <0.05,respectively].(2)Neonatal anthropometry:The birth weight of the study group was significantly higher than that of the control group[(3.4 ±0.4) kg vs (3.3±0.4) kg,P <0.05],but no significant difference was shown in any other neonatal anthropometric results between the study and

  4. Control of voltage-gated potassium channel Kv2.2 expression by pyruvate-isocitrate cycling regulates glucose-stimulated insulin secretion.

    Jensen, Mette V; Haldeman, Jonathan M; Zhang, Hengtao; Lu, Danhong; Huising, Mark O; Vale, Wylie W; Hohmeier, Hans E; Rosenberg, Paul; Newgard, Christopher B

    2013-08-09

    Recent studies have shown that the pyruvate-isocitrate cycling pathway, involving the mitochondrial citrate/isocitrate carrier and the cytosolic NADP-dependent isocitrate dehydrogenase (ICDc), is involved in control of glucose-stimulated insulin secretion (GSIS). Here we demonstrate that pyruvate-isocitrate cycling regulates expression of the voltage-gated potassium channel family member Kv2.2 in islet β-cells. siRNA-mediated suppression of ICDc, citrate/isocitrate carrier, or Kv2.2 expression impaired GSIS, and the effect of ICDc knockdown was rescued by re-expression of Kv2.2. Moreover, chronic exposure of β-cells to elevated fatty acids, which impairs GSIS, resulted in decreased expression of Kv2.2. Surprisingly, knockdown of ICDc or Kv2.2 increased rather than decreased outward K(+) current in the 832/13 β-cell line. Immunoprecipitation studies demonstrated interaction of Kv2.1 and Kv2.2, and co-overexpression of the two channels reduced outward K(+) current compared with overexpression of Kv2.1 alone. Also, siRNA-mediated knockdown of ICDc enhanced the suppressive effect of the Kv2.1-selective inhibitor stromatoxin1 on K(+) currents. Our data support a model in which a key function of the pyruvate-isocitrate cycle is to maintain levels of Kv2.2 expression sufficient to allow it to serve as a negative regulator of Kv channel activity.

  5. FGF19 Regulates Cell Proliferation, Glucose and Bile Acid Metabolism via FGFR4-Dependent and Independent Pathways

    Ai-Luen Wu; Sally Coulter; Christopher Liddle; Anne Wong; Jeffrey Eastham-Anderson; French, Dorothy M.; Peterson, Andrew S.; Junichiro Sonoda

    2011-01-01

    Fibroblast growth factor 19 (FGF19) is a hormone-like protein that regulates carbohydrate, lipid and bile acid metabolism. At supra-physiological doses, FGF19 also increases hepatocyte proliferation and induces hepatocellular carcinogenesis in mice. Much of FGF19 activity is attributed to the activation of the liver enriched FGF Receptor 4 (FGFR4), although FGF19 can activate other FGFRs in vitro in the presence of the coreceptor βKlotho (KLB). In this report, we investigate the role of FGFR4...

  6. 糖耐量异常对冠心病支架植入术后主要心脏事件的影响%Impact of abnormal glucose metabolism on major adverse cardiac event in patients after coronary artery gent implantation

    纪军; 何胜虎

    2008-01-01

    目的 探讨糖耐量异常对冠心病支架植入术后冠心病患者主要心脏事件的影响.方法 215例冠状动脉造影资料齐全的支架术后的患者,分为合并2型糖尿病(2-DM)组(A组)、糖耐量异常组(B组)、糖代谢正常组(NDM)(C组),比较三组在住院期间和随访期间发生典型心绞痛、非致死性心肌梗死、心源性死亡和靶血管重建等主要心脏事件(MACE)的发生率.结果 A组与B组主要心脏事件发生率显著高于C组(P<0.01);A组与B组间差异无统计学意义;A组再狭窄发生率高于B组(P<0.01).结论 冠心病合并糖耐量异常患者与冠心病合并糖尿病患者一样,有较高的心脏事件发生率,故对合并糖耐量异常的冠心病患者应及早干预,积极控制血糖.%Objective To investigate impact of abnormal slucose metabolism on major adverse cardiac event in patients after coronary artery stent implantation.Methods Two hundred and fifteen patients whose data were available were enrolled in this study,and the patients were divided into 3 groups,diabetes group(group A),abnormal glucose metabolism group(group B),normal glucose tolerance group(group C).The clinica,coronary artery lesion characteristics and major adverse cardiac event(MACE)rate during in hospital and follow up periods were compared.Resuits There was a higher occurrence of MACE in group A and group B than that in group C(P<0.01).There was no significant difference between group A and group B.Conclusion The patients of coronary heart disease with abnormal slucose metabolism have higher MACE rate than abnormal slueese metabolism.

  7. The prevalence of depression in white-European and South-Asian people with impaired glucose regulation and screen-detected type 2 diabetes mellitus.

    Navneet Aujla

    Full Text Available BACKGROUND: There is a clear relationship between depression and diabetes. However, the directionality of the relationship remains unclear and very little research has considered a multi-ethnic population. The aim of this study was to determine the prevalence of depression in a White-European (WE and South-Asian (SA population attending a community diabetes screening programme, and to explore the association of depression with screen-detected Type 2 diabetes mellitus (T2DM and impaired glucose regulation (IGR. METHODOLOGY/PRINCIPAL FINDINGS: Participants were recruited from general practices in Leicestershire (United Kingdom between August 2004 and December 2007. 4682 WE (40-75 years and 1327 SA participants (25-75 years underwent an Oral Glucose Tolerance Test, detailed history, anthropometric measurements and completed the World Health Organisation-Five (WHO-5 Wellbeing Index. Depression was defined by a WHO-5 wellbeing score < or =13. Unadjusted prevalence of depression for people in the total sample with T2DM and IGR was 21.3% (21.6% in WE, 20.6% in SA, p = 0.75 and 26.0% (25.3% in WE, 28.9% in SA, p = 0.65 respectively. For people with normal glucose tolerance, the prevalence was 25.1% (24.9% in WE, 26.4% in SA, p = 0.86. Age-adjusted prevalences were higher for females than males. Odds ratios adjusted for age, gender, and ethnicity, showed no significant increase in prevalent depression for people with T2DM (OR = 0.95, 95%CI 0.62 to 1.45 or IGR (OR = 1.17, 95%CI 0.96 to 1.42. CONCLUSIONS: Prior to the knowledge of diagnosis, depression was not significantly more prevalent in people with screen detected T2DM or IGR. Differences in prevalent depression between WE and SA people were also not identified. In this multi-ethnic population, female gender was significantly associated with depression.

  8. Interactions between zinc transporter-8 gene (SLC30A8) and plasma zinc concentrations for impaired glucose regulation and type 2 diabetes.

    Shan, Zhilei; Bao, Wei; Zhang, Yan; Rong, Ying; Wang, Xia; Jin, Yilin; Song, Yadong; Yao, Ping; Sun, Changhao; Hu, Frank B; Liu, Liegang

    2014-05-01

    Although both SLC30A8 rs13266634 single nucleotide polymorphism and plasma zinc concentrations have been associated with impaired glucose regulation (IGR) and type 2 diabetes (T2D), their interactions for IGR and T2D remain unclear. Therefore, to assess zinc-SLC30A8 interactions, we performed a case-control study in 1,796 participants: 218 newly diagnosed IGR patients, 785 newly diagnosed T2D patients, and 793 individuals with normal glucose tolerance. After adjustment for age, sex, BMI, family history of diabetes, and hypertension, the multivariable odds ratio (OR) of T2D associated with a 10 µg/dL higher plasma zinc level was 0.87 (95% CI 0.85-0.90). Meanwhile, the OR of SLC30A8 rs13266634 homozygous genotypes CC compared with TT was 1.53 (1.11-2.09) for T2D. Similar associations were found in IGR and IGR&T2D groups. Each 10 µg/dL increment of plasma zinc was associated with 22% (OR 0.78 [0.72-0.85]) lower odds of T2D in TT genotype carriers, 17% (0.83 [0.80-0.87]) lower odds in CT genotype carriers, and 7% (0.93 [0.90-0.97]) lower odds in CC genotype carriers (P for interaction = 0.01). Our study suggested that the C allele of rs13266634 was associated with higher odds of T2D, and higher plasma zinc was associated with lower odds. The inverse association of plasma zinc concentrations with T2D was modified by SLC30A8 rs13266634. Further studies are warranted to confirm our findings and clarify the mechanisms underlying the interaction between plasma zinc and the SLC30A8 gene in relation to T2D.

  9. Genetic and Diet-Induced Obesity Increased Intestinal Tumorigenesis in the Double Mutant Mouse Model Multiple Intestinal Neoplasia X Obese via Disturbed Glucose Regulation and Inflammation

    Ha Thi Ngo

    2015-01-01

    Full Text Available We have studied how spontaneous or carcinogen-induced intestinal tumorigenesis was affected by genetic or diet-induced obesity in C57BL/6J-ApcMin/+ X C57BL/6J-Lepob/+ mice. Obesity was induced by the obese (ob mutation in the lep gene coding for the hormone leptin, or by a 45% fat diet. The effects of obesity were examined on spontaneous intestinal tumors caused by the multiple intestinal neoplasia (Min mutation in the adenomatous polyposis coli (Apc gene and on tumors induced by the dietary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP. F1 ob/ob (homozygous mutated mice had increased body weight (bw and number of spontaneous and PhIP-induced small intestinal tumors (in ApcMin/+ mice, versus ob/wt (heterozygous mutated and wt/wt mice (homozygous wild-type. A 45% fat diet exacerbated bw and spontaneous tumor numbers versus 10% fat, but not PhIP-induced tumors. Except for bw, ob/wt and wt/wt were not significantly different. The obesity caused hyperglucosemia and insulinemia in ob/ob mice. A 45% fat diet further increased glucose, but not insulin. Inflammation was seen as increased TNFα levels in ob/ob mice. Thus the results implicate disturbed glucose regulation and inflammation as mechanisms involved in the association between obesity and intestinal tumorigenesis. Ob/ob mice had shorter lifespan than ob/wt and wt/wt mice.

  10. SOX6 attenuates glucose-stimulated insulin secretion by repressing PDX1 transcriptional activity and is down-regulated in hyperinsulinemic obese mice.

    Iguchi, Haruhisa; Ikeda, Yukio; Okamura, Masashi; Tanaka, Toshiya; Urashima, Yasuyo; Ohguchi, Hiroto; Takayasu, Shinobu; Kojima, Noriaki; Iwasaki, Satoshi; Ohashi, Riuko; Jiang, Shuying; Hasegawa, Go; Ioka, Ryoichi X; Magoori, Kenta; Sumi, Koichi; Maejima, Takashi; Uchida, Aoi; Naito, Makoto; Osborne, Timothy F; Yanagisawa, Masashi; Yamamoto, Tokuo T; Kodama, Tatsuhiko; Sakai, Juro

    2005-11-11

    In obesity-related insulin resistance, pancreatic islets compensate for insulin resistance by increasing secretory capacity. Here, we report the identification of sex-determining region Y-box 6 (SOX6), a member of the high mobility group box superfamily of transcription factors, as a co-repressor for pancreatic-duodenal homeobox factor-1 (PDX1). SOX6 mRNA levels were profoundly reduced by both a long term high fat feeding protocol in normal mice and in genetically obese ob/ob mice on a normal chow diet. Interestingly, we show that SOX6 is expressed in adult pancreatic insulin-producing beta-cells and that overexpression of SOX6 decreased glucose-stimulated insulin secretion, which was accompanied by decreased ATP/ADP ratio, Ca(2+) mobilization, proinsulin content, and insulin gene expression. In a complementary fashion, depletion of SOX6 by small interfering RNAs augmented glucose-stimulated insulin secretion in insulinoma mouse MIN6 and rat INS-1E cells. These effects can be explained by our mechanistic studies that show SOX6 acts to suppress PDX1 stimulation of the insulin II promoter through a direct protein/protein interaction. Furthermore, SOX6 retroviral expression decreased acetylation of histones H3 and H4 in chromatin from the promoter for the insulin II gene, suggesting that SOX6 may decrease PDX1 stimulation through changes in chromatin structure at specific promoters. These results suggest that perturbations in transcriptional regulation that are coordinated through SOX6 and PDX1 in beta-cells may contribute to the beta-cell adaptation in obesity-related insulin resistance.

  11. Sterol Regulatory Element-Binding Protein-1c Regulates Inflammasome Activation in Gingival Fibroblasts Infected with High-Glucose-Treated Porphyromonas gingivalis

    Kuo, Hsing-Chun; Chang, Li-Ching; Chen, Te-Chuan; Lee, Ko-Chao; Lee, Kam-Fai; Chen, Cheng-Nan; Yu, Hong-Ren

    2016-01-01

    Background: Porphyromonas gingivalis is a major bacterial species implicated in the progression of periodontal disease, which is recognized as a common complication of diabetes. The interleukin (IL)-1β, processed by the NLR family pyrin domain containing 3 (NLRP3) inflammasome, has been identified as a target for pathogenic infection of the inflammatory response. However, the effect of P. gingivalis in a high-glucose situation in the modulation of inflammasome activation in human gingival fibroblasts (HGFs) is not well-understood. Methods: P. gingivalis strain CCUG25226 was used to study the mechanisms underlying the regulation of HGF NLRP3 expression by the infection of high-glucose-treated P. gingivalis (HGPg). Results: HGF infection with HGPg increases the expression of IL-1β and NLRP3. We further demonstrated that the upregulation of sterol regulatory element-binding protein (SREBP)-1c by activation of the Akt and p70S6K pathways is critical for HGPg-induced NLRP3 expression. We showed that the inhibition of Janus kinase 2 (JAK2) blocks the Akt- and p70S6K-mediated SREBP-1c, NLRP3, and IL-1β expression. The effect of HGPg on HGF signaling and NLRP3 expression is mediated by β1 integrin. In addition, gingival tissues from diabetic patients with periodontal disease exhibited higher NLRP3 and SREBP-1c expression. Conclusions: Our findings identify the molecular pathways underlying HGPg-dependent NLRP3 inflammasome expression in HGFs, providing insight into the effect of P. gingivalis invasion in HGFs. PMID:28083517

  12. Endoplasmic Reticulum-resident Heat Shock Protein 90 (HSP90) Isoform Glucose-regulated Protein 94 (GRP94) Regulates Cell Polarity and Cancer Cell Migration by Affecting Intracellular Transport.

    Ghosh, Suman; Shinogle, Heather E; Galeva, Nadezhda A; Dobrowsky, Rick T; Blagg, Brian S J

    2016-04-15

    Heat shock protein 90 (HSP90) is a molecular chaperone that is up-regulated in cancer and is required for the folding of numerous signaling proteins. Consequently, HSP90 represents an ideal target for the development of new anti-cancer agents. The human HSP90 isoform, glucose-regulated protein 94 (GRP94), resides in the endoplasmic reticulum and regulates secretory pathways, integrins, and Toll-like receptors, which contribute to regulating immunity and metastasis. However, the cellular function of GRP94 remains underinvestigated. We report that GRP94 knockdown cells are defective in intracellular transport and, consequently, negatively impact the trafficking of F-actin toward the cellular cortex, integrin α2 and integrin αL toward the cell membrane and filopodia, and secretory vesicles containing the HSP90α-AHA1-survivin complex toward the leading edge. As a result, GRP94 knockdown cells form a multipolar spindle instead of bipolar morphology and consequently manifest a defect in cell migration and adhesion.

  13. Metabolic Abnormalities in Children with Asthma

    2010-01-01

    Rationale: Childhood asthma and obesity have reached epidemic proportions worldwide, and the latter is also contributing to increasing rates of related metabolic disorders, such as diabetes. Yet, the relationship between asthma, obesity, and abnormal lipid and glucose metabolism is not well understood, nor has it been adequately explored in children.

  14. Neuroendocrine abnormalities in Parkinson's disease.

    De Pablo-Fernández, Eduardo; Breen, David P; Bouloux, Pierre M; Barker, Roger A; Foltynie, Thomas; Warner, Thomas T

    2017-02-01

    Neuroendocrine abnormalities are common in Parkinson's disease (PD) and include disruption of melatonin secretion, disturbances of glucose, insulin resistance and bone metabolism, and body weight changes. They have been associated with multiple non-motor symptoms in PD and have important clinical consequences, including therapeutics. Some of the underlying mechanisms have been implicated in the pathogenesis of PD and represent promising targets for the development of disease biomarkers and neuroprotective therapies. In this systems-based review, we describe clinically relevant neuroendocrine abnormalities in Parkinson's disease to highlight their role in overall phenotype. We discuss pathophysiological mechanisms, clinical implications, and pharmacological and non-pharmacological interventions based on the current evidence. We also review recent advances in the field, focusing on the potential targets for development of neuroprotective drugs in Parkinson's disease and suggest future areas for research.

  15. 妊娠期糖代谢异常与尿酸、C肽、超敏C反应蛋白、糖化血红蛋白相关性%Correlation of gestational abnormal glucose metabolism and uric acid,C peptide,high sensitivity C reactive protein,glycated hemoglobin

    周静姝; 金海甲; 刘飞; 郝凤燕

    2015-01-01

    目的:探讨C肽、超敏C反应蛋白、糖化血红蛋白、尿酸及血脂等多因素与妊娠期糖代谢异常的相关性。方法:2010年1月-2011年8月收集分娩孕妇,统计其在孕24~28周前后检测的血糖与尿酸、CRP、血脂、超敏CRP、C肽、糖化血红蛋白、体重、血压及文化背景等,其中异常23例;随机抽取40例正常者为对照。C肽采用电化学发光方法,超敏C反应蛋白采用芬兰试剂,糖化血红蛋白用TDM100糖化血红蛋白分析仪测定。采用多因素分析评价其相关性。结果:多因素联合分析比单个独立因素评价糖代谢异常相关性高。结论:多项联合检测能提前预测糖代谢异常的发生,提前采取治疗措施,预防疾病发生,得到很好的预后效果。%Objective:To explore the correlation of gestational abnormal glucose metabolism and C peptide,high sensitivity C reactive protein,glycated hemoglobin,uric acid,blood lipid and other factors.Methods:Childbirth pregnant womens were selected from January 2010 to August 2011.The blood glucose and uric acid,CRP,blood lipid,high sensitivity CRP,C peptide,glycated hemoglobin that were detected before and after pregnancy 24 to 28 weeks.Weight,blood pressure and cultural background were statistically analyzed,in which 23 cases were abnormal.A random sample of 40 normal persons was as the control.C peptide used electrochemiluminescence method,the high sensitive C reactive protein used finland reagent,the glycated hemoglobin was detected by TDM100 glycated hemoglobin analyzer instrument.The correlation was analyzed and evaluated by multi factors. Results:The multi factor combined analysis in the evaluation of abnormal glucose metabolism correlation was higher than a single independent factor.Conclusion:The multiple combined detection can predict abnormal glucose metabolism in advance.It can advance to take treatment,prevent disease,and obtain very good prognosis effect.

  16. GDNF pre-treatment aggravates neuronal cell loss in oxygen-glucose deprived hippocampal slice cultures: a possible effect of glutamate transporter up-regulation.

    Bonde, C; Sarup, A; Schousboe, A; Gegelashvili, G; Noraberg, J; Zimmer, J

    2003-01-01

    Besides its neurotrophic and neuroprotective effects on dopaminergic neurons and spinal motoneurons, glial cell line-derived neurotrophic factor (GDNF) has potent neuroprotective effects in cerebral ischemia. The protective effect has so far been related to reduced activation of N-methyl-D-aspartate receptors (NMDAr). This study tested the effects of GDNF on glutamate transporter expression, with the hypothesis that modulation of glutamate transporter activity would affect the outcome of cerebral ischemia. Organotypic hippocampal slice cultures, derived from 1-week-old rats, were treated with 100 ng/ml GDNF for either 2 or 5 days, followed by Western blot analysis of NMDAr subunit 1 (NR1) and two glutamate transporter subtypes, GLAST and GLT-1. After 5-day exposure to GDNF, expression of GLAST and GLT-1 was up-regulated to 169 and 181% of control values, respectively, whereas NR1 was down-regulated to 64% of control. However, despite these changes that potentially would support neuronal resistance to excitotoxicity, the long-term treatment with GDNF was found to aggravate the neuronal damage induced by oxygen-glucose deprivation (OGD). The increased cell death, assessed by propidium iodide (PI) uptake, occurred not only among the most susceptible CA1 pyramidal cells, but also in CA3 and fascia dentata. Given that glutamate transporters are able to release glutamate by reversed action during energy failure, it is suggested that the observed increase in OGD-induced cell death in the GDNF-pretreated cultures was caused by the build-up of excitotoxic concentrations of extracellular glutamate released through the glutamate transporters, which were up-regulated by GDNF. Although the extent and consequences of glutamate release via reversal of GLAST and GLT-1 transporters seem to vary in different energy failure models, the present findings should be taken into account in clinical trials of GDNF.

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

    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.

  18. Glucose repression in Saccharomyces cerevisiae

    Kayikci, Omur; Nielsen, Jens

    2015-01-01

    Glucose is the primary source of energy for the budding yeast Saccharomyces cerevisiae. Although yeast cells can utilize a wide range of carbon sources, presence of glucose suppresses molecular activities involved in the use of alternate carbon sources as well as it represses respiration and gluc......Glucose is the primary source of energy for the budding yeast Saccharomyces cerevisiae. Although yeast cells can utilize a wide range of carbon sources, presence of glucose suppresses molecular activities involved in the use of alternate carbon sources as well as it represses respiration...... and gluconeogenesis. This dominant effect of glucose on yeast carbon metabolism is coordinated by several signaling and metabolic interactions that mainly regulate transcriptional activity but are also effective at post-transcriptional and post-translational levels. This review describes effects of glucose repression...

  19. Rye-Based Evening Meals Favorably Affected Glucose Regulation and Appetite Variables at the Following Breakfast; A Randomized Controlled Study in Healthy Subjects.

    Jonna C Sandberg

    Full Text Available Whole grain has shown potential to prevent obesity, cardiovascular disease and type 2 diabetes. Possible mechanism could be related to colonic fermentation of specific indigestible carbohydrates, i.e. dietary fiber (DF. The aim of this study was to investigate effects on cardiometabolic risk factors and appetite regulation the next day when ingesting rye kernel bread rich in DF as an evening meal.Whole grain rye kernel test bread (RKB or a white wheat flour based bread (reference product, WWB was provided as late evening meals to healthy young adults in a randomized cross-over design. The test products RKB and WWB were provided in two priming settings: as a single evening meal or as three consecutive evening meals prior to the experimental days. Test variables were measured in the morning, 10.5-13.5 hours after ingestion of RKB or WWB. The postprandial phase was analyzed for measures of glucose metabolism, inflammatory markers, appetite regulating hormones and short chain fatty acids (SCFA in blood, hydrogen excretion in breath and subjective appetite ratings.With the exception of serum CRP, no significant differences in test variables were observed depending on length of priming (P>0.05. The RKB evening meal increased plasma concentrations of PYY (0-120 min, P<0.001, GLP-1 (0-90 min, P<0.05 and fasting SCFA (acetate and butyrate, P<0.05, propionate, P = 0.05, compared to WWB. Moreover, RKB decreased blood glucose (0-120 min, P = 0.001, serum insulin response (0-120 min, P<0.05 and fasting FFA concentrations (P<0.05. Additionally, RKB improved subjective appetite ratings during the whole experimental period (P<0.05, and increased breath hydrogen excretion (P<0.001, indicating increased colonic fermentation activity.The results indicate that RKB evening meal has an anti-diabetic potential and that the increased release of satiety hormones and improvements of appetite sensation could be beneficial in preventing obesity. These effects could

  20. Steroid receptor coactivator-3 regulates glucose metabolism in bladder cancer cells through coactivation of hypoxia inducible factor 1α.

    Zhao, Wei; Chang, Cunjie; Cui, Yangyan; Zhao, Xiaozhi; Yang, Jun; Shen, Lan; Zhou, Ji; Hou, Zhibo; Zhang, Zhen; Ye, Changxiao; Hasenmayer, Donald; Perkins, Robert; Huang, Xiaojing; Yao, Xin; Yu, Like; Huang, Ruimin; Zhang, Dianzheng; Guo, Hongqian; Yan, Jun

    2014-04-18

    Cancer cell proliferation is a metabolically demanding process, requiring high glycolysis, which is known as "Warburg effect," to support anabolic growth. Steroid receptor coactivator-3 (SRC-3), a steroid receptor coactivator, is overexpressed and/or amplified in multiple cancer types, including non-steroid targeted cancers, such as urinary bladder cancer (UBC). However, whether SRC-3 regulates the metabolic reprogramming for cancer cell growth is unknown. Here, we reported that overexpression of SRC-3 accelerated UBC cell growth, accompanied by the increased expression of genes involved in glycolysis. Knockdown of SRC-3 reduced the UBC cell glycolytic rate under hypoxia, decreased tumor growth in nude mice, with reduction of proliferating cell nuclear antigen and lactate dehydrogenase expression levels. We further revealed that SRC-3 could interact with hypoxia inducible factor 1α (HIF1α), which is a key transcription factor required for glycolysis, and coactivate its transcriptional activity. SRC-3 was recruited to the promoters of HIF1α-target genes, such as glut1 and pgk1. The positive correlation of expression levels between SRC-3 and Glut1 proteins was demonstrated in human UBC patient samples. Inhibition of glycolysis through targeting HK2 or LDHA decelerated SRC-3 overexpression-induced cell growth. In summary, overexpression of SRC-3 promoted glycolysis in bladder cancer cells through HIF1α to facilitate tumorigenesis, which may be an intriguing drug target for bladder cancer therapy.

  1. Scientific Opinion on the substantiation of a health claim related to FRUIT UP® and a reduction of post-prandial blood glucose responses pursuant to Article 13(5) of Regulation (EC) No 1924/2006

    Tetens, Inge

    Following an application from WILD-Valencia SAU, submitted for authorisation of a health claim pursuant to Article 13(5) of Regulation (EC) No 1924/2006 via the Competent Authority of Spain, the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) was asked to deliver an opinion...... on the scientific substantiation of a health claim related to FRUIT UP® and a reduction of post-prandial blood glucose responses. The Panel considers that the food, FRUIT UP®, and the food (i.e. glucose, sucrose) that FRUIT UP® should replace in foods or beverages are both sufficiently characterised in relation...

  2. Effects of cereal breakfasts on postprandial glucose, appetite regulation and voluntary energy intake at a subsequent standardized lunch; focusing on rye products

    Björck Inger ME

    2011-01-01

    Full Text Available Abstract Background Rye products have been demonstrated to lower the acute insulin demand, induce a low and prolonged blood glucose response (high Glycemic Profile, GP and reduce subclinical inflammation. These products may therefore contribute to a lowered risk of obesity, type 2 diabetes and cardio vascular disease. The objective of the present paper was to evaluate the mechanism for a reduced postprandial insulin demand with rye products, and to explore possible appetite regulating properties. Methods 10 healthy subjects were served breakfast meals (50 g of available starch with endosperm- or whole grain rye breads, with and without lactic acid, boiled whole grain rye- (RK or wheat (WK kernels, or white wheat bread reference (WWB in random order in a cross-over design. Plasma concentrations of glucose, ghrelin, serum insulin, free fatty acids, adiponectin, breath hydrogen excretion (H2, and subjective satiety was evaluated during the postprandial phase. 270 min after the breakfast, an ad lib lunch buffet was served and the voluntary energy intake (EI was registered. Results All rye products and WK induced lower insulinemic indices (II than WWB. A lower incremental insulin peak following breakfast correlated with a lower EI at lunch (r = 0.38. A low II was related to improved satiety in the early postprandial phase (fullness AUC 0-60 min, r = -0.36. RK induced a higher GP compared to WWB and WK. A higher GP was related to a lowered desire to eat before lunch (AUC 210-270 and to a lower concentration of ghrelin in the late postprandial phase after breakfast (270 min, r = -0.29 and -0.29, which in turn was related to a lower voluntary EI (r = 0.43 and 0.33. The RK breakfast improved satiety in the early postprandial phase (0-60 min compared to WWB, and induced a lower EI at lunch (-16%. A high content of indigestible carbohydrates in the breakfast products was related to improved satiety (0-60 min, r = 0.68 for fullness, and a higher breath H2

  3. Determinación del valor umbral de tamizaje de la glicemia en ayunas, para identificar la intolerancia a los carbohidratos, en mujeres con síndrome de ovarios poliquísticos Determination of fasting plasma glucose cut-off valuefor the identification of abnormal carbohydrate tolerance in women with polycystic ovarian syndrome

    Yai-Linn Chang

    2012-12-01

    Full Text Available Objetivo: determinar el valor predictivo de la glucosa en ayunas, para identificar intolerancia a los carbohidratos en pacientes con síndrome de ovario poliquístico. Materiales y métodos: a 100 mujeres con diagnóstico de síndrome de ovario poliquístico, se les realizó una prueba de tolerancia a 75 g de glucosa. Resultados: la sensibilidad para una cifra umbral de 101 mg/dl, fue de un 41,7%, IC 95%: 23% - 63%, y la especificidad de un 92,1%, IC95 %:83% - 97%. Con un valor predictivo positivo del 62,5%, y negativo del 83,3%.El valor de corte óptimo fue de 93mg /dl, con una sensibilidad del 75%, IC 95%: 53%-89%, y una especificidad del 73,7%, IC 95%: 62%-83%. La cifra de corte umbral óptima de la glicemia en ayunas para el tamizaje de intolerancia en mujeres con SOPQ, fue de 93 mg/dl. Conclusiones: las recomendaciones actuales para diagnosticar intolerancia a los carbohidratos, en mujeres con síndrome de ovario poliquístico, no son apropiadas.Objective: To determine the predictive value of fasting glucose to identify abnormal carbohydrate tolerance in patients with polycystic ovary syndrome. Materials and methods: 100 women diagnosed with polycystic ovary syndrome underwent a tolerance test toa 75 gdose of glucose. Results: Sensitivity for a threshold value of 101 mg/dl was 41.7% (95% C.I.: 23% - 63% and specificity 92.1% (95% C.I.: 83% - 97%; with a positive predictive value of 62.5% and a negative predictive value of 83.3%. The optimum cut-off value was 93 mg/dL, with a sensitivity of 75% (95% C.I.: 53% - 89% and a specificity of 73.7% (95% C.I.: 62% - 83%. The optimum fasting plasma glucose cut-off value for intolerance in women with PCOS was 93md/dL. Conclusions: The current recommendations for diagnosing abnormal carbohydrate tolerance in women with polycystic ovary syndrome are not appropriate.

  4. bFGF-Regulating MAPKs Are Involved in High Glucose-Mediated ROS Production and Delay of Vascular Endothelial Cell Migration.

    Zhong Xin Zhu

    Full Text Available High blood sugar is a symptom of diabetes mellitus (DM. Vascular endothelial cells (VECs directly contact the blood and are damaged when blood sugar levels are high. However, the molecular mechanism underlying this process remains elusive. To analyze the effects of DM on migration, we simulated DM by applying high glucose (HG to the human VEC. HG delayed cell migration and induced phosphorylation of MAPKs (JNK and ERK. By contrast, in presence of bFGF, cell migration was promoted and MAPK phosphorylation levels were reduced. Furthermore, treatment with JNK and ERK inhibitors rescued HG-mediated delay of cell migration. Molecular and cell biological studies demonstrated that HG increased ROS production, whereas treatment with bFGF or JNK/ERK inhibitors blocked HG-induced ROS accumulation. Addition of MnTMPyP, a ROS scavenger, reduced HG-induced ROS production and accelerated cell migration, suggesting that the influence of HG on bFGF-MAPK signaling causes accumulation of ROS, which in turn regulate cell migration. This is the first study to elucidate the molecular mechanism of HG-mediated VEC migration; these findings could facilitate the development of novel therapies for DM.

  5. The Methionine Transamination Pathway Controls Hepatic Glucose Metabolism through Regulation of the GCN5 Acetyltransferase and the PGC-1α Transcriptional Coactivator.

    Tavares, Clint D J; Sharabi, Kfir; Dominy, John E; Lee, Yoonjin; Isasa, Marta; Orozco, Jose M; Jedrychowski, Mark P; Kamenecka, Theodore M; Griffin, Patrick R; Gygi, Steven P; Puigserver, Pere

    2016-05-13

    Methionine is an essential sulfur amino acid that is engaged in key cellular functions such as protein synthesis and is a precursor for critical metabolites involved in maintaining cellular homeostasis. In mammals, in response to nutrient conditions, the liver plays a significant role in regulating methionine concentrations by altering its flux through the transmethylation, transsulfuration, and transamination metabolic pathways. A comprehensive understanding of how hepatic methionine metabolism intersects with other regulatory nutrient signaling and transcriptional events is, however, lacking. Here, we show that methionine and derived-sulfur metabolites in the transamination pathway activate the GCN5 acetyltransferase promoting acetylation of the transcriptional coactivator PGC-1α to control hepatic gluconeogenesis. Methionine was the only essential amino acid that rapidly induced PGC-1α acetylation through activating the GCN5 acetyltransferase. Experiments employing metabolic pathway intermediates revealed that methionine transamination, and not the transmethylation or transsulfuration pathways, contributed to methionine-induced PGC-1α acetylation. Moreover, aminooxyacetic acid, a transaminase inhibitor, was able to potently suppress PGC-1α acetylation stimulated by methionine, which was accompanied by predicted alterations in PGC-1α-mediated gluconeogenic gene expression and glucose production in primary murine hepatocytes. Methionine administration in mice likewise induced hepatic PGC-1α acetylation, suppressed the gluconeogenic gene program, and lowered glycemia, indicating that a similar phenomenon occurs in vivo These results highlight a communication between methionine metabolism and PGC-1α-mediated hepatic gluconeogenesis, suggesting that influencing methionine metabolic flux has the potential to be therapeutically exploited for diabetes treatment.

  6. Hyperbaric oxygen preconditioning induces tolerance against oxidative injury and oxygen-glucose deprivation by up-regulating heat shock protein 32 in rat spinal neurons.

    Guoyang Huang

    Full Text Available OBJECTIVE: Hyperbaric oxygen (HBO preconditioning (HBO-PC has been testified to have protective effects on spinal cord injury (SCI. However, the mechanisms remain enigmatic. The present study aimed to explore the effects of HBO-PC on primary rat spinal neurons against oxidative injury and oxygen-glucose deprivation (OGD and the relationship with heat shock proteins (HSPs. METHODS: Primary rat spinal neurons after 7 days of culture were used in this study. HSPs were detected in rat spinal neurons following a single exposure to HBO at different time points by Western blot. Using lactate dehydrogenase release assay and cell counting kit-8 assay, the injuries induced by hydrogen peroxide (H2O2 insult or OGD were determined and compared among neurons treated with HBO-PC with or without HSP inhibitors. RESULTS: The results of Western blot showed that HSP27, HSP70 and HSP90 have a slight but not significant increase in primary neurons following HBO exposure. However, HSP32 expression significantly increased and reached highest at 12 h following HBO exposure. HBO-PC significantly increased the cell viability and decreased the medium lactate dehydrogenase content in cultures treated with H2O2 or OGD. Pretreatment with zinc protoporphyrin IX, a specific inhibitor of HSP32, significantly blocked the protective effects of HBO-PC. CONCLUSIONS: These results suggest that HBO-PC could protect rat spinal neurons in vitro against oxidative injury and OGD mostly by up-regulating of HSP32 expression.

  7. Near infrared radiation protects against oxygen-glucose deprivation-induced neurotoxicity by down-regulating neuronal nitric oxide synthase (nNOS) activity in vitro.

    Yu, Zhanyang; Li, Zhaoyu; Liu, Ning; Jizhang, Yunneng; McCarthy, Thomas J; Tedford, Clark E; Lo, Eng H; Wang, Xiaoying

    2015-06-01

    Near infrared radiation (NIR) has been shown to be neuroprotective against neurological diseases including stroke and brain trauma, but the underlying mechanisms remain poorly understood. In the current study we aimed to investigate the hypothesis that NIR may protect neurons by attenuating oxygen-glucose deprivation (OGD)-induced nitric oxide (NO) production and modulating cell survival/death signaling. Primary mouse cortical neurons were subjected to 4 h OGD and NIR was applied at 2 h reoxygenation. OGD significantly increased NO level in primary neurons compared to normal control, which was significantly ameliorated by NIR at 5 and 30 min post-NIR. Neither OGD nor NIR significantly changed neuronal nitric oxide synthase (nNOS) mRNA or total protein levels compared to control groups. However, OGD significantly increased nNOS activity compared to normal control, and this effect was significantly diminished by NIR. Moreover, NIR significantly ameliorated the neuronal death induced by S-Nitroso-N-acetyl-DL-penicillamine (SNAP), a NO donor. Finally, NIR significantly rescued OGD-induced suppression of p-Akt and Bcl-2 expression, and attenuated OGD-induced upregulation of Bax, BAD and caspase-3 activation. These results suggest NIR may protect against OGD at least partially through reducing NO production by down-regulating nNOS activity, and modulating cell survival/death signaling.

  8. HIGD1A Regulates Oxygen Consumption, ROS Production, and AMPK Activity during Glucose Deprivation to Modulate Cell Survival and Tumor Growth

    Kurosh Ameri

    2015-02-01

    Full Text Available Hypoxia-inducible gene domain family member 1A (HIGD1A is a survival factor induced by hypoxia-inducible factor 1 (HIF-1. HIF-1 regulates many responses to oxygen deprivation, but viable cells within hypoxic perinecrotic solid tumor regions frequently lack HIF-1α. HIGD1A is induced in these HIF-deficient extreme environments and interacts with the mitochondrial electron transport chain to repress oxygen consumption, enhance AMPK activity, and lower cellular ROS levels. Importantly, HIGD1A decreases tumor growth but promotes tumor cell survival in vivo. The human Higd1a gene is located on chromosome 3p22.1, where many tumor suppressor genes reside. Consistent with this, the Higd1a gene promoter is differentially methylated in human cancers, preventing its hypoxic induction. However, when hypoxic tumor cells are confronted with glucose deprivation, DNA methyltransferase activity is inhibited, enabling HIGD1A expression, metabolic adaptation, and possible dormancy induction. Our findings therefore reveal important new roles for this family of mitochondrial proteins in cancer biology.

  9. Volume regulated anion channel currents of rat hippocampal neurons and their contribution to oxygen-and-glucose deprivation induced neuronal death.

    Huaqiu Zhang

    Full Text Available Volume-regulated anion channels (VRAC are widely expressed chloride channels that are critical for the cell volume regulation. In the mammalian central nervous system, the physiological expression of neuronal VRAC and its role in cerebral ischemia are issues largely unknown. We show that hypoosmotic medium induce an outwardly rectifying chloride conductance in CA1 pyramidal neurons in rat hippocampal slices. The induced chloride conductance was sensitive to some of the VRAC inhibitors, namely, IAA-94 (300 µM and NPPB (100 µM, but not to tamoxifen (10 µM. Using oxygen-and-glucose deprivation (OGD to simulate ischemic conditions in slices, VRAC activation appeared after OGD induced anoxic depolarization (AD that showed a progressive increase in current amplitude over the period of post-OGD reperfusion. The OGD induced VRAC currents were significantly inhibited by inhibitors for glutamate AMPA (30 µM NBQX and NMDA (40 µM AP-5 receptors in the OGD solution, supporting the view that induction of AD requires an excessive Na(+-loading via these receptors that in turn to activate neuronal VRAC. In the presence of NPPB and DCPIB in the post-OGD reperfusion solution, the OGD induced CA1 pyramidal neuron death, as measured by TO-PRO-3-I staining, was significantly reduced, although DCPIB did not appear to be an effective neuronal VRAC blocker. Altogether, we show that rat hippocampal pyramidal neurons express functional VRAC, and ischemic conditions can initial neuronal VRAC activation that may contribute to ischemic neuronal damage.

  10. Glutamine:fructose-6-phosphate amidotransferase activity in cultured human skeletal muscle cells: relationship to glucose disposal rate in control and non-insulin-dependent diabetes mellitus subjects and regulation by glucose and insulin.

    1996-01-01

    We examined the activity of the rate-limiting enzyme for hexosamine biosynthesis, glutamine:fructose-6-phosphate amidotransferase (GFA) in human skeletal muscle cultures (HSMC), from 17 nondiabetic control and 13 subjects with non-insulin-dependent diabetes. GFA activity was assayed from HSMC treated with low (5 mM) or high (20 mM) glucose and low (22 pM) or high (30 microM) concentrations of insulin. In control subjects GFA activity decreased with increasing glucose disposal rate (r = -0.68,...

  11. 甲状腺功能异常患者血糖、血脂、血尿酸水平变化的相关分析%Variation of serum glucose, lipid and uric acid level in patients with abnormal thyroid function

    费扬; 李红

    2011-01-01

    Objective To investigate the variation of serum glucose, lipid and uric acid level in patients with abnormal thyroid function. Methods 105 patients with abnormal thyroid function were included and divided into three groups according to their thyroid function: clinical hyperthyroidism, clinical hypothyroidism and subclinical hypothyroidism. Their fast glucose (GLU),total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL- C) and uric acid (UA) levels were measured and compared with 46 healthy controls. Rsults After adjusting for age, sex, blood pressure and body weight, we got the following res ults: 1. fast glucose level was higher in patients with clinical hyperthyroidism (P <0.01 ) and lower in those with clinical hypothyroidism (P <0.05) compared to healthy controls; patients with subclinical hypothyroidism had lower glucose level but without significant difference compared to normal controls; 2. serum lipid level including TG, TC and LDL- C, decreased in patients with clinical hyperthyroidism (P <0.01 ) and increased in those with those with clinical hypothyroidism (P <0.01 ); patients with subclinical hypothyroidism had in creased lipid level but no significant difference was found when compared to control group; 3. serum uric acid level increased in all the three groups (P<0.01) compared to healthy controls, but no difference was found among these three groups. Conclusion Besides serum glucose and lipid levels, physicians should also pay attention to serum uric acid level of patients with abnormalthyroid function which changes significantly.%目的 探讨甲状腺功能异常患者血糖、血脂、血尿酸水平变化及临床意义.方法 根据甲状腺功能测定结果将105例甲状腺功能异常患者分为临床甲亢组、亚临床甲减组和临床甲减组,并设健康对照组46例,同时分别测定各组空腹血糖(FPG)和血总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDL-C

  12. Glucose-6-phosphatase deficiency

    Labrune Philippe

    2011-05-01

    Full Text Available Abstract Glucose-6-phosphatase deficiency (G6P deficiency, or glycogen storage disease type I (GSDI, is a group of inherited metabolic diseases, including types Ia and Ib, characterized by poor tolerance to fasting, growth retardation and hepatomegaly resulting from accumulation of glycogen and fat in the liver. Prevalence is unknown and annual incidence is around 1/100,000 births. GSDIa is the more frequent type, representing about 80% of GSDI patients. The disease commonly manifests, between the ages of 3 to 4 months by symptoms of hypoglycemia (tremors, seizures, cyanosis, apnea. Patients have poor tolerance to fasting, marked hepatomegaly, growth retardation (small stature and delayed puberty, generally improved by an appropriate diet, osteopenia and sometimes osteoporosis, full-cheeked round face, enlarged kydneys and platelet dysfunctions leading to frequent epistaxis. In addition, in GSDIb, neutropenia and neutrophil dysfunction are responsible for tendency towards infections, relapsing aphtous gingivostomatitis, and inflammatory bowel disease. Late complications are hepatic (adenomas with rare but possible transformation into hepatocarcinoma and renal (glomerular hyperfiltration leading to proteinuria and sometimes to renal insufficiency. GSDI is caused by a dysfunction in the G6P system, a key step in the regulation of glycemia. The deficit concerns the catalytic subunit G6P-alpha (type Ia which is restricted to expression in the liver, kidney and intestine, or the ubiquitously expressed G6P transporter (type Ib. Mutations in the genes G6PC (17q21 and SLC37A4 (11q23 respectively cause GSDIa and Ib. Many mutations have been identified in both genes,. Transmission is autosomal recessive. Diagnosis is based on clinical presentation, on abnormal basal values and absence of hyperglycemic response to glucagon. It can be confirmed by demonstrating a deficient activity of a G6P system component in a liver biopsy. To date, the diagnosis is most

  13. Glucose-6-phosphatase deficiency.

    Froissart, Roseline; Piraud, Monique; Boudjemline, Alix Mollet; Vianey-Saban, Christine; Petit, François; Hubert-Buron, Aurélie; Eberschweiler, Pascale Trioche; Gajdos, Vincent; Labrune, Philippe

    2011-05-20

    Glucose-6-phosphatase deficiency (G6P deficiency), or glycogen storage disease type I (GSDI), is a group of inherited metabolic diseases, including types Ia and Ib, characterized by poor tolerance to fasting, growth retardation and hepatomegaly resulting from accumulation of glycogen and fat in the liver. Prevalence is unknown and annual incidence is around 1/100,000 births. GSDIa is the more frequent type, representing about 80% of GSDI patients. The disease commonly manifests, between the ages of 3 to 4 months by symptoms of hypoglycemia (tremors, seizures, cyanosis, apnea). Patients have poor tolerance to fasting, marked hepatomegaly, growth retardation (small stature and delayed puberty), generally improved by an appropriate diet, osteopenia and sometimes osteoporosis, full-cheeked round face, enlarged kydneys and platelet dysfunctions leading to frequent epistaxis. In addition, in GSDIb, neutropenia and neutrophil dysfunction are responsible for tendency towards infections, relapsing aphtous gingivostomatitis, and inflammatory bowel disease. Late complications are hepatic (adenomas with rare but possible transformation into hepatocarcinoma) and renal (glomerular hyperfiltration leading to proteinuria and sometimes to renal insufficiency). GSDI is caused by a dysfunction in the G6P system, a key step in the regulation of glycemia. The deficit concerns the catalytic subunit G6P-alpha (type Ia) which is restricted to expression in the liver, kidney and intestine, or the ubiquitously expressed G6P transporter (type Ib). Mutations in the genes G6PC (17q21) and SLC37A4 (11q23) respectively cause GSDIa and Ib. Many mutations have been identified in both genes,. Transmission is autosomal recessive. Diagnosis is based on clinical presentation, on abnormal basal values and absence of hyperglycemic response to glucagon. It can be confirmed by demonstrating a deficient activity of a G6P system component in a liver biopsy. To date, the diagnosis is most commonly confirmed

  14. [Recent knowledge of the function of glucose transport molecules in cell membranes, of the regulation of their composition and of modification of their activity and changes in concentration in diseases (diabetes mellitus, Tumors)].

    Kolb, E

    1991-11-01

    In the outer membrane of animal cells there exist different isoforms of glucose-transporters (GluT), that contain pores for the facilitative intake of glucose. The content of the various forms of GluT in the different cells is influenced by the stage of development and by the plasma-concentration of glucose. In the regulation of the glucose-concentration in the plasma the content of the skeletal musculature and of the adipose tissue in GluT type 4 plays an important role: It is insulin-dependent. In diabetes mellitus the content of the outer membranes of the cells of the mentioned tissues in GluT 4 is - in dependence of the degree of the disturbance - more or less reduced. The binding of insulin to the receptor in the musculature and in adipose tissue stimulates the transport of GluT 4 from the interior of the cells to the outer membrane. Fasting causes an increase in the content of GluT 4 in the musculature and a decrease in the adipose tissue. Tumor-cells have an increased uptake of glucose with the help of GluT.

  15. RNAi screening in primary human hepatocytes of genes implicated in genome-wide association studies for roles in type 2 diabetes identifies roles for CAMK1D and CDKAL1, among others, in hepatic glucose regulation.

    Steven Haney

    Full Text Available Genome-wide association (GWA studies have described a large number of new candidate genes that contribute to of Type 2 Diabetes (T2D. In some cases, small clusters of genes are implicated, rather than a single gene, and in all cases, the genetic contribution is not defined through the effects on a specific organ, such as the pancreas or liver. There is a significant need to develop and use human cell-based models to examine the effects these genes may have on glucose regulation. We describe the development of a primary human hepatocyte model that adjusts glucose disposition according to hormonal signals. This model was used to determine whether candidate genes identified in GWA studies regulate hepatic glucose disposition through siRNAs corresponding to the list of identified genes. We find that several genes affect the storage of glucose as glycogen (glycolytic response and/or affect the utilization of pyruvate, the critical step in gluconeogenesis. Of the genes that affect both of these processes, CAMK1D, TSPAN8 and KIF11 affect the localization of a mediator of both gluconeogenesis and glycolysis regulation, CRTC2, to the nucleus in response to glucagon. In addition, the gene CDKAL1 was observed to affect glycogen storage, and molecular experiments using mutant forms of CDK5, a putative target of CDKAL1, in HepG2 cells show that this is mediated by coordinate regulation of CDK5 and PKA on MEK, which ultimately regulates the phosphorylation of ribosomal protein S6, a critical step in the insulin signaling pathway.

  16. RNAi screening in primary human hepatocytes of genes implicated in genome-wide association studies for roles in type 2 diabetes identifies roles for CAMK1D and CDKAL1, among others, in hepatic glucose regulation.

    Haney, Steven; Zhao, Juan; Tiwari, Shiwani; Eng, Kurt; Guey, Lin T; Tien, Eric

    2013-01-01

    Genome-wide association (GWA) studies have described a large number of new candidate genes that contribute to of Type 2 Diabetes (T2D). In some cases, small clusters of genes are implicated, rather than a single gene, and in all cases, the genetic contribution is not defined through the effects on a specific organ, such as the pancreas or liver. There is a significant need to develop and use human cell-based models to examine the effects these genes may have on glucose regulation. We describe the development of a primary human hepatocyte model that adjusts glucose disposition according to hormonal signals. This model was used to determine whether candidate genes identified in GWA studies regulate hepatic glucose disposition through siRNAs corresponding to the list of identified genes. We find that several genes affect the storage of glucose as glycogen (glycolytic response) and/or affect the utilization of pyruvate, the critical step in gluconeogenesis. Of the genes that affect both of these processes, CAMK1D, TSPAN8 and KIF11 affect the localization of a mediator of both gluconeogenesis and glycolysis regulation, CRTC2, to the nucleus in response to glucagon. In addition, the gene CDKAL1 was observed to affect glycogen storage, and molecular experiments using mutant forms of CDK5, a putative target of CDKAL1, in HepG2 cells show that this is mediated by coordinate regulation of CDK5 and PKA on MEK, which ultimately regulates the phosphorylation of ribosomal protein S6, a critical step in the insulin signaling pathway.

  17. Glucose-stimulated DNA synthesis through mammalian target of rapamycin (mTOR) is regulated by KATP channels: effects on cell cycle progression in rodent islets.

    Kwon, Guim; Marshall, Connie A; Liu, Hui; Pappan, Kirk L; Remedi, Maria S; McDaniel, Michael L

    2006-02-10

    The aim of this study was to define metabolic signaling pathways that mediate DNA synthesis and cell cycle progression in adult rodent islets to devise strategies to enhance survival, growth, and proliferation. Since previous studies indicated that glucose-stimulated activation of mammalian target of rapamycin (mTOR) leads to [3H]thymidine incorporation and that mTOR activation is mediated, in part, through the K(ATP) channel and changes in cytosolic Ca2+, we determined whether glyburide, an inhibitor of K(ATP) channels that stimulates Ca2+ influx, modulates [3H]thymidine incorporation. Glyburide (10-100 nm) at basal glucose stimulated [3H]thymidine incorporation to the same magnitude as elevated glucose and further enhanced the ability of elevated glucose to increase [3H]thymidine incorporation. Diazoxide (250 microm), an activator of KATP channels, paradoxically potentiated glucose-stimulated [3H]thymidine incorporation 2-4-fold above elevated glucose alone. Cell cycle analysis demonstrated that chronic exposure of islets to basal glucose resulted in a typical cell cycle progression pattern that is consistent with a low level of proliferation. In contrast, chronic exposure to elevated glucose or glyburide resulted in progression from G0/G1 to an accumulation in S phase and a reduction in G2/M phase. Rapamycin (100 nm) resulted in an approximately 62% reduction of S phase accumulation. The enhanced [3H]thymidine incorporation with chronic elevated glucose or glyburide therefore appears to be associated with S phase accumulation. Since diazoxide significantly enhanced [3H]thymidine incorporation without altering S phase accumulation under chronic elevated glucose, this increase in DNA synthesis also appears to be primarily related to an arrest in S phase and not cell proliferation.

  18. Redox/methylation mediated abnormal DNA methylation as regulators of ambient fine particulate matter-induced neurodevelopment related impairment in human neuronal cells

    Wei, Hongying; Liang, Fan; Meng, Ge; Nie, Zhiqing; Zhou, Ren; Cheng, Wei; Wu, Xiaomeng; Feng, Yan; Wang, Yan

    2016-09-01

    Fine particulate matter (PM2.5) has been implicated as a risk factor for neurodevelopmental disorders including autism in children. However, the underlying biological mechanism remains unclear. DNA methylation is suggested to be a fundamental mechanism for the neuronal responses to environmental cues. We prepared whole particle of PM2.5 (PM2.5), water-soluble extracts (Pw), organic extracts (Po) and carbon core component (Pc) and characterized their chemical constitutes. We found that PM2.5 induced significant redox imbalance, decreased the levels of intercellular methyl donor S-adenosylmethionine and caused global DNA hypomethylation. Furthermore, PM2.5 exposure triggered gene-specific promoter DNA hypo- or hypermethylation and abnormal mRNA expression of autism candidate genes. PM2.5-induced DNA hypermethylation in promoter regions of synapse related genes were associated with the decreases in their mRNA and protein expression. The inhibiting effects of antioxidative reagents, a methylation-supporting agent and a DNA methyltransferase inhibitor demonstrated the involvement of redox/methylation mechanism in PM2.5-induced abnormal DNA methylation patterns and synaptic protein expression. The biological effects above generally followed a sequence of PM2.5 ≥ Pwo > Po > Pw > Pc. Our results implicated a novel epigenetic mechanism for the neurodevelopmental toxicity of particulate air pollution, and that eliminating the chemical components could mitigate the neurotoxicity of PM2.5.

  19. Redox/methylation mediated abnormal DNA methylation as regulators of ambient fine particulate matter-induced neurodevelopment related impairment in human neuronal cells.

    Wei, Hongying; Liang, Fan; Meng, Ge; Nie, Zhiqing; Zhou, Ren; Cheng, Wei; Wu, Xiaomeng; Feng, Yan; Wang, Yan

    2016-09-14

    Fine particulate matter (PM2.5) has been implicated as a risk factor for neurodevelopmental disorders including autism in children. However, the underlying biological mechanism remains unclear. DNA methylation is suggested to be a fundamental mechanism for the neuronal responses to environmental cues. We prepared whole particle of PM2.5 (PM2.5), water-soluble extracts (Pw), organic extracts (Po) and carbon core component (Pc) and characterized their chemical constitutes. We found that PM2.5 induced significant redox imbalance, decreased the levels of intercellular methyl donor S-adenosylmethionine and caused global DNA hypomethylation. Furthermore, PM2.5 exposure triggered gene-specific promoter DNA hypo- or hypermethylation and abnormal mRNA expression of autism candidate genes. PM2.5-induced DNA hypermethylation in promoter regions of synapse related genes were associated with the decreases in their mRNA and protein expression. The inhibiting effects of antioxidative reagents, a methylation-supporting agent and a DNA methyltransferase inhibitor demonstrated the involvement of redox/methylation mechanism in PM2.5-induced abnormal DNA methylation patterns and synaptic protein expression. The biological effects above generally followed a sequence of PM2.5 ≥ Pwo > Po > Pw > Pc. Our results implicated a novel epigenetic mechanism for the neurodevelopmental toxicity of particulate air pollution, and that eliminating the chemical components could mitigate the neurotoxicity of PM2.5.

  20. Dopamine and glucose, obesity and Reward Deficiency Syndrome

    Kenneth eBlum

    2014-09-01

    Full Text Available Obesity and many well described eating disorders are accurately considered a global epidemic. The consequences of Reward Deficiency Syndrome, a genetic and epigenetic phenomena that involves the interactions of powerful neurotransmitters, are impairments of brain reward circuitry, hypodopaminergic function and abnormal craving behavior. Numerous sound neurochemical and genetic studies provide strong evidence that food addiction is similar to psychoactive drug addiction. Important facts which could translate to potential therapeutic targets espoused in this review include: 1 brain dopamine (DA production and use is stimulated by consumption of alcohol in large quantities or carbohydrates bingeing; 2 in the mesolimbic system the enkephalinergic neurons are in close proximity, to glucose receptors; 3 highly concentrated glucose activates the calcium channel to stimulate dopamine release from P12 cells; 4 blood glucose and cerebrospinal fluid concentrations of homovanillic acid, the dopamine metabolite, are significantly correlated and 5 2-deoxyglucose the glucose analogue, in pharmacological doses associates with enhanced dopamine turnover and causes acute glucoprivation. Evidence from animal studies and human fMRI support the hypothesis that multiple, but similar brain circuits are disrupted in obesity and drug dependence and DA-modulated reward circuits are involved in pathologic eating behaviors. Treatment for addiction to glucose and drugs alike, based on a consensus of neuroscience research, should incorporate dopamine agonist therapy, in contrast to current theories and practices that use dopamine antagonists. Until now, powerful dopamine-D2 agonists have failed clinically, due to chronic down regulation of D2 receptors instead, consideration of novel less powerful D2 agonists that up-regulate D2 receptors seems prudent. We encourage new strategies targeted at improving DA function in the treatment and prevention of obesity a subtype of

  1. Urine - abnormal color

    ... medlineplus.gov/ency/article/003139.htm Urine - abnormal color To use the sharing features on this page, please enable JavaScript. The usual color of urine is straw-yellow. Abnormally colored urine ...

  2. The feasibility study of screening of metabolic syndrome and impaired glucose regulation in overweight and obese children and adolescents using blood glucose meter.%用血糖仪筛查不同年龄段儿童青少年代谢综合征和糖调节异常的可行性

    彭易清; 梁晶晶; 李珍宇; 聂伟明

    2011-01-01

    Objective To evaluate the feasibility of MS and TGR screening in overweight and obese children and adolescents by measuring the FGB and 2hBG using the blood glucose meter and automatic biochemistry analyzer. Methods From May to October 2010, 6096 middle school students aged 7 to 18 in city of Donguan were censured. The fingertip fasting capillary glucose was screened by blood glucose meter. Students who met any abnormal indexes were included in MS group. On the basis of voluntary principle, 557 male students and 541 female students, who conformed to MS, were assigned into overweight group (Ob); while 469 male health students and 446 female health students were assigned into normal control (NC) group. FCBG, FBG, 2hCBG, 2hBG and Fins were measured at the same time. Subgroup analysis was carried out according to different age groups (7 - l0ys, 11 - 14ys and 14 - 18ys). Results 1. Significant impairments were revealed with striating analysis according to different age groups and genders in systolic pressure, diastolic pressure, FCBG, FBG, 2hCBG, 2hBG, CIFG, IFC, CIGT, CT, Fins, IR and IS in Ob group, comparing with those in NC group ( P < 0. 05 ). Although significantly higher detection rate of IFC was revealed in fingertip blood than that in vein blood, lower detection rate of IGT was found. IFC prevalence was higher in male than female by 20 and 12% at the age of 7 - l0ys and 11 - 14ys, respectively, in Ob group. However, no difference was revealed in IFG prevalence between male and female with age of 15 - 18ys in Ob group. 2. No significant difference was revealed in IFG or IGT detection between fingertip blood and venous screenings in male or female groups ( P > 0. 05 ). Conclusion Screening of metabolic syndrome and the impaired glucose regulation situation in overweight and obese in children and adolescents is feasible.%目的 分析用血糖仪筛查不同年龄段儿童青少年代谢综合征(MS)和糖调节异常(IGR)的可行性.方法 根据志

  3. 非编码 RNA 与肝脏糖脂代谢调控%Noncoding RNA in the Regulation of Hepatic Glucose and Lipid Metabolism

    杨卫利; 王君佩; 崔庆华; 杨吉春

    2016-01-01

    In the past decades,diabetes,in particular type 2 diabetes (T2D)mainly characterized by global insulin resistance and pancreatic beta cell failure,had become epidemic and a severe public health threat worldwide with the development of economy and change of lifestyle.The interactions between envi-ronment factors and genetic background play vital roles in the development and progression of T2D.More recently,it had been revealed that non-coding RNA including microRNA (miRNA)and long noncoding RNA (LncRNA)are widely involved inthe regulation of glucose and lipid metabolism.So far,it had been established that deregulated miRNA and LncRNA profile in main metabolic tissues is tightly associ-ated with T2D,and intensive studies on non-coding RNAs had shed light on understanding the pathogen-esis of T2D.The current review aimed to briefly summarize and discuss the latest findings regarding the role and mechanism of miRNAs and LncRNAs in the regulation hepatic glucose and lipid metabolism.%随着经济的迅速发展、人们饮食习惯的改变和身体活动的减少,糖尿病成为了现代社会的非传染性的流行病,给家庭和社会造成了极大的危害和经济负担。其中以全身性胰岛素抵抗及胰岛功能衰竭为主要发病特征的2型糖尿病(type 2 diabetes,T2D)已在世界范围引起广泛关注。T2D的发生发展涉及许多组织及糖代谢的各个环节,遗传因素和环境因素共同引起的糖脂代谢通路任一环节的失调均可导致 T2D 的发生。近年来,包括 microRNA (miRNA)及长非编码 RNA (Ln-cRNA)在内的非编码 RNA(ncRNA)的发现及其在人体生理和病理生理过程中的重要调控作用不断被揭示,为进一步了解 T2D 的发病机制注入了新理念和信息。miRNAs 及 LncRNAs 的表达具有组织特异性,其表达水平的异常通常与疾病相关。本文主要对 miRNAs 和 LncRNAs 在肝脏糖脂代谢调控及 T2D 的发生发展中的作用及

  4. Novel targeted nuclear imaging agent for gastric cancer diagnosis: glucose-regulated protein 78 binding peptide-guided 111In-labeled polymeric micelles

    Cheng CC

    2013-04-01

    Full Text Available Chun-Chia Cheng,1,2,* Chiung-Fang Huang,3,4,* Ai-Sheng Ho,5 Cheng-Liang Peng,6 Chun-Chao Chang,7,8 Fu-Der Mai,1,9 Ling-Yun Chen,10 Tsai-Yueh Luo,2 Jungshan Chang1,11,121Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, 2Institute of Nuclear Energy Research, Atomic Energy Council, Taoyuan, 3School of Dental Technology, Taipei Medical University, Taipei, 4Division of Family and Operative Dentistry, Department of Dentistry, Taipei Medical University Hospital, Taipei, 5Division of Gastroenterology, Cheng Hsin General Hospital, Taipei, 6Institute of Biomedical Engineering, National Taiwan University, Taipei, 7Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, 8Department of Internal Medicine, Taipei Medical University, Taipei, 9Department of Biochemistry, Taipei Medical University, Taipei, 10Institute of Biochemistry and Biotechnology, Chung Shan Medical University, Taichung, 11Neuroscience Research Center, Taipei Medical University Hospital, Taipei, 12Research Center for Biomedical Implants and Microsurgery Devices, Taipei Medical University, Taipei, Taiwan*These authors contributed equally to this workAbstract: Increased expression of cellular membrane bound glucose-regulated protein 78 (GRP78 is considered to be one of the biomarkers for gastric cancers. Therefore, peptides or molecules with specific recognition to GRP78 can act as a guiding probe to direct conjugated imaging agents to localized cancers. Based on this rationale, GRP78-guided polymeric micelles were designed and manufactured for nuclear imaging detection of tumors. Thiolated GRP78 binding peptide (GRP78BP was first labeled with maleimide-terminated poly(ethylene glycol–poly(ε-caprolactone and then mixed with diethylenetriaminepentaacetic acid (DTPA-linked poly(ethylene glycol–poly(ε-caprolactone to form DTPA/GRP78BP-conjugated micelles. The coupling efficiency of micelles with

  5. Potassium-3-beta-hydroxy-20-oxopregn-5-en-17-alpha-yl sulfate: a novel inhibitor of 78 kDa glucose-regulated protein

    Mhaidat NM

    2016-02-01

    Full Text Available Nizar M Mhaidat,1,2 Qosay A Al-Balas,1 Karem H Alzoubi,1 Rowan F AlEjielat2 1Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, 2Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Hashemite University, Zarqa, Jordan Background: Previous studies have shown the central role of 78 kDa glucose-regulated protein (GRP78 in colorectal cancer (CRC survival and chemoresistance. In the present study, we aimed to design a GRP78 inhibitor and test its potential to inhibit CRC cells growth. Materials and methods: Computer-aided drug design was used to establish novel compounds as potential inhibitors of GRP78. Discovery Studio 3.5 software was used to evaluate a series of designed compounds and assess their mode of binding to the active site of the protein. The cytotoxicity of the designed compounds was evaluated using the MTT assay and the propidium iodide method. The effect of the inhibitor on the expression of GRP78 was evaluated by immunoblotting. Results: Among the designed compounds, only potassium-3-beta-hydroxy-20-oxopregn-5-en-17-alpha-yl sulfate (PHOS has a potential to inhibit the growth of CRC cells. Inhibition of cellular growth was largely attributed to downregulation of GRP78 and induction of apoptotic cell death. Conclusion: These results introduce PHOS as a promising GRP78 inhibitor that could be used in future studies as a combination with chemotherapy in the treatment of CRC patients. Our ongoing studies aim to characterize PHOS safety profile as well as its mechanism of action. Keywords: UPR, apoptosis, GRP78, CRC, chemotherapy, computer-aided drug design (CADD

  6. Expression of the 78 kD glucose-regulated protein is induced by endoplasmic reticulum stress in development of hepatopulmonary syndrome

    Zhang, Huiying; Lv, Minli; Jia, Jiantao; Zhao, Zhongfu; Zhang, Lili; Lai, Lina; Wu, Yanjun; Li, Baohong; Li, Chen; Liu, Yan; Li, Xujiong; Tian, Xiaoxia; Pang, Hui; Guo, Jianhong; Wang, Limin; Fan, Yimin; Zhang, Cuiying; Ji, Jingquan; Han, Dewu; Ji, Cheng

    2014-01-01

    Objective This study is to explore the role of 78 kD glucose-regulated protein (GRP78) in development of hepatopulmonary syndrome (HPS) in rats. Methods The rat model of liver cirrhosis and HPS were induced with multiple pathogenic factors. Hematoxylin and eosin (H & E) staining was performed to detect the pathological changes of the lung and liver tissues. The levels of alanine transferase (ALT), endotoxin, and tumor necrosis factor-α (TNF-α) in plasma and TNF-α and malondialdehyde (MDA) in lung tissues were detected. RT-PCR and Western blotting were conducted to detect the mRNA and protein expression levels of GRP78 in lungs. Results The plasma endotoxin level was gradually increased as HPS developed, and the mRNA and protein expression levels of GRP78 in lungs were also increased as the disease progressed. The levels of ALT and TNF-α in plasma and the contents of TNF-α and MDA in lung tissues were gradually increased along with the disease progression, with a strong positive correlation. Compared with controls, the plasma TNF-α level and the mRNA and protein expression levels of GRP78 in lung tissues were significantly higher in rats with HPS. The levels of endotoxin and ALT in plasma and the level of MDA in lungs were significantly higher in rats with HPS than controls. Conclusions The increased GRP78 expression is indicative of endoplasmic reticulum stress response during HPS, which may play an important role in the disease pathogenesis. PMID:24334118

  7. Increased expression of 78 kD glucose-regulated protein promotes cardiomyocyte apoptosis in a rat model of liver cirrhosis

    Zhang, Lili; Zhang, Huiying; Lv, Minli; Jia, Jiantao; Fan, Yimin; Tian, Xiaoxia; Li, Xujiong; Li, Baohong; Ji, Jingquan; Wang, Limin; Zhao, Zhongfu; Han, Dewu; Ji, Cheng

    2015-01-01

    Aims: This study was to investigate the role and underlying mechanism of 78 kD glucose-regulated protein (GRP78) in cardiomyocyte apoptosis in a rat model of liver cirrhosis. Methods: A rat model of liver cirrhosis was established with multiple pathogenic factors. A total of 42 male SD rats were randomly divided into the liver cirrhosis group and control group. Cardiac structure analysis was performed to assess alterations in cardiac structure. Cardiomyocytes apoptosis was detected by TdT-mediated dUTP nick end labeling method. Expression of GRP78, CCAAT/enhancer-binding protein homologous protein (CHOP), caspase-12, nuclear factor kappa-light-chain-enhancer of activated B cells p65 subunit (NF-κB p65) and B cell lymphoma-2 (Bcl-2) was detected by immunohistochemical staining. Results: The ratios of left ventricular wall thickness to heart weight and heart weight to body weight were significantly increased with the progression of liver cirrhosis (P < 0.05). Apoptosis index of cardiomyocytes was significantly increased with the progression of liver cirrhosis (P < 0.05). The expression levels of GRP78, CHOP and caspase-12 were significantly increased in the progression of liver cirrhosis (P < 0.05). The expression levels of NF-κB p65 and Bcl-2 were highest in the 4-wk liver cirrhosis, and they were decreased in the 6-wk and 8-wk in the progression of liver cirrhosis. GRP78 expression levels were positively correlated with apoptosis index, CHOP and caspase-12 expression levels (P < 0.05). CHOP expression levels were negatively correlated with NF-κB p65 and Bcl-2 expression levels (P < 0.05). Conclusion: Increased expression of GRP78 promotes cardiomyocyte apoptosis in rats with cirrhotic cardiomyopathy. PMID:26464674

  8. Glucose-regulated protein 78 may play a crucial role in promoting the pulmonary microvascular remodeling in a rat model of hepatopulmonary syndrome

    Zhang, Huiying; Lv, Minli; Zhao, Zhongfu; Jia, Jiantao; Zhang, Lili; Xiao, Peng; Wang, Limin; Li, Chen; Ji, Jingquan; Tian, Xiaoxia; Li, Xujiong; Fan, Yimin; Lai, Lina; Liu, Yan; Li, Baohong; Zhang, Cuiying; Liu, Mingshe; Guo, Jianhong; Han, Dewu; Ji, Cheng

    2015-01-01

    Objective This study is to investigate the role of glucose-regulated protein 78 (GRP78) in the pulmonary microvascular remodeling during hepatopulmonary syndrome (HPS) development. Methods The rat models with liver cirrhosis and HPS were induced by multiple pathogenic factors for 4 to 8 wk. The concentrations of alanine transferase (ALT) and endotoxin in plasma were detected in the models, followed by the detection of GRP78 expression. RT-PCR, quantitative real-time PCR and Western blotting were employed to assess the mRNA and protein expression levels of vascular endothelial growth factor (VEGF), respectively. Immunohistochemistry staining was used to examine the expression of a specific vascular marker, factor VIII-related antigen (FVIII-RAg), and several cell proliferation- and apoptosis-related proteins, including CHOP/GADD153, caspase-12, Bcl-2 and nuclear factor (NF)-κB. Results The levels of endotoxin and ALT in plasma were gradually increased as the disease progressed, so did GRP78, which were in a positive correlation. The expression levels of VEGF (both mRNA and protein) and FVIII-RAg were significantly elevated in the HPS models, indicating active angiogenesis, which was also positively correlated with GRP78 expression. Furthermore, the expression levels of the pro-apoptotic proteins of CHOP/GADD153 and caspase-12 were dramatically decreased, while the anti-apoptotic proteins of Bcl-2 and NF-κB were significantly elevated, in the HPS models. There were also close correlations between these proteins and GRP78. Conclusions Over-expression of GRP78 in lungs may be the critical pathogenic factor for HPS. Through promoting cell proliferation and survival and inhibiting apoptosis, GRP78 may promote the pulmonary microvascular remodeling in HPS pathogenesis. Our results provide a potential therapeutic target for clinical prevention and treatment for HPS and related complications. PMID:24768185

  9. Abnormal apoptosis of trophoblastic cells is related to the up-regulation of CYP11A gene in placenta of preeclampsia patients.

    Guolin He

    Full Text Available Abnormal placenta trophoblast proliferation and apoptosis is related to the pathogenesis of preeclampsia. Emerging evidence has also indicated that key pregnancy-associated hormones, such as hCG, progesterone, are found in high concentration at the maternal-fetal interface. The purpose of this study was to investigate the expression of CYP11A, a key enzyme in steroid hormone synthesis and metabolism, in normal pregnancy and severe preeclampsia placenta and to explore the underlying mechanism of the relationship between the altered CYP11A expression and onset of preeclampsia. Immunohistochemistry method was used to study the localization of CYP11A-encoded protein P450scc in the placenta; reverse transcription polymerase chain reaction (RT-PCR and Western blotting were used to examine CYP11A expression at mRNA and protein levels in patients with severe preeclampsia and normal placental tissue. CYP11A overexpression in trophoblastic cells was used to evaluate the effect on viability. TUNEL staining was used to determine whether overexpression of CYP11A could affect trophoblastic cell apoptosis. The results showed that CYP11A was selectively expressed in the cytoplasm of the placental trophoblastic cells. CYP11A expression were significantly increased in severe preeclampsia compared with normal pregnancy in both mRNA and protein levels. Multiple regression analysis indicated that CYP11A gene expression was positively correlated to ALT level and Plt, while negatively correlated to INR. Overexpression of CYP11A reduced trophoblastic cell proliferation and induced HTR8/SVneo cells apoptosis through activation of activated caspase-3 expression. These results suggest that abnormally high expression of CYP11A inhibits trophoblastic proliferation and increases apoptosis and therefore could be involved in the pathogenesis of preeclampsia.

  10. Continuous glucose monitoring, oral glucose tolerance, and insulin - glucose parameters in adolescents with simple obesity.

    El Awwa, A; Soliman, A; Al-Ali, M; Yassin, M; De Sanctis, V

    2012-09-01

    In obese adolescents pancreatic beta-cells may not be able to cope with insulin resistance leading to hyperglycemia and type2 diabetes (T2DM To assess oral glucose tolerance, 72-h continuous blood glucose concentrations (CGM) and calculate homeostatic model assessment (HOMA), and the quantitative insulin sensitivity check index (QUICKI) in 13 adolescents with simple obesity (BMI SDS=4 ± 1.06). OGTT performed in 13 obese adolescents (13.47 ± 3 years) revealed 3 cases (23%) with impaired fasting glucose (IFG: fasting glucose >5.6 mmol/L), 4 cases (30%) with impaired glucose tolerance (IGT: 2h blood glucose >7.8 7.8 and 11.1 mmol/L (diabetes) in one case (7.6%). Five cases had a minimum BG recorded of 2.6 and QUICKI values <0.35 denoting insulin resistance. Beta cell mass percent (B %) = 200 ± 94.8% and insulin sensitivity values (IS)=50.4 ± 45.5% denoted insulin resistance with hyper-insulinaemia and preserved beta cell mass. In obese adolescents, CGMS is superior to OGTT and HbA1C in detecting glycemic abnormalities, which appears to be secondary to insulin resistance.

  11. Development of evaluation tool for the risk level of abnormal glucose metabolism morbidity in middle-aged and elder populations%中老年人群糖代谢异常患病危险度评估工具的开发研究

    黄晓波; 黄斌; 魏东; 曾伟; 欧阳凌云; 刘雅; 栾荣生; 张廷杰; 徐俊波; 赵思勤; 李秀钧

    2010-01-01

    目的 研究开发适合中老年人群的糖代谢异常患病危险度评估工具.方法 于2008年4至11月采用分层整群抽样的方法,在成都城乡地区40~79岁中老年人口中开展问卷调查,并进行血压、空腹血糖、葡萄糖75 g餐后血糖、血脂、血尿酸、身高、体质量、腰围等检测,共获取有效调查资料5205份.进行判别分析及多因素Logistic回归分析,建立量化评分体系,ROC分析筛选量化评分体系的界点,336例体检人群验证简易评分模型判别效能.结果 判别分析男女模型准确度分别为79.04%和81.35%.年龄、工作体力强度、体育锻炼、家族史、兄弟姐妹糖尿病史、体质指数、腹型肥胖和高血压病史8个指标构成男性简易评分模型;年龄、工作体力强度、体育锻炼、家族史、兄弟姐妹糖尿病史、体质指数、腹型肥胖、高血压病史、分娩次数和妊娠糖尿病史构成女性简易评分模型.ROC曲线下面积男性模型为0.702,女性模型为0.728.在其他人群应用中男性模型灵敏度和特异度分别为86.86%和65.12%,女性模型灵敏度和特异度分别为88.89%和72.97%.结论 初步开发的中老年人群糖代谢异常患病危险度评估工具简便可行,有一定实用性,可应用于中老年人群糖代谢异常的筛查.%Objective To develop the evaluation tool for the risk level of abnormal glucose metabolism morbidity in the middle-aged and elder populations. Methods By the stratified cluster sampling method, a survey was conducted in middle-aged and elder populations aged 40 -70 years old in urban and rural areas of Chengdu during April-November 2008. The parameters included blood pressure, fasting blood glucose, blood glucose after oral administration of 75 g glucose, blood lipid, blood uric acid, height, body weight and waistline, etc. A total of 5205 valid copies of questionnaires were obtained. A discriminant analysis and a multifactorial logistic regression

  12. Up-regulation of the mammalian target of rapamycin complex 1 subunit Raptor by aldosterone induces abnormal pulmonary artery smooth muscle cell survival patterns to promote pulmonary arterial hypertension.

    Aghamohammadzadeh, Reza; Zhang, Ying-Yi; Stephens, Thomas E; Arons, Elena; Zaman, Paula; Polach, Kevin J; Matar, Majed; Yung, Lai-Ming; Yu, Paul B; Bowman, Frederick P; Opotowsky, Alexander R; Waxman, Aaron B; Loscalzo, Joseph; Leopold, Jane A; Maron, Bradley A

    2016-07-01

    Activation of the mammalian target of rapamycin complex 1 (mTORC1) subunit Raptor induces cell growth and is a downstream target of Akt. Elevated levels of aldosterone activate Akt, and, in pulmonary arterial hypertension (PAH), correlate with pulmonary arteriole thickening, which suggests that mTORC1 regulation by aldosterone may mediate adverse pulmonary vascular remodeling. We hypothesized that aldosterone-Raptor signaling induces abnormal pulmonary artery smooth muscle cell (PASMC) survival patterns to promote PAH. Remodeled pulmonary arterioles from SU-5416/hypoxia-PAH rats and monocrotaline-PAH rats with hyperaldosteronism expressed increased levels of the Raptor target, p70S6K, which provided a basis for investigating aldosterone-Raptor signaling in human PASMCs. Aldosterone (10(-9) to 10(-7) M) increased Akt/mTOR/Raptor to activate p70S6K and increase proliferation, viability, and apoptosis resistance in PASMCs. In PASMCs transfected with Raptor-small interfering RNA or treated with spironolactone/eplerenone, aldosterone or pulmonary arterial plasma from patients with PAH failed to increase p70S6K activation or to induce cell survival in vitro Optimal inhibition of pulmonary arteriole Raptor was achieved by treatment with Staramine-monomethoxy polyethylene glycol that was formulated with Raptor-small interfering RNA plus spironolactone in vivo, which decreased arteriole muscularization and pulmonary hypertension in 2 experimental animal models of PAH in vivo Up-regulation of mTORC1 by aldosterone is a critical pathobiologic mechanism that controls PASMC survival to promote hypertrophic vascular remodeling and PAH.-Aghamohammadzadeh, R., Zhang, Y.-Y., Stephens, T. E., Arons, E., Zaman, P., Polach, K. J., Matar, M., Yung, L.-M., Yu, P. B., Bowman, F. P., Opotowsky, A. R., Waxman, A. B., Loscalzo, J., Leopold, J. A., Maron, B. A. Up-regulation of the mammalian target of rapamycin complex 1 subunit Raptor by aldosterone induces abnormal pulmonary artery smooth

  13. Effect of impaired glucose tolerance on cardiac dysfunction in a rat model of prediabetes

    LIANG Jia-liang; FENG Zhi-kuan; LIU Xiao-ying; LIN Qiu-xiong; FU Yong-heng; SHAN Zhi-xin; ZHU Jie-ning; LIN Shu-guang; YU Xi-yong

    2011-01-01

    Background The effect of impaired glucose tolerance (IGT) on cardiac function during the chronic prediabetes state is complicated and plays an important role in clinical outcome. However, the molecular mechanisms are not fully understood. This study was designed to observe cardiac dysfunction in prediabetic rats with IGT and to determine whether glucose metabolic abnormalities, inflammation and apoptosis are linked to it.Methods The IGT rat models were induced by streptozocin, and the heart functions were assessed by echocardiography.Myocardial glucose metabolism was analyzed by glycogen periodic acid-Schiff staining, and the pro-apoptotic effect of IGT was evaluated by TUNEL staining. Additionally, caspase-3 activation, macrophage migration inhibitory factor (MIF) and G-protein coupled receptor kinase 2 (GRK2) were detected by Western blotting in cardiac tissue lysates.Results Area-under-the-curve of blood glucose in rats injected with streptozotocin was higher than that in controls,increased by 16.28%, 38.60% and 38.61% at 2, 4 and 6 weeks respectively (F=15.370, P=0.003). Abnormal cardiac functions and apoptotic cardiomyocytes were observed in the IGT rats, the ejection fraction (EF) being (68.59±6.62)% in IGT rats vs. (81.07±4.59)% in controls (t=4.020, P=0.002). There was more glucose which was converted to glycogen in the myocardial tissues of IGT rats, especially in cardiac perivascular tissues. Compared to controls, the cleaved caspase-3, MIF and GRK2 were expressed at higher levels in the myocardial tissues of IGT rats.Conclusions IGT in the prediabetes period resulted in cardiac dysfunction linked to abnormal glycogen storage and apoptosis. Additionally, MIF and GRK2 may be involved in the pathogenesis of cardiac dysfunction in prediabetes and their regulation may contribute to the design of novel diagnostic and therapeutic strategies for those who have potential risks for diabetic cardiovascular complications.

  14. Glucose metabolism and hyperglycemia.

    Giugliano, Dario; Ceriello, Antonio; Esposito, Katherine

    2008-01-01

    Islet dysfunction and peripheral insulin resistance are both present in type 2 diabetes and are both necessary for the development of hyperglycemia. In both type 1 and type 2 diabetes, large, prospective clinical studies have shown a strong relation between time-averaged mean values of glycemia, measured as glycated hemoglobin (HbA1c), and vascular diabetic complications. These studies are the basis for the American Diabetes Association's current recommended treatment goal that HbA1c should be regulation is accompanied by a significant improvement of many pathways supposed to be involved in diabetic complications, including oxidative stress, endothelial dysfunction, inflammation, and nuclear factor-kappaB activation. The goal of therapy should be to achieve glycemic status as near to normal as safely possible in all 3 components of glycemic control: HbA1c, fasting glucose, and postmeal glucose peak.

  15. Computational Analysis of AMPK-Mediated Neuroprotection Suggests Acute Excitotoxic Bioenergetics and Glucose Dynamics Are Regulated by a Minimal Set of Critical Reactions.

    Niamh M C Connolly

    Full Text Available Loss of ionic homeostasis during excitotoxic stress depletes ATP levels and activates the AMP-activated protein kinase (AMPK, re-establishing energy production by increased expression of glucose transporters on the plasma membrane. Here, we develop a computational model to test whether this AMPK-mediated glucose import can rapidly restore ATP levels following a transient excitotoxic insult. We demonstrate that a highly compact model, comprising a minimal set of critical reactions, can closely resemble the rapid dynamics and cell-to-cell heterogeneity of ATP levels and AMPK activity, as confirmed by single-cell fluorescence microscopy in rat primary cerebellar neurons exposed to glutamate excitotoxicity. The model further correctly predicted an excitotoxicity-induced elevation of intracellular glucose, and well resembled the delayed recovery and cell-to-cell heterogeneity of experimentally measured glucose dynamics. The model also predicted necrotic bioenergetic collapse and altered calcium dynamics following more severe excitotoxic insults. In conclusion, our data suggest that a minimal set of critical reactions may determine the acute bioenergetic response to transient excitotoxicity and that an AMPK-mediated increase in intracellular glucose may be sufficient to rapidly recover ATP levels following an excitotoxic insult.

  16. Human β Cell Transcriptome Analysis Uncovers lncRNAs That Are Tissue-Specific, Dynamically Regulated, and Abnormally Expressed in Type 2 Diabetes

    Morán, Ignasi; Akerman, İldem; van de Bunt, Martijn; Xie, Ruiyu; Benazra, Marion; Nammo, Takao; Arnes, Luis; Nakić, Nikolina; García-Hurtado, Javier; Rodríguez-Seguí, Santiago; Pasquali, Lorenzo; Sauty-Colace, Claire; Beucher, Anthony; Scharfmann, Raphael; van Arensbergen, Joris; Johnson, Paul R; Berry, Andrew; Lee, Clarence; Harkins, Timothy; Gmyr, Valery; Pattou, François; Kerr-Conte, Julie; Piemonti, Lorenzo; Berney, Thierry; Hanley, Neil A; Gloyn, Anna L; Sussel, Lori; Langman, Linda; Brayman, Kenneth L; Sander, Maike; McCarthy, Mark I.; Ravassard, Philippe; Ferrer, Jorge

    2012-01-01

    SUMMARY A significant portion of the genome is transcribed as long non-coding RNAs (lncRNAs), several of which are known to control gene expression. The repertoire and regulation of lncRNAs in disease-relevant tissues, however, has not been systematically explored. We report a comprehensive strand-specific transcriptome map of human pancreatic islets and β-cells, and uncover >1100 intergenic and antisense islet-cell lncRNA genes. We find islet lncRNAs that are dynamically regulated, and show that they are an integral component of the β-cell differentiation and maturation program. We sequenced the mouse islet transcriptome, and identify lncRNA orthologs that are regulated like their human counterparts. Depletion of HI-LNC25, a β-cell specific lncRNA, downregulated GLIS3 mRNA, thus exemplifying a gene regulatory function of islet lncRNAs. Finally, selected islet lncRNAs were dysregulated in type 2 diabetes or mapped to genetic loci underlying diabetes susceptibility. These findings reveal a new class of islet-cell genes relevant to β-cell programming and diabetes pathophysiology. PMID:23040067

  17. Maternal low-protein diet up-regulates the neuropeptide Y system in visceral fat and leads to abdominal obesity and glucose intolerance in a sex- and time-specific manner.

    Han, Ruijun; Li, Aiyun; Li, Lijun; Kitlinska, Joanna B; Zukowska, Zofia

    2012-08-01

    Neuropeptide Y (NPY) mediates stress-induced obesity in adult male mice by activating its Y2 receptor (Y2R) in visceral adipose tissue (VAT). Here, we studied whether the NPY-Y2R system is also activated by maternal low-protein diet (LPD) and linked to obesity in offspring. Prenatal LPD offspring had lower birth weights compared to normal-protein diet (NPD) offspring. Female prenatal and lactation stress (PLS) offspring from mothers fed an LPD developed abdominal adiposity and glucose intolerance associated with a 5-fold up-regulation of NPY mRNA and a 6-fold up-regulation of Y2R mRNA specifically in VAT, in addition to elevated platelet-rich-plasma (PRP) NPY, compared to control females fed a high-fat diet (HFD). Conversely, PLS male offspring showed lower NPY in PRP, a 10-fold decrease of Y2R mRNA in VAT, lower adiposity, and improved glucose tolerance compared to control males. Interestingly, prenatal LPD offspring cross-fostered to control lactating mothers had completely inverse metabolic and NPY phenotypes. Taken together, these findings suggested that maternal LPD activates the VAT NPY-Y2R system and increases abdominal adiposity and glucose intolerance in a sex- and time-specific fashion, suggesting that the peripheral NPY system is a potential mediator of programming for the offspring's vulnerability to obesity and metabolic syndrome.

  18. Correlation between the amplitude of glucose excursion and plasma 8-iso prostaglandin F2α level in subjects with different types of glucose regulation%不同糖调节者血糖波动与血浆8-异前列腺素F2α水平的相关性研究

    郑芬萍; 王舟; 李红; 贾程芳; 张楠; 袁红娣

    2009-01-01

    Objective To investigate the effect of glucose excursion on oxidative stress that is expressed by plasma 8-isu prostaglandin F2α (8-iso) level. Methods Continuous glucose monitory system (CGMS) was used to calculate the mean amplitude of glycemic excursion (MAGE), mean blood glucose (MBG) and its standard deviation (SDBG), mean 1 h preprandial glucose value (1 h-prePG) and 3 h post-prandial glucose value (3 h PPG) over 24 h period, area under the ROC curve when the blood glucose within 24 h > 5.6 mmol/L (AUC 5.6), mean of daily differences (MODD), and mean postprandial glucose excursion (MPPGE) on 33 individuals with normal glucose regulation (NGR), 25 subjects with impaired glucose regulation (IGR), and 25 patients with newly diagnosed type 2 diabetes mellitus (T2DM) for 3 days. Plasma 8-iso level was determined by EIA. Results The plasma 8-iso level of the T2DM patients was 230 ng/L, significantly higher than that of the subjects with IGR (199 ng/L, P5.6 mmol/L的曲线下而积(AUC 5.6)、日内血糖波动幅度(MAGE)、日内平均餐后血糖漂移幅度(MPPGE)及日间血糖平均绝对差(MODD).结果 (1)T2DM组血浆8-iso水平中位数为230 ng/L,高于IGR(199 ng/L,P<0.05)和NGR组(156ng/L,P<0.01);(2)T2DM组糖化血红蛋白(HbAlc)、MBG、SDBG、24 h各时段平均血糖、AUC5.6、MAGE、MPPGE和MODD均高于IGR组(P<0.05,0.01),IGR组的上述指标高于NGR组(P<0.05,0.01);(3)血浆8-iso水平(对数)与MAGE(r=0.747,P=0.00)、SDBG(r=0.691,P=0.00)、MPPGE(r=0.615,P=0.00)、MBG(r=0.562,P=0.0)、AUC5.6、MODD、24 h各时段平均血糖及HbAlc(r=0.463,P=0.00)呈正相关;以血浆8-iso水平为应变量,MAGE、MBG和SDBG进入多元线性回归模型(R2=0.55,P<0.05),MAGE为影响血浆8-iso水平的最主要因素(r=0.694,P=0.000).结论 IGR和T2DM患者存在明显的日内和日间血糖波动,氧化应激增加;日内血糖波动对氧化应激的作用强于持续高血糖.

  19. 不同糖调节受损状态对早期动脉粥样硬化的影响%Association between different impaired glucose regulation and the early-stage arteriosclerosis

    赵静; 梁军; 窦连军; 龚莹; 腾飞

    2012-01-01

    目的:探讨糖尿病前期不同血糖水平对颈-股动脉脉搏波传导速度(carotid-to-femoral pulse wave velocity,c-f PWV)的影响.方法:对5 098例非糖尿病者的空腹血糖、口服葡萄糖耐量试验2小时血糖 (2-hour oral glucose tolerance test,2h OGTT)、糖化血红蛋白(hemoglobin A1c,HbA1c)和c-f PWV水平进行分析.结果:空腹血糖受损(impaired fasting glucose,IFG)组、糖耐量受损 (impaired glucose tolerance,IGT)组和高HbA1c组与糖耐量正常组的c-f PWV差异分别为0.97 m/s、1.08 m/s 和 0.92 m/s,差异有统计学意义(P<0.01).高HbA1c合并IFG、高HbA1c合并IGT的c-f PWV明显高于单纯高HbA1c(P=0.036,P=0.03).IFG合并高HbA1c、IGT合并高HbA1c的c-f PWV明显高于单纯IFG 和单纯IGT (P=0.02,P=0.04).结论:c-f PWV水平与糖尿病前期相关联,并独立于其他代谢因素.IFG合并高HbA1c、IGT合并高HbA1c对c-f PWV水平的影响呈叠加效应,提示糖尿病前期不同糖调节受损状态均可引起血管弹性的改变,导致早期动脉粥样硬化发生.%Objective: To explore the associations of glucose exposure and carotid-to-femoral pulse wave velocity ( c-f PWV ) in prediabetes adults. Methods: Fasting plasma glucose, 2-hour oral glucose tolerance test ( 2h OGTT ), hemoglobin Alc( HbAlc ) and c-f PWV were analysed in 5 098 non-diabetes subjects. Results: We found that the differences in c-f PWV between individuals with impaired fasting glucose ( IFG ), impaired glucose tolerance ( IGT ), high HbAlc and those without these abnormalities were 0. 97 m/s, 1. 08 m/s and 0. 92 m/s ( P <0. 01 ). In addition, our data indicated that individuals of both high HbAlc and IFG or IGT had significantly higher levels of c-f PWV compared with those who only had high HbAl c ( P = 0. 036 and 0. 03 , respectively ); or those only had IFG ( P - 0. 02 ); or only had IGT ( P = 0.04 ). Conclusion: c-f PWV was associated with prediabetes, independent of metabolic risk factors. We found that individuals of

  20. Loss of arylformamidase with reduced thymidine kinase expression leads to impaired glucose tolerance

    Alison J. Hugill

    2015-11-01

    Full Text Available Tryptophan metabolites have been linked in observational studies with type 2 diabetes, cognitive disorders, inflammation and immune system regulation. A rate-limiting enzyme in tryptophan conversion is arylformamidase (Afmid, and a double knockout of this gene and thymidine kinase (Tk has been reported to cause renal failure and abnormal immune system regulation. In order to further investigate possible links between abnormal tryptophan catabolism and diabetes and to examine the effect of single Afmid knockout, we have carried out metabolic phenotyping of an exon 2 Afmid gene knockout. These mice exhibit impaired glucose tolerance, although their insulin sensitivity is unchanged in comparison to wild-type animals. This phenotype results from a defect in glucose stimulated insulin secretion and these mice show reduced islet mass with age. No evidence of a renal phenotype was found, suggesting that this published phenotype resulted from loss of Tk expression in the double knockout. However, despite specifically removing only exon 2 of Afmid in our experiments we also observed some reduction of Tk expression, possibly due to a regulatory element in this region. In summary, our findings support a link between abnormal tryptophan metabolism and diabetes and highlight beta cell function for further mechanistic analysis.

  1. Abnormal Regulation of Ubiquitin-Proteasome Pathway in Chronic Alcoholism%慢性酒精中毒性疾病与泛素-蛋白酶体途径异常调节的研究

    杨海玉(综述); 刘勇(审校)

    2014-01-01

    Ubiquitin-proteasome pathway is the main way for intracellular protein degradation and plays an important role in a variety of cellular processes.Studies have confirmed that chronic alcoholism leads to abnormal regulation of ubiquitin-proteasome pathway involving alterations of proteasome activity,ubiquitin synthesis and related protein expression.Moreover,the abnormal regulation of ubiquitin-proteasome pathway is correlated with the pathogenesis of chronic alcohol-ic diseases,including alcoholic liver disease,alcoholic encephalopathy and alcoholic myopathy. These findings provide an important research direction for further revealing the molecular mecha-nisms of alcohol-induced tissue inj uries and developing new drugs for the treatment of chronic al-coholic diseases.%泛素-蛋白酶体途径是细胞内蛋白质降解的主要途径,在多种细胞生命过程中发挥重要作用。目前研究证实慢性酒精中毒可导致泛素-蛋白酶体途径异常调节,主要涉及蛋白酶体活性、泛素分子合成以及相关蛋白分子表达改变等,并且与一些慢性酒精中毒性疾病的发生有关,包括酒精中毒性肝病、酒精中毒性脑病和酒精中毒性肌病。这些发现为进一步揭示酒精诱导损伤的分子机制以及研发治疗慢性酒精中毒性疾病的新型药物提供了重要的研究方向。

  2. No Islet Cell Hyperfunction, but Altered Gut-Islet Regulation and Postprandial Hypoglycemia in Glucose-Tolerant Patients 3 Years After Gastric Bypass Surgery

    Dirksen, Carsten; Eiken, Aleksander; Bojsen-Møller, Kirstine N

    2016-01-01

    Postprandial hyperinsulinemia characterizes Roux-en-Y gastric bypass (RYGB) and sometimes leads to reactive hypoglycemia. We prospectively evaluated changes in beta cell function in seven RYGB-operated patients with a median follow-up of 2.9 years with hyperglycemic clamps and oral glucose tolera...

  3. Inhibitors of Fatty Acid Synthesis Induce PPAR α -Regulated Fatty Acid β -Oxidative Genes: Synergistic Roles of L-FABP and Glucose.

    Huang, Huan; McIntosh, Avery L; Martin, Gregory G; Petrescu, Anca D; Landrock, Kerstin K; Landrock, Danilo; Kier, Ann B; Schroeder, Friedhelm

    2013-01-01

    While TOFA (acetyl CoA carboxylase inhibitor) and C75 (fatty acid synthase inhibitor) prevent lipid accumulation by inhibiting fatty acid synthesis, the mechanism of action is not simply accounted for by inhibition of the enzymes alone. Liver fatty acid binding protein (L-FABP), a mediator of long chain fatty acid signaling to peroxisome proliferator-activated receptor- α (PPAR α ) in the nucleus, was found to bind TOFA and its activated CoA thioester, TOFyl-CoA, with high affinity while binding C75 and C75-CoA with lower affinity. Binding of TOFA and C75-CoA significantly altered L-FABP secondary structure. High (20 mM) but not physiological (6 mM) glucose conferred on both TOFA and C75 the ability to induce PPAR α transcription of the fatty acid β -oxidative enzymes CPT1A, CPT2, and ACOX1 in cultured primary hepatocytes from wild-type (WT) mice. However, L-FABP gene ablation abolished the effects of TOFA and C75 in the context of high glucose. These effects were not associated with an increased cellular level of unesterified fatty acids but rather by increased intracellular glucose. These findings suggested that L-FABP may function as an intracellular fatty acid synthesis inhibitor binding protein facilitating TOFA and C75-mediated induction of PPAR α in the context of high glucose at levels similar to those in uncontrolled diabetes.

  4. AMP-Activated Protein Kinase Plays an Important Evolutionary Conserved Role in the Regulation of Glucose Metabolism in Fish Skeletal Muscle Cells

    Magnoni, L.J.; Vraskou, Y.; Palstra, A.P.; Planas, J.V.

    2012-01-01

    AMPK, a master metabolic switch, mediates the observed increase of glucose uptake in locomotory muscle of mammals during exercise. AMPK is activated by changes in the intracellular AMP:ATP ratio when ATP consumption is stimulated by contractile activity but also by AICAR and metformin, compounds tha

  5. Hereditary urea cycle abnormality

    ... vitro so the specific genetic cause is known. Teamwork between parents, the affected child, and doctors can help prevent severe illness. Alternative Names Abnormality of the urea cycle - hereditary; Urea cycle - hereditary abnormality Images Male urinary system Urea cycle References Lichter-Konecki ...

  6. 糖代谢异常对原发性高血压患者动脉粥样硬化及血压的影响%Roles of impaired glucose metabolism in the pathologic process of atherosclerosis and abnormal fluctuation of blood pressure in essential hypertension patients

    王钢

    2015-01-01

    目的探讨糖代谢异常(IGM)在原发性高血压(EH)患者动脉粥样硬化(AS)病变及动态血压异常中的作用。方法选取46例单纯 EH 及36例合并2型糖尿病(T2DM)的 EH 患者,对比分析两组患者的血糖、血脂、血尿酸、纤维蛋白原等代谢参数及颈动脉 AS 病变与24 h 动态血压参数的差异,然后对合并 T2DM 的 EH 患者颈动脉内膜中层厚度(CIMT)与血糖代谢参数,以及 CIMT 与动态血压参数之间的相关性进行分析。结果合并 T2DM 的 EH 患者体质量指数(BMI)、空腹血糖(FBG)、餐后2 h 血糖(2 h PBG)、糖化血红蛋白(HbA1 c)、三酰甘油(TG)、总胆固醇(TC)、低密度脂蛋白胆固醇脂(LDL-C)、载脂蛋白 B(apo-B)、尿酸、纤维蛋白原浓度等代谢参数均显著高于单纯 EH 患者(P 0.05)。 Pearson 相关分析显示,在合并 T2DM 的 EH 患者中,其 CIMT 与 FPG (r =0.418, P =0.011)、HbA1 c(r =0.719,P 0.05);而动态血压参数中24 h-mSBP(r =0.414,P =0.012)、dmSBP(r =0.422,P =0.01)、nmSBP(r =0.372,P =0.026)及24 h-mPP(r =0.639,P 0.05)。结论糖代谢异常可与其他心血管疾病(CVD)危险因素协同作用,加重 EH 患者 AS 病变,进而导致血压波动异常。因此,改善这些 EH 患者的糖代谢状态可降低其心脑血管疾病并发症的危险。%Objective To explore the roles of impaired glucose metabolism (IGM) in the pathologic process of atherosclerosis (AS) and abnormal fluctuation of blood pressure in the essential hypertension (EH) patients. Methods Patients with simple EH (n = 46) and with EH combined with type 2 diabetes mellitus (T2DM) (n =36) were enrolled in the study. We conducted comparisons on the meta-bolic parameters [such as blood glucose, blood lipids, body mass index (BMI), serum uric acid (UA) and fibrinogen (Fib), along with detection of atherosclerotic plaques as well as ambulatory blood pressure (ABP)] between the two groups of patients, and then ana-lyzed the correlation in the patients

  7. [Prevalence of abnormal glucose tolerance in hypertensive patients].

    Rubio-Guerra, Alberto Francisco; Rodríguez-López, Leticia; Lozano-Nuevo, José Juan; Vargas-Ayala, German; Beltrán-Soto, José Martín; Durán-Salgado, Montserrat Berenice

    2014-01-01

    Introducción: la hipertensión arterial y la diabetes mellitus tipo 2 tienden a coexistir en el mismo paciente. La hiperglucemia postprandial de dos horas es un predictor de enfermedad cardiovascular. Nuestro objetivo fue investigar la prevalencia de tolerancia a la glucosa alterada en sujetos hipertensos con glucosa de ayuno normal. Métodos: se incluyeron 65 pacientes hipertensos no diabéticos y con glucosa plasmática de ayuno glucosa. Resultados: encontramos tolerancia a la glucosa alterada en 32 pacientes (49.2 %), 29 en rango de intolerancia a la glucosa y tres casos en rango de diabetes mellitus. No hallamos relación entre glucosa postprandial con cifras de presión arterial ni con la edad, pero sí una correlación significativa entre intolerancia a la glucosa e índice de masa corporal > 32.6 (R = 0.59, p glucosa alterada, particularmente aquellos con índice de masa corporal aumentado, y que la glucosa de ayuno no es suficiente como prueba de monitoreo para diabetes mellitus tipo 2 en ese tipo de pacientes.

  8. Short-term reproducibility of impaired fasting glycaemia, impaired glucose tolerance and diabetes The ADDITION study, DK

    Rasmussen, S S; Glümer, C; Sandbæk, Annelli;

    2007-01-01

    BG) individuals with impaired fasting glycaemia (IFG), impaired glucose tolerance (IGT) and diabetes had a second test done after 14 days. Intra-individual coefficients of variation (CV) were estimated in each glucose tolerance class using the approximation CV(2)(x)=var(ln(x)). Bland-Altman plots with limits...... of agreement were made. In the total population, the CV(intra) was 7.9% and 13.8% for FBG and 2hBG, respectively. Limits of agreement ranged from -1.15 to 1.67mmol/l for FBG and from - 2.62 to 3.27mmol/l for 2hBG. One individual with IFG and 22.5% with IGT had diabetes at the second test, 76.1% with diabetes...... persistently classified with abnormal glucose regulation; diabetes was confirmed in 76% of the cases. Udgivelsesdato: 2007-Dec-12...

  9. Prader-Willi Critical Region, a Non-Translated, Imprinted Central Regulator of Bone Mass: Possible Role in Skeletal Abnormalities in Prader-Willi Syndrome.

    Ee-Cheng Khor

    Full Text Available Prader-Willi Syndrome (PWS, a maternally imprinted disorder and leading cause of obesity, is characterised by insatiable appetite, poor muscle development, cognitive impairment, endocrine disturbance, short stature and osteoporosis. A number of causative loci have been located within the imprinted Prader-Willi Critical Region (PWCR, including a set of small non-translated nucleolar RNA's (snoRNA. Recently, micro-deletions in humans identified the snoRNA Snord116 as a critical contributor to the development of PWS exhibiting many of the classical symptoms of PWS. Here we show that loss of the PWCR which includes Snord116 in mice leads to a reduced bone mass phenotype, similar to that observed in humans. Consistent with reduced stature in PWS, PWCR KO mice showed delayed skeletal development, with shorter femurs and vertebrae, reduced bone size and mass in both sexes. The reduction in bone mass in PWCR KO mice was associated with deficiencies in cortical bone volume and cortical mineral apposition rate, with no change in cancellous bone. Importantly, while the length difference was corrected in aged mice, consistent with continued growth in rodents, reduced cortical bone formation was still evident, indicating continued osteoblastic suppression by loss of PWCR expression in skeletally mature mice. Interestingly, deletion of this region included deletion of the exclusively brain expressed Snord116 cluster and resulted in an upregulation in expression of both NPY and POMC mRNA in the arcuate nucleus. Importantly, the selective deletion of the PWCR only in NPY expressing neurons replicated the bone phenotype of PWCR KO mice. Taken together, PWCR deletion in mice, and specifically in NPY neurons, recapitulates the short stature and low BMD and aspects of the hormonal imbalance of PWS individuals. Moreover, it demonstrates for the first time, that a region encoding non-translated RNAs, expressed solely within the brain, can regulate bone mass in health

  10. Abnormal glycometabolism in tumor cells%肿瘤细胞的异常糖代谢

    孙洁; 孟祥军

    2013-01-01

    The abnormal glucose metabolism of tumor cells is associated with a variety of mechanisms.Hypoxia inducible factor (HIF) is able to activate the glycolytic enzymes,which is conducive to getting energy through glycolysis.The dysfunction or the depletion in numbers of mitochondria can inhibit the oxidative phosphorylation pathway of glucose to some extent.The activation of oncogenes and the inactivation of tumor suppressor genes are also involved in the regulation of mitochondrial respiratory chain and glycolytic enzymes,thus affecting the process of glucose metabolism.Compared with normal cells,the synthesis of oxidative phosphorylation enzymes is inhibited in cancer cells.In addition,the abnormal glucose metabolism plays an important role in the growth,invasion and metastasis of tumor cells.%肿瘤细胞糖代谢异常与多种机制有关,如缺氧诱导因子(HIF)的参与可激活糖酵解相关酶类,有利于肿瘤细胞采取糖酵解方式获能;线粒体功能低下或数量减少可一定程度抑制葡萄糖氧化磷酸化途径;某些癌基因的激活及抑癌基因的失活也参与调节线粒体氧化呼吸链及糖酵解相关酶类,从而影响糖代谢过程;肿瘤细胞氧化磷酸化的相关酶类合成受到抑制等.此外,糖代谢异常对肿瘤细胞的生长、侵袭和转移具有重要作用.

  11. Low Blood Glucose (Hypoglycemia)

    ... Disease, & Other Dental Problems Diabetes & Sexual & Urologic Problems Low Blood Glucose (Hypoglycemia) What is hypoglycemia? Hypoglycemia, also called low blood glucose or low blood sugar, occurs when ...

  12. ATF3 expression is induced by low glucose in pancreatic α and β cells and regulates glucagon but not insulin gene transcription.

    Lee, Yong-Soo; Kobayashi, Masaki; Kikuchi, Osamu; Sasaki, Tsutomu; Yokota-Hashimoto, Hiromi; Susanti, Vina Yanti; Ido Kitamura, Yukari; Kitamura, Tadahiro

    2014-01-01

    The pancreas is critical for maintaining glucose homeostasis. Activating transcription factor 3 (ATF3) is an adaptive response transcription factor. There are major discrepancies in previous reports on pancreatic ATF3; therefore, its role in the pancreas is unclear. To better elucidate the role of ATF3 in the pancreas, we conducted in vitro studies using pancreatic α and β cell lines, and also evaluated the use of ATF3 antibodies for immunohistochemistry. We determined ATF3 expression was increased by low glucose and decreased by high glucose in both αTC-1.6 and βTC3 cells. We also showed that adenovirus-mediated ATF3 overexpression increased glucagon promoter activity and glucagon mRNA levels in αTC-1.6 cells; whereas, it had no effect on insulin promoter activity and insulin mRNA levels in βTC3 cells. Although immunostaining with the C-19 ATF3 antibody demonstrated predominant expression in α cells rather than β cells, ATF3 staining was still detected in ATF3 knockout mice as clearly as in control mice. On the other hand, another ATF3 antibody (H-90) detected ATF3 in both α cells and β cells, and was clearly diminished in ATF3 knockout mice. These results indicate that previous discrepancies in ATF3 expression patterns in the pancreas were caused by the varying specificities of the ATF3 antibodies used, and that ATF3 is actually expressed in both α cells and β cells.

  13. 黄芪调节糖尿病患者血糖稳态作用的研究进展%The research progress of astragalus in regulating blood glucose steady state of diabetes patients

    沙雯君; 陆灏

    2015-01-01

    糖尿病因其日益增高的患病率、较高的致残率和致死率引起社会及医学界的广泛重视,控制血糖可提高糖尿病患者的生存质量。而强化的降糖治疗往往引发低血糖,反复低血糖可致血糖逆向调节障碍,表现为血糖波动较大,阻碍患者血糖趋于正常。黄芪具有控制血糖、减少低血糖、改善胰岛素抵抗的作用,现就黄芪在血糖调节机制中的研究进展进行综述。%In recent decades, the mortality and morbidity of diabetes have increased such that it is becoming a major worldwide public health problem. Intensive blood glucose control could significantly raise the patients life and their survival quality nevertheless it develops hypoglycaemia. Repeated hypoglycemia leads to glucose conterregulate deficiencyand hamper reaching glucose target goals. Astragalus, a traditional Chinese herb used in diabetic therapy for thousands years, has also proven its glucose counterregulationeffect on preventing hypoglycemia. Here, we summarize its glycemic regulation mechanism in different extracts. It is projected that the efficacy and safety of astragalus extracts will be proven in clinical trials and animal experiments in future, and this herb extract might be known as a new class of anti-diabetic drug without hypolycemia danger.

  14. "Jeopardy" in Abnormal Psychology.

    Keutzer, Carolin S.

    1993-01-01

    Describes the use of the board game, Jeopardy, in a college level abnormal psychology course. Finds increased student interaction and improved application of information. Reports generally favorable student evaluation of the technique. (CFR)

  15. Chromosomal Abnormalities in ADHD

    J Gordon Millichap

    2002-07-01

    Full Text Available The prevalence of fragile X syndrome, velocardiofacial syndrome (VCFS, and other cytogenetic abnormalities among 100 children (64 boys with combined type ADHD and normal intelligence was assessed at the NIMH and Georgetown University Medical Center.

  16. Abnormal menstrual periods (image)

    ... may have a variety of causes, such as endometrial hyperplasia, endometrial polyps, uterine fibroids, and abnormal thyroid or ... the endometrium becomes unusually thick it is called endometrial ... Hyperplasia may cause profuse or extended menstrual bleeding.

  17. Chromosomal abnormalities and autism

    Farida El-Baz

    2016-01-01

    Conclusion: Chromosomal abnormalities were not detected in the studied autistic children, and so the relation between the genetics and autism still needs further work up with different study methods and techniques.

  18. Abnormal protein aggregationand neurodegenerativediseases

    2001-01-01

    Abnormal protein aggregation or amyloid is the major cause ofmany neurodegenerative disorders. The present review focuses on the correlation between sequence and structure features of proteins related to the diseases and abnormal protein aggregation. Recent progress has improved our knowledge on understand-ing the mechanism of amyloid formation. We suggest a nucleation model for ordered protein aggregation, which can also explain pathogenesis mechanisms of these neurodegenerative diseases in vivo.

  19. Identification of Isn1 and Sdt1 as glucose- and vitamin-regulated nicotinamide mononucleotide and nicotinic acid mononucleotide [corrected] 5'-nucleotidases responsible for production of nicotinamide riboside and nicotinic acid riboside.

    Bogan, Katrina L; Evans, Charles; Belenky, Peter; Song, Peng; Burant, Charles F; Kennedy, Robert; Brenner, Charles

    2009-12-11

    Recently, we discovered that nicotinamide riboside and nicotinic acid riboside are biosynthetic precursors of NAD(+), which are utilized through two pathways consisting of distinct enzymes. In addition, we have shown that exogenously supplied nicotinamide riboside is imported into yeast cells by a dedicated transporter, and it extends replicative lifespan on high glucose medium. Here, we show that nicotinamide riboside and nicotinic acid riboside are authentic intracellular metabolites in yeast. Secreted nicotinamide riboside was detected with a biological assay, and intracellular levels of nicotinamide riboside, nicotinic acid riboside, and other NAD(+) metabolites were determined by a liquid chromatography-mass spectrometry method. A biochemical genomic screen indicated that three yeast enzymes possess nicotinamide mononucleotide 5'-nucleotidase activity in vitro. Metabolic profiling of knock-out mutants established that Isn1 and Sdt1 are responsible for production of nicotinamide riboside and nicotinic acid riboside in cells. Isn1, initially classified as an IMP-specific 5'-nucleotidase, and Sdt1, initially classified as a pyrimidine 5'-nucleotidase, are additionally responsible for dephosphorylation of pyridine mononucleotides. Sdt1 overexpression is growth-inhibitory to cells in a manner that depends on its active site and correlates with reduced cellular NAD(+). Expression of Isn1 protein is positively regulated by the availability of nicotinic acid and glucose. These results reveal unanticipated and highly regulated steps in NAD(+) metabolism.

  20. 儿童及青少年肥胖症糖脂代谢异常早期诊断和干预的研究%Research into abnormal glucose and lipid metabolism in early diagnosis and intervention in obese children and adolescents.

    穆亚平; 韩萍; 辛颖; 赵方; 马洪刚; 刘立旻; 李娜; 王岩; 李玢; 关丽君; 李书琴

    2011-01-01

    Objective To explore the relationship between obesity and glucose and lipid metabolism , and the damage of the related target organs such as liver and heart in order to take early intervention. Methods Totally 516 children with simple obesity made up obesity group, 100 normal-weight children as a control group. Detect the fasting plasma glucose (FPC) , triglyceride (TC) , total cholesterol (TC) , alanine aminotransferase (ALT) , fasting insulin (FINS) and other projects; calculate the insulin resistance index (HOMA-IR) and insulin value of f$-cell function (HOMA-p ) ; oral glucose tolerance test (OGTT) and insulin release test were done in obese children; perform liver and heart ultrasonogra-phy in all children. Results Obese children's systolic and diastolic blood pressure were higher than the control group (P< 0.05) .hypertension was detected in 12.0% (62/516)of obese children; the FBG, FINS, HOMA-IR and HOMA-B of obese children were higher than the control group (P < 0.05) ; the TC, TC, LDL-C were higher than the control group, while HDL-C lower than the control group, the differences being significant (P < 0.05) ; the incidence of fatty liver of the light moderate and severe groups were significantly different (P < 0.001). With the increase of the obesity degree, fatty liver was significantly increased ( X2 = 12.97, P < 0.001). External fat thickness of the pericardium increasedin 268 cases of obese group, external fat thickness of the pericardium being 3.372 ± 0.098 (mm) ;compared with the control group the difference was significant (P < 0.001). Early joint intervention was done in 97 MS pa-tients, including dieting and increasing physical activity, combined with oral metformin drugs,and the FINS and HDL-C improvement was of significant difference (P < 0.001) .Conclusion The risk of hypertension in obese children is higher than non-obese children.Abnormal glucose metabolism is more comman in obese children than in non-obese children; children with mild

  1. 二甲双胍和吡格列酮对初诊糖代谢异常伴腹型肥胖患者血清ghrelin水平的影响%Effects of metformin and pioglitazone on plasma ghrelin in patients with newly diagnosed abnormal glucose metabolism and abdominal obesity

    张淼; 郭毅飞; 时立新; 吴丹荣; 张松; 胡颖; 徐毅; 林巧

    2012-01-01

    Objective To investigate the effects of metformin and pioglitazone on plasma ghrelin in patients with newly diagnosed abnormal glucose metabolism and abdominal obesity.Methods From April to September 2010,39 patients with abnormal glucose metabolism (including impaired glucose tolerance and newly diagnosed type diabetes mellitus,glycated hemoglobin A1c(HbA1c) <7% ) and obesity were enrolled in the study.They were randomly assigned to metformin group(500 mg tid,n =20,15 females and 5 males,aged (51±9) years,MET group) or pioglitazone group (30 mg/d,n =19,11 females and 8 males,aged (53 ±7) years,PIO group) on the basis of diet and exercise therapy for3 months.Three males in PIO group with drawed because of itching and edema.At baseline and after 3 months,plasma glucose,serum insulin and ghrelin levels during oral glucose tolerance test( OGTT,0 min,0.5,1.0,2.0,3.0 h),body weight,body mass index(BMI),HbA1c,etc were measured.The t test or Wilcoxon rank-sum test was used for statistical analysis. Partial correlation and multiple regression analysis were performed to examine the association between serum ghrelin levels and influencing factors.Results ( 1 ) In PIO group,serum ghrelin levels after treatment were OGTT 0 min (1069 ±467)ng/L,0.5 h (898 ±407)ng/L,1.0 h (812 ±371) ng/L,2.0 h (705 ± 328) ng/L and 3.0 h ( 1059 ± 606 ) ng/L,respectively.All increased than those before treatment ( (905 ±449),(688 ±378),(614 ±358),(572 ± 334)and(720 ±403)ng/L,Z value was from -2.354 to - 3.351,respectively,all P < 0.05 ).(2) In MET group,serum ghrelin levels at OGTT 0 min,1.0,2.0,3.0 h after treatment were (731 ± 241 ),(642 ± 208 ),( 525 ± 195 ),(462 ± 146 ) and ( 611 ± 267 ) ng/L,respectively.Compared with the ghrelin levels before treatment( (731 ± 241 ),(642 ± 208 ),(525 ± 195 ),(462 ± 146) and (611 ± 267)ng/L),only the difference at 0 min,2.0,3.0 h was statistically significant (all P<0.05).Serum ghrelin levels of MET group at OGTT 0.5,1.0 and 3.0 h

  2. Fish oil supplemented for 9 months does not improve glycaemic control or insulin sensitivity in subjects with impaired glucose regulation: a parallel randomised controlled trial.

    Clark, Louise F; Thivierge, M C; Kidd, Claire A; McGeoch, Susan C; Abraham, Prakash; Pearson, Donald W M; Horgan, Graham W; Holtrop, Grietje; Thies, Frank; Lobley, Gerald E

    2016-01-14

    The effects of fish oil (FO) supplementation on glycaemic control are unclear, and positive effects may occur only when the phospholipid content of tissue membranes exceeds 14% as n-3 PUFA. Subjects (n 36, thirty-three completed) were paired based on metabolic parameters and allocated into a parallel double-blind randomised trial with one of each pair offered daily either 6 g of FO (3·9 g n-3 PUFA) or 6 g of maize oil (MO) for 9 months. Hyperinsulinaemic-euglycaemic-euaminoacidaemic (HIEGEAA) clamps (with [6,6 2H2 glucose]) were performed at the start and end of the intervention. Endogenous glucose production (EGP) and whole-body protein turnover (WBPT) were each measured after an overnight fast. The primary outcome involved the effect of oil type on insulin sensitivity related to glycaemic control. The secondary outcome involved the effect of oil type on WBPT. Subjects on FO (n 16) had increased erythrocyte n-3 PUFA concentrations >14%, whereas subjects on MO (n 17) had unaltered n-3 PUFA concentrations at 9%. Type of oil had no effect on fasting EGP, insulin sensitivity or total glucose disposal during the HIEGEAA clamp. In contrast, under insulin-stimulated conditions, total protein disposal (P=0·007) and endogenous WBPT (P=0·001) were both increased with FO. In an associated pilot study (n 4, three completed), although n-3 PUFA in erythrocyte membranes increased to >14% with the FO supplement, th