Pregestational diabetes with extreme insulin resistance: use of U-500 insulin in pregnancy.

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Zuckerwise, Lisa C; Werner, Erika F; Pettker, Christian M; McMahon-Brown, Erin K; Thung, Stephen F; Han, Christina S

2012-08-01

Increased insulin requirements in pregnancy can hinder attainment of glycemic control in diabetic patients. U-500 insulin is a concentrated form of regular insulin that can be a valuable tool in the treatment of patients with severe insulin resistance. A 24-year-old woman with pregestational diabetes mellitus experienced increasing insulin requirements during pregnancy, peaking at 650 units daily. The frequent, large-volume injections of standard-concentration insulin were poorly tolerated by the patient and resulted in nonadherence. She subsequently achieved glycemic control on thrice-daily U-500 insulin. Pregnancy exacerbates insulin resistance in diabetic patients, and these patients may require high doses of insulin. U-500 insulin is an effective alternative for patients with severe insulin resistance and should be considered for pregnant women with difficulty achieving glycemic control.

Parity and increased risk of insulin resistance in postmenopausal women: the 2010 Korean National Health and Nutrition Examination Survey.

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Kim, Jin Hwi; Lee, Sung Jong

2017-07-01

The objective of this study was to assess the association between parity and insulin resistance in nondiabetic, postmenopausal women. This cross-sectional study was conducted using data from the 2010 Korean National Health and Nutrition Examination Survey administered by the Korean Ministry of Health and Welfare. A total of 1,243 nondiabetic postmenopausal women were included in this study and subdivided into three groups according to parity (1-2, 3-4, and ≥5 live births). Insulin resistance was measured using the homeostasis model assessment of insulin resistance (HOMA-IR) index. The relationship between parity and insulin resistance was investigated using analysis of covariance. HOMA-IR showed a positive relationship with parity. Mean HOMA-IR (geometric mean and 95% CI) increased according to increasing parity group (1-2, 3-4, and ≥5 live births) after adjustment for age, smoking, alcohol consumption, exercise, education, income, and body mass index as follows: 2.1 (2.0-2.2) insulin resistance was accompanied by obesity. The mean parity of the obese and insulin-resistant group was significantly higher than that of the nonobese insulin-sensitive group (3.6 ± 0.1 vs 3.2 ± 0.1, P = 0.047). Our study provides the first evidence that parity is significantly associated with insulin resistance in nondiabetic postmenopausal women. Further prospective longitudinal studies are needed to confirm the impact of parity on insulin resistance.

Insulin Resistance of Puberty.

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Kelsey, Megan M; Zeitler, Philip S

2016-07-01

Puberty is a time of considerable metabolic and hormonal change. Notably, puberty is associated with a marked decrease in insulin sensitivity, on par with that seen during pregnancy. In otherwise healthy youth, there is a nadir in insulin sensitivity in mid-puberty, and then it recovers at puberty completion. However, there is evidence that insulin resistance (IR) does not resolve in youth who are obese going into puberty and may result in increased cardiometabolic risk. Little is known about the underlying pathophysiology of IR in puberty, and how it might contribute to increased disease risk (e.g., type 2 diabetes). In this review, we have outlined what is known about the IR in puberty in terms of pattern, potential underlying mechanisms and other mediating factors. We also outline other potentially related metabolic changes that occur during puberty, and effects of underlying insulin resistant states (e.g., obesity) on pubertal changes in insulin sensitivity.

Serum Insulin, Glucose, Indices of Insulin Resistance, and Risk of Lung Cancer.

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Argirion, Ilona; Weinstein, Stephanie J; Männistö, Satu; Albanes, Demetrius; Mondul, Alison M

2017-10-01

Background: Although insulin may increase the risk of some cancers, few studies have examined fasting serum insulin and lung cancer risk. Methods: We examined serum insulin, glucose, and indices of insulin resistance [insulin:glucose molar ratio and homeostasis model assessment of insulin resistance (HOMA-IR)] and lung cancer risk using a case-cohort study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study of Finnish men. A total of 196 cases and 395 subcohort members were included. Insulin and glucose were measured in fasting serum collected 5 to 12 years before diagnosis. Cox proportional hazards models were utilized to estimate the relative risk of lung cancer. Results: The average time between blood collection and lung cancer was 9.6 years. Fasting serum insulin levels were 8.7% higher in subcohort members than cases. After multivariable adjustment, men in the fourth quartile of insulin had a significantly higher risk of lung cancer than those in the first quartile [HR = 2.10; 95% confidence interval (CI), 1.12-3.94]. A similar relationship was seen with HOMA-IR (HR = 1.83; 95% CI, 0.99-3.38). Risk was not strongly associated with glucose or the insulin:glucose molar ratio ( P trend = 0.55 and P trend = 0.27, respectively). Conclusions: Higher fasting serum insulin concentrations, as well as the presence of insulin resistance, appear to be associated with an elevated risk of lung cancer development. Impact: Although insulin is hypothesized to increase risk of some cancers, insulin and lung cancer remain understudied. Higher insulin levels and insulin resistance were associated with increased lung cancer risk. Although smoking cessation is the best method of lung cancer prevention, other lifestyle changes that affect insulin concentrations and sensitivity may reduce lung cancer risk. Cancer Epidemiol Biomarkers Prev; 26(10); 1519-24. ©2017 AACR . ©2017 American Association for Cancer Research.

Metabolism and insulin signaling in common metabolic disorders and inherited insulin resistance.

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Højlund, Kurt

2014-07-01

Type 2 diabetes, obesity and polycystic ovary syndrome (PCOS) are common metabolic disorders which are observed with increasing prevalences, and which are caused by a complex interplay between genetic and environmental factors, including increased calorie intake and physical inactivity. These metabolic disorders are all characterized by reduced plasma adiponectin and insulin resistance in peripheral tissues. Quantitatively skeletal muscle is the major site of insulin resistance. Both low plasma adiponectin and insulin resistance contribute to an increased risk of type 2 diabetes and cardiovascular disease. In several studies, we have investigated insulin action on glucose and lipid metabolism, and at the molecular level, insulin signaling to glucose transport and glycogen synthesis in skeletal muscle from healthy individuals and in obesity, PCOS and type 2 diabetes. Moreover, we have described a novel syndrome characterized by postprandial hyperinsulinemic hypoglycemia and insulin resistance. This syndrome is caused by a mutation in the tyrosine kinase domain of the insulin receptor gene (INSR). We have studied individuals with this mutation as a model of inherited insulin resistance. Type 2 diabetes, obesity and PCOS are characterized by pronounced defects in the insulin-stimulated glucose uptake, in particular glycogen synthesis and to a lesser extent glucose oxidation, and the ability of insulin to suppress lipid oxidation. In inherited insulin resistance, however, only insulin action on glucose uptake and glycogen synthesis is impaired. This suggests that the defects in glucose and lipid oxidation in the common metabolic disorders are secondary to other factors. In young women with PCOS, the degree of insulin resistance was similar to that seen in middle-aged patients with type 2 diabetes. This supports the hypothesis of an unique pathogenesis of insulin resistance in PCOS. Insulin in physiological concentrations stimulates glucose uptake in human skeletal

Insulin resistance: vascular function and exercise

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Moon-Hyon Hwang

2016-09-01

Full Text Available Insulin resistance associated with metabolic syndrome and Type 2 diabetes mellitus is an epidemic metabolic disorder, which increases the risk of cardiovascular complications. Impaired vascular endothelial function is an early marker for atherosclerosis, which causes cardiovascular complications. Both experimental and clinical studies indicate that endothelial dysfunction in vasculatures occurs with insulin resistance. The associated physiological mechanisms are not fully appreciated yet, however, it seems that augmented oxidative stress, a physiological imbalance between oxidants and antioxidants, in vascular cells is a possible mechanism involved in various vascular beds with insulin resistance and hyperglycemia. Regardless of the inclusion of resistance exercise, aerobic exercise seems to be beneficial for vascular endothelial function in both large conduit and small resistance vessels in both clinical and experimental studies with insulin resistance. In clinical cases, aerobic exercise over 8 weeks with higher intensity seems more beneficial than the cases with shorter duration and lower intensity. However, more studies are needed in the future to elucidate the physiological mechanisms by which vascular endothelial function is impaired in insulin resistance and improved with aerobic exercise.

Relationship between increased serum tumor necrosis factor levels and insulin resistance in patients with essential hypertension

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Wang Weimin; Li Jinliang; Huang Yongqiang

2010-01-01

Objective: To investigate the relationship between serum tumor necrosis factor-α (TNF-α) levels and insulin resistance (IR) in patients with essential by pertension. Methods: Serum TNF-α and free insulin (fINS)levels were measured with RIA in 41 patients with essential hypertension and 38 controls. Insulin resistance was calculated with insulin resistance index (HOMA-IR). Results: The serum TNF-α levels were significantly higher in patients with essential hypertension than those in the controls (P<0.001). The HOMA-IR was also significantly higher in hypertension group than that in controls (P<0.001). Serum TNF-α levels was positively correlated with BMI, HOMA-IR and SBP both in hypertension group and control group (P<0.05). Conclusion: Serum TNF-α level was increased in hypertensive patients and positively correlated with obesity and IR. (authors)

Insulin resistance alters islet morphology in nondiabetic humans

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Mezza, Teresa; Muscogiuri, Giovanna; Sorice, Gian Pio

2014-01-01

Type 2 diabetes is characterized by poor glucose uptake in metabolic tissues and manifests when insulin secretion fails to cope with worsening insulin resistance. In addition to its effects on skeletal muscle, liver, and adipose tissue metabolism, it is evident that insulin resistance also affects...... pancreatic β-cells. To directly examine the alterations that occur in islet morphology as part of an adaptive mechanism to insulin resistance, we evaluated pancreas samples obtained during pancreatoduodenectomy from nondiabetic subjects who were insulin-resistant or insulin-sensitive. We also compared...... insulin sensitivity, insulin secretion, and incretin levels between the two groups. We report an increased islet size and an elevated number of β- and α-cells that resulted in an altered β-cell-to-α-cell area in the insulin- resistant group. Our data in this series of studies suggest that neogenesis from...

Increased CD19+CD24+CD27+ B regulatory cells are associated with insulin resistance in patients with type I Hashimoto's thyroiditis.

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Yang, Min; Du, Changji; Wang, Yinping; Liu, Jun

2017-06-01

Hashimoto's thyroiditis (HT) is characterized by dysregulated immune responses and is commonly associated with insulin resistance. However, the mechanism of insulin resistance in HT remains to be fully elucidated. The aim of the present study was to investigate the correlation between the percentage of B regulatory lymphocytes (Bregs) and insulin resistance in patients with HT but with normal thyroid function (type I). A total of 59 patients with type I HT and 38 healthy volunteers were enrolled in the study. An oral glucose tolerance test was performed to measure insulin secretion and assess β‑cell functions. Flow cytometry was performed to examine the percentages of lymphocyte populations. The patients with HT exhibited normal fasting and postprandial glucose and fasting insulin secretion, but increased secretion of early‑phase and total insulin. The patients with HT also had insufficient β‑cell compensation for insulin resistance, indicated by a reduced disposition index, in the fasting state. An elevation in the percentage of CD19+CD24+CD27+ Bregs was also observed, which correlated positively with insulin secretion and insulin resistance in the fasting state. The patients with type I HT had postprandial insulin resistance and insufficient β‑cell compensation for fasting insulin resistance. Therefore, the increase in CD19+CD24+CD27+ Bregs was closely associated with fasting insulin secretion. These results provide novel insight into the mechanism of insulin resistance in HT.

Insulin resistance and improvements in signal transduction.

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Musi, Nicolas; Goodyear, Laurie J

2006-02-01

Type 2 diabetes and obesity are common metabolic disorders characterized by resistance to the actions of insulin to stimulate skeletal muscle glucose disposal. Insulin-resistant muscle has defects at several steps of the insulin-signaling pathway, including decreases in insulin-stimulated insulin receptor and insulin receptor substrate-1 tyrosine phosphorylation, and phosphatidylinositol 3-kinase (PI 3-kinase) activation. One approach to increase muscle glucose disposal is to reverse/improve these insulin-signaling defects. Weight loss and thiazolidinediones (TZDs) improve glucose disposal, in part, by increasing insulin-stimulated insulin receptor and IRS-1 tyrosine phosphorylation and PI 3-kinase activity. In contrast, physical training and metformin improve whole-body glucose disposal but have minimal effects on proximal insulin-signaling steps. A novel approach to reverse insulin resistance involves inhibition of the stress-activated protein kinase Jun N-terminal kinase (JNK) and the protein tyrosine phosphatases (PTPs). A different strategy to increase muscle glucose disposal is by stimulating insulin-independent glucose transport. AMP-activated protein kinase (AMPK) is an enzyme that works as a fuel gauge and becomes activated in situations of energy consumption, such as muscle contraction. Several studies have shown that pharmacologic activation of AMPK increases glucose transport in muscle, independent of the actions of insulin. AMPK activation is also involved in the mechanism of action of metformin and adiponectin. Moreover, in the hypothalamus, AMPK regulates appetite and body weight. The effect of AMPK to stimulate muscle glucose disposal and to control appetite makes it an important pharmacologic target for the treatment of type 2 diabetes and obesity.

Blueberries? Impact on Insulin Resistance and Glucose Intolerance

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Stull, April J.

2016-01-01

Blueberries are a rich source of polyphenols, which include anthocyanin bioactive compounds. Epidemiological evidence indicates that incorporating blueberries into the diet may lower the risk of developing type 2 diabetes (T2DM). These findings are supported by pre-clinical and clinical studies that have shown improvements in insulin resistance (i.e., increased insulin sensitivity) after obese and insulin-resistant rodents or humans consumed blueberries. Insulin resistance was assessed by hom...

Skeletal muscle inflammation and insulin resistance in obesity

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Wu, Huaizhu; Ballantyne, Christie M.

2017-01-01

Obesity is associated with chronic inflammation, which contributes to insulin resistance and type 2 diabetes mellitus. Under normal conditions, skeletal muscle is responsible for the majority of insulin-stimulated whole-body glucose disposal; thus, dysregulation of skeletal muscle metabolism can strongly influence whole-body glucose homeostasis and insulin sensitivity. Increasing evidence suggests that inflammation occurs in skeletal muscle in obesity and is mainly manifested by increased immune cell infiltration and proinflammatory activation in intermyocellular and perimuscular adipose tissue. By secreting proinflammatory molecules, immune cells may induce myocyte inflammation, adversely regulate myocyte metabolism, and contribute to insulin resistance via paracrine effects. Increased influx of fatty acids and inflammatory molecules from other tissues, particularly visceral adipose tissue, can also induce muscle inflammation and negatively regulate myocyte metabolism, leading to insulin resistance. PMID:28045398

C-Peptide, Baseline and Postprandial Insulin Resistance after a Carbohydrate-Rich Test Meal - Evidence for an Increased Insulin Clearance in PCOS Patients?

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Stassek, J; Erdmann, J; Ohnolz, F; Berg, F D; Kiechle, M; Seifert-Klauss, V

2017-01-01

Introduction Known characteristics of patients with PCOS include infertility, menstrual disorders, hirsutism and also often insulin resistance. These symptoms increase with increasing body weight. In the LIPCOS study ( L ifestyle I ntervention for Patients with Polycystic Ovary Syndrome [ PCOS ]) long-term changes of the PCOS in dependence on pregnancy and parenthood were systematically assessed. In the framework of the LIPCOS study, PCOS patients were given a standardised carbohydrate-rich test meal in order to examine glucose homeostasis and insulin secretion. The results were compared with those of a eumenorrhoeic control group who all had corresponding BMI values and corresponding ages. Methods and Patients 41 PCOS patients (without diabetes) and 68 controls received a standardised carbohydrate-rich test meal (260 kcal, 62 % carbohydrates, 32 % fat, 6 % proteins) in order to generate a submaximal insulin and glucose stimulation. The values were determined at baseline and postprandial after 60, 120 and 180 minutes. In addition, the corresponding C-peptide levels were recorded. Results In the PCOS patients (n = 41), the insulin secretion test after a standardised test meal showed almost identical baseline and postprandial insulin levels when compared with those of the age- and BMI-matched eumenorrhoeic controls (n = 68). In the PCOS patients, the baseline and postprandial glucose levels were significantly elevated (92.88 ± 10.28 [PCOS] vs. 85.07 ± 9.42 mg/dL [controls]; p PCOS patients formally exhibit a higher fasting insulin resistance than controls. In spite of the higher stimulated C-peptide levels, the insulin levels did not increase more strongly with increasing glucose levels than in controls which may be indicative of a higher insulin clearance in PCOS patients.

Possible increase in insulin resistance and concealed glucose-coupled potassium-lowering mechanisms during acute coronary syndrome documented by covariance structure analysis.

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Ito, Satoshi; Nagoshi, Tomohisa; Minai, Kosuke; Kashiwagi, Yusuke; Sekiyama, Hiroshi; Yoshii, Akira; Kimura, Haruka; Inoue, Yasunori; Ogawa, Kazuo; Tanaka, Toshikazu D; Ogawa, Takayuki; Kawai, Makoto; Yoshimura, Michihiro

2017-01-01

Although glucose-insulin-potassium (GIK) therapy ought to be beneficial for ischemic heart disease in general, variable outcomes in many clinical trials of GIK in acute coronary syndrome (ACS) had a controversial impact. This study was designed to examine whether "insulin resistance" is involved in ACS and to clarify other potential intrinsic compensatory mechanisms for GIK tolerance through highly statistical procedure. We compared the degree of insulin resistance during ACS attack and remission phase after treatment in individual patients (n = 104). During ACS, homeostasis model assessment of insulin resistance (HOMA-IR) values were significantly increased (Pcovariance structure analysis with a strong impact (β: 0.398, P = 0.015). Intriguingly, a higher incidence of myocardial infarction relative to unstable angina pectoris, as well as a longer hospitalization period were observed in patients with larger ΔK, indicating that ΔK also reflects disease severity of ACS. Insulin resistance most likely increases during ACS; however, ΔK was positively correlated with plasma glucose level, which overwhelmed insulin resistance condition. The present study with covariance structure analysis suggests that there are potential endogenous glucose-coupled potassium lowering mechanisms, other than insulin, regulating glucose metabolism during ACS.

Glycine Increases Insulin Sensitivity and Glutathione Biosynthesis and Protects against Oxidative Stress in a Model of Sucrose-Induced Insulin Resistance

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Mohammed El-Hafidi

2018-01-01

Full Text Available Oxidative stress and redox status play a central role in the link between insulin resistance (IR and lipotoxicity in metabolic syndrome. This mechanistic link may involve alterations in the glutathione redox state. We examined the effect of glycine supplementation to diet on glutathione biosynthesis, oxidative stress, IR, and insulin cell signaling in liver from sucrose-fed (SF rats characterized by IR and oxidative stress. Our hypothesis is that the correction of glutathione levels by glycine treatment leads to reduced oxidative stress, a mechanism associated with improved insulin signaling and IR. Glycine treatment decreases the levels of oxidative stress markers in liver from SF rats and increases the concentrations of glutathione (GSH and γ-glutamylcysteine and the amount of γ-glutamylcysteine synthetase (γ-GCS, a key enzyme of GSH biosynthesis in liver from SF rats. In liver from SF rats, glycine also decreases the insulin-induced phosphorylation of insulin receptor substrate-1 (ISR-1 in serine residue and increases the phosphorylation of insulin receptor β-subunit (IR-β in tyrosine residue. Thus, supplementing diets with glycine to correct GSH deficiency and to reduce oxidative stress provides significant metabolic benefits to SF rats by improving insulin sensitivity.

LPS-Induced Low-Grade Inflammation Increases Hypothalamic JNK Expression and Causes Central Insulin Resistance Irrespective of Body Weight Changes.

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Rorato, Rodrigo; Borges, Beatriz de Carvalho; Uchoa, Ernane Torres; Antunes-Rodrigues, José; Elias, Carol Fuzeti; Elias, Lucila Leico Kagohara

2017-07-04

Metabolic endotoxemia contributes to low-grade inflammation in obesity, which causes insulin resistance due to the activation of intracellular proinflammatory pathways, such as the c-Jun N-terminal Kinase (JNK) cascade in the hypothalamus and other tissues. However, it remains unclear whether the proinflammatory process precedes insulin resistance or it appears because of the development of obesity. Hypothalamic low-grade inflammation was induced by prolonged lipopolysaccharide (LPS) exposure to investigate if central insulin resistance is induced by an inflammatory stimulus regardless of obesity. Male Wistar rats were treated with single (1 LPS) or repeated injections (6 LPS) of LPS (100 μg/kg, IP) to evaluate the phosphorylation of the insulin receptor substrate-1 (IRS1), Protein kinase B (AKT), and JNK in the hypothalamus. Single LPS increased the expression of pIRS1, pAKT, and pJNK, whereas the repeated LPS treatment failed to recruit pIRS1 and pAKT. The 6 LPS treated rats showed increased total JNK and pJNK. The 6 LPS rats became unresponsive to the hypophagic effect induced by central insulin administration (12 μM/5 μL, ICV). Prolonged exposure to LPS (24 h) impaired the insulin-induced AKT phosphorylation and the translocation of the transcription factor forkhead box protein O1 (FoxO1) from the nucleus to the cytoplasm of the cultured hypothalamic GT1-7 cells. Central administration of the JNK inhibitor (20 μM/5 μL, ICV) restored the ability of insulin to phosphorylate IRS1 and AKT in 6 LPS rats. The present data suggest that an increased JNK activity in the hypothalamus underlies the development of insulin resistance during prolonged exposure to endotoxins. Our study reveals that weight gain is not mandatory for the development of hypothalamic insulin resistance and the blockade of proinflammatory pathways could be useful for restoring the insulin signaling during prolonged low-grade inflammation as seen in obesity.

Lipid metabolism disturbances contribute to insulin resistance and decrease insulin sensitivity by malathion exposure in Wistar rat.

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Lasram, Mohamed Montassar; Bouzid, Kahena; Douib, Ines Bini; Annabi, Alya; El Elj, Naziha; El Fazaa, Saloua; Abdelmoula, Jaouida; Gharbi, Najoua

2015-04-01

Several studies showed that organophosphorus pesticides disturb glucose homeostasis and can increase incidence of metabolic disorders and diabetes via insulin resistance. The current study investigates the influence of malathion on glucose metabolism regulation, in vivo, during subchronic exposure. Malathion was administered orally (200 mg/kg), once a day for 28 consecutive days. Plasma glucose, insulin and Glycated hemoglobin levels were significantly increased while hepatic glycogen content was decreased in intoxicated animals compared with the control group. Furthermore, there was a significant disturbance of lipid content in subchronic treated and post-treated rats deprived of malathion for one month. In addition, we used the homeostasis model assessment (HOMA) to assess insulin resistance (HOMA-IR) and pancreatic β-cell function (HOMA-β). Our results show that malathion increases insulin resistance biomarkers and decreases insulin sensitivity indices. Statistical analysis demonstrates that there was a positive and strong significant correlation between insulin level and insulin resistance indices, HOMA-IR, HOMA-β. Similarly, a negative and significant correlation was also found between insulin level and insulin sensitivity indices. For the first time, we demonstrate that malathion induces insulin resistance in vivo using homeostasis model assessment and these changes were detectable one month after the end of exposure. To explain insulin resistance induced by malathion we focus on lipid metabolism disturbances and their interaction with many proteins involved in insulin signaling pathways.

Mechanisms linking brain insulin resistance to Alzheimer's disease

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Matioli, Maria Niures P.S.; Nitrini, Ricardo

2015-01-01

Several studies have indicated that Diabetes Mellitus (DM) can increase the risk of developing Alzheimer's disease (AD). This review briefly describes current concepts in mechanisms linking DM and insulin resistance/deficiency to AD. Insulin/insulin-like growth factor (IGF) resistance can contribute to neurodegeneration by several mechanisms which involve: energy and metabolism deficits, impairment of Glucose transporter-4 function, oxidative and endoplasmic reticulum stress, mitochondrial dysfunction, accumulation of AGEs, ROS and RNS with increased production of neuro-inflammation and activation of pro-apoptosis cascade. Impairment in insulin receptor function and increased expression and activation of insulin-degrading enzyme (IDE) have also been described. These processes compromise neuronal and glial function, with a reduction in neurotransmitter homeostasis. Insulin/IGF resistance causes the accumulation of AβPP-Aβ oligomeric fibrils or insoluble larger aggregated fibrils in the form of plaques that are neurotoxic. Additionally, there is production and accumulation of hyper-phosphorylated insoluble fibrillar tau which can exacerbate cytoskeletal collapse and synaptic disconnection. PMID:29213950

Mechanisms linking brain insulin resistance to Alzheimer's disease

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Maria Niures P.S. Matioli

Full Text Available Several studies have indicated that Diabetes Mellitus (DM can increase the risk of developing Alzheimer's disease (AD. This review briefly describes current concepts in mechanisms linking DM and insulin resistance/deficiency to AD. Insulin/insulin-like growth factor (IGF resistance can contribute to neurodegeneration by several mechanisms which involve: energy and metabolism deficits, impairment of Glucose transporter-4 function, oxidative and endoplasmic reticulum stress, mitochondrial dysfunction, accumulation of AGEs, ROS and RNS with increased production of neuro-inflammation and activation of pro-apoptosis cascade. Impairment in insulin receptor function and increased expression and activation of insulin-degrading enzyme (IDE have also been described. These processes compromise neuronal and glial function, with a reduction in neurotransmitter homeostasis. Insulin/IGF resistance causes the accumulation of AβPP-Aβ oligomeric fibrils or insoluble larger aggregated fibrils in the form of plaques that are neurotoxic. Additionally, there is production and accumulation of hyper-phosphorylated insoluble fibrillar tau which can exacerbate cytoskeletal collapse and synaptic disconnection.

Selective insulin resistance in hepatocyte senescence

International Nuclear Information System (INIS)

Aravinthan, Aloysious; Challis, Benjamin; Shannon, Nicholas; Hoare, Matthew; Heaney, Judith; Alexander, Graeme J.M.

2015-01-01

Insulin resistance has been described in association with chronic liver disease for decades. Hepatocyte senescence has been demonstrated in chronic liver disease and as many as 80% of hepatocytes show a senescent phenotype in advanced liver disease. The aim of this study was to understand the role of hepatocyte senescence in the development of insulin resistance. Senescence was induced in HepG2 cells via oxidative stress. The insulin metabolic pathway was studied in control and senescent cells following insulin stimulation. GLUT2 and GLUT4 expressions were studied in HepG2 cells and human liver tissue. Further, GLUT2 and GLUT4 expressions were studied in three independent chronic liver disease cohorts. Signalling impairment distal to Akt in phosphorylation of AS160 and FoxO1 was evident in senescent HepG2 cells. Persistent nuclear localisation of FoxO1 was demonstrated in senescent cells despite insulin stimulation. Increased GLUT4 and decreased GLUT2 expressions were evident in senescent cells, human cirrhotic liver tissue and publically available liver disease datasets. Changes in GLUT expressions were associated with a poor clinical prognosis. In conclusion, selective insulin resistance is evident in senescent HepG2 cells and changes in GLUT expressions can be used as surrogate markers of hepatocyte senescence. - Highlights: • Senescent hepatocytes demonstrate selective insulin resistance. • GLUT changes act as markers of hepatocyte senescence and have prognostic value. • Study offers insight into long noticed intimacy of cirrhosis and insulin resistance

Selective insulin resistance in hepatocyte senescence

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Aravinthan, Aloysious [Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge (United Kingdom); Challis, Benjamin [Institute of Metabolic Sciences, University of Cambridge, Cambridge (United Kingdom); Shannon, Nicholas [Cancer Research UK Cambridge Institute, Cambridge (United Kingdom); Hoare, Matthew [Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge (United Kingdom); Cancer Research UK Cambridge Institute, Cambridge (United Kingdom); Heaney, Judith [Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge (United Kingdom); Foundation for Liver Research, Institute of Hepatology, London (United Kingdom); Alexander, Graeme J.M., E-mail: gja1000@doctors.org.uk [Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge (United Kingdom)

2015-02-01

Insulin resistance has been described in association with chronic liver disease for decades. Hepatocyte senescence has been demonstrated in chronic liver disease and as many as 80% of hepatocytes show a senescent phenotype in advanced liver disease. The aim of this study was to understand the role of hepatocyte senescence in the development of insulin resistance. Senescence was induced in HepG2 cells via oxidative stress. The insulin metabolic pathway was studied in control and senescent cells following insulin stimulation. GLUT2 and GLUT4 expressions were studied in HepG2 cells and human liver tissue. Further, GLUT2 and GLUT4 expressions were studied in three independent chronic liver disease cohorts. Signalling impairment distal to Akt in phosphorylation of AS160 and FoxO1 was evident in senescent HepG2 cells. Persistent nuclear localisation of FoxO1 was demonstrated in senescent cells despite insulin stimulation. Increased GLUT4 and decreased GLUT2 expressions were evident in senescent cells, human cirrhotic liver tissue and publically available liver disease datasets. Changes in GLUT expressions were associated with a poor clinical prognosis. In conclusion, selective insulin resistance is evident in senescent HepG2 cells and changes in GLUT expressions can be used as surrogate markers of hepatocyte senescence. - Highlights: • Senescent hepatocytes demonstrate selective insulin resistance. • GLUT changes act as markers of hepatocyte senescence and have prognostic value. • Study offers insight into long noticed intimacy of cirrhosis and insulin resistance.

Insulin resistance in obese children and adolescents.

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Romualdo, Monica Cristina dos Santos; Nóbrega, Fernando José de; Escrivão, Maria Arlete Meil Schimith

2014-01-01

To evaluate the presence of insulin resistance and its association with other metabolic abnormalities in obese children and adolescents. Retrospective study of 220 children and adolescents aged 5-14 years. Anthropometric measurements were performed (weight, height, and waist circumference) and clinical (gender, age, pubertal stage, and degree of obesity) and biochemical (glucose, insulin, total cholesterol, and fractions, triglycerides) data were analyzed. Insulin resistance was identified by the homeostasis model assessment for insulin resistance (HOMA-IR) index. The analysis of the differences between the variables of interest and the HOMA-IR quartiles was performed by ANOVA or Kruskal-Wallis tests. Insulin resistance was diagnosed in 33.20% of the sample. It was associated with low levels of high-density lipoprotein cholesterol (HDL-C; p=0.044), waist circumference measurement (p=0.030), and the set of clinical and metabolic (p=0.000) alterations. Insulin-resistant individuals had higher mean age (p=0.000), body mass index (BMI; p=0.000), abdominal circumference (p=0.000), median triglycerides (p=0.001), total cholesterol (p≤0.042), and low-density lipoprotein cholesterol (LDL-C; p≤0.027); and lower HDL-C levels (p=0.005). There was an increase in mean BMI (p=0.000), abdominal circumference (p=0.000), and median triglycerides (p=0.002) as the values of HOMA -IR increased, with the exception of HDL-C, which decreased (p=0.001). Those with the highest number of simultaneous alterations were between the second and third quartiles of the HOMA-IR index (p=0.000). The results confirmed that insulin resistance is present in many obese children and adolescents, and that this condition is associated with alterations that represent an increased risk for developing metabolic disorders in adulthood. Copyright © 2014 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

Paediatrics, insulin resistance and the kidney.

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Marlais, Matko; Coward, Richard J

2015-08-01

Systemic insulin resistance is becoming more prevalent in the young due to modern lifestyles predisposing to the metabolic syndrome and obesity. There is also evidence that there are critical insulin-resistant phases for the developing child, including puberty, and that renal disease per se causes systemic insulin resistance. This review considers the factors that render children insulin resistant, as well as the accumulating evidence that the kidney is an insulin-responsive organ and could be affected by insulin resistance.

Molecular Mechanisms of Insulin Resistance in Chronic Kidney Disease

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Thomas, Sandhya S.; Zhang, Liping; Mitch, William E.

2015-01-01

Insulin resistance refers to reduced sensitivity of organs to insulin-initiated biologic processes that result in metabolic defects. Insulin resistance is common in patients with end-stage renal disease but also occurs in patients with chronic kidney disease (CKD), even when the serum creatinine is minimally increased. Following insulin binding to its receptor, auto-phosphorylation of the insulin receptor is followed by kinase reactions that phosphorylate insulin receptor substrate-1 (IRS-1), phosphatidylinositol 3-kinase (PI3K) and Akt. In fact, low levels of Akt phosphorylation (p-Akt) identifies the presence of the insulin resistance that leads to metabolic defects in insulin-initiated metabolism of glucose, lipids and muscle proteins. Besides CKD, other complex conditions (e.g., inflammation, oxidative stress, metabolic acidosis, aging and excess angiotensin II) reduce p-Akt resulting in insulin resistance. Insulin resistance in each of these conditions is due to activation of different, E3 ubiquitin ligases which specifically conjugate ubiquitin to IRS-1 marking it for degradation in the ubiquitin-proteasome system (UPS). Consequently, IRS-1 degradation suppresses insulin-induced intracellular signaling, causing insulin resistance. Understanding mechanisms of insulin resistance could lead to therapeutic strategies that improve the metabolism of patients with CKD. PMID:26444029

Insulin resistance induced by hydrocortisone is increased in patients with abdominal obesity.

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Darmon, Patrice; Dadoun, Frédéric; Boullu-Ciocca, Sandrine; Grino, Michel; Alessi, Marie-Christine; Dutour, Anne

2006-11-01

Glucocorticoids hypersensitivity may be involved in the development of abdominal obesity and insulin resistance. Eight normal weight and eight obese women received on two occasions a 3-h intravenous infusion of saline or hydrocortisone (HC) (1.5 microg x kg(-1) x min(-1)). Plasma cortisol, insulin, and glucose levels were measured every 30 min from time(-30) (min) (time(-30)) to time(240). Free fatty acids, adiponectin, and plasminogen activator inhibitor-1 (PAI-1) levels were measured at time(-30), time(180), and time(240). At time(240), subjects underwent an insulin tolerance test to obtain an index of insulin sensitivity (K(ITT)). Mean(30-240) cortisol level was similar in control and obese women after saline (74 +/- 16 vs. 75 +/- 20 microg/l) and HC (235 +/- 17 vs. 245 +/- 47 microg/l). The effect of HC on mean(180-240) insulin, mean(180-240) insulin resistance obtained by homeostasis model assessment (HOMA-IR), and K(ITT) was significant in obese (11.4 +/- 2.0 vs. 8.2 +/- 1.3 mU/l, P obese women (+25%) than in controls (+12%) (P obese women than in controls. These deleterious effects are correlated with the amount of visceral fat.

Selective Insulin Resistance in Adipocytes*

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Tan, Shi-Xiong; Fisher-Wellman, Kelsey H.; Fazakerley, Daniel J.; Ng, Yvonne; Pant, Himani; Li, Jia; Meoli, Christopher C.; Coster, Adelle C. F.; Stöckli, Jacqueline; James, David E.

2015-01-01

Aside from glucose metabolism, insulin regulates a variety of pathways in peripheral tissues. Under insulin-resistant conditions, it is well known that insulin-stimulated glucose uptake is impaired, and many studies attribute this to a defect in Akt signaling. Here we make use of several insulin resistance models, including insulin-resistant 3T3-L1 adipocytes and fat explants prepared from high fat-fed C57BL/6J and ob/ob mice, to comprehensively distinguish defective from unaffected aspects of insulin signaling and its downstream consequences in adipocytes. Defective regulation of glucose uptake was observed in all models of insulin resistance, whereas other major actions of insulin such as protein synthesis and anti-lipolysis were normal. This defect corresponded to a reduction in the maximum response to insulin. The pattern of change observed for phosphorylation in the Akt pathway was inconsistent with a simple defect at the level of Akt. The only Akt substrate that showed consistently reduced phosphorylation was the RabGAP AS160 that regulates GLUT4 translocation. We conclude that insulin resistance in adipose tissue is highly selective for glucose metabolism and likely involves a defect in one of the components regulating GLUT4 translocation to the cell surface in response to insulin. PMID:25720492

Increased plasma levels of FABP4 and PTEN is associated with more severe insulin resistance in women with gestational diabetes mellitus.

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Li, Yuan-yuan; Xiao, Rui; Li, Cai-ping; Huangfu, Jian; Mao, Jiang-feng

2015-02-08

The aim of this study was to investigate the relationship between plasma fatty acid binding protein 4 (FABP4), phosphatase and tensin homolog (PTEN), and insulin resistance in patients with gestational diabetes mellitus (GDM). Plasma FABP4 and PTEN were determined by ELISA in GDM patients (GDM group, n=30) and in euglycemic pregnant women (control group, n=30). The clinical features, body mass index (BMI), homeostasis model assessment of insulin resistance (HOMA-IR), and lipid profiles were compared between the 2 groups. The influence of risk factors on insulin resistance, including BMI, lipid profiles, FABP4, and PTEN, were further investigated by multiple-factor stepwise regression analysis. Higher levels of BMI, ΔBMI, triglyceride (TG), fasting plasma glucose (FPG), 2-hour plasma glucose (2hPG), fasting insulin, HOMA-IR, FABP4, PTEN, and lower level of high-density lipoprotein cholesterol (HDL-C) were found in the GDM patients than in the controls (all Pinsulin resistance. GDM patients have more severe insulin resistance compared to euglycemic pregnant women. Higher levels of plasma FABP4 and PTEN are associated with increased insulin resistance and may participate in the pathogenesis of insulin resistance during gestation.

Insulin Resistance Induced by Hyperinsulinemia Coincides with a Persistent Alteration at the Insulin Receptor Tyrosine Kinase Domain

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Catalano, Karyn J.; Maddux, Betty A.; Szary, Jaroslaw; Youngren, Jack F.; Goldfine, Ira D.; Schaufele, Fred

2014-01-01

Insulin resistance, the diminished response of target tissues to insulin, is associated with the metabolic syndrome and a predisposition towards diabetes in a growing proportion of the worldwide population. Under insulin resistant states, the cellular response of the insulin signaling pathway is diminished and the body typically responds by increasing serum insulin concentrations to maintain insulin signaling. Some evidence indicates that the increased insulin concentration may itself further dampen insulin response. If so, insulin resistance would worsen as the level of circulating insulin increases during compensation, which could contribute to the transition of insulin resistance to more severe disease. Here, we investigated the consequences of excess insulin exposure to insulin receptor (IR) activity. Cells chronically exposed to insulin show a diminished the level of IR tyrosine and serine autophosphorylation below that observed after short-term insulin exposure. The diminished IR response did not originate with IR internalization since IR amounts at the cell membrane were similar after short- and long-term insulin incubation. Förster resonance energy transfer between fluorophores attached to the IR tyrosine kinase (TK) domain showed that a change in the TK domain occurred upon prolonged, but not short-term, insulin exposure. Even though the altered ‘insulin refractory’ IR TK FRET and IR autophosphorylation levels returned to baseline (non-stimulated) levels after wash-out of the original insulin stimulus, subsequent short-term exposure to insulin caused immediate re-establishment of the insulin-refractory levels. This suggests that some cell-based ‘memory’ of chronic hyperinsulinemic exposure acts directly at the IR. An improved understanding of that memory may help define interventions to reset the IR to full insulin responsiveness and impede the progression of insulin resistance to more severe disease states. PMID:25259572

Insulin resistance induced by hyperinsulinemia coincides with a persistent alteration at the insulin receptor tyrosine kinase domain.

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Karyn J Catalano

Full Text Available Insulin resistance, the diminished response of target tissues to insulin, is associated with the metabolic syndrome and a predisposition towards diabetes in a growing proportion of the worldwide population. Under insulin resistant states, the cellular response of the insulin signaling pathway is diminished and the body typically responds by increasing serum insulin concentrations to maintain insulin signaling. Some evidence indicates that the increased insulin concentration may itself further dampen insulin response. If so, insulin resistance would worsen as the level of circulating insulin increases during compensation, which could contribute to the transition of insulin resistance to more severe disease. Here, we investigated the consequences of excess insulin exposure to insulin receptor (IR activity. Cells chronically exposed to insulin show a diminished the level of IR tyrosine and serine autophosphorylation below that observed after short-term insulin exposure. The diminished IR response did not originate with IR internalization since IR amounts at the cell membrane were similar after short- and long-term insulin incubation. Förster resonance energy transfer between fluorophores attached to the IR tyrosine kinase (TK domain showed that a change in the TK domain occurred upon prolonged, but not short-term, insulin exposure. Even though the altered 'insulin refractory' IR TK FRET and IR autophosphorylation levels returned to baseline (non-stimulated levels after wash-out of the original insulin stimulus, subsequent short-term exposure to insulin caused immediate re-establishment of the insulin-refractory levels. This suggests that some cell-based 'memory' of chronic hyperinsulinemic exposure acts directly at the IR. An improved understanding of that memory may help define interventions to reset the IR to full insulin responsiveness and impede the progression of insulin resistance to more severe disease states.

Related Factors of Insulin Resistance in Korean Children: Adiposity and Maternal Insulin Resistance

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Kang-Sook Lee

2011-12-01

Full Text Available Increased adiposity and unhealthy lifestyle augment the risk for type 2 diabetes in children with familial predisposition. Insulin resistance (IR is an excellent clinical marker for identifying children at high risk for type 2 diabetes. This study was conducted to investigate parental, physiological, behavioral and socio-economic factors related to IR in Korean children. This study is a cross-sectional study using data from 111 children aged 7 years and their parents. Homeostasis model assessment of insulin resistance (HOMA-IR was calculated using fasting glucose and insulin level as a marker of IR. All children’s adiposity indices (r = 0.309–0.318, all P-value = 0.001 and maternal levels of fasting insulin (r = 0.285, P-value = 0.003 and HOMA-IR (r = 0.290, P-value = 0.002 were positively correlated with children’s HOMA-IR level. There was no statistical difference of children’s HOMA-IR level according to children’s lifestyle habits and socioeconomic status of families. An increase of 1 percentage point in body fat was related to 2.7% increase in children’s HOMA-IR (P-value < 0.001 and an increase of 1% of maternal level of HOMA-IR was related to 0.2% increase in children’s HOMA-IR (P-value = 0.002. This study shows that children’s adiposity and maternal IR are positively associated with children’s IR.

Mechanism of insulin resistance in normal pregnancy.

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Hodson, K; Man, C Dalla; Smith, F E; Thelwall, P E; Cobelli, C; Robson, S C; Taylor, R

2013-08-01

Normal pregnancy is associated with insulin resistance although the mechanism is not understood. Increased intramyocellular lipid is closely associated with the insulin resistance of type 2 diabetes and obesity, and the aim of this study was to determine whether this was so for the physiological insulin resistance of pregnancy. Eleven primiparous healthy pregnant women (age: 27-39 years, body mass index 24.0±3.1 kg/m2) and no personal or family history of diabetes underwent magnetic resonance studies to quantify intramyocellular lipid, plasma lipid fractions, and insulin sensitivity. The meal-related insulin sensitivity index was considerably lower in pregnancy (45.6±9.9 vs. 193.0±26.1; 10(-4) dl/kg/min per pmol/l, p=0.0002). Fasting plasma triglyceride levels were elevated 3-fold during pregnancy (2.3±0.2 vs. 0.8±0.1 mmol/l, pinsulin resistance is distinct from that underlying type 2 diabetes. © Georg Thieme Verlag KG Stuttgart · New York.

Poor zinc status is associated with increased risk of insulin resistance in Spanish children.

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Ortega, R M; Rodríguez-Rodríguez, E; Aparicio, A; Jiménez, A I; López-Sobaler, A M; González-Rodríguez, L G; Andrés, P

2012-02-01

Zn plays a key role in the synthesis and action of insulin. The aim of the present work was to determine whether a poorer Zn status was associated with insulin resistance in a group of 357 Spanish schoolchildren. Zn intake was determined by using a 3 d food record (i.e. Sunday to Tuesday). The body weight, height and waist and hip circumferences of all subjects were recorded and fasting plasma glucose, insulin and Zn concentrations were determined. Insulin resistance was determined using the homoeostasis model assessment (HOMA) marker. Children (11·5 %) with Zn deficiency (serum Zn concentration 3·16 made a significantly smaller contribution to the coverage of those recommended (59·7 (sd 14·7) %) than observed in children with lower HOMA values (73·6 (sd 18·2) %; P health and nutritional status of these children, and thus contribute to diminish problems of insulin resistance.

Xylitol prevents NEFA-induced insulin resistance in rats

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Kishore, P.; Kehlenbrink, S.; Hu, M.; Zhang, K.; Gutierrez-Juarez, R.; Koppaka, S.; El-Maghrabi, M. R.

2013-01-01

Aims/hypothesis Increased NEFA levels, characteristic of type 2 diabetes mellitus, contribute to skeletal muscle insulin resistance. While NEFA-induced insulin resistance was formerly attributed to decreased glycolysis, it is likely that glucose transport is the rate-limiting defect. Recently, the plant-derived sugar alcohol xylitol has been shown to have favourable metabolic effects in various animal models. Furthermore, its derivative xylulose 5-phosphate may prevent NEFA-induced suppression of glycolysis. We therefore examined whether and how xylitol might prevent NEFA-induced insulin resistance. Methods We examined the ability of xylitol to prevent NEFA-induced insulin resistance. Sustained ~1.5-fold elevations in NEFA levels were induced with Intralipid/heparin infusions during 5 h euglycaemic–hyperinsulinaemic clamp studies in 24 conscious non-diabetic Sprague-Dawley rats, with or without infusion of xylitol. Results Intralipid infusion reduced peripheral glucose uptake by ~25%, predominantly through suppression of glycogen synthesis. Co-infusion of xylitol prevented the NEFA-induced decreases in both glucose uptake and glycogen synthesis. Although glycolysis was increased by xylitol infusion alone, there was minimal NEFA-induced suppression of glycolysis, which was not affected by co-infusion of xylitol. Conclusions/interpretation We conclude that xylitol prevented NEFA-induced insulin resistance, with favourable effects on glycogen synthesis accompanying the improved insulin-mediated glucose uptake. This suggests that this pentose sweetener has beneficial insulin-sensitising effects. PMID:22460760

Insulin Resistance in Alzheimer's Disease

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Dineley, Kelly T; Jahrling, Jordan B; Denner, Larry

2014-01-01

Insulin is a key hormone regulating metabolism. Insulin binding to cell surface insulin receptors engages many signaling intermediates operating in parallel and in series to control glucose, energy, and lipids while also regulating mitogenesis and development. Perturbations in the function of any of these intermediates, which occur in a variety of diseases, cause reduced sensitivity to insulin and insulin resistance with consequent metabolic dysfunction. Chronic inflammation ensues which exacerbates compromised metabolic homeostasis. Since insulin has a key role in learning and memory as well as directly regulating ERK, a kinase required for the type of learning and memory compromised in early Alzheimer's disease (AD), insulin resistance has been identified as a major risk factor for the onset of AD. Animal models of AD or insulin resistance or both demonstrate that AD pathology and impaired insulin signaling form a reciprocal relationship. Of note are human and animal model studies geared toward improving insulin resistance that have led to the identification of the nuclear receptor and transcription factor, peroxisome proliferator-activated receptor gamma (PPARγ) as an intervention tool for early AD. Strategic targeting of alternate nodes within the insulin signaling network has revealed disease-stage therapeutic windows in animal models that coalesce with previous and ongoing clinical trial approaches. Thus, exploiting the connection between insulin resistance and AD provides powerful opportunities to delineate therapeutic interventions that slow or block the pathogenesis of AD. PMID:25237037

Insulin resistance in brain and possible therapeutic approaches.

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Cetinkalp, Sevki; Simsir, Ilgin Y; Ertek, Sibel

2014-01-01

Although the brain has long been considered an insulin-independent organ, recent research has shown that insulin has significant effects on the brain, where it plays a role in maintaining glucose and energy homeostasis. To avoid peripheral insulin resistance, the brain may act via hypoinsulinemic responses, maintaining glucose metabolism and insulin sensitivity within its own confines; however, brain insulin resistance may develop due to environmental factors. Insulin has two important functions in the brain: controlling food intake and regulating cognitive functions, particularly memory. Notably, defects in insulin signaling in the brain may contribute to neurodegenerative disorders. Insulin resistance may damage the cognitive system and lead to dementia states. Furthermore, inflammatory processes in the hypothalamus, where insulin receptors are expressed at high density, impair local signaling systems and cause glucose and energy metabolism disorders. Excessive caloric intake and high-fat diets initiate insulin and leptin resistance by inducing mitochondrial dysfunction and endoplasmic reticulum stress in the hypothalamus. This may lead to obesity and diabetes mellitus (DM). Exercise can enhance brain and hypothalamic insulin sensitivity, but it is the option least preferred and/or continuously practiced by the general population. Pharmacological treatments that increase brain and hypothalamic insulin sensitivity may provide new insights into the prevention of dementia disorders, obesity, and type 2 DM in the future.

Insulin Resistance and Prediabetes

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... Your Baby is Born Monogenic Diabetes Insulin Resistance & Prediabetes Insulin resistance and prediabetes occur when your body ... will stay in the healthy range. What is prediabetes? Prediabetes means your blood glucose levels are higher ...

Circulating zonulin, a marker of intestinal permeability, is increased in association with obesity-associated insulin resistance.

Science.gov (United States)

Moreno-Navarrete, José María; Sabater, Mònica; Ortega, Francisco; Ricart, Wifredo; Fernández-Real, José Manuel

2012-01-01

Zonulin is the only physiological mediator known to regulate intestinal permeability reversibly by modulating intercellular tight junctions. To investigate the relationship between intestinal permeability and obesity-associated metabolic disturbances in humans, we aimed to study circulating zonulin according to obesity and insulin resistance. Circulating zonulin (ELISA) was measured in 123 caucasian men in association with inflammatory and metabolic parameters (including minimal model-measured insulin sensitivity). Circulating zonulin increased with body mass index (BMI), waist to hip ratio (WHR), fasting insulin, fasting triglycerides, uric acid and IL-6, and negatively correlated with HDL-cholesterol and insulin sensitivity. In multiple regression analysis, insulin sensitivity (p = 0.002) contributed independently to circulating zonulin variance, after controlling for the effects of BMI, fasting triglycerides and age. When circulating IL-6 was added to this model, only BMI (p = 0.01) contributed independently to circulating zonulin variance. In conclusion, the relationship between insulin sensitivity and circulating zonulin might be mediated through the obesity-related circulating IL-6 increase.

Immunohistochemical expression of insulin, glucagon, and somatostatin in pancreatic islets of horses with and without insulin resistance.

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Newkirk, Kim M; Ehrensing, Gordon; Odoi, Agricola; Boston, Raymond C; Frank, Nicholas

2018-02-01

OBJECTIVE To assess insulin, glucagon, and somatostatin expression within pancreatic islets of horses with and without insulin resistance. ANIMALS 10 insulin-resistant horses and 13 insulin-sensitive horses. PROCEDURES For each horse, food was withheld for at least 10 hours before a blood sample was collected for determination of serum insulin concentration. Horses with a serum insulin concentration horses with a serum insulin concentration > 20 μU/mL underwent a frequently sampled IV glucose tolerance test to determine sensitivity to insulin by minimal model analysis. Horses with a sensitivity to insulin horses were euthanized with a barbiturate overdose, and pancreatic specimens were harvested and immunohistochemically stained for determination of insulin, glucagon, and somatostatin expression in pancreatic islets. Islet hormone expression was compared between insulin-resistant and insulin-sensitive horses. RESULTS Cells expressing insulin, glucagon, and somatostatin made up approximately 62%, 12%, and 7%, respectively, of pancreatic islet cells in insulin-resistant horses and 64%, 18%, and 9%, respectively, of pancreatic islet cells in insulin-sensitive horses. Expression of insulin and somatostatin did not differ between insulin-resistant and insulin-sensitive horses, but the median percentage of glucagon-expressing cells in the islets of insulin-resistant horses was significantly less than that in insulin-sensitive horses. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that, in insulin-resistant horses, insulin secretion was not increased but glucagon production might be downregulated as a compensatory response to hyperinsulinemia.

Macrophage-secreted factors induce adipocyte inflammation and insulin resistance

International Nuclear Information System (INIS)

Permana, Paska A.; Menge, Christopher; Reaven, Peter D.

2006-01-01

Macrophage infiltration into adipose tissue increases with obesity, a condition associated with low-grade inflammation and insulin resistance. We investigated the direct effects of macrophage-secreted factors on adipocyte inflammation and insulin resistance. 3T3-L1 adipocytes incubated with media conditioned by RAW264.7 macrophages (RAW-CM) showed dramatically increased transcription of several inflammation-related genes, greater nuclear factor kappa B (NF-κB) activity, and enhanced binding of U937 monocytes. All of these effects were prevented by co-incubation with pyrrolidinedithiocarbamate, an NF-κB inhibitor. Adipocytes incubated with RAW-CM also released more non-esterified fatty acids and this increased lipolysis was not suppressed by insulin. In addition, RAW-CM treatment decreased insulin-stimulated glucose uptake in adipocytes. Taken together, these results indicate that macrophage-secreted factors induce inflammatory responses and reduce insulin responsiveness in adipocytes. These effects of macrophage-secreted factors on adipocytes may contribute significantly to the systemic inflammation and insulin resistance associated with obesity

Insulin resistance in obesity can be reliably identified from fasting plasma insulin

NARCIS (Netherlands)

ter Horst, K. W.; Gilijamse, P. W.; Koopman, K. E.; de Weijer, B. A.; Brands, M.; Kootte, R. S.; Romijn, J. A.; Ackermans, M. T.; Nieuwdorp, M.; Soeters, M. R.; Serlie, M. J.

2015-01-01

Insulin resistance is the major contributor to cardiometabolic complications of obesity. We aimed to (1) establish cutoff points for insulin resistance from euglycemic hyperinsulinemic clamps (EHCs), (2) identify insulin-resistant obese subjects and (3) predict insulin resistance from routinely

Insulin Resistance and Cancer Risk: An Overview of the Pathogenetic Mechanisms

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Biagio Arcidiacono

2012-01-01

Full Text Available Insulin resistance is common in individuals with obesity or type 2 diabetes (T2D, in which circulating insulin levels are frequently increased. Recent epidemiological and clinical evidence points to a link between insulin resistance and cancer. The mechanisms for this association are unknown, but hyperinsulinaemia (a hallmark of insulin resistance and the increase in bioavailable insulin-like growth factor I (IGF-I appear to have a role in tumor initiation and progression in insulin-resistant patients. Insulin and IGF-I inhibit the hepatic synthesis of sex-hormone binding globulin (SHBG, whereas both hormones stimulate the ovarian synthesis of sex steroids, whose effects, in breast epithelium and endometrium, can promote cellular proliferation and inhibit apoptosis. Furthermore, an increased risk of cancer among insulin-resistant patients can be due to overproduction of reactive oxygen species (ROS that can damage DNA contributing to mutagenesis and carcinogenesis. On the other hand, it is possible that the abundance of inflammatory cells in adipose tissue of obese and diabetic patients may promote systemic inflammation which can result in a protumorigenic environment. Here, we summarize recent progress on insulin resistance and cancer, focusing on various implicated mechanisms that have been described recently, and discuss how these mechanisms may contribute to cancer initiation and progression.

Whole-Body and Hepatic Insulin Resistance in Obese Children

Science.gov (United States)

Ibarra-Reynoso, Lorena del Rocío; Pisarchyk, Liudmila; Pérez-Luque, Elva Leticia; Garay-Sevilla, Ma. Eugenia; Malacara, Juan Manuel

2014-01-01

Background Insulin resistance may be assessed as whole body or hepatic. Objective To study factors associated with both types of insulin resistance. Methods Cross-sectional study of 182 obese children. Somatometric measurements were registered, and the following three adiposity indexes were compared: BMI, waist-to-height ratio and visceral adiposity. Whole-body insulin resistance was evaluated using HOMA-IR, with 2.5 as the cut-off point. Hepatic insulin resistance was considered for IGFBP-1 level quartiles 1 to 3 (HOMA-IR was negatively associated with IGFBP-1 and positively associated with BMI, triglycerides, leptin and mother's BMI. Girls had increased HOMA-IR. IGFBP-1 was negatively associated with waist-to-height ratio, age, leptin, HOMA-IR and IGF-I. We did not find HOMA-IR or IGFBP-1 associated with fatty liver. Conclusion In school-aged children, BMI is the best metric to predict whole-body insulin resistance, and waist-to-height ratio is the best predictor of hepatic insulin resistance, indicating that central obesity is important for hepatic insulin resistance. The reciprocal negative association of IGFBP-1 and HOMA-IR may represent a strong interaction of the physiological processes of both whole-body and hepatic insulin resistance. PMID:25411786

Blueberries’ Impact on Insulin Resistance and Glucose Intolerance

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April J. Stull

2016-11-01

Full Text Available Blueberries are a rich source of polyphenols, which include anthocyanin bioactive compounds. Epidemiological evidence indicates that incorporating blueberries into the diet may lower the risk of developing type 2 diabetes (T2DM. These findings are supported by pre-clinical and clinical studies that have shown improvements in insulin resistance (i.e., increased insulin sensitivity after obese and insulin-resistant rodents or humans consumed blueberries. Insulin resistance was assessed by homeostatic model assessment-estimated insulin resistance (HOMA-IR, insulin tolerance tests, and hyperinsulinemic-euglycemic clamps. Additionally, the improvements in glucose tolerance after blueberry consumption were assessed by glucose tolerance tests. However, firm conclusions regarding the anti-diabetic effect of blueberries cannot be drawn due to the small number of existing clinical studies. Although the current evidence is promising, more long-term, randomized, and placebo-controlled trials are needed to establish the role of blueberries in preventing or delaying T2DM.

Hepatocyte DACH1 Is Increased in Obesity via Nuclear Exclusion of HDAC4 and Promotes Hepatic Insulin Resistance

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Lale Ozcan

2016-06-01

Full Text Available Defective insulin signaling in hepatocytes is a key factor in type 2 diabetes. In obesity, activation of calcium/calmodulin-dependent protein kinase II (CaMKII in hepatocytes suppresses ATF6, which triggers a PERK-ATF4-TRB3 pathway that disrupts insulin signaling. Elucidating how CaMKII suppresses ATF6 is therefore essential to understanding this insulin resistance pathway. We show that CaMKII phosphorylates and blocks nuclear translocation of histone deacetylase 4 (HDAC4. As a result, HDAC4-mediated SUMOylation of the corepressor DACH1 is decreased, which protects DACH1 from proteasomal degradation. DACH1, together with nuclear receptor corepressor (NCOR, represses Atf6 transcription, leading to activation of the PERK-TRB3 pathway and defective insulin signaling. DACH1 is increased in the livers of obese mice and humans, and treatment of obese mice with liver-targeted constitutively nuclear HDAC4 or DACH1 small hairpin RNA (shRNA increases ATF6, improves hepatocyte insulin signaling, and protects against hyperglycemia and hyperinsulinemia. Thus, DACH1-mediated corepression in hepatocytes emerges as an important link between obesity and insulin resistance.

Estradiol Protects Proopiomelanocortin Neurons Against Insulin Resistance.

Science.gov (United States)

Qiu, Jian; Bosch, Martha A; Meza, Cecilia; Navarro, Uyen-Vy; Nestor, Casey C; Wagner, Edward J; Rønnekleiv, Oline K; Kelly, Martin J

2018-02-01

Insulin resistance is at the core of the metabolic syndrome, and men exhibit a higher incidence of metabolic syndrome than women in early adult life, but this sex advantage diminishes sharply when women reach the postmenopausal state. Because 17β-estradiol (E2) augments the excitability of the anorexigenic proopiomelanocortin (POMC) neurons, we investigated the neuroprotective effects of E2 against insulin resistance in POMC neurons from diet-induced obese (DIO) female and male mice. The efficacy of insulin to activate canonical transient receptor potential 5 (TRPC5) channels and depolarize POMC neurons was significantly reduced in DIO male mice but not in DIO female mice. However, the insulin response in POMC neurons was abrogated in ovariectomized DIO females but restored with E2 replacement. E2 increased T-type calcium channel Cav3.1 messenger RNA (mRNA) expression and whole-cell currents but downregulated stromal-interaction molecule 1 mRNA, which rendered POMC neurons more excitable and responsive to insulin-mediated TRPC5 channel activation. Moreover, E2 prevented the increase in suppressor of cytokine signaling-3 mRNA expression with DIO as seen in DIO males. As proof of principle, insulin [intracerebroventricular injection into the third ventricle (ICV)] decreased food intake and increased metabolism in female but not male guinea pigs fed a high-fat diet. The uncoupling of the insulin receptor from its downstream effector system was corroborated by the reduced expression of phosphorylated protein kinase B in the arcuate nucleus of male but not female guinea pigs following insulin. Therefore, E2 protects female POMC neurons from insulin resistance by enhancing POMC neuronal excitability and the coupling of insulin receptor to TRPC5 channel activation. Copyright © 2018 Endocrine Society.

Insulin Sensitivity Determines Effects of Insulin and Meal Ingestion on Systemic Vascular Resistance in Healthy Subjects.

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Woerdeman, Jorn; Meijer, Rick I; Eringa, Etto C; Hoekstra, Trynke; Smulders, Yvo M; Serné, Erik H

2016-01-01

In addition to insulin's metabolic actions, insulin can dilate arterioles which increase blood flow to metabolically active tissues. This effect is blunted in insulin-resistant subjects. Insulin's effect on SVR, determined by resistance arterioles, has, however, rarely been examined directly. We determined the effects of both hyperinsulinemia and a mixed meal on SVR and its relationship with insulin sensitivity. Thirty-seven lean and obese women underwent a hyperinsulinemic-euglycemic clamp, and 24 obese volunteers underwent a mixed-meal test. SVR was assessed using CPP before and during hyperinsulinemia as well as before and 60 and 120 minutes after a meal. SVR decreased significantly during hyperinsulinemia (-13%; p Insulin decreased SVR more strongly in insulin-sensitive individuals (standardized β: -0.44; p = 0.01). In addition, SVR at 60 minutes after meal ingestion was inversely related to the Matsuda index (β: -0.39; p = 0.04) and the change in postprandial SVR was directly related to postprandial glycemia (β: 0.53; p insulin resistance. This suggests that resistance to insulin-induced vasodilatation contributes to regulation of vascular resistance. © 2015 John Wiley & Sons Ltd.

Insulin resistance in dairy cows.

Science.gov (United States)

De Koster, Jenne D; Opsomer, Geert

2013-07-01

Glucose is the molecule that drives milk production, and insulin plays a pivotal role in the glucose metabolism of dairy cows. The effect of insulin on the glucose metabolism is regulated by the secretion of insulin by the pancreas and the insulin sensitivity of the skeletal muscles, the adipose tissue, and the liver. Insulin resistance may develop as part of physiologic (pregnancy and lactation) and pathologic processes, which may manifest as decreased insulin sensitivity or decreased insulin responsiveness. A good knowledge of the normal physiology of insulin is needed to measure the in vivo insulin resistance of dairy cows. Copyright © 2013 Elsevier Inc. All rights reserved.

Persistent Organic Pollutant Exposure Leads to Insulin Resistance Syndrome

DEFF Research Database (Denmark)

Ruzzin, Jérôme; Petersen, Rasmus; Meugnier, Emmanuelle

2010-01-01

BACKGROUND: The incidence of the insulin resistance syndrome has increased at an alarming rate worldwide creating a serious challenge to public health care in the 21st century. Recently, epidemiological studies have associated the prevalence of type 2 diabetes with elevated body burdens...... of persistent organic pollutants (POPs). However, experimental evidence demonstrating a causal link between POPs and the development of insulin resistance is lacking. OBJECTIVE: We investigated whether exposure to POPs contributes to insulin resistance and metabolic disorders. METHODS: Wistar rats were exposed...... salmon oil. We measured body weight, whole-body insulin sensitivity, POP accumulation, lipid and glucose homeostasis, gene expression and performed microarray analysis. RESULTS: Adult male rats exposed to crude, but not refined, salmon oil developed insulin resistance, abdominal obesity...

Vitamin D deficiency impairs glucose-stimulated insulin secretion and increases insulin resistance by reducing PPAR-γ expression in nonobese Type 2 diabetic rats.

Science.gov (United States)

Park, Sunmin; Kim, Da Sol; Kang, Suna

2016-01-01

Human studies have provided relatively strong associations of poor vitamin D status with Type 2 diabetes but do not explain the nature of the association. Here, we explored the physiological pathways that may explain how vitamin D status modulates energy, lipid and glucose metabolisms in nonobese Type 2 diabetic rats. Goto-Kakizaki (GK) rats were fed high-fat diets containing 25 (VD-low), 1000 (VD-normal) or 10,000 (VD-high) cholecalciferol-IU/kg diet for 8 weeks. Energy expenditure, insulin resistance, insulin secretory capacity and lipid metabolism were measured. Serum 25-OH-D levels, an index of vitamin D status, increased dose dependently with dietary vitamin D. VD-low resulted in less fat oxidation without a significant difference in energy expenditure and less lean body mass in the abdomen and legs comparison to the VD-normal group. In comparison to VD-low, VD-normal had lower serum triglycerides and intracellular fat accumulation in the liver and skeletal muscles which was associated with down-regulation of the mRNA expressions of sterol regulatory element binding protein-1c and fatty acid synthase and up-regulation of gene expressions of peroxisome proliferator-activated receptors (PPAR)-α and carnitine palmitoyltransferase-1. In euglycemic hyperinsulinemic clamp, whole-body and hepatic insulin resistance was exacerbated in the VD-low group but not in the VD-normal group, possibly through decreasing hepatic insulin signaling and PPAR-γ expression in the adipocytes. In 3T3-L1 adipocytes 1,25-(OH)2-D (10 nM) increased triglyceride accumulation by elevating PPAR-γ expression and treatment with a PPAR-γ antagonist blocked the triglyceride deposition induced by 1,25-(OH)2-D treatment. VD-low impaired glucose-stimulated insulin secretion in hyperglycemic clamp and decreased β-cell mass by decreasing β-cell proliferation. In conclusion, vitamin D deficiency resulted in the dysregulation of glucose metabolism in GK rats by simultaneously increasing insulin

The evolutionary benefit of insulin resistance

NARCIS (Netherlands)

Soeters, Maarten R.; Soeters, Peter B.

2012-01-01

Insulin resistance is perceived as deleterious, associated with conditions as the metabolic syndrome, type 2 diabetes mellitus and critical illness. However, insulin resistance is evolutionarily well preserved and its persistence suggests that it benefits survival. Insulin resistance is important in

Circulating zonulin, a marker of intestinal permeability, is increased in association with obesity-associated insulin resistance.

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José María Moreno-Navarrete

Full Text Available Zonulin is the only physiological mediator known to regulate intestinal permeability reversibly by modulating intercellular tight junctions. To investigate the relationship between intestinal permeability and obesity-associated metabolic disturbances in humans, we aimed to study circulating zonulin according to obesity and insulin resistance. Circulating zonulin (ELISA was measured in 123 caucasian men in association with inflammatory and metabolic parameters (including minimal model-measured insulin sensitivity. Circulating zonulin increased with body mass index (BMI, waist to hip ratio (WHR, fasting insulin, fasting triglycerides, uric acid and IL-6, and negatively correlated with HDL-cholesterol and insulin sensitivity. In multiple regression analysis, insulin sensitivity (p = 0.002 contributed independently to circulating zonulin variance, after controlling for the effects of BMI, fasting triglycerides and age. When circulating IL-6 was added to this model, only BMI (p = 0.01 contributed independently to circulating zonulin variance. In conclusion, the relationship between insulin sensitivity and circulating zonulin might be mediated through the obesity-related circulating IL-6 increase.

Insulin resistance in obesity can be reliably identified from fasting plasma insulin.

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ter Horst, K W; Gilijamse, P W; Koopman, K E; de Weijer, B A; Brands, M; Kootte, R S; Romijn, J A; Ackermans, M T; Nieuwdorp, M; Soeters, M R; Serlie, M J

2015-12-01

Insulin resistance is the major contributor to cardiometabolic complications of obesity. We aimed to (1) establish cutoff points for insulin resistance from euglycemic hyperinsulinemic clamps (EHCs), (2) identify insulin-resistant obese subjects and (3) predict insulin resistance from routinely measured variables. We assembled data from non-obese (n=112) and obese (n=100) men who underwent two-step EHCs using [6,6-(2)H2]glucose as tracer (insulin infusion dose 20 and 60 mU m(-2) min(-1), respectively). Reference ranges for hepatic and peripheral insulin sensitivity were calculated from healthy non-obese men. Based on these reference values, obese men with preserved insulin sensitivity or insulin resistance were identified. Cutoff points for insulin-mediated suppression of endogenous glucose production (EGP) and insulin-stimulated glucose disappearance rate (Rd) were 46.5% and 37.3 μmol kg(-)(1) min(-)(1), respectively. Most obese men (78%) had EGP suppression within the reference range, whereas only 12% of obese men had Rd within the reference range. Obese men with Rd obese men in age, body mass index (BMI), body composition, fasting glucose or cholesterol, but did have higher fasting insulin (110±49 vs 63±29 pmol l(-1), Pobese men could be identified with good sensitivity (80%) and specificity (75%) from fasting insulin >74 pmol l(-1). Most obese men have hepatic insulin sensitivity within the range of non-obese controls, but below-normal peripheral insulin sensitivity, that is, insulin resistance. Fasting insulin (>74 pmol l(-1) with current insulin immunoassay) may be used for identification of insulin-resistant (or metabolically unhealthy) obese men in research and clinical settings.

Insulin Increases Ceramide Synthesis in Skeletal Muscle

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M. E. Hansen

2014-01-01

Full Text Available Aims. The purpose of this study was to determine the effect of insulin on ceramide metabolism in skeletal muscle. Methods. Skeletal muscle cells were treated with insulin with or without palmitate for various time periods. Lipids (ceramides and TAG were isolated and gene expression of multiple biosynthetic enzymes were quantified. Additionally, adult male mice received daily insulin injections for 14 days, followed by muscle ceramide analysis. Results. In muscle cells, insulin elicited an increase in ceramides comparable to palmitate alone. This is likely partly due to an insulin-induced increase in expression of multiple enzymes, particularly SPT2, which, when knocked down, prevented the increase in ceramides. In mice, 14 days of insulin injection resulted in increased soleus ceramides, but not TAG. However, insulin injections did significantly increase hepatic TAG compared with vehicle-injected animals. Conclusions. This study suggests that insulin elicits an anabolic effect on sphingolipid metabolism in skeletal muscle, resulting in increased ceramide accumulation. These findings reveal a potential mechanism of the deleterious consequences of the hyperinsulinemia that accompanies insulin resistance and suggest a possible novel therapeutic target to mitigate its effects.

SOCS-1 deficiency does not prevent diet-induced insulin resistance

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Emanuelli, Brice; Macotela, Yazmin; Boucher, Jérémie

2008-01-01

Obesity is associated with inflammation and increased expression of suppressor of cytokine signaling (SOCS) proteins, which inhibit cytokine and insulin signaling. Thus, reducing SOCS expression could prevent the development of obesity-induced insulin resistance. Using SOCS-1 knockout mice, we...... investigated the contribution of SOCS-1 in the development of insulin resistance induced by a high-fat diet (HFD). SOCS-1 knockout mice on HFD gained 70% more weight, displayed a 2.3-fold increase in epididymal fat pads mass and increased hepatic lipid content. This was accompanied by increased mRNA expression...... of leptin and the macrophage marker CD68 in white adipose tissue and of SREBP1c and FAS in liver. HFD also induced hyperglycemia in SOCS-1 deficient mice with impairment of glucose and insulin tolerance tests. Thus, despite the role of SOCS proteins in obesity-related insulin resistance, SOCS-1 deficiency...

Patients with psoriasis are insulin resistant

DEFF Research Database (Denmark)

Gyldenløve, Mette; Storgaard, Heidi; Holst, Jens Juul

2015-01-01

BACKGROUND: Patients with psoriasis have increased risk of type 2 diabetes. The pathophysiology is largely unknown, but it is hypothesized that systemic inflammation causes insulin resistance. Insulin sensitivity has only been sparsely investigated in patients with psoriasis, and previous studies...... with healthy control subjects. This supports that psoriasis may be a prediabetic condition....

Effects of intranasal insulin on endogenous glucose production in insulin-resistant men.

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Xiao, Changting; Dash, Satya; Stahel, Priska; Lewis, Gary F

2018-03-14

The effects of intranasal insulin on the regulation of endogenous glucose production (EGP) in individuals with insulin resistance were assessed in a single-blind, crossover study. Overweight or obese insulin-resistant men (n = 7; body mass index 35.4 ± 4.4 kg/m 2 , homeostatic model assessment of insulin resistance 5.6 ± 1.6) received intranasal spray of either 40 IU insulin lispro or placebo in 2 randomized visits. Acute systemic spillover of intranasal insulin into the circulation was matched with a 30-minute intravenous infusion of insulin lispro in the nasal placebo arm. EGP was assessed under conditions of a pancreatic clamp with a primed, constant infusion of glucose tracer. Under these experimental conditions, compared with placebo, intranasal administration of insulin did not significantly affect plasma glucose concentrations, EGP or glucose disposal in overweight/obese, insulin-resistant men, in contrast to our previous study, in which an equivalent dose of intranasal insulin significantly suppressed EGP in lean, insulin-sensitive men. Insulin resistance is probably associated with impairment in centrally mediated insulin suppression of EGP. © 2018 John Wiley & Sons Ltd.

Insulin resistance and atherosclerosis : the role of visceral fat

NARCIS (Netherlands)

Gast, K.B.

2016-01-01

The main objective of this thesis was to unravel relationships between obesity, insulin resistance, hyperglycemia, and atherosclerosis. It is well-established that patients with type 2 diabetes have a 2- to 3-fold increased risk of cardiovascular disease. We investigated whether insulin resistance

Effects of niacin supplementation on the insulin resistance in Holstein cows during early lactation

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Talija Hristovska

2017-01-01

Full Text Available Insulin resistance in early lactation includes low glucose concentration, low insulin release and responsiveness and high lipolysis. Niacin is important antilipolytic agent and leads to increase glucose and insulin concentration. The objectives of this study were to determine the influence of niacin on the insulin resistance in cows during early lactation using the difference of value and regression analysis between blood non-esterified fatty acid (NEFA, glucose and insulin concentrations, revised quantitative insulin sensitivity check index and glucose-to-insulin ratio. Niacin supplementation led to a decrease of NEFA concentration and an increase of glucose and insulin concentrations during the first three weeks after calving. Cows in the niacin group which were more resistant to insulin showed higher concentrations of non-esterified fatty acid in comparison with more sensitive cows from the same group, but still lower than the control. The regression analyses suggest the following characteristics of cows supplemented with niacin in comparison with the control group: the insulin response to glucose was more intense; the antilipolytic effect of insulin was lower; insulin efficiency expressed as glucose-to-insulin ratio increase with a decrease in NEFA. The metabolic changes due to niacin supplementation showed a dual influence on the insulin resistance in dairy cows during early lactation: decreased NEFA concentrations led to a decrease in the insulin resistance (due to an increase in insulin efficiency and insulin sensitivity index, but increased concentrations of insulin and glucose possibly caused an increase in the insulin resistance in dairy cows (due to lower insulin sensitivity index and possibly lower antilipolytic effects of insulin.

Pathogenesis of Insulin Resistance in Skeletal Muscle

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Muhammad A. Abdul-Ghani

2010-01-01

Full Text Available Insulin resistance in skeletal muscle is manifested by decreased insulin-stimulated glucose uptake and results from impaired insulin signaling and multiple post-receptor intracellular defects including impaired glucose transport, glucose phosphorylation, and reduced glucose oxidation and glycogen synthesis. Insulin resistance is a core defect in type 2 diabetes, it is also associated with obesity and the metabolic syndrome. Dysregulation of fatty acid metabolism plays a pivotal role in the pathogenesis of insulin resistance in skeletal muscle. Recent studies have reported a mitochondrial defect in oxidative phosphorylation in skeletal muscle in variety of insulin resistant states. In this review, we summarize the cellular and molecular defects that contribute to the development of insulin resistance in skeletal muscle.

Whole-blood viscosity and the insulin-resistance syndrome.

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Høieggen, A; Fossum, E; Moan, A; Enger, E; Kjeldsen, S E

1998-02-01

In a previous study we found that elevated blood viscosity was linked to the insulin resistance syndrome, and we proposed that high blood viscosity may increase insulin resistance. That study was based on calculated viscosity. To determine whether directly measured whole-blood viscosity was related to the insulin-resistance syndrome in the same way as calculated viscosity had been found to be. Healthy young men were examined with the hyperinsulinemic isoglycemic glucose clamp technique, and we related insulin sensitivity (glucose disposal rate) to other metabolic parameters and to blood viscosity. We established a technique for direct measurement of whole-blood viscosity. There were statistically significant negative correlations between glucose disposal rate and whole-blood viscosity at low and high shear rates (r = -0.41, P = 0.007 for both, n = 42). Whole-blood viscosity was correlated positively (n = 15) to serum triglyceride (r = 0.54, P = 0.04) and total cholesterol (r = 0.52, P = 0.05), and negatively with high-density lipoprotein cholesterol (r = -0.53, P = 0.04) concentrations. Insulin sensitivity index was correlated positively to high-density lipoprotein cholesterol (r = 0.54, P = 0.04) and negatively to serum triglyceride (r = -0.69, P = 0.005) and to total cholesterol (r = -0.81, P = 0.0003) concentrations. The present results demonstrate for the first time that there is a negative relationship between directly measured whole-blood viscosity and insulin sensitivity as a part of the insulin-resistance syndrome. Whole-blood viscosity contributes to the total peripheral resistance, and these results support the hypothesis that insulin resistance has a hemodynamic basis.

Deletion of skeletal muscle SOCS3 prevents insulin resistance in obesity

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Beck Jørgensen, Sebastian; O'Neill, Hayley M; Sylow, Lykke

2013-01-01

Obesity is associated with chronic low-grade inflammation that contributes to defects in energy metabolism and insulin resistance. Suppressor of cytokine signaling (SOCS)-3 expression is increased in skeletal muscle of obese humans. SOCS3 inhibits leptin signaling in the hypothalamus and insulin...... of hyperinsulinemia and insulin resistance because of enhanced skeletal muscle insulin receptor substrate 1 (IRS1) and Akt phosphorylation that resulted in increased skeletal muscle glucose uptake. These data indicate that skeletal muscle SOCS3 does not play a critical role in regulating muscle development or energy...... expenditure, but it is an important contributing factor for inhibiting insulin sensitivity in obesity. Therapies aimed at inhibiting SOCS3 in skeletal muscle may be effective in reversing obesity-related glucose intolerance and insulin resistance....

Treatment of severe insulin resistance in pregnancy with 500 units per milliliter of concentrated insulin.

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Mendez-Figueroa, Hector; Maggio, Lindsay; Dahlke, Joshua D; Daley, Julie; Lopes, Vrishali V; Coustan, Donald R; Rouse, Dwight J

2013-07-01

To evaluate glycemic control and pregnancy outcomes among pregnant women with severe insulin resistance treated with 500 units/mL concentrated insulin. Retrospective analysis of gravid women with severe insulin resistance (need for greater than 100 units of insulin per injection or greater than 200 units/d) treated with either 500 units/mL concentrated insulin or conventional insulin therapy. We performed a two-part analysis: 1) between gravid women treated with and without 500 units/mL concentrated insulin; and 2) among gravid women treated with 500 units/mL concentrated insulin, comparing glycemic control before and after its initiation. Seventy-three pregnant women with severe insulin resistance were treated with 500 units/mL concentrated insulin and 78 with conventional insulin regimens. Patients treated with 500 units/mL concentrated insulin were older and more likely to have type 2 diabetes mellitus. Average body mass index was comparable between both groups (38.6 compared with 40.4, P=.11) as were obstetric and perinatal outcomes and glycemic control during the last week of gestation. Within the 500 units/mL concentrated insulin cohort, after initiation of this medication, fasting and postprandial blood glucose concentrations improved. However, the rates of blood glucose values less than 60 mg/dL and less than 50 mg/dL were higher in the 500 units/mL concentrated insulin group after initiation than before, 4.8% compared with 2.0% (Pinsulin in severely obese insulin-resistant pregnant women confers similar glycemic control compared with traditional insulin regimens but may increase the risk of hypoglycemia. II.

Childhood obesity and insulin resistance: how should it be managed?

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Ho, Mandy; Garnett, Sarah P; Baur, Louise A

2014-12-01

Concomitant with the rise in global pediatric obesity in the past decades, there has been a significant increase in the number of children and adolescents with clinical signs of insulin resistance. Given insulin resistance is the important link between obesity and the associated metabolic abnormalities and cardiovascular risk, clinicians should be aware of high risk groups and treatment options. As there is no universally accepted biochemical definition of insulin resistance in children and adolescents, identification and diagnosis of insulin resistance usually relies on clinical features such as acanthosis nigricans, polycystic ovary syndrome, hypertension, dyslipidemia, and nonalcoholic fatty liver disease. Treatment for reducing insulin resistance and other obesity-associated comorbidities should focus on changes in health behaviors to achieve effective weight management. Lifestyle interventions incorporating dietary change, increased physical activity, and decreased sedentary behaviors, with the involvement of family and adoption of a developmentally appropriate approach, should be used as the first line treatment. Current evidence suggests that the primary objective of dietary interventions should be to reduce total energy intake and a combination of aerobic and resistance training should be encouraged. Metformin can be used in conjunction with a lifestyle intervention program in obese adolescents with clinical insulin resistance to achieve weight loss and to improve insulin sensitivity. Ongoing evaluation and research are required to explore optimal protocol and long-term effectiveness of lifestyle interventions, as well as to determine whether the improvements in insulin sensitivity induced by lifestyle interventions and weight loss will lead to a clinical benefit including reduced cardiovascular morbidity and mortality.

Absence of down-regulation of the insulin receptor by insulin. A possible mechanism of insulin resistance in the rat.

OpenAIRE

Walker, A P; Flint, D J

1983-01-01

Insulin resistance occurs in rat adipocytes during pregnancy and lactation despite increased or normal insulin binding respectively; this suggests that a post-receptor defect exists. The possibility has been examined that, although insulin binding occurs normally, internalization of insulin or its receptor may be impaired in these states. Insulin produced a dose-dependent reduction in the number of insulin receptors on adipocytes from virgin rats maintained in culture medium, probably due to ...

Cancer-drug induced insulin resistance : Innocent bystander or unusual suspect

NARCIS (Netherlands)

Ariaans, G.; de Jong, S.; Gietema, J. A.; Lefrandt, J. D.; de Vries, E. G. E.; Jalving, M.

Epidemiological and experimental evidence strongly suggests an association between type 2 diabetes mellitus and cancer. Insulin resistance, causing hyperinsulinaemia and eventually hyperglycaemia, appears to increase cancer incidence and disease progression. In addition, insulin resistance seems to

Selective Insulin Resistance in the Kidney

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Horita, Shoko; Nakamura, Motonobu; Suzuki, Masashi; Satoh, Nobuhiko; Suzuki, Atsushi; Seki, George

2016-01-01

Insulin resistance has been characterized as attenuation of insulin sensitivity at target organs and tissues, such as muscle and fat tissues and the liver. The insulin signaling cascade is divided into major pathways such as the PI3K/Akt pathway and the MAPK/MEK pathway. In insulin resistance, however, these pathways are not equally impaired. For example, in the liver, inhibition of gluconeogenesis by the insulin receptor substrate (IRS) 2 pathway is impaired, while lipogenesis by the IRS1 pathway is preserved, thus causing hyperglycemia and hyperlipidemia. It has been recently suggested that selective impairment of insulin signaling cascades in insulin resistance also occurs in the kidney. In the renal proximal tubule, insulin signaling via IRS1 is inhibited, while insulin signaling via IRS2 is preserved. Insulin signaling via IRS2 continues to stimulate sodium reabsorption in the proximal tubule and causes sodium retention, edema, and hypertension. IRS1 signaling deficiency in the proximal tubule may impair IRS1-mediated inhibition of gluconeogenesis, which could induce hyperglycemia by preserving glucose production. In the glomerulus, the impairment of IRS1 signaling deteriorates the structure and function of podocyte and endothelial cells, possibly causing diabetic nephropathy. This paper mainly describes selective insulin resistance in the kidney, focusing on the proximal tubule. PMID:27247938

Acupuncture Alters Expression of Insulin Signaling Related Molecules and Improves Insulin Resistance in OLETF Rats

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Xin-Yu Huang

2016-01-01

Full Text Available To determine effect of acupuncture on insulin resistance in Otsuka Long-Evans Tokushima Fatty (OLETF rats and to evaluate expression of insulin signaling components. Rats were divided into three groups: Sprague-Dawley (SD rats, OLETF rats, and acupuncture+OLETF rats. Acupuncture was subcutaneously applied to Neiguan (PC6, Zusanli (ST36, and Sanyinjiao (SP6; in contrast, acupuncture to Shenshu (BL23 was administered perpendicularly. For Neiguan (PC6 and Zusanli (ST36, needles were connected to an electroacupuncture (EA apparatus. Fasting blood glucose (FPG was measured by glucose oxidase method. Plasma fasting insulin (FINS and serum C peptide (C-P were determined by ELISA. Protein and mRNA expressions of insulin signaling molecules were determined by Western blot and real-time RT-PCR, respectively. OLETF rats exhibit increased levels of FPG, FINS, C-P, and homeostasis model assessment-estimated insulin resistance (HOMA-IR, which were effectively decreased by acupuncture treatment. mRNA expressions of several insulin signaling related molecules IRS1, IRS2, Akt2, aPKCζ, and GLUT4 were decreased in OLETF rats compared to SD controls. Expression of these molecules was restored back to normal levels upon acupuncture administration. PI3K-p85α was increased in OLETF rats; this increase was also reversed by acupuncture treatment. Acupuncture improves insulin resistance in OLETF rats, possibly via regulating expression of key insulin signaling related molecules.

MODELS OF INSULIN RESISTANCE AND HEART FAILURE

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Velez, Mauricio; Kohli, Smita; Sabbah, Hani N.

2013-01-01

The incidence of heart failure (HF) and diabetes mellitus is rapidly increasing and is associated with poor prognosis. In spite of the advances in therapy, HF remains a major health problem with high morbidity and mortality. When HF and diabetes coexist, clinical outcomes are significantly worse. The relationship between these two conditions has been studied in various experimental models. However, the mechanisms for this interrelationship are complex, incompletely understood, and have become a matter of considerable clinical and research interest. There are only few animal models that manifest both HF and diabetes. However, the translation of results from these models to human disease is limited and new models are needed to expand our current understanding of this clinical interaction. In this review, we discuss mechanisms of insulin signaling and insulin resistance, the clinical association between insulin resistance and HF and its proposed pathophysiologic mechanisms. Finally, we discuss available animal models of insulin resistance and HF and propose requirements for future new models. PMID:23456447

Tau hyperphosphorylation induces oligomeric insulin accumulation and insulin resistance in neurons.

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Rodriguez-Rodriguez, Patricia; Sandebring-Matton, Anna; Merino-Serrais, Paula; Parrado-Fernandez, Cristina; Rabano, Alberto; Winblad, Bengt; Ávila, Jesús; Ferrer, Isidre; Cedazo-Minguez, Angel

2017-12-01

Insulin signalling deficiencies and insulin resistance have been directly linked to the progression of neurodegenerative disorders like Alzheimer's disease. However, to date little is known about the underlying molecular mechanisms or insulin state and distribution in the brain under pathological conditions. Here, we report that insulin is accumulated and retained as oligomers in hyperphosphorylated tau-bearing neurons in Alzheimer's disease and in several of the most prevalent human tauopathies. The intraneuronal accumulation of insulin is directly dependent on tau hyperphosphorylation, and follows the tauopathy progression. Furthermore, cells accumulating insulin show signs of insulin resistance and decreased insulin receptor levels. These results suggest that insulin retention in hyperphosphorylated tau-bearing neurons is a causative factor for the insulin resistance observed in tauopathies, and describe a novel neuropathological concept with important therapeutic implications. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Associations between depressive symptoms and insulin resistance

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Adriaanse, M C; Dekker, J M; Nijpels, G

2006-01-01

AIMS/HYPOTHESIS: The association between depression and insulin resistance has been investigated in only a few studies, with contradictory results reported. The aim of this study was to determine whether the association between symptoms of depression and insulin resistance varies across glucose...... established type 2 diabetes mellitus. Main outcome measures were insulin resistance defined by the homeostasis model assessment for insulin resistance (HOMA-IR) and symptoms of depression using the Centre for Epidemiologic Studies Depression Scale (CES-D). RESULTS: In the total sample, we found a weak.......942). The association between depressive symptoms and insulin resistance was similar for men and women. CONCLUSIONS/INTERPRETATION: We found only weak associations between depressive symptoms and insulin resistance, which did not differ among different glucose metabolism subgroups or between men and women....

Role of mitochondrial function in insulin resistance

NARCIS (Netherlands)

Brands, Myrte; Verhoeven, Arthur J.; Serlie, Mireille J.

2012-01-01

The obesity pandemic increases the prevalence of type 2 diabetes (DM2).DM2 develops when pancreatic β-cells fail and cannot compensate for the decrease in insulin sensitivity. How excessive caloric intake and weight gain cause insulin resistance has not completely been elucidated.Skeletal muscle is

Aβ-Induced Insulin Resistance and the Effects of Insulin on the Cholesterol Synthesis Pathway and Aβ Secretion in Neural Cells.

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Najem, Dema; Bamji-Mirza, Michelle; Yang, Ze; Zhang, Wandong

2016-06-01

Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) toxicity, tau pathology, insulin resistance, neuroinflammation, and dysregulation of cholesterol homeostasis, all of which play roles in neurodegeneration. Insulin has polytrophic effects on neurons and may be at the center of these pathophysiological changes. In this study, we investigated possible relationships among insulin signaling and cholesterol biosynthesis, along with the effects of Aβ42 on these pathways in vitro. We found that neuroblastoma 2a (N2a) cells transfected with the human gene encoding amyloid-β protein precursor (AβPP) (N2a-AβPP) produced Aβ and exhibited insulin resistance by reduced p-Akt and a suppressed cholesterol-synthesis pathway following insulin treatment, and by increased phosphorylation of insulin receptor subunit-1 at serine 612 (p-IRS-S612) as compared to parental N2a cells. Treatment of human neuroblastoma SH-SY5Y cells with Aβ42 also increased p-IRS-S612, suggesting that Aβ42 is responsible for insulin resistance. The insulin resistance was alleviated when N2a-AβPP cells were treated with higher insulin concentrations. Insulin increased Aβ release from N2a-AβPP cells, by which it may promote Aβ clearance. Insulin increased cholesterol-synthesis gene expression in SH-SY5Y and N2a cells, including 24-dehydrocholesterol reductase (DHCR24) and 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR) through sterol-regulatory element-binding protein-2 (SREBP2). While Aβ42-treated SH-SY5Y cells exhibited increased HMGCR expression and c-Jun phosphorylation as pro-inflammatory responses, they also showed down-regulation of neuro-protective/anti-inflammatory DHCR24. These results suggest that Aβ42 may cause insulin resistance, activate JNK for c-Jun phosphorylation, and lead to dysregulation of cholesterol homeostasis, and that enhancing insulin signaling may relieve the insulin-resistant phenotype and the dysregulated cholesterol-synthesis pathway to promote A�

Insulin resistance in therapeutic clinic

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Anna V. Pashentseva

2017-09-01

Full Text Available Today an obesity became the global epidemic striking both children, and adults and represents one of the most important problems of health care worldwide. Excess accumulation of fatty tissue is resulted by insulin resistance and a compensatory hyperinsulinaemia which are the main predictors of development of a diabetes mellitus type 2. Insulin resistance is also one of key links of a pathogenesis of such diseases as cardiovascular pathology, not-alcoholic fatty liver disease, a polycystic ovary syndrome, gestational diabetes and many others. Depression of sensitivity of tissues to insulin can be physiological reaction of an organism to stress factors and pathological process. The endogenic reasons also take part in development of insulin resistance besides factors of the external environment. The role of genetic predisposition, a subclinical inflammation of fatty tissue, thyroid hormones, adipokines and vitamin D in formation of this pathological process is studied. As insulin resistance takes part in a pathogenesis of various diseases, methods of its diagnostics and correction are of great importance in therapeutic practice. At purpose of treatment it is worth giving preference to the drugs which are positively influencing sensitivity of tissues to insulin.

Endothelial Fcγ Receptor IIB Activation Blunts Insulin Delivery to Skeletal Muscle to Cause Insulin Resistance in Mice

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Tanigaki, Keiji; Chambliss, Ken L.; Yuhanna, Ivan S.; Sacharidou, Anastasia; Ahmed, Mohamed; Atochin, Dmitriy N.; Huang, Paul L.

2016-01-01

Modest elevations in C-reactive protein (CRP) are associated with type 2 diabetes. We previously revealed in mice that increased CRP causes insulin resistance and mice globally deficient in the CRP receptor Fcγ receptor IIB (FcγRIIB) were protected from the disorder. FcγRIIB is expressed in numerous cell types including endothelium and B lymphocytes. Here we investigated how endothelial FcγRIIB influences glucose homeostasis, using mice with elevated CRP expressing or lacking endothelial FcγRIIB. Whereas increased CRP caused insulin resistance in mice expressing endothelial FcγRIIB, mice deficient in the endothelial receptor were protected. The insulin resistance with endothelial FcγRIIB activation was due to impaired skeletal muscle glucose uptake caused by attenuated insulin delivery, and it was associated with blunted endothelial nitric oxide synthase (eNOS) activation in skeletal muscle. In culture, CRP suppressed endothelial cell insulin transcytosis via FcγRIIB activation and eNOS antagonism. Furthermore, in knock-in mice harboring constitutively active eNOS, elevated CRP did not invoke insulin resistance. Collectively these findings reveal that by inhibiting eNOS, endothelial FcγRIIB activation by CRP blunts insulin delivery to skeletal muscle to cause insulin resistance. Thus, a series of mechanisms in endothelium that impairs insulin movement has been identified that may contribute to type 2 diabetes pathogenesis. PMID:27207525

Microvascular Recruitment in Insulin Resistance

DEFF Research Database (Denmark)

Sjøberg, Kim Anker

the resonating sound from the microbubbles in the systemic circulation were recorded for determination of microvascular recruitment in designated muscle segments. Results showed that microvascular recruitment increased with insulin stimulation by ~30% in rats and ~40% in humans (study I). Furthermore......, it was observed that muscle contractions increased muscle perfusion rapidly by 3-4 fold and by 1-2 fold compared to basal and insulin, respectively, in both rat and human skeletal muscle (study I). The real-time contrast-enhanced ultrasound method was applied to investigate the vaso-active effect of the incretin...... hormone glucagon-like-peptide-1 (GLP-1) in the microcirculation. Glucagon-like-peptide-1 analogs are drugs used for treatments of insulin resistance and type 2 diabetes but the vascular effects of GLP-1 in vivo are elusive. Here it was shown that GLP-1 rapidly increased the microvascular recruitment...

Role of PTEN in TNFα induced insulin resistance

International Nuclear Information System (INIS)

Bulger, David A.; Conley, Jermaine; Conner, Spencer H.; Majumdar, Gipsy; Solomon, Solomon S.

2015-01-01

Aims/hypothesis: PTEN may play a reversible role in TNFα induced insulin resistance, which has been linked to obesity-associated insulin resistance (IR). Methods: Western blots for PTEN and p-Akt were performed on H-411E liver cells incubated with insulin, TNFα, and in selected experiments VO-OHpic vanadium complex in the presence and absence of PTEN siRNA. Total PTEN was compared to β-actin loading control and p-Akt was compared to total Akt. Results: Western blot and Real Time RT-PCR experiments showed increased PTEN after TNFα treatment (p = 0.04); slightly decreased PTEN after insulin treatment; and slightly increased PTEN after insulin + TNFα treatment. PTEN siRNA markedly inhibited the TNFα-induced increase in PTEN (p < 0.01) without significantly changing the p-Akt levels. The vanadium complex, exhibiting insulin-like effects, also significantly prevented the TNFα-induced increase in PTEN. Combining insulin and VO-OHpic was additive, providing both proof of concept and insight into mechanism. Discussion: The PTEN increase due to TNFα treatment was reversible by both PTEN siRNA knockdown and VO-OHpic treatment. Thus, PTEN is identified as a potential new therapeutic target for reducing IR in Type 2 DM. - Highlights: • TNFα treatment induced a significant increase in PTEN in H-411E liver cells. • PTEN siRNA knockdown prevented this effect. • VO-OHpic (vanadium complex) treatment, like insulin, decreased PTEN protein levels. • Thus, PTEN is identified as a potential therapeutic target in DM Type 2

Role of PTEN in TNFα induced insulin resistance

Energy Technology Data Exchange (ETDEWEB)

Bulger, David A. [Departments of Medicine and Pharmacology, University of Tennessee Health Science Center, Memphis, TN 38163 (United States); Medicine and Research Services, Veterans Association Medical Center, Memphis, TN 38104 (United States); Wellcome Trust Medical Research Council Institute of Metabolic Science, Cambridge CB2 0QQ (United Kingdom); National Institute of Diabetes & Digestive & Kidney Disease, National Institutes of Health, Bethesda, MD 20892 (United States); Conley, Jermaine [Medicine and Research Services, Veterans Association Medical Center, Memphis, TN 38104 (United States); Conner, Spencer H.; Majumdar, Gipsy [Departments of Medicine and Pharmacology, University of Tennessee Health Science Center, Memphis, TN 38163 (United States); Medicine and Research Services, Veterans Association Medical Center, Memphis, TN 38104 (United States); Solomon, Solomon S., E-mail: ssolomon@uthsc.edu [Departments of Medicine and Pharmacology, University of Tennessee Health Science Center, Memphis, TN 38163 (United States); Medicine and Research Services, Veterans Association Medical Center, Memphis, TN 38104 (United States)

2015-06-05

Aims/hypothesis: PTEN may play a reversible role in TNFα induced insulin resistance, which has been linked to obesity-associated insulin resistance (IR). Methods: Western blots for PTEN and p-Akt were performed on H-411E liver cells incubated with insulin, TNFα, and in selected experiments VO-OHpic vanadium complex in the presence and absence of PTEN siRNA. Total PTEN was compared to β-actin loading control and p-Akt was compared to total Akt. Results: Western blot and Real Time RT-PCR experiments showed increased PTEN after TNFα treatment (p = 0.04); slightly decreased PTEN after insulin treatment; and slightly increased PTEN after insulin + TNFα treatment. PTEN siRNA markedly inhibited the TNFα-induced increase in PTEN (p < 0.01) without significantly changing the p-Akt levels. The vanadium complex, exhibiting insulin-like effects, also significantly prevented the TNFα-induced increase in PTEN. Combining insulin and VO-OHpic was additive, providing both proof of concept and insight into mechanism. Discussion: The PTEN increase due to TNFα treatment was reversible by both PTEN siRNA knockdown and VO-OHpic treatment. Thus, PTEN is identified as a potential new therapeutic target for reducing IR in Type 2 DM. - Highlights: • TNFα treatment induced a significant increase in PTEN in H-411E liver cells. • PTEN siRNA knockdown prevented this effect. • VO-OHpic (vanadium complex) treatment, like insulin, decreased PTEN protein levels. • Thus, PTEN is identified as a potential therapeutic target in DM Type 2.

Endothelin-1 exacerbates development of hypertension and atherosclerosis in modest insulin resistant syndrome

International Nuclear Information System (INIS)

Lin, Yan-Jie; Juan, Chi-Chang; Kwok, Ching-Fai; Hsu, Yung-Pei; Shih, Kuang-Chung; Chen, Chin-Chang; Ho, Low-Tone

2015-01-01

Endothelin-1 (ET-1) is known as potent vasoconstrictor, by virtue of its mitogenic effects, and may deteriorate the process of hypertension and atherosclerosis by aggravating hyperplasia and migration in VSMCs. Our previous study demonstrated that insulin infusion caused sequential induction of hyperinsulinemia, hyperendothelinemia, insulin resistance, and then hypertension in rats. However, the underlying mechanism of ET-1 interfere insulin signaling in VSMCs remains unclear. To characterize insulin signaling during modest insulin resistant syndrome, we established and monitored rats by feeding high fructose-diet (HFD) until high blood pressure and modest insulin resistance occurred. To explore the role of ET-1/ET A R during insulin resistance, ET A R expression, ET-1 binding, and insulin signaling were investigated in the HFD-fed rats and cultured A-10 VSMCs. Results showed that high blood pressure, tunica medial wall thickening, plasma ET-1 and insulin, and accompanied with modest insulin resistance without overweight and hyperglycemia occurred in early-stage HFD-fed rats. In the endothelium-denuded aorta from HFD-fed rats, ET A R expression, but not ET B R, and ET-1 binding in aorta were increased. Moreover, decreasing of insulin-induced Akt phosphorylation and increasing of insulin-induced ERK phosphorylation were observed in aorta during modest insulin resistance. Interestingly, in ET-1 pretreated VSMCs, the increment of insulin-induced Akt phosphorylation was decreased whereas the increment of insulin-induced ERK phosphorylation was increased. In addition, insulin potentiated ET-1-induced VSMCs migration and proliferation due to increasing ET-1 binding. ETAR antagonist reversed effects of ET-1 on insulin-induced signaling and VSMCs migration and proliferation. In summary, modest insulin resistance syndrome accompanied with hyperinsulinemia leading to the potentiation on ET-1-induced actions in aortic VSMCs. ET-1 via ET A R pathway suppressed insulin

Mechanisms for greater insulin-stimulated glucose uptake in normal and insulin-resistant skeletal muscle after acute exercise

Science.gov (United States)

2015-01-01

Enhanced skeletal muscle and whole body insulin sensitivity can persist for up to 24–48 h after one exercise session. This review focuses on potential mechanisms for greater postexercise and insulin-stimulated glucose uptake (ISGU) by muscle in individuals with normal or reduced insulin sensitivity. A model is proposed for the processes underlying this improvement; i.e., triggers initiate events that activate subsequent memory elements, which store information that is relayed to mediators, which translate memory into action by controlling an end effector that directly executes increased insulin-stimulated glucose transport. Several candidates are potential triggers or memory elements, but none have been conclusively verified. Regarding potential mediators in both normal and insulin-resistant individuals, elevated postexercise ISGU with a physiological insulin dose coincides with greater Akt substrate of 160 kDa (AS160) phosphorylation without improved proximal insulin signaling at steps from insulin receptor binding to Akt activity. Causality remains to be established between greater AS160 phosphorylation and improved ISGU. The end effector for normal individuals is increased GLUT4 translocation, but this remains untested for insulin-resistant individuals postexercise. Following exercise, insulin-resistant individuals can attain ISGU values similar to nonexercising healthy controls, but after a comparable exercise protocol performed by both groups, ISGU for the insulin-resistant group has been consistently reported to be below postexercise values for the healthy group. Further research is required to fully understand the mechanisms underlying the improved postexercise ISGU in individuals with normal or subnormal insulin sensitivity and to explain the disparity between these groups after similar exercise. PMID:26487009

Mechanism by which arylamine N-acetyltransferase 1 ablation causes insulin resistance in mice

DEFF Research Database (Denmark)

Camporez, João Paulo; Wang, Yongliang; Faarkrog, Kasper

2017-01-01

A single-nucleotide polymorphism in the human arylamine N-acetyltransferase 2 (Nat2) gene has recently been identified as associated with insulin resistance in humans. To understand the cellular and molecular mechanisms by which alterations in Nat2 activity might cause insulin resistance, we...... examined murine ortholog Nat1 knockout (KO) mice. Nat1 KO mice manifested whole-body insulin resistance, which could be attributed to reduced muscle, liver, and adipose tissue insulin sensitivity. Hepatic and muscle insulin resistance were associated with marked increases in both liver and muscle...... adipose tissue, and hepatocytes. Taken together, these studies demonstrate that Nat1 deletion promotes reduced mitochondrial activity and is associated with ectopic lipid-induced insulin resistance. These results provide a potential genetic link among mitochondrial dysfunction with increased ectopic lipid...

Effect of thiazolidinedione treatment on resistin levels in insulin resistant sprague dawley rats

International Nuclear Information System (INIS)

Yousaf, I.; Hameed, W.; Rajput, T.A.

2015-01-01

Insulin resistance is manifested by decreased effect of fixed quantity of insulin on glucose metabolism leading to type 2 diabetes mellitus. Visceral obesity has been positively correlated with insulin resistance but its mechanism is not fully defined. Insulin resistance may be the consequence of adipocytokines including visfatin and resistin. This study was designed to see the effect of thiazolidinediones on levels of resistin in insulin resistant rats. Methods: Ninety Sprague Dawley rats were randomly divided into three groups. Group I served as control. Rats in Group II and III were made insulin resistant diabetics. Group III was treated with rosiglitazone after development of diabetes. Plasma glucose, serum triglycerides, HDL, TG:HDL ratio and serum resistin levels were analysed. Results: Body weight and plasma glucose were significantly increased (p<0.05) along with TG:HDL ratio (p<0.05) in group II and group III at the end of 4th week. Serum resistin levels also increased significantly (p<0.05) in group II and III at the end of 4th week. Treatment of group III with rosiglitazone led to improvement in insulin resistance with decrease in serum resistin levels (p<0.05). Conclusion: Increased serum resistin level indicates insulin resistance and impending hyperglycaemia. Thiazolidinediones augment sensitivity of insulin to restore normoglycaemia by decreasing serum resistin level. (author)

Insulin-like growth factor 1, liver enzymes, and insulin resistance in patients with PCOS and hirsutism.

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Çakir, Evrim; Topaloğlu, Oya; Çolak Bozkurt, Nujen; Karbek Bayraktar, Başak; Güngüneş, Aşkın; Sayki Arslan, Müyesser; Öztürk Ünsal, İlknur; Tutal, Esra; Uçan, Bekir; Delıbaşi, Tuncay

2014-01-01

Hyperinsulinemia and insulin resistance are commonly seen in patients with hirsutism and polycystic ovary syndrome (PCOS), and are associated with cardiovascular disease risk. However, it is not yet known whether insulin-like growth factor I (IGF-I) and alanine transaminase (ALT) produced by the liver play roles in hyperinsulinemia and subclinical atherosclerotic process in patients with PCOS and idiopathic hirsutism (IH). This was a prospective case-controlled study. The study population consisted of 25 reproductive-age PCOS women, 33 women with IH, and 25 control subjects. Mean IGF-I levels and median ALT levels were higher in patients with IH and PCOS than controls, but these differences were not statistically significant. The participants who had a homeostasis model assessment insulin resistance index (HOMA-IR) greater than 2.7 had significantly higher IGF-1 and ALT levels. ALT levels were positively correlated with body mass index, FG, insulin and HOMA-IR. The study illustrated that IGF-1 and ALT levels were significantly higher in patients with increased insulin resistance. Due to short disease duration in younger participants, we did not observe any correlation between IGF-1 and hyperinsulinemia. These findings suggest that increased hepatic production of IGF-I and ALT might be an early indicator of insulin resistance in hirsutism.

Consumption of a liquid high-fat meal increases triglycerides but decreases high-density lipoprotein cholesterol in abdominally obese subjects with high postprandial insulin resistance.

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Wang, Feng; Lu, Huixia; Liu, Fukang; Cai, Huizhen; Xia, Hui; Guo, Fei; Xie, Yulan; Huang, Guiling; Miao, Miao; Shu, Guofang; Sun, Guiju

2017-07-01

Abdominal obesity is associated with an increased risk of insulin resistance, which may be a potential contributor to dyslipidemia. However, the relationship between postprandial insulin resistance and lipid metabolism in abdominally obese subjects remains unknown. We hypothesized that postprandial dyslipidemia would be exaggerated in abdominally obese subjects with high postprandial insulin resistance. To test this hypothesis, serum glucose, insulin, triglycerides, total cholesterol, high-density lipoprotein cholesterol, and apolipoprotein B were measured at baseline and postprandial state at 0.5, 1, 2, 4, 6, and 8 hours after a liquid high-fat meal in non-abdominally obese controls (n=44) and abdominally obese subjects with low (AO-LPIR, n=40), middle (n=40), and high postprandial insulin resistance (AO-HPIR, n=40) based on the tertiles ratio of the insulin to glucose areas under the curve (AUC). Their serum adipokines were tested at baseline only. Fasting serum leptin was higher (Pinsulin resistance and controls. The present study indicated that the higher degree of postprandial insulin resistance, the more adverse lipid profiles in abdominally obese subjects, which provides insight into opportunity for screening in health. Copyright © 2017 Elsevier Inc. All rights reserved.

Relationship between insulin resistance and tissue blood flow in preeclampsia.

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Anim-Nyame, Nick; Gamble, John; Sooranna, Suren R; Johnson, Mark R; Steer, Philip J

2015-05-01

Preeclampsia is characterized by generalized endothelial dysfunction and impaired maternal tissue perfusion, and insulin resistance is a prominent feature of this disease. The aim of this study was to test the hypothesis that insulin resistance in preeclampsia is related to the reduced resting tissue blood flow. We used venous occlusion plethysmography to compare the resting calf muscle blood flow (measured as QaU) in 20 nulliparous women with preeclampsia and 20 normal pregnant controls matched for maternal age, gestational age, parity and BMI during the third trimester. Fasting blood samples were obtained to measure the plasma concentrations of insulin and glucose, and to calculate the fasting insulin resistance index (FIRI), a measure of insulin resistance in both groups of women. Calf blood flow was significantly reduced in the preeclampsia group (1.93 ± 0.86 QaU), compared with normal pregnant controls (3.94 ± 1.1 QaU, P insulin concentrations and Insulin Resistance Index were significantly higher in preeclampsia compared with normal pregnancy (P insulin concentrations (r = -0.57, P = 0.008) and FIRI (r = -0.59, P = 0.006) in preeclampsia, but not in normal pregnancy. These findings support our hypothesis and raise the possibility that reduced tissue blood flow may a play a role in the increased insulin resistance seen in preeclampsia.

Midkine, a potential link between obesity and insulin resistance.

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Nengguang Fan

Full Text Available Obesity is associated with increased production of inflammatory mediators in adipose tissue, which contributes to chronic inflammation and insulin resistance. Midkine (MK is a heparin-binding growth factor with potent proinflammatory activities. We aimed to test whether MK is associated with obesity and has a role in insulin resistance. It was found that MK was expressed in adipocytes and regulated by inflammatory modulators (TNF-α and rosiglitazone. In addition, a significant increase in MK levels was observed in adipose tissue of obese ob/ob mice as well as in serum of overweight/obese subjects when compared with their respective controls. In vitro studies further revealed that MK impaired insulin signaling in 3T3-L1 adipocytes, as indicated by reduced phosphorylation of Akt and IRS-1 and decreased translocation of glucose transporter 4 (GLUT4 to the plasma membrane in response to insulin stimulation. Moreover, MK activated the STAT3-suppressor of cytokine signaling 3 (SOCS3 pathway in adipocytes. Thus, MK is a novel adipocyte-secreted factor associated with obesity and inhibition of insulin signaling in adipocytes. It may provide a potential link between obesity and insulin resistance.

Association of Serum Ferritin Levels with Metabolic Syndrome and Insulin Resistance.

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Padwal, Meghana K; Murshid, Mohsin; Nirmale, Prachee; Melinkeri, R R

2015-09-01

The impact of CVDs and Type II DM is increasing over the last decade. It has been estimated that by 2025 their incidence will double. Ferritin is one of the key proteins regulating iron homeostasis and is a widely available clinical biomarker of iron status. Some studies suggest that prevalence of atherosclerosis and insulin resistance increases significantly with increasing serum ferritin. Metabolic syndrome is known to be associated with increased risk of atherosclerosis as well as insulin resistance. The present study was designed to explore the association of serum ferritin levels with metabolic syndrome and insulin resistance. The present study was prospective, cross sectional. The study protocol was approved by IEC. The study group consisted of 90 participants (50 cases of metabolic syndrome and 40 age and sex matched controls). Diagnosis of metabolic syndrome was done as per NCEP ATP III criteria. Estimation of serum Ferritin and Insulin was done by Chemiluminescence Immunoassay (CLIA) while Glucose by Glucose Oxidase and Peroxidase (GOD-POD) method. Insulin Resistance was calculated by HOMA IR score. Data obtained was statistically analysed by using student t-test. We found statistically significant rise in the levels of serum ferritin (p=syndrome as compared with controls. High serum ferritin levels though within normal range are significantly associated with both metabolic syndrome and insulin resistance.

Fanconi anemia links reactive oxygen species to insulin resistance and obesity.

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Li, Jie; Sipple, Jared; Maynard, Suzette; Mehta, Parinda A; Rose, Susan R; Davies, Stella M; Pang, Qishen

2012-10-15

Insulin resistance is a hallmark of obesity and type 2 diabetes. Reactive oxygen species (ROS) have been proposed to play a causal role in insulin resistance. However, evidence linking ROS to insulin resistance in disease settings has been scant. Since both oxidative stress and diabetes have been observed in patients with the Fanconi anemia (FA), we sought to investigate the link between ROS and insulin resistance in this unique disease model. Mice deficient for the Fanconi anemia complementation group A (Fanca) or Fanconi anemia complementation group C (Fancc) gene seem to be diabetes-prone, as manifested by significant hyperglycemia and hyperinsulinemia, and rapid weight gain when fed with a high-fat diet. These phenotypic features of insulin resistance are characterized by two critical events in insulin signaling: a reduction in tyrosine phosphorylation of the insulin receptor (IR) and an increase in inhibitory serine phosphorylation of the IR substrate-1 in the liver, muscle, and fat tissues from the insulin-challenged FA mice. High levels of ROS, spontaneously accumulated or generated by tumor necrosis factor alpha in these insulin-sensitive tissues of FA mice, were shown to underlie the FA insulin resistance. Treatment of FA mice with the natural anti-oxidant Quercetin restores IR signaling and ameliorates the diabetes- and obesity-prone phenotypes. Finally, pairwise screen identifies protein-tyrosine phosphatase (PTP)-α and stress kinase double-stranded RNA-dependent protein kinase (PKR) that mediate the ROS effect on FA insulin resistance. These findings establish a pathogenic and mechanistic link between ROS and insulin resistance in a unique human disease setting. ROS accumulation contributes to the insulin resistance in FA deficiency by targeting both PTP-α and PKR.

Insulin-stimulated glucose uptake in healthy and insulin-resistant skeletal muscle

DEFF Research Database (Denmark)

Deshmukh, Atul S

2016-01-01

transporter protein 4 (GLUT4) to the plasma membrane which leads to facilitated diffusion of glucose into the cell. Understanding the precise signaling events guiding insulin-stimulated glucose uptake is pivotal, because impairment in these signaling events leads to development of insulin resistance and type...... 2 diabetes. This review summarizes current understanding of insulin signaling pathways mediating glucose uptake in healthy and insulin-resistant skeletal muscle....

Insulin Resistance and Increased Muscle Cytokine Levels in Patients With Mitochondrial Myopathy

DEFF Research Database (Denmark)

Rue, Nana; Vissing, John; Galbo, Henrik

2014-01-01

CONTEXT: Mitochondrial dysfunction has been proposed to cause insulin resistance and that might stimulate cytokine production. OBJECTIVE: The objective of the study was to elucidate the association between mitochondrial myopathy, insulin sensitivity, and cytokine levels in muscle. DESIGN......: The intervention included a 120-minute hyperinsulinemic, euglycemic clamp. Another morning, microdialysis of both vastus lateralis muscles for 4 hours, including one-legged, knee extension exercise for 30 minutes, was performed. MAIN OUTCOME MEASURES: Glucose infusion rate during 90-120 minutes of insulin infusion...... was measured. Cytokine concentrations in dialysate were also measured. RESULTS: Muscle strength, percentage fat mass, and creatine kinase in plasma did not differ between groups. The maximal oxygen uptake was 21 ± 3 (SE) (P) and 36 ± 3(C) mL/kg·min (2P insulin, C-peptide, and glucagon were higher...

Metabolic syndrome and insulin resistance in obese adolescents

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Amanda Oliva Gobato

2014-03-01

Full Text Available Objective: To verify the prevalence of metabolic syndrome and insulin resistance in obese adolescents and its relationship with different body composition indicators. Methods: A cross-sectional study comprising 79 adolescents aged ten to 18 years old. The assessed body composition indicators were: body mass index (BMI, body fat percentage, abdominal circumference, and subcutaneous fat. The metabolic syndrome was diagnosed according to the criteria proposed by Cook et al. The insulin resistance was determined by the Homeostasis Model Assessment for Insulin Resistance (HOMA-IR index for values above 3.16. The analysis of ROC curves was used to assess the BMI and the abdominal circumference, aiming to identify the subjects with metabolic syndrome and insulin resistance. The cutoff point corresponded to the percentage above the reference value used to diagnose obesity. Results: The metabolic syndrome was diagnosed in 45.5% of the patients and insulin resistance, in 29.1%. Insulin resistance showed association with HDL-cholesterol (p=0.032 and with metabolic syndrome (p=0.006. All body composition indicators were correlated with insulin resistance (p<0.01. In relation to the cutoff point evaluation, the values of 23.5 and 36.3% above the BMI reference point allowed the identification of insulin resistance and metabolic syndrome. The best cutoff point for abdominal circumference to identify insulin resistance was 40%. Conclusions: All body composition indicators, HDL-cholesterol and metabolic syndrome showed correlation with insulin resistance. The BMI was the most effective anthropometric indicator to identify insulin resistance.

Differential insulin and steroidogenic signaling in insulin resistant and non-insulin resistant human luteinized granulosa cells-A study in PCOS patients.

Science.gov (United States)

Belani, Muskaan; Deo, Abhilash; Shah, Preeti; Banker, Manish; Singal, Pawan; Gupta, Sarita

2018-04-01

Insulin resistance (IR) is one of the significant aberrations in polycystic ovarian syndrome (PCOS), however is only observed in 70%-80% of obese PCOS and 20%-25% of lean PCOS. Hyperinsulinemia accompanies PCOS-IR along with hyperandrogenemia against normal insulin and androgen levels in PCOS-non insulin resistance (NIR). This could possibly be due to defects in the downstream signaling pathways. The study thus aims to unravel insulin and steroidogenic signaling pathways in luteinized granulosa cells isolated from PCOS-IR and NIR vs matched controls. Luteinized granulosa cells from 30 controls and 39 PCOS were classified for IR based on a novel method of down regulation of protein expression of insulin receptor-β (INSR- β) as shown in our previous paper. We evaluated expression of molecules involved in insulin, steroidogenic signaling and lipid metabolism in luteinized granulosa cells followed by analysis of estradiol, progesterone and testosterone in follicular fluid. Protein expression of INSR- β, pIRS (ser 307), PI(3)K, PKC-ζ, pAkt, ERK1/2, pP38MAPK and gene expression of IGF showed differential expression in the two groups. Increased protein expression of PPAR-γ was accompanied by up regulation in SREBP1c, FAS, CPT-1 and ACC-1 genes in PCOS-IR group. Expression of StAR, CYP19A1, 17 β- HSD and 3 β- HSD demonstrated significant decrease along with increase in CYP11A1, FSH-R and LH-R in both the groups. Follicular fluid testosterone increased and progesterone decreased in PCOS-IR group. This study shows how candidate molecules that were differentially expressed, aid in designing targeted therapy against the two phenotypes of PCOS. Copyright © 2018 Elsevier Ltd. All rights reserved.

Fucosterol activates the insulin signaling pathway in insulin resistant HepG2 cells via inhibiting PTP1B.

Science.gov (United States)

Jung, Hyun Ah; Bhakta, Himanshu Kumar; Min, Byung-Sun; Choi, Jae Sue

2016-10-01

Insulin resistance is a characteristic feature of type 2 diabetes mellitus (T2DM) and is characterized by defects in insulin signaling. This study investigated the modulatory effects of fucosterol on the insulin signaling pathway in insulin-resistant HepG2 cells by inhibiting protein tyrosine phosphatase 1B (PTP1B). In addition, molecular docking simulation studies were performed to predict binding energies, the specific binding site of fucosterol to PTP1B, and to identify interacting residues using Autodock 4.2 software. Glucose uptake was determined using a fluorescent D-glucose analogue and the glucose tracer 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxyglucose, and the signaling pathway was detected by Western blot analysis. We found that fucosterol enhanced insulin-provoked glucose uptake and conjointly decreased PTP1B expression level in insulin-resistant HepG2 cells. Moreover, fucosterol significantly reduced insulin-stimulated serine (Ser307) phosphorylation of insulin receptor substrate 1 (IRS1) and increased phosphorylation of Akt, phosphatidylinositol-3-kinase, and extracellular signal- regulated kinase 1 at concentrations of 12.5, 25, and 50 µM in insulin-resistant HepG2 cells. Fucosterol inhibited caspase-3 activation and nuclear factor kappa B in insulin-resistant hepatocytes. These results suggest that fucosterol stimulates glucose uptake and improves insulin resistance by downregulating expression of PTP1B and activating the insulin signaling pathway. Thus, fucosterol has potential for development as an anti-diabetic agent.

Endothelin-1 exacerbates development of hypertension and atherosclerosis in modest insulin resistant syndrome

Energy Technology Data Exchange (ETDEWEB)

Lin, Yan-Jie [Institute of Physiology, National Yang-Ming University, Taipei, Taiwan (China); Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan (China); Juan, Chi-Chang [Institute of Physiology, National Yang-Ming University, Taipei, Taiwan (China); Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan (China); Kwok, Ching-Fai [Division of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan (China); Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan (China); Hsu, Yung-Pei [Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan (China); Shih, Kuang-Chung [Division of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan (China); Chen, Chin-Chang [Institute of Physiology, National Yang-Ming University, Taipei, Taiwan (China); Ho, Low-Tone, E-mail: ltho@vghtpe.gov.tw [Institute of Physiology, National Yang-Ming University, Taipei, Taiwan (China); Division of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan (China); Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan (China); Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan (China)

2015-05-08

Endothelin-1 (ET-1) is known as potent vasoconstrictor, by virtue of its mitogenic effects, and may deteriorate the process of hypertension and atherosclerosis by aggravating hyperplasia and migration in VSMCs. Our previous study demonstrated that insulin infusion caused sequential induction of hyperinsulinemia, hyperendothelinemia, insulin resistance, and then hypertension in rats. However, the underlying mechanism of ET-1 interfere insulin signaling in VSMCs remains unclear. To characterize insulin signaling during modest insulin resistant syndrome, we established and monitored rats by feeding high fructose-diet (HFD) until high blood pressure and modest insulin resistance occurred. To explore the role of ET-1/ET{sub A}R during insulin resistance, ET{sub A}R expression, ET-1 binding, and insulin signaling were investigated in the HFD-fed rats and cultured A-10 VSMCs. Results showed that high blood pressure, tunica medial wall thickening, plasma ET-1 and insulin, and accompanied with modest insulin resistance without overweight and hyperglycemia occurred in early-stage HFD-fed rats. In the endothelium-denuded aorta from HFD-fed rats, ET{sub A}R expression, but not ET{sub B}R, and ET-1 binding in aorta were increased. Moreover, decreasing of insulin-induced Akt phosphorylation and increasing of insulin-induced ERK phosphorylation were observed in aorta during modest insulin resistance. Interestingly, in ET-1 pretreated VSMCs, the increment of insulin-induced Akt phosphorylation was decreased whereas the increment of insulin-induced ERK phosphorylation was increased. In addition, insulin potentiated ET-1-induced VSMCs migration and proliferation due to increasing ET-1 binding. ETAR antagonist reversed effects of ET-1 on insulin-induced signaling and VSMCs migration and proliferation. In summary, modest insulin resistance syndrome accompanied with hyperinsulinemia leading to the potentiation on ET-1-induced actions in aortic VSMCs. ET-1 via ET{sub A}R pathway

Obesogenic memory can confer long-term increases in adipose tissue but not liver inflammation and insulin resistance after weight loss

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J. Schmitz

2016-05-01

Conclusions: These results demonstrate that although sustained weight loss improves systemic glucose homeostasis, primarily through improved inflammation and insulin action in liver, a remarkable obesogenic memory can confer long-term increases in adipose tissue inflammation and insulin resistance in mice as well as in a significant subpopulation of obese patients.

Insulin resistance in non-obese subjects is associated with activation of the JNK pathway and impaired insulin signaling in skeletal muscle.

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Umesh B Masharani

2011-05-01

Full Text Available The pathogenesis of insulin resistance in the absence of obesity is unknown. In obesity, multiple stress kinases have been identified that impair the insulin signaling pathway via serine phosphorylation of key second messenger proteins. These stress kinases are activated through various mechanisms related to lipid oversupply locally in insulin target tissues and in various adipose depots.To explore whether specific stress kinases that have been implicated in the insulin resistance of obesity are potentially contributing to insulin resistance in non-obese individuals, twenty healthy, non-obese, normoglycemic subjects identified as insulin sensitive or resistant were studied. Vastus lateralis muscle biopsies obtained during euglycemic, hyperinsulinemic clamp were evaluated for insulin signaling and for activation of stress kinase pathways. Total and regional adipose stores and intramyocellular lipids (IMCL were assessed by DXA, MRI and (1H-MRS. In muscle of resistant subjects, phosphorylation of JNK was increased (1.36±0.23 vs. 0.78±0.10 OD units, P<0.05, while there was no evidence for activation of p38 MAPK or IKKβ. IRS-1 serine phosphorylation was increased (1.30±0.09 vs. 0.22±0.03 OD units, P<0.005 while insulin-stimulated tyrosine phosphorylation decreased (10.97±0.95 vs. 0.89±0.50 OD units, P<0.005. IMCL levels were twice as high in insulin resistant subjects (3.26±0.48 vs. 1.58±0.35% H(2O peak, P<0.05, who also displayed increased total fat and abdominal fat when compared to insulin sensitive controls.This is the first report demonstrating that insulin resistance in non-obese, normoglycemic subjects is associated with activation of the JNK pathway related to increased IMCL and higher total body and abdominal adipose stores. While JNK activation is consistent with a primary impact of muscle lipid accumulation on metabolic stress, further work is necessary to determine the relative contributions of the various mediators of impaired

Sweet taste of saccharin induces weight gain without increasing caloric intake, not related to insulin-resistance in Wistar rats.

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Foletto, Kelly Carraro; Melo Batista, Bruna Aparecida; Neves, Alice Magagnin; de Matos Feijó, Fernanda; Ballard, Cíntia Reis; Marques Ribeiro, Maria Flávia; Bertoluci, Marcello Casaccia

2016-01-01

In a previous study, we showed that saccharin can induce weight gain when compared with sucrose in Wistar rats despite similar total caloric intake. We now question whether it could be due to the sweet taste of saccharin per se. We also aimed to address if this weight gain is associated with insulin-resistance and to increases in gut peptides such as leptin and PYY in the fasting state. In a 14 week experiment, 16 male Wistar rats received either saccharin-sweetened yogurt or non-sweetened yogurt daily in addition to chow and water ad lib. We measured daily food intake and weight gain weekly. At the end of the experiment, we evaluated fasting leptin, glucose, insulin, PYY and determined insulin resistance through HOMA-IR. Cumulative weight gain and food intake were evaluated through linear mixed models. Results showed that saccharin induced greater weight gain when compared with non-sweetened control (p = 0.027) despite a similar total caloric intake. There were no differences in HOMA-IR, fasting leptin or PYY levels between groups. We conclude that saccharin sweet taste can induce mild weight gain in Wistar rats without increasing total caloric intake. This weight gain was not related with insulin-resistance nor changes in fasting leptin or PYY in Wistar rats. Copyright © 2015 Elsevier Ltd. All rights reserved.

Insulin resistance and bone: a biological partnership.

Science.gov (United States)

Conte, Caterina; Epstein, Solomon; Napoli, Nicola

2018-04-01

Despite a clear association between type 2 diabetes (T2D) and fracture risk, the pathogenesis of bone fragility in T2D has not been clearly elucidated. Insulin resistance is the primary defect in T2D. Insulin signalling regulates both bone formation and bone resorption, but whether insulin resistance can affect bone has not been established. On the other hand, evidence exists that bone might play a role in the regulation of glucose metabolism. This article reviews the available experimental and clinical evidence on the interplay between bone and insulin resistance. Interestingly, a bilateral relationship between bone and insulin resistance seems to exist that unites them in a biological partnership.

Association of insulin resistance with obesity in children

International Nuclear Information System (INIS)

Siddiqui, S.A.; Bashir, S.; Shabbir, I.; Sherwani, M.K.; Aasim, M.

2011-01-01

Background: Insulin resistance is the primary metabolic disorder associated with obesity. Little is known about its role as a determinant of the metabolic syndrome in obese children. Objectives: To assess the association of insulin resistance with metabolic syndrome in obese and non obese children. Study type and settings: Cross sectional analytical study conducted among children of ten Municipal Corporation high schools of Data Ganj Buksh Town Lahore. Subjects and Methods: A total of 46 obese and 49 non obese children with consent were recruited for the study. Fasting blood glucose, serum insulin, high density lipoprotein in cholesterol, triglycerides, cholesterol, non HDL-cholesterol LDL-cholesterol were measured using standard methods. Data were analyzed by using statistical software SPSS-Version 15. Results: A total of 95 children 49 obese and 46 non obese were recruited for the study. A significant association of serum triglyceride(p<0.001), high density lipoprotein cholesterol(p<0.001), fasting blood glucose(p<0.001), and insulin levels (p<0.001) , was seen between the two groups. For each component of metabolic syndrome, when insulin resistance increased so did odds ratios for cardio metabolic risk factors. Conclusions: Insulin resistance was seen in 34.7% children. Metabolic syndrome was found in 31.6% children reflecting that obese children are at high risk for metabolic syndrome and have low HDL-cholesterol and high triglycerides levels. (author)

Roles of mitochondrial fragmentation and reactive oxygen species in mitochondrial dysfunction and myocardial insulin resistance

International Nuclear Information System (INIS)

Watanabe, Tomoyuki; Saotome, Masao; Nobuhara, Mamoru; Sakamoto, Atsushi; Urushida, Tsuyoshi; Katoh, Hideki; Satoh, Hiroshi; Funaki, Makoto; Hayashi, Hideharu

2014-01-01

Purpose: Evidence suggests an association between aberrant mitochondrial dynamics and cardiac diseases. Because myocardial metabolic deficiency caused by insulin resistance plays a crucial role in heart disease, we investigated the role of dynamin-related protein-1 (DRP1; a mitochondrial fission protein) in the pathogenesis of myocardial insulin resistance. Methods and Results: DRP1-expressing H9c2 myocytes, which had fragmented mitochondria with mitochondrial membrane potential (ΔΨ m ) depolarization, exhibited attenuated insulin signaling and 2-deoxy-D-glucose (2-DG) uptake, indicating insulin resistance. Treatment of the DRP1-expressing myocytes with Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin pentachloride (TMPyP) significantly improved insulin resistance and mitochondrial dysfunction. When myocytes were exposed to hydrogen peroxide (H 2 O 2 ), they increased DRP1 expression and mitochondrial fragmentation, resulting in ΔΨ m depolarization and insulin resistance. When DRP1 was suppressed by siRNA, H 2 O 2 -induced mitochondrial dysfunction and insulin resistance were restored. Our results suggest that a mutual enhancement between DRP1 and reactive oxygen species could induce mitochondrial dysfunction and myocardial insulin resistance. In palmitate-induced insulin-resistant myocytes, neither DRP1-suppression nor TMPyP restored the ΔΨ m depolarization and impaired 2-DG uptake, however they improved insulin signaling. Conclusions: A mutual enhancement between DRP1 and ROS could promote mitochondrial dysfunction and inhibition of insulin signal transduction. However, other mechanisms, including lipid metabolite-induced mitochondrial dysfunction, may be involved in palmitate-induced insulin resistance. - Highlights: • DRP1 promotes mitochondrial fragmentation and insulin-resistance. • A mutual enhancement between DRP1 and ROS ipromotes insulin-resistance. • Palmitate increases DRP1 expression and induces insulin-resistance. • Inhibition of DRP or ROS

Roles of mitochondrial fragmentation and reactive oxygen species in mitochondrial dysfunction and myocardial insulin resistance

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Watanabe, Tomoyuki [Internal Medicine III, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192 (Japan); Saotome, Masao, E-mail: msaotome@hama-med.ac.jp [Internal Medicine III, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192 (Japan); Nobuhara, Mamoru; Sakamoto, Atsushi; Urushida, Tsuyoshi; Katoh, Hideki; Satoh, Hiroshi [Internal Medicine III, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192 (Japan); Funaki, Makoto [Clinical Research Center for Diabetes, Tokushima University Hospital, 2-50-1 Kuramoto-cho, Tokushima 770-8503 (Japan); Hayashi, Hideharu [Internal Medicine III, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192 (Japan)

2014-05-01

Purpose: Evidence suggests an association between aberrant mitochondrial dynamics and cardiac diseases. Because myocardial metabolic deficiency caused by insulin resistance plays a crucial role in heart disease, we investigated the role of dynamin-related protein-1 (DRP1; a mitochondrial fission protein) in the pathogenesis of myocardial insulin resistance. Methods and Results: DRP1-expressing H9c2 myocytes, which had fragmented mitochondria with mitochondrial membrane potential (ΔΨ{sub m}) depolarization, exhibited attenuated insulin signaling and 2-deoxy-D-glucose (2-DG) uptake, indicating insulin resistance. Treatment of the DRP1-expressing myocytes with Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin pentachloride (TMPyP) significantly improved insulin resistance and mitochondrial dysfunction. When myocytes were exposed to hydrogen peroxide (H{sub 2}O{sub 2}), they increased DRP1 expression and mitochondrial fragmentation, resulting in ΔΨ{sub m} depolarization and insulin resistance. When DRP1 was suppressed by siRNA, H{sub 2}O{sub 2}-induced mitochondrial dysfunction and insulin resistance were restored. Our results suggest that a mutual enhancement between DRP1 and reactive oxygen species could induce mitochondrial dysfunction and myocardial insulin resistance. In palmitate-induced insulin-resistant myocytes, neither DRP1-suppression nor TMPyP restored the ΔΨ{sub m} depolarization and impaired 2-DG uptake, however they improved insulin signaling. Conclusions: A mutual enhancement between DRP1 and ROS could promote mitochondrial dysfunction and inhibition of insulin signal transduction. However, other mechanisms, including lipid metabolite-induced mitochondrial dysfunction, may be involved in palmitate-induced insulin resistance. - Highlights: • DRP1 promotes mitochondrial fragmentation and insulin-resistance. • A mutual enhancement between DRP1 and ROS ipromotes insulin-resistance. • Palmitate increases DRP1 expression and induces insulin-resistance

Insulin and GLP-1 infusions demonstrate the onset of adipose-specific insulin resistance in a large fasting mammal: potential glucogenic role for GLP-1.

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Viscarra, Jose A; Rodriguez, Ruben; Vazquez-Medina, Jose Pablo; Lee, Andrew; Tift, Michael S; Tavoni, Stephen K; Crocker, Daniel E; Ortiz, Rudy M

2013-08-01

Prolonged food deprivation increases lipid oxidation and utilization, which may contribute to the onset of the insulin resistance associated with fasting. Because insulin resistance promotes the preservation of glucose and oxidation of fat, it has been suggested to be an adaptive response to food deprivation. However, fasting mammals exhibit hypoinsulinemia, suggesting that the insulin resistance-like conditions they experience may actually result from reduced pancreatic sensitivity to glucose/capacity to secrete insulin. To determine whether fasting results in insulin resistance or in pancreatic dysfunction, we infused early- and late-fasted seals (naturally adapted to prolonged fasting) with insulin (0.065 U/kg), and a separate group of late-fasted seals with low (10 pM/kg) or high (100 pM/kg) dosages of glucagon-like peptide-1 (GLP-1) immediately following a glucose bolus (0.5g/kg), and measured the systemic and cellular responses. Because GLP-1 facilitates glucose-stimulated insulin secretion, these infusions provide a method to assess pancreatic insulin-secreting capacity. Insulin infusions increased the phosphorylation of insulin receptor and Akt in adipose and muscle of early and late fasted seals; however the timing of the signaling response was blunted in adipose of late fasted seals. Despite the dose-dependent increases in insulin and increased glucose clearance (high dose), both GLP-1 dosages produced increases in plasma cortisol and glucagon, which may have contributed to the glucogenic role of GLP-1. Results suggest that fasting induces adipose-specific insulin resistance in elephant seal pups, while maintaining skeletal muscle insulin sensitivity, and therefore suggests that the onset of insulin resistance in fasting mammals is an evolved response to cope with prolonged food deprivation.

Novel and Reversible Mechanisms of Smoking-Induced Insulin Resistance in Humans

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Bergman, Bryan C.; Perreault, Leigh; Hunerdosse, Devon; Kerege, Anna; Playdon, Mary; Samek, Ali M.; Eckel, Robert H.

2012-01-01

Smoking is the most common cause of preventable morbidity and mortality in the United States, in part because it is an independent risk factor for the development of insulin resistance and type 2 diabetes. However, mechanisms responsible for smoking-induced insulin resistance are unclear. In this study, we found smokers were less insulin sensitive compared with controls, which increased after either 1 or 2 weeks of smoking cessation. Improvements in insulin sensitivity after smoking cessation...

Is Shift Work Associated with Lipid Disturbances and Increased Insulin Resistance?

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Alefishat, Eman; Abu Farha, Rana

2015-11-01

Shift work is associated with higher risk of metabolic disturbances and cardiovascular diseases. There are contradictory reports on the effect of shift work on lipid parameters in the literature. No studies have investigated any possible association between shift work and the ratio of serum triglyceride to high density lipoprotein cholesterol (TG/HDL-C ratio). This ratio can be used as a predictor for insulin resistance. The main aim of the present cross-sectional study was to investigate the association between shift work and serum TG/HDL-C ratio, TG level, and HDL-C level. One hundred and forty adult Jordanian employees were recruited. Demographic data, lifestyle habits, clinical parameters, and working patterns data were documented through a well-structured questionnaire. Serum TG and HDL-C levels were measured after at least 9 hours fasting using enzymatic assay procedure. Compared with daytime workers (58 subjects), shift workers (82 subjects) displayed higher TG/HDL-C ratio (r = 0.217, P = 0.013), higher serum TG levels (r = 0.220, P = 0.012), and lower HDL-C levels (r = -0.200, P = 0.016). Among shift workers, 30.5% were found to have a TG/HDL-C ratio >3.5 compared with 8.6% of daytime workers (P = 0.002). In the present study, shift work was shown to be associated with higher TG/HDL-C ratio, higher serum TG, and lower HDL-C levels. These findings might indicate that shift work is associated with increased insulin resistance and consequently higher risk of metabolic syndrome and cardiovascular diseases.

Rebelling against the (Insulin Resistance: A Review of the Proposed Insulin-Sensitizing Actions of Soybeans, Chickpeas, and Their Bioactive Compounds

Directory of Open Access Journals (Sweden)

Jaime L. Clark

2018-03-01

Full Text Available Insulin resistance is a major risk factor for diseases such as type 2 diabetes and metabolic syndrome. Current methods for management of insulin resistance include pharmacological therapies and lifestyle modifications. Several clinical studies have shown that leguminous plants such as soybeans and pulses (dried beans, dried peas, chickpeas, lentils are able to reduce insulin resistance and related type 2 diabetes parameters. However, to date, no one has summarized the evidence supporting a mechanism of action for soybeans and pulses that explains their ability to lower insulin resistance. While it is commonly assumed that the biological activities of soybeans and pulses are due to their antioxidant activities, these bioactive compounds may operate independent of their antioxidant properties and, thus, their ability to potentially improve insulin sensitivity via alternative mechanisms needs to be acknowledged. Based on published studies using in vivo and in vitro models representing insulin resistant states, the proposed mechanisms of action for insulin-sensitizing actions of soybeans, chickpeas, and their bioactive compounds include increasing glucose transporter-4 levels, inhibiting adipogenesis by down-regulating peroxisome proliferator-activated receptor-γ, reducing adiposity, positively affecting adipokines, and increasing short-chain fatty acid-producing bacteria in the gut. Therefore, this review will discuss the current evidence surrounding the proposed mechanisms of action for soybeans and certain pulses, and their bioactive compounds, to effectively reduce insulin resistance.

Insulin resistance and serum parameters of iron status in type 2 diabetics

International Nuclear Information System (INIS)

Zafar, U.

2011-01-01

Background: Type 2 diabetes mellitus (T2DM) is a predominant public health concern worldwide, accounting for 90% of the cases of diabetes globally. Pathogenesis of T2DM involves insulin resistance, defective insulin secretion and increased glucose production by the liver. Subclinical haemochromatosis has been considered as one of the probable causes of insulin resistance and diabetes mellitus. The aim of this study was to determine and correlate insulin resistance and serum parameters of iron status (serum ferritin and transferrin saturation) in type 2 diabetics. Methods: It was a correlational study. This study was conducted on sixty male patients with type 2 diabetes mellitus. Fasting blood sample was taken from each subject and analysed for glucose, haemoglobin, insulin, iron, Total Iron Binding Capacity (TIBC) and ferritin. Insulin resistance was determined by HOMA-IR index. Transferrin saturation was calculated from serum iron and TIBC. Data was analysed using SPSS-17. Results: There was significant positive correlation between insulin resistance and transferrin saturation, but there was no significant correlation of insulin resistance with blood haemoglobin, serum iron and serum ferritin in type 2 diabetics. Conclusion: Correlation between insulin resistance and transferrin saturation reveals that iron has negative impact on insulin sensitivity in type 2 diabetics. (author)

A short leucocyte telomere length is associated with development of insulin resistance

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Verhulst, Simon; Dalgård, Christine; Labat, Carlos

2016-01-01

AIMS/HYPOTHESIS: A number of studies have shown that leucocyte telomere length (LTL) is inversely associated with insulin resistance and type 2 diabetes mellitus. The aim of the present longitudinal cohort study, utilising a twin design, was to assess whether shorter LTL predicts insulin resistance...... and insulin resistance over an average of 12 years were performed in a subset of the Registry consisting of 338 (184 monozygotic and 154 dizygotic) same-sex twin pairs. RESULTS: Age at baseline examination was 37.4 ± 9.6 (mean ± SD) years. Baseline insulin resistance was not associated with age......-dependent changes in LTL (attrition) over the follow-up period, whereas baseline LTL was associated with changes in insulin resistance during this period. The shorter the LTL at baseline, the more pronounced was the increase in insulin resistance over the follow-up period (p 

Globular adiponectin ameliorates metabolic insulin resistance via AMPK-mediated restoration of microvascular insulin responses

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Zhao, Lina; Fu, Zhuo; Wu, Jing; Aylor, Kevin W; Barrett, Eugene J; Cao, Wenhong; Liu, Zhenqi

2015-01-01

Abstract Hypoadiponectinaemia is closely associated with endothelial dysfunction and insulin resistance, and microvasculature plays a critical role in the regulation of insulin action in muscle. Here we tested whether adiponectin replenishment could improve metabolic insulin sensitivity in male rats fed a high-fat diet (HFD) via the modulation of microvascular insulin responses. Male Sprague–Dawley rats were fed either a HFD or low-fat diet (LFD) for 4 weeks. Small resistance artery myograph changes in tension, muscle microvascular recruitment and metabolic response to insulin were determined. Compared with rats fed a LFD, HFD feeding abolished the vasodilatory actions of globular adiponectin (gAd) and insulin on pre-constricted distal saphenous arteries. Pretreatment with gAd improved insulin responses in arterioles isolated from HFD rats, which was blocked by AMP-activated protein kinase (AMPK) inhibition. Similarly, HFD abolished microvascular responses to either gAd or insulin and decreased insulin-stimulated glucose disposal by ∼60%. However, supplementing gAd fully rescued insulin’s microvascular action and significantly improved the metabolic responses to insulin in HFD male rats and these actions were abolished by inhibition of either AMPK or nitric oxide production. We conclude that HFD induces vascular adiponectin and insulin resistance but gAd administration can restore vascular insulin responses and improve insulin’s metabolic action via an AMPK- and nitric oxide-dependent mechanism in male rats. Key points Adiponectin is an adipokine with anti-inflammatory and anti-diabetic properties. Hypoadiponectinaemia is closely associated with endothelial dysfunction and insulin resistance in obesity and diabetes. Insulin resistance is present in muscle microvasculature and this may contribute to decreased insulin delivery to, and action in, muscle. In this study we examined whether adiponectin ameliorates metabolic insulin resistance by affecting muscle

Insulin resistance and maximal oxygen uptake

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Seibaek, Marie; Vestergaard, Henrik; Burchardt, Hans

2003-01-01

BACKGROUND: Type 2 diabetes, coronary atherosclerosis, and physical fitness all correlate with insulin resistance, but the relative importance of each component is unknown. HYPOTHESIS: This study was undertaken to determine the relationship between insulin resistance, maximal oxygen uptake......, and the presence of either diabetes or ischemic heart disease. METHODS: The study population comprised 33 patients with and without diabetes and ischemic heart disease. Insulin resistance was measured by a hyperinsulinemic euglycemic clamp; maximal oxygen uptake was measured during a bicycle exercise test. RESULTS......: There was a strong correlation between maximal oxygen uptake and insulin-stimulated glucose uptake (r = 0.7, p = 0.001), and maximal oxygen uptake was the only factor of importance for determining insulin sensitivity in a model, which also included the presence of diabetes and ischemic heart disease. CONCLUSION...

Peripheral nervous system insulin resistance in ob/ob mice

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2013-01-01

Background A reduction in peripheral nervous system (PNS) insulin signaling is a proposed mechanism that may contribute to sensory neuron dysfunction and diabetic neuropathy. Neuronal insulin resistance is associated with several neurological disorders and recent evidence has indicated that dorsal root ganglion (DRG) neurons in primary culture display altered insulin signaling, yet in vivo results are lacking. Here, experiments were performed to test the hypothesis that the PNS of insulin-resistant mice displays altered insulin signal transduction in vivo. For these studies, nondiabetic control and type 2 diabetic ob/ob mice were challenged with an intrathecal injection of insulin or insulin-like growth factor 1 (IGF-1) and downstream signaling was evaluated in the DRG and sciatic nerve using Western blot analysis. Results The results indicate that insulin signaling abnormalities documented in other “insulin sensitive” tissues (i.e. muscle, fat, liver) of ob/ob mice are also present in the PNS. A robust increase in Akt activation was observed with insulin and IGF-1 stimulation in nondiabetic mice in both the sciatic nerve and DRG; however this response was blunted in both tissues from ob/ob mice. The results also suggest that upregulated JNK activation and reduced insulin receptor expression could be contributory mechanisms of PNS insulin resistance within sensory neurons. Conclusions These findings contribute to the growing body of evidence that alterations in insulin signaling occur in the PNS and may be a key factor in the pathogenesis of diabetic neuropathy. PMID:24252636

Testosterone treatment increases androgen receptor and aromatase gene expression in myotubes from patients with PCOS and controls, but does not induce insulin resistance

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Eriksen, Mette Brandt; Glintborg, Dorte; Nielsen, Michael Friberg Bruun

2014-01-01

Polycystic ovary syndrome (PCOS) is associated with insulin resistance and increased risk of type 2 diabetes. Skeletal muscle is the major site of insulin mediated glucose disposal and the skeletal muscle tissue is capable to synthesize, convert and degrade androgens. Insulin sensitivity is conse......Polycystic ovary syndrome (PCOS) is associated with insulin resistance and increased risk of type 2 diabetes. Skeletal muscle is the major site of insulin mediated glucose disposal and the skeletal muscle tissue is capable to synthesize, convert and degrade androgens. Insulin sensitivity...... is conserved in cultured myotubes (in vitro) from patients with PCOS, but the effect of testosterone on this insulin sensitivity is unknown. We investigated the effect of 7days testosterone treatment (100nmol/l) on glucose transport and gene expression levels of hormone receptors and enzymes involved...... in the synthesis and conversion of testosterone (HSD17B1, HSD17B2, CYP19A1, SRD5A1-2, AR, ER-α, HSD17B6 and AKR1-3) in myotubes from ten patients with PCOS and ten matched controls. Testosterone treatment significantly increased aromatase and androgen receptor gene expression levels in patients and controls...

Genetics Home Reference: type A insulin resistance syndrome

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... Conditions Type A insulin resistance syndrome Type A insulin resistance syndrome Printable PDF Open All Close All Enable ... view the expand/collapse boxes. Description Type A insulin resistance syndrome is a rare disorder characterized by severe ...

Insulin resistance in porphyria cutanea tarda.

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Calcinaro, F; Basta, G; Lisi, P; Cruciani, C; Pietropaolo, M; Santeusanio, F; Falorni, A; Calafiore, R

1989-06-01

It has been reported that patients with porphyria cutanea tarda (PCT) develop carbohydrate (CHO) intolerance and manifest diabetes melitus (DM) more frequently than the normal population. In order to verify whether this is due to insulin resistance we studied 5 patients with PCT and 5 normal subjects matched for age, sex and weight. In all the patients an evaluation consisted of the glycemic curve and insulin response to an iv glucose tolerance test (IVGTT: 0.33 g/kg) as well as of an evaluation of the circulating monocyte insulin receptors. Blood samples were drawn in the basal state to measure plasma levels of NEFA, glycerol, and intermediate metabolites. The patients with PCT showed normal glucose tolerance which was obtained, however, at the expense of the elevated insulin levels: therefore a condition of insulin resistance was demonstrated in these subjects. An involvement of the lipid metabolism, observed by the raised levels of plasma NEFA and glycerol, was also evident. The insulin binding to circulating monocytes was reduced but not enough to justify the degree of insulin resistance observed. Therefore, it could be hypothesized, in agreement with similar studies, that a postreceptor defect is responsible for the insulin-resistance observed in patients with PCT and that the reduction of insulin receptors is determined by the down regulation in response to elevated insulinemic levels. An alteration of the porphyrin metabolism might be responsible for this disorder.

A human model of dietary saturated fatty acid induced insulin resistance.

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Koska, Juraj; Ozias, Marlies K; Deer, James; Kurtz, Julie; Salbe, Arline D; Harman, S Mitchell; Reaven, Peter D

2016-11-01

Increased consumption of high-fat diets is associated with the development of insulin resistance and type 2 diabetes. Current models to study the mechanisms of high-fat diet-induced IR in humans are limited by their long duration or low efficacy. In the present study we developed and characterized an acute dietary model of saturated fatty acid-enriched diet induced insulin resistance. High caloric diets enriched with saturated fatty acids (SFA) or carbohydrates (CARB) were evaluated in subjects with normal and impaired glucose tolerance (NGT or IGT). Both diets were compared to a standard eucaloric American Heart Association (AHA) control diet in a series of crossover studies. Whole body insulin resistance was estimated as steady state plasma glucose (SSPG) concentrations during the last 30min of a 3-h insulin suppression test. SSPG was increased after a 24-h SFA diet (by 83±74% vs. control, n=38) in the entire cohort, which was comprised of participants with NGT (92±82%, n=22) or IGT (65±55%, n=16) (all pinsulin resistance in both NGT and IGT subjects. Insulin resistance persisted overnight after the last SFA meal and was attenuated by one day of a healthy diet. This model offers opportunities for identifying early mechanisms and potential treatments of dietary saturated fat induced insulin resistance. Published by Elsevier Inc.

Higher fetal insulin resistance in Chinese pregnant women with gestational diabetes mellitus and correlation with maternal insulin resistance.

Science.gov (United States)

Wang, Qiuwei; Huang, Ruiping; Yu, Bin; Cao, Fang; Wang, Huiyan; Zhang, Ming; Wang, Xinhong; Zhang, Bin; Zhou, Hong; Zhu, Ziqiang

2013-01-01

The aim of this study was to determine the effect of gestational diabetes mellitus (GDM) on fetal insulin resistance or β-cell function in Chinese pregnant women with GDM. Maternal fasting blood and venous cord blood samples (reflecting fetal condition) were collected in 65 well-controlled Chinese GDM mothers (only given dietary intervention) and 83 control subjects. The insulin, glucose and proinsulin concentrations of both maternal and cord blood samples were measured, and the homeostasis model assessment of insulin resistance (HOMA-IR) and the proinsulin-to-insulin ratios (an indicator of fetal β-cell function) were calculated in maternal and cord blood respectively. Both maternal and fetal levels of insulin, proinsulin and HOMA-IR but not proinsulin-to-insulin ratios were significantly higher in the GDM group than in the control group (maternal insulin, 24.8 vs. 15.4 µU/mL, P = 0.004, proinsulin, 23.3 vs. 16.2 pmol/L, P = 0.005, and HOMA-IR, 5.5 vs. 3.5, P = 0.041, respectively; fetal: insulin, 15.1 vs. 7.9 µU/mL, Pinsulin ratios was significantly correlated to maternal HOMA-IR (r = 0.307, P = 0.019), in the pregnant women with GDM. Fetal insulin resistance was higher in Chinese pregnant women with GDM than control subjects, and correlated with maternal insulin resistance.

Radiation resistivity of frozen insulin solutions and suspensions

Energy Technology Data Exchange (ETDEWEB)

Soboleva, N N; Ivanova, A I; Talrose, V L; Trofimov, V I; Fedotov, V P [AN SSSR, Moscow. Inst. Fizicheskoj Khimii; Research Institute for Biological Testing of Chemicals, Moscow (USSR); Institute of Experimental Endocrinology and Hormon Chemistry, Moscow (USSR))

1981-10-01

The effect of great increase in radiation resistance of insulin solutions and suspensions after irradiation at low temperatures in the frozen state was observed by absorption spectrophotometry, paper chromatography and biological analysis. The data obtained suggest irradiation of frozen insulin solutions and suspensions as a method for its sterilization.

High Uric Acid Induces Insulin Resistance in Cardiomyocytes In Vitro and In Vivo.

Directory of Open Access Journals (Sweden)

Li Zhi

Full Text Available Clinical studies have shown hyperuricemia strongly associated with insulin resistance as well as cardiovascular disease. Direct evidence of how high uric acid (HUA affects insulin resistance in cardiomyocytes, but the pathological mechanism of HUA associated with cardiovascular disease remains to be clarified. We aimed to examine the effect of HUA on insulin sensitivity in cardiomyocytes and on insulin resistance in hyperuricemic mouse model. We exposed primary cardiomyocytes and a rat cardiomyocyte cell line, H9c2 cardiomyocytes, to HUA, then quantified glucose uptake with a fluorescent glucose analog, 2-NBDG, after insulin challenge and detected reactive oxygen species (ROS production. Western blot analysis was used to examine the levels of insulin receptor (IR, phosphorylated insulin receptor substrate 1 (IRS1, Ser307 and phospho-Akt (Ser473. We monitored the impact of HUA on insulin resistance, insulin signaling and IR, phospho-IRS1 (Ser307 and phospho-Akt levels in myocardial tissue of an acute hyperuricemia mouse model established by potassium oxonate treatment. HUA inhibited insulin-induced glucose uptake in H9c2 and primary cardiomyocytes. It increased ROS production; pretreatment with N-acetyl-L-cysteine (NAC, a ROS scavenger, reversed HUA-inhibited glucose uptake induced by insulin. HUA exposure directly increased the phospho-IRS1 (Ser307 response to insulin and inhibited that of phospho-Akt in H9C2 cardiomyocytes, which was blocked by NAC. Furthermore, the acute hyperuricemic mice model showed impaired glucose tolerance and insulin tolerance accompanied by increased phospho-IRS1 (Ser307 and inhibited phospho-Akt response to insulin in myocardial tissues. HUA inhibited insulin signaling and induced insulin resistance in cardiomyocytes in vitro and in vivo, which is a novel potential mechanism of hyperuricemic-related cardiovascular disease.

Insulin-resistant glucose metabolism in patients with microvascular angina--syndrome X

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Vestergaard, H; Skøtt, P; Steffensen, R

1995-01-01

Studies in patients with microvascular angina (MA) or the cardiologic syndrome X have shown a hyperinsulinemic response to an oral glucose challenge, suggesting insulin resistance and a role for increased serum insulin in coronary microvascular dysfunction. The aim of the present study was to exa......Studies in patients with microvascular angina (MA) or the cardiologic syndrome X have shown a hyperinsulinemic response to an oral glucose challenge, suggesting insulin resistance and a role for increased serum insulin in coronary microvascular dysfunction. The aim of the present study...... was to examine whether patients with MA are insulin-resistant. Nine patients with MA and seven control subjects were studied. All were sedentary and glucose-tolerant. Coronary arteriography was normal in all participants, and exercise-induced coronary ischemia was demonstrated in all MA patients. A euglycemic...... metabolism (8.4 +/- 0.9 v 12.5 +/- 1.3 mg.kg FFM-1.min-1, P

Glucose-induced insulin resistance of skeletal-muscle glucose transport and uptake

DEFF Research Database (Denmark)

Richter, Erik; Hansen, B F; Hansen, S A

1988-01-01

in the presence of glucose and insulin. The data indicate that exposure to a moderately increased glucose concentration (12 mM) leads to rapidly developing resistance of skeletal-muscle glucose transport and uptake to maximal insulin stimulation. The effect of glucose is enhanced by simultaneous insulin exposure......, whereas exposure for 5 h to insulin itself does not cause measurable resistance to maximal insulin stimulation.......The ability of glucose and insulin to modify insulin-stimulated glucose transport and uptake was investigated in perfused skeletal muscle. Here we report that perfusion of isolated rat hindlimbs for 5 h with 12 mM-glucose and 20,000 microunits of insulin/ml leads to marked, rapidly developing...

Insulin Resistance

DEFF Research Database (Denmark)

Jensen, Benjamin Anderschou Holbech

Insulin resistance (IR) is escalating with alarming pace and is no longer restricted to westernized countries. As a forerunner for some of the most serious threats to human health including metabolic syndrome, cardiovascular diseases, and type 2-diabetes, the need for new treatment modalities...... interventions. We further show that improving the inflammatory toning, using fish oil as fat source, protects mice against diet induced obesity and -inflammation while preserving insulin sensitivity, even in the absence of free fatty acid receptor 4. Conversely, HFD-induced intestinal dysbiosis is associated...

Peripheral insulin resistance and impaired insulin signaling contribute to abnormal glucose metabolism in preterm baboons.

Science.gov (United States)

Blanco, Cynthia L; McGill-Vargas, Lisa L; Gastaldelli, Amalia; Seidner, Steven R; McCurnin, Donald C; Leland, Michelle M; Anzueto, Diana G; Johnson, Marney C; Liang, Hanyu; DeFronzo, Ralph A; Musi, Nicolas

2015-03-01

Premature infants develop hyperglycemia shortly after birth, increasing their morbidity and death. Surviving infants have increased incidence of diabetes as young adults. Our understanding of the biological basis for the insulin resistance of prematurity and developmental regulation of glucose production remains fragmentary. The objective of this study was to examine maturational differences in insulin sensitivity and the insulin-signaling pathway in skeletal muscle and adipose tissue of 30 neonatal baboons using the euglycemic hyperinsulinemic clamp. Preterm baboons (67% gestation) had reduced peripheral insulin sensitivity shortly after birth (M value 12.5 ± 1.5 vs 21.8 ± 4.4 mg/kg · min in term baboons) and at 2 weeks of age (M value 12.8 ± 2.6 vs 16.3 ± 4.2, respectively). Insulin increased Akt phosphorylation, but these responses were significantly lower in preterm baboons during the first week of life (3.2-fold vs 9.8-fold). Preterm baboons had lower glucose transporter-1 protein content throughout the first 2 weeks of life (8%-12% of term). In preterm baboons, serum free fatty acids (FFAs) did not decrease in response to insulin, whereas FFAs decreased by greater than 80% in term baboons; the impaired suppression of FFAs in the preterm animals was paired with a decreased glucose transporter-4 protein content in adipose tissue. In conclusion, peripheral insulin resistance and impaired non-insulin-dependent glucose uptake play an important role in hyperglycemia of prematurity. Impaired insulin signaling (reduced Akt) contributes to the defect in insulin-stimulated glucose disposal. Counterregulatory hormones are not major contributors.

Insulin resistance and associated factors: a cross-sectional study of bank employees.

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Salaroli, Luciane Bresciani; Cattafesta, Monica; Molina, Maria Del Carmen Bisi; Zandonade, Eliana; Bissoli, Nazaré Souza

2017-04-01

Insulin resistance is characterized by the failure of target cells to respond to normal levels of circulating insulin, and this condition is related to cardiovascular disease. This study sought to evaluate the prevalence of insulin resistance and its association with markers of metabolic abnormalities and metabolic syndrome in bank employees. A cross-sectional study was performed on 498 working men and women aged ≥20 years old. The Homeostasis Model Assessment (HOMA-IR) was used to determine the presence of insulin resistance based on cut-off values of ≤2.71 for normal insulin levels and >2.71 for insulin resistance, as established for the adult Brazilian population. It was observed that the 52 (10.4%) overweight individuals with insulin resistance were 4.97 times (95%CI 1.31-18.83) more likely to have high HOMA-IR values than the normal-weight participants; among those who were obese, the likelihood increased to 17.87 (95%CI 4.36-73.21). Individuals with large waist circumferences were 3.27 times (95%CI 1.03-10.38) more likely to develop insulin resistance than those who were within normal parameters. The HOMA-IR values differed between subjects with and without metabolic syndrome, with values of 2.83±2.5 and 1.10±0.81 (p=0.001), respectively. The levels of insulin, ultrasensitive C-reactive protein and uric acid were also associated with insulin resistance. The prevalence of insulin resistance among bank employees is high, and insulin resistance is associated with and serves as a marker of metabolic syndrome. Cardiovascular disease and metabolic syndrome-associated metabolic abnormalities were observed, and insulin resistance may be a risk factor in this group of professionals.

Cognitively impaired elderly exhibit insulin resistance and no memory improvement with infused insulin.

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Morris, Jill K; Vidoni, Eric D; Mahnken, Jonathan D; Montgomery, Robert N; Johnson, David K; Thyfault, John P; Burns, Jeffrey M

2016-03-01

Insulin resistance is a risk factor for Alzheimer's disease (AD), although its role in AD etiology is unclear. We assessed insulin resistance using fasting and insulin-stimulated measures in 51 elderly subjects with no dementia (ND; n = 37) and with cognitive impairment (CI; n = 14). CI subjects exhibited either mild CI or AD. Fasting insulin resistance was measured using the homeostatic model assessment of insulin resistance (HOMA-IR). Insulin-stimulated glucose disposal was assessed using the hyperinsulinemic-euglycemic clamp to calculate glucose disposal rate into lean mass, the primary site of insulin-stimulated glucose disposal. Because insulin crosses the blood-brain barrier, we also assessed whether insulin infusion would improve verbal episodic memory compared to baseline. Different but equivalent versions of cognitive tests were administered in counterbalanced order in the basal and insulin-stimulated state. Groups did not differ in age or body mass index. Cognitively impaired subjects exhibited greater insulin resistance as measured at fasting (HOMA-IR; ND: 1.09 [1.1] vs. CI: 2.01 [2.3], p = 0.028) and during the hyperinsulinemic clamp (glucose disposal rate into lean mass; ND: 9.9 (4.5) vs. AD 7.2 (3.2), p = 0.040). Cognitively impaired subjects also exhibited higher fasting insulin compared to ND subjects, (CI: 8.7 [7.8] vs. ND: 4.2 [3.8] μU/mL; p = 0.023) and higher fasting amylin (CI: 24.1 [39.1] vs. 8.37 [14.2]; p = 0.050) with no difference in fasting glucose. Insulin infusion elicited a detrimental effect on one test of verbal episodic memory (Free and Cued Selective Reminding Test) in both groups (p insulin resistance was observed in cognitively impaired subjects compared to ND controls, insulin infusion did not improve memory. Furthermore, a significant correlation between HOMA-IR and glucose disposal rate was present only in ND (p = 0.0002) but not in cognitively impaired (p = 0.884) subjects, indicating potentially important

Antibody-Mediated Extreme Insulin Resistance: A Report of Three Cases.

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Kim, Han Na; Fesseha, Betiel; Anzaldi, Laura; Tsao, Allison; Galiatsatos, Panagis; Sidhaye, Aniket

2018-01-01

Type 2 diabetes mellitus is characterized by relative insulin deficiency and insulin resistance. Features suggesting severe insulin resistance include acanthosis nigricans, hyperandrogenism, weight loss, and recurrent hospital admissions for diabetic ketoacidosis. In rare circumstances, hyperglycemia persists despite administration of massive doses of insulin. In these cases, it is important to consider autoimmune etiologies for insulin resistance, such as type B insulin resistance and insulin antibody-mediated extreme insulin resistance, which carry high morbidity and mortality if untreated. Encouragingly, immunomodulatory regimens have recently been published that induce remission at high rates. We describe 3 cases of extreme insulin resistance mediated by anti-insulin receptor autoantibodies or insulin autoantibodies. All cases were effectively treated with an immunomodulatory regimen. Although cases of extreme insulin resistance are rare, it is important to be aware of autoimmune causes, recognize suggestive signs and symptoms, and pursue appropriate diagnostic evaluation. Prompt treatment with immunomodulators is key to restoring euglycemia in patients with autoimmune etiologies of insulin resistance. Copyright © 2018 Elsevier Inc. All rights reserved.

Fructose induced neurogenic hypertension mediated by overactivation of p38 MAPK to impair insulin signaling transduction caused central insulin resistance.

Science.gov (United States)

Cheng, Pei-Wen; Lin, Yu-Te; Ho, Wen-Yu; Lu, Pei-Jung; Chen, Hsin-Hung; Lai, Chi-Cheng; Sun, Gwo-Ching; Yeh, Tung-Chen; Hsiao, Michael; Tseng, Ching-Jiunn; Liu, Chun-Peng

2017-11-01

Type 2 diabetes are at a high risk of complications related to hypertension, and reports have indicated that insulin levels may be associated with blood pressure (BP). Fructose intake has recently been reported to promote insulin resistance and superoxide formation. The aim of this study is to investigate whether fructose intake can enhance superoxide generation and impair insulin signaling in the NTS and subsequently elevate BP in rats with fructose-induced hypertension. Treatment with fructose for 4 weeks increased the BP, serum fasting insulin, glucose, homeostatic model assessment-insulin resistance, and triglyceride levels and reduced the serum direct high-density lipoprotein level in the fructose group. The Tempol treatment recovered the fructose-induced decrease in nitric oxide production in the NTS. Immunoblotting and immunofluorescence analyses further showed that fructose increased the p38- and fructose-induced phosphorylation of insulin receptor substrate 1 (IRS1 S307 ) and suppressed Akt S473 and neuronal nitric oxide synthase phosphorylation. Similarly, fructose was able to impair insulin sensitivity and increase insulin levels in the NTS. Fructose intake also increased the production of superoxide in the NTS. The results of this study suggest that fructose might induce central insulin resistance and elevate BP by enhancing superoxide production and activating p38 phosphorylation in the NTS. Copyright © 2017 Elsevier Inc. All rights reserved.

Ghrelin- and GH-induced insulin resistance

DEFF Research Database (Denmark)

Vestergaard, Esben Thyssen; Krag, Morten B; Poulsen, Morten M

2013-01-01

Supraphysiological levels of ghrelin and GH induce insulin resistance. Serum levels of retinol-binding protein-4 (RBP4) correlate inversely with insulin sensitivity in patients with type 2 diabetes. We aimed to determine whether ghrelin and GH affect RBP4 levels in human subjects.......Supraphysiological levels of ghrelin and GH induce insulin resistance. Serum levels of retinol-binding protein-4 (RBP4) correlate inversely with insulin sensitivity in patients with type 2 diabetes. We aimed to determine whether ghrelin and GH affect RBP4 levels in human subjects....

Influence of Gut Microbiota on Subclinical Inflammation and Insulin Resistance

Directory of Open Access Journals (Sweden)

Bruno Melo Carvalho

2013-01-01

Full Text Available Obesity is the main condition that is correlated with the appearance of insulin resistance, which is the major link among its comorbidities, such as type 2 diabetes, nonalcoholic fatty liver disease, cardiovascular and neurodegenerative diseases, and several types of cancer. Obesity affects a large number of individuals worldwide; it degrades human health and quality of life. Here, we review the role of the gut microbiota in the pathophysiology of obesity and type 2 diabetes, which is promoted by a bacterial diversity shift mediated by overnutrition. Whole bacteria, their products, and metabolites undergo increased translocation through the gut epithelium to the circulation due to degraded tight junctions and the consequent increase in intestinal permeability that culminates in inflammation and insulin resistance. Several strategies focusing on modulation of the gut microbiota (antibiotics, probiotics, and prebiotics are being experimentally employed in metabolic derangement in order to reduce intestinal permeability, increase the production of short chain fatty acids and anorectic gut hormones, and promote insulin sensitivity to counteract the inflammatory status and insulin resistance found in obese individuals.

Insulin sensitizers prevent fine particulate matter-induced vascular insulin resistance and changes in endothelial progenitor cell homeostasis.

Science.gov (United States)

Haberzettl, Petra; McCracken, James P; Bhatnagar, Aruni; Conklin, Daniel J

2016-06-01

Exposure to fine particular matter (PM2.5) increases the risk of developing cardiovascular disease and Type 2 diabetes. Because blood vessels are sensitive targets of air pollutant exposure, we examined the effects of concentrated ambient PM2.5 (CAP) on vascular insulin sensitivity and circulating levels of endothelial progenitor cells (EPCs), which reflect cardiovascular health. We found that CAP exposure for 9 days decreased insulin-stimulated Akt phosphorylation in the aorta of mice maintained on control diet. This change was accompanied by the induction of IL-1β and increases in the abundance of cleaved IL-18 and p10 subunit of Casp-1, consistent with the activation of the inflammasome pathway. CAP exposure also suppressed circulating levels of EPCs (Flk-1(+)/Sca-1(+) cells), while enhancing the bone marrow abundance of these cells. Although similar changes in vascular insulin signaling and EPC levels were observed in mice fed high-fat diet, CAP exposure did not exacerbate diet-induced changes in vascular insulin resistance or EPC homeostasis. Treatment with an insulin sensitizer, metformin or rosiglitazone, prevented CAP-induced vascular insulin resistance and NF-κB and inflammasome activation and restored peripheral blood and bone marrow EPC levels. These findings suggest that PM2.5 exposure induces diet-independent vascular insulin resistance and inflammation and prevents EPC mobilization, and that this EPC mobilization defect could be mediated by vascular insulin resistance. Impaired vascular insulin sensitivity may be an important mechanism underlying PM2.5-induced vascular injury, and pharmacological sensitization to insulin action could potentially prevent deficits in vascular repair and mitigate vascular inflammation due to exposure to elevated levels of ambient air pollution. Copyright © 2016 the American Physiological Society.

Homeostatic Model Assessment for Insulin Resistance (HOMA-IR): A Better Marker for Evaluating Insulin Resistance Than Fasting Insulin in Women with Polycystic Ovarian Syndrome.

Science.gov (United States)

Majid, Hafsa; Masood, Qamar; Khan, Aysha Habib

2017-03-01

To assess the utility of HOMA-IR in assessing insulin resistance in patients with polycystic ovary syndrome (PCOS) and compare it with fasting insulin for assessing insulin resistance (IR). Observational study. Section of Clinical Chemistry, Department of Pathology and Laboratory Medicine, The Aga Khan University Hospital, Karachi, from January 2009 to September 2012. Medical chart review of all women diagnosed with PCOS was performed. Of the 400 PCOS women reviewed, 91 met the inclusion criteria. Insulin resistance was assessed by calculating HOMA-IR using the formula (fasting glucose x fasting insulin)/405, taking normal value HOMA-IR of women was 3.1 ±1.7, respectively with IR in 69% (n=63) women, while hyperinsulinemia was present in 60% (n=55) women (fasting Insulin 18.5 ±5.8 µIU/ml). Hyperandrogenism was present in 53.8% (n=49), whereas 38.5% (n=35) women had primary infertility or subfertility, while 65.9% (n=60) had menstrual irregularities; and higher frequencies were observed in women with IR. Eight subjects with IR and endocrine abnormalities were missed by fasting insulin. Insulin resistance is common in PCOS and it is likely a pathogenic factor for development of PCOS. HOMAIR model performed better than hyperinsulinemia alone for diagnosing IR.

Plasma adiponectin levels are increased despite insulin resistance in corticotropin-releasing hormone transgenic mice, an animal model of Cushing syndrome.

Science.gov (United States)

Shinahara, Masayuki; Nishiyama, Mitsuru; Iwasaki, Yasumasa; Nakayama, Shuichi; Noguchi, Toru; Kambayashi, Machiko; Okada, Yasushi; Tsuda, Masayuki; Stenzel-Poore, Mary P; Hashimoto, Kozo; Terada, Yoshio

2009-01-01

Adiponectin (AdN), an adipokine derived from the adipose tissue, has an insulin-sensitizing effect, and plasma AdN is shown to be decreased in obesity and/or insulin resistant state. To clarify whether changes in AdN are also responsible for the development of glucocorticoid-induced insulin resistance, we examined AdN concentration in plasma and AdN expression in the adipose tissue, using corticotropin-releasing hormone (CRH) transgenic mouse (CRH-Tg), an animal model of Cushing syndrome. We found, unexpectedly, that plasma AdN levels in CRHTg were significantly higher than those in wild-type littermates (wild-type: 19.7+/-2.5, CRH-Tg: 32.4+/-3.1 microg/mL, pAdN mRNA and protein levels were significantly decreased in the adipose tissue of CRH-Tg. Bilateral adrenalectomy in CRH-Tg eliminated both their Cushing's phenotype and their increase in plasma AdN levels (wild-type/sham: 9.4+/-0.5, CRH-Tg/sham: 15.7+/-2.0, CRH-Tg/ADX: 8.5+/-0.4 microg/mL). These results strongly suggest that AdN is not a major factor responsible for the development of insulin resistance in Cushing syndrome. Our data also suggest that glucocorticoid increases plasma AdN levels but decreases AdN expression in adipocytes, the latter being explained possibly by the decrease in AdN metabolism in the Cushing state.

PEDF-induced alteration of metabolism leading to insulin resistance.

Science.gov (United States)

Carnagarin, Revathy; Dharmarajan, Arunasalam M; Dass, Crispin R

2015-02-05

Pigment epithelium-derived factor (PEDF) is an anti-angiogenic, immunomodulatory, and neurotrophic serine protease inhibitor protein. PEDF is evolving as a novel metabolic regulatory protein that plays a causal role in insulin resistance. Insulin resistance is the central pathogenesis of metabolic disorders such as obesity, type 2 diabetes mellitus, polycystic ovarian disease, and metabolic syndrome, and PEDF is associated with them. The current evidence suggests that PEDF administration to animals induces insulin resistance, whereas neutralisation improves insulin sensitivity. Inflammation, lipolytic free fatty acid mobilisation, and mitochondrial dysfunction are the proposed mechanism of PEDF-mediated insulin resistance. This review summarises the probable mechanisms adopted by PEDF to induce insulin resistance, and identifies PEDF as a potential therapeutic target in ameliorating insulin resistance. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Insulin resistance and polycystic ovary syndrome.

Science.gov (United States)

Galluzzo, Aldo; Amato, Marco Calogero; Giordano, Carla

2008-09-01

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in humans, affecting approximately 7-8% of women of reproductive age. Despite the criteria adopted, PCOS is considered to be a predominantly hyperandrogenetic syndrome and the evaluation of metabolic parameters and insulin sensitivity is not mandatory. Most women with PCOS also exhibit features of the metabolic syndrome, including insulin resistance, obesity and dyslipidaemia. While the association with type 2 diabetes is well established, whether the incidence of cardiovascular disease is increased in women with PCOS remains unclear. Acknowledging the strong impact of insulin-resistance in the genesis of PCOS could be helpful not only to make the diagnosis more robust, but also for conferring better cardiovascular risk prevention. Several current studies support a strong recommendation that women with PCOS should undergo comprehensive evaluation for the metabolic syndrome and recognized cardiovascular risk factors, and receive appropriate treatment as needed. Lifestyle modifications remain the first-line therapy for all obese women with PCOS. However, many of these women do not lose weight easily. Insulin-sensitizing drugs are discussed as a promising and unique therapeutic option for the chronic treatment of PCOS.

Obesity, insulin resistance, and type 1 diabetes mellitus.

Science.gov (United States)

Polsky, Sarit; Ellis, Samuel L

2015-08-01

To summarize recent studies about obesity, insulin resistance, and type 1 diabetes mellitus (T1DM). Overweight and obesity continue to be prevalent among individuals with T1DM. Obesity rates appear to have reached a plateau among children with T1DM in some parts of the world. The risk for development of T1DM is increased by obesity and may occur at an earlier age among obese individuals with a predisposition. Obesity increases the risk for comorbidities among individuals with T1DM, especially metabolic syndrome, and microvascular and macrovascular diseases. Metformin, glucagon-like peptide-1 agonist therapy, sodium glucose cotransporter-2 inhibitor therapy, and bariatric surgery may be beneficial therapies for glucose control, comorbidity management, and obesity among adults with T1DM. Insulin resistance may be improved among obese individuals with T1DM by biguanides (metformin) and glucagon-like peptide-1 agonists (exenatide). We review the last 18 months of literature on obesity, insulin resistance, and T1DM to highlight new epidemiologic results and treatments.

Excessive Refined Carbohydrates and Scarce Micronutrients Intakes Increase Inflammatory Mediators and Insulin Resistance in Prepubertal and Pubertal Obese Children Independently of Obesity

Directory of Open Access Journals (Sweden)

Mardia López-Alarcón

2014-01-01

Full Text Available Background. Low-grade inflammation is the link between obesity and insulin resistance. Because physiologic insulin resistance occurs at puberty, obese pubertal children are at higher risk for insulin resistance. Excessive diets in refined carbohydrates and saturated fats are risk factors for insulin resistance, but calcium, magnesium, vitamin-D, and the omega-3 fatty acids likely protect against inflammation and insulin resistance. Objective. To analyze interactions among dietary saturated fat, refined carbohydrates, calcium, magnesium, vitamin D, and omega-3 fatty acids on the risk of inflammation and insulin resistance in a sample of prepubertal and pubertal children. Methods. A sample of 229 children from Mexico City was analyzed in a cross-sectional design. Anthropometric measurements, 24 h recall questionnaires, and blood samples were obtained. Serum insulin, glucose, calcium, magnesium, 25-OHD3, C-reactive protein, leptin, adiponectin, and erythrocytes fatty acids were measured. Parametric and nonparametric statistics were used for analysis. Results. While mean macronutrients intake was excessive, micronutrients intake was deficient (P<0.01. Inflammation determinants were central obesity and magnesium-deficient diets. Determinants of insulin resistance were carbohydrates intake and circulating magnesium and adiponectin. Conclusions. Magnesium-deficient diets are determinants of inflammation, while high intake of refined carbohydrates is a risk factor for insulin resistance, independently of central adiposity.

A novel surrogate index for hepatic insulin resistance.

LENUS (Irish Health Repository)

Vangipurapu, J

2011-03-01

In epidemiological and genetic studies surrogate indices are needed to investigate insulin resistance in different insulin-sensitive tissues. Our objective was to develop a surrogate index for hepatic insulin resistance.

Molecular characterization of insulin resistance and glycolytic metabolism in the rat uterus

Science.gov (United States)

Zhang, Yuehui; Sun, Xue; Sun, Xiaoyan; Meng, Fanci; Hu, Min; Li, Xin; Li, Wei; Wu, Xiao-Ke; Brännström, Mats; Shao, Ruijin; Billig, Håkan

2016-01-01

Peripheral insulin resistance and hyperandrogenism are the primary features of polycystic ovary syndrome (PCOS). However, how insulin resistance and hyperandrogenism affect uterine function and contribute to the pathogenesis of PCOS are open questions. We treated rats with insulin alone or in combination with human chorionic gonadotropin (hCG) and showed that peripheral insulin resistance and hyperandrogenism alter uterine morphology, cell phenotype, and cell function, especially in glandular epithelial cells. These defects are associated with an aberration in the PI3K/Akt signaling pathway that is used as an indicator for the onset of insulin resistance in classical metabolic tissues. Concomitantly, increased GSK3β (Ser-9) phosphorylation and decreased ERK1/2 phosphorylation in rats treated with insulin and hCG were also observed. We also profiled the expression of glucose transporter (Glut) isoform genes in the uterus under conditions of insulin resistance and/or hyperandrogenism. Finally, we determined the expression pattern of glycolytic enzymes and intermediates during insulin resistance and hyperandrogenism in the uterus. These findings suggest that the PI3K/Akt and MAPK/ERK signaling pathways play a role in the onset of uterine insulin resistance, and they also suggest that changes in specific Glut isoform expression and alterations to glycolytic metabolism contribute to the endometrial dysfunction observed in PCOS patients. PMID:27461373

[Insulin resistance in the pathogenesis of polycystic ovarian disease (PCOD)].

Science.gov (United States)

Jakowicki, J

1994-10-01

In polycystic ovarian disease there is a strong association between hyperinsulinemia and hyperandrogenism but not with obesity alone. The magnitude of peripheral insulin resistance is similar to that seen in non-insulin-dependent diabetes mellitus. Mild hyperinsulinemia in PCOD patients is not impair the carbohydrate metabolism. The elimination of the cause of hyperandrogenism by bilateral oophorectomy, long-acting Gn-RH agonist or antiandrogen cyproterone acetate did not improve the associated insulin resistance. In opposition to insulin resistance in the tissues responsible for metabolism of carbohydrate, the ovary remains sensitive to the effects of pancreatic hormone. Presumably this mechanism involved the interaction with IGF-I receptors to stimulate thecal and stromal androgen production. Insulin may sensitize the stroma to the stimulatory effect of LH. In the mechanism of follicular arrest take part increased level of binding proteins for IGF-I, mainly IGFBP 2, -4 and 5 inhibit FSH and IGF-I action.

PGBR extract ameliorates TNF-α induced insulin resistance in hepatocytes

Directory of Open Access Journals (Sweden)

Fu-Chih Chen

2018-01-01

Full Text Available Pre-germinated brown rice (PGBR could ameliorate metabolic syndrome, however, not much research estimates the effect of PGBR extract on insulin resistance. The aim of this study is to examine the effects of PGBR extract in TNF-α induced insulin resistance. HepG2 cells, hepatocytes, were cultured in DMEM medium and added with 5 μM insulin or with insulin and 30 ng/ml TNF-α or with insulin, TNF-α and PGBR extract (50, 100, 300 μg/ml. The glucose levels of the medium were decreased by insulin, demonstrating insulin promoted glucose uptake into cell. However, TNF-α inhibited glucose uptake into cells treated with insulin. Moreover, insulin increased the protein expressions of AMP-activated protein kinase (AMPK, insulin receptor substrate-1 (IRS-1, phosphatidylinositol-3-kinase-α (PI3K-α, serine/threonine kinase PI3K-linked protein kinase B (Akt/PKB, glucose transporter-2 (GLUT-2, glucokinase (GCK, peroxisome proliferator activated receptor-α (PPAR-α and PPAR-γ. TNF-α activated p65 and MAPKs (JNK1/2 and ERK1/2 which worsened the expressions of AMPK, IRS-1, PI3K-α, Akt/PKB, GLUT-2, GCK, glycogen synthase kinase-3 (GSK-3, PPAR-α and PPAR-γ. Once this relationship was established, we added PGBR extract to cell with insulin and TNF-α. We found glucose levels of medium were lowered and that the protein expressions of AMPK, IRS-1, PI3K-α, Akt/PKB, GLUT-2, GCK, GSK-3, PPAR-α, PPAR-γ and p65, JNK1/2 were also recovered. In conclusion, this study found that TNF-α inhibited insulin stimulated glucose uptake and aggravated related proteins expressions, suggesting that it might cause insulin resistance. PGBR extract was found to ameliorate this TNF-α induced insulin resistance, suggesting that it might be used in the future to help control insulin resistance.

Molecular mechanism of insulin resistance

Indian Academy of Sciences (India)

Free fatty acids are known to play a key role in promoting loss of insulin sensitivity, thereby causing insulin resistance and type 2 diabetes. However, the underlying mechanism involved is still unclear. In searching for the cause of the mechanism, it has been found that palmitate inhibits insulin receptor (IR) gene expression, ...

Molecular Mechanisms of Chromium in Alleviating Insulin Resistance

Science.gov (United States)

Hua, Yinan; Clark, Suzanne; Ren, Jun; Sreejayan, Nair

2011-01-01

Type 2 diabetes is often associated with obesity, dyslipidemia, and cardiovascular anomalies and is a major health problem approaching global epidemic proportions. Insulin resistance, a prediabetic condition, precedes the onset of frank type 2 diabetes and offers potential avenues for early intervention to treat the disease. Although lifestyle modifications and exercise can reduce the incidence of diabetes, compliance has proved to be difficult, warranting pharmacological interventions. However, most of the currently available drugs that improve insulin sensitivity have adverse effects. Therefore, attractive strategies to alleviate insulin resistance include dietary supplements. One such supplement is chromium, which has been shown reduce insulin resistance in some, but not all, studies. Furthermore, the molecular mechanisms of chromium in alleviating insulin resistance remain elusive. This review examines emerging reports on the effect of chromium, as well as molecular and cellular mechanisms by which chromium may provide beneficial effects in alleviating insulin resistance. PMID:22423897

Alternative translation initiation of Caveolin-2 desensitizes insulin signaling through dephosphorylation of insulin receptor by PTP1B and causes insulin resistance.

Science.gov (United States)

Kwon, Hayeong; Jang, Donghwan; Choi, Moonjeong; Lee, Jaewoong; Jeong, Kyuho; Pak, Yunbae

2018-06-01

Insulin resistance, defined as attenuated sensitivity responding to insulin, impairs insulin action. Direct causes and molecular mechanisms of insulin resistance have thus far remained elusive. Here we show that alternative translation initiation (ATI) of Caveolin-2 (Cav-2) regulates insulin sensitivity. Cav-2β isoform yielded by ATI desensitizes insulin receptor (IR) via dephosphorylation by protein-tyrosine phosphatase 1B (PTP1B), and subsequent endocytosis and lysosomal degradation of IR, causing insulin resistance. Blockage of Cav-2 ATI protects against insulin resistance by preventing Cav-2β-PTP1B-directed IR desensitization, thereby normalizing insulin sensitivity and glucose uptake. Our findings show that Cav-2β is a negative regulator of IR signaling, and identify a mechanism causing insulin resistance through control of insulin sensitivity via Cav-2 ATI. Copyright © 2018 Elsevier B.V. All rights reserved.

Osteocalcin improves insulin resistance and inflammation in obese mice: Participation of white adipose tissue and bone.

Science.gov (United States)

Guedes, J A C; Esteves, J V; Morais, M R; Zorn, T M; Furuya, D T

2017-11-26

The discovery of osteocalcin, a protein synthetized by osteoblasts, as a hormone that has positive effects on insulin resistance, contributed to support the concept of bone as an endocrine organ. However, very little is known about the molecular pathways involved in osteocalcin improved-insulin resistance. The present study aimed to investigate the mechanisms of action of osteocalcin on insulin resistance and inflammation in obese mice and 3T3-L1 adipocytes. Lean control, saline-treated obese and uncarboxylated osteocalcin (uOC)-treated obese mice were subjected to insulin tolerance test in vivo. Blood was collect for biochemical/metabolic profile analysis; and, skeletal muscle, white adipose tissue (WAT) and bone were collected for protein (Western blotting) and mRNA (RT-qPCR) analysis. uOC effects on insulin resistance and inflammation were also investigated in 3T3-L1 adipocytes challenged with tumor necrosis factor. Osteocalcin treatment improved in vivo insulin resistance in obese mice. In WAT, osteocalcin had positive effects such as (1) WAT weight reduction; (2) upregulation of glucose transporter (GLUT) 4 protein and its mRNA (Slc2a4); (3) improved insulin-induced AKT phosphorylation; (4) downregulation of several genes involved in inflammation and inflammassome transcriptional machinery, and (5) reduction of the density of macrophage in crown-like structures (histomorphometrical analysis). Notably, in 3T3-L1 adipocytes, osteocalcin restored Slc2a4/GLUT4 content and reduced the expression of inflammatory genes after TNF-a challenge; moreover, osteocalcin treatment increased AKT phosphorylation induced by insulin. Finally, it was observed that in bone, osteocalcin improves insulin resistance by increasing insulin-induced AKT phosphorylation and reducing the expression of genes involved in bone insulin resistance, resulting in increased secretion of uncarboxylated osteocalcin in circulation. We provided some mechanisms of action for osteocalcin in the

Insulin resistance in Nigerians with essential hypertension

African Journals Online (AJOL)

EB

2013-09-03

Sep 3, 2013 ... Keywords: Hypertension, Insulin resistance, Homeostasis model assessment ... worldwide and its prevalence is predicted to increase by 60% by 2025, when a ... model is derived from a mathematical assessment .... Drug type.

Insulin resistance and increased muscle cytokine levels in patients with mitochondrial myopathy.

Science.gov (United States)

Rue, Nana; Vissing, John; Galbo, Henrik

2014-10-01

Mitochondrial dysfunction has been proposed to cause insulin resistance and that might stimulate cytokine production. The objective of the study was to elucidate the association between mitochondrial myopathy, insulin sensitivity, and cytokine levels in muscle. This was an experimental, controlled study in outpatients. Eight overnight-fasted patients (P) with various inherited mitochondrial myopathies and eight healthy subjects (C) matched for sex, age, weight, height, and physical activity participated in the study. The intervention included a 120-minute hyperinsulinemic, euglycemic clamp. Another morning, microdialysis of both vastus lateralis muscles for 4 hours, including one-legged, knee extension exercise for 30 minutes, was performed. Glucose infusion rate during 90-120 minutes of insulin infusion was measured. Cytokine concentrations in dialysate were also measured. Muscle strength, percentage fat mass, and creatine kinase in plasma did not differ between groups. The maximal oxygen uptake was 21 ± 3 (SE) (P) and 36 ± 3(C) mL/kg·min (2P fatty acids and glycerol at 120 minutes were higher in P vs C (2P myopathies, insulin sensitivity of muscle, adipose tissue, and pancreatic A cells is reduced, supporting that mitochondrial function influences insulin action. Furthermore, a local, low-grade inflammation of potential clinical importance exists in the muscle of these patients.

Higher fetal insulin resistance in Chinese pregnant women with gestational diabetes mellitus and correlation with maternal insulin resistance.

Directory of Open Access Journals (Sweden)

Qiuwei Wang

Full Text Available OBJECTIVE: The aim of this study was to determine the effect of gestational diabetes mellitus (GDM on fetal insulin resistance or β-cell function in Chinese pregnant women with GDM. MEASUREMENTS: Maternal fasting blood and venous cord blood samples (reflecting fetal condition were collected in 65 well-controlled Chinese GDM mothers (only given dietary intervention and 83 control subjects. The insulin, glucose and proinsulin concentrations of both maternal and cord blood samples were measured, and the homeostasis model assessment of insulin resistance (HOMA-IR and the proinsulin-to-insulin ratios (an indicator of fetal β-cell function were calculated in maternal and cord blood respectively. RESULTS: Both maternal and fetal levels of insulin, proinsulin and HOMA-IR but not proinsulin-to-insulin ratios were significantly higher in the GDM group than in the control group (maternal insulin, 24.8 vs. 15.4 µU/mL, P = 0.004, proinsulin, 23.3 vs. 16.2 pmol/L, P = 0.005, and HOMA-IR, 5.5 vs. 3.5, P = 0.041, respectively; fetal: insulin, 15.1 vs. 7.9 µU/mL, P<0.001, proinsulin, 25.8 vs. 15.1 pmol/L, P = 0.015, and HOMA-IR, 2.8 vs. 1.4, P = 0.017, respectively. Fetal HOMA-IR but not proinsulin-to-insulin ratios was significantly correlated to maternal HOMA-IR (r = 0.307, P = 0.019, in the pregnant women with GDM. CONCLUSIONS: Fetal insulin resistance was higher in Chinese pregnant women with GDM than control subjects, and correlated with maternal insulin resistance.

Fumosorinone, a novel PTP1B inhibitor, activates insulin signaling in insulin-resistance HepG2 cells and shows anti-diabetic effect in diabetic KKAy mice

International Nuclear Information System (INIS)

Liu, Zhi-Qin; Liu, Ting; Chen, Chuan; Li, Ming-Yan; Wang, Zi-Yu; Chen, Ruo-song; Wei, Gui-xiang; Wang, Xiao-yi; Luo, Du-Qiang

2015-01-01

Insulin resistance is a characteristic feature of type 2 diabetes mellitus (T2DM) and is characterized by defects in insulin signaling. Protein tyrosine phosphatase 1B (PTP1B) is a key negative regulator of the insulin signaling pathways, and its increased activity and expression are implicated in the pathogenesis of insulin resistance. Therefore, the inhibition of PTP1B is anticipated to become a potential therapeutic strategy to treat T2DM. Fumosorinone (FU), a new natural product isolated from insect fungi Isaria fumosorosea, was found to inhibit PTP1B activity in our previous study. Herein, the effects of FU on insulin resistance and mechanism in vitro and in vivo were investigated. FU increased the insulin-provoked glucose uptake in insulin-resistant HepG2 cells, and also reduced blood glucose and lipid levels of type 2 diabetic KKAy mice. FU decreased the expression of PTP1B both in insulin-resistant HepG2 cells and in liver tissues of diabetic KKAy mice. Furthermore, FU increased the phosphorylation of IRβ, IRS-2, Akt, GSK3β and Erk1/2 in insulin-resistant HepG2 cells, as well as the phosphorylation of IRβ, IRS-2, Akt in liver tissues of diabetic KKAy mice. These results showed that FU increased glucose uptake and improved insulin resistance by down-regulating the expression of PTP1B and activating the insulin signaling pathway, suggesting that it may possess antidiabetic properties. - Highlights: • Fumosorinone is a new PTP1B inhibitor isolated from insect pathogenic fungi. • Fumosorinone attenuated the insulin resistance both in vitro and in vivo. • Fumosorinone decreased the expression of PTP1B both in vitro and in vivo. • Fumosorinone activated the insulin signaling pathway both in vitro and in vivo

Fumosorinone, a novel PTP1B inhibitor, activates insulin signaling in insulin-resistance HepG2 cells and shows anti-diabetic effect in diabetic KKAy mice

Energy Technology Data Exchange (ETDEWEB)

Liu, Zhi-Qin [College of Life Sciences, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, Hebei University, Baoding 071002 (China); College of Pharmaceutical Sciences, key laboratory of pharmaceutical quality control of Hebei province, Hebei University, Baoding 071002 (China); Liu, Ting; Chen, Chuan [College of Life Sciences, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, Hebei University, Baoding 071002 (China); Li, Ming-Yan; Wang, Zi-Yu; Chen, Ruo-song; Wei, Gui-xiang; Wang, Xiao-yi [College of Pharmaceutical Sciences, key laboratory of pharmaceutical quality control of Hebei province, Hebei University, Baoding 071002 (China); Luo, Du-Qiang, E-mail: duqiangluo999@126.com [College of Life Sciences, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, Hebei University, Baoding 071002 (China)

2015-05-15

Insulin resistance is a characteristic feature of type 2 diabetes mellitus (T2DM) and is characterized by defects in insulin signaling. Protein tyrosine phosphatase 1B (PTP1B) is a key negative regulator of the insulin signaling pathways, and its increased activity and expression are implicated in the pathogenesis of insulin resistance. Therefore, the inhibition of PTP1B is anticipated to become a potential therapeutic strategy to treat T2DM. Fumosorinone (FU), a new natural product isolated from insect fungi Isaria fumosorosea, was found to inhibit PTP1B activity in our previous study. Herein, the effects of FU on insulin resistance and mechanism in vitro and in vivo were investigated. FU increased the insulin-provoked glucose uptake in insulin-resistant HepG2 cells, and also reduced blood glucose and lipid levels of type 2 diabetic KKAy mice. FU decreased the expression of PTP1B both in insulin-resistant HepG2 cells and in liver tissues of diabetic KKAy mice. Furthermore, FU increased the phosphorylation of IRβ, IRS-2, Akt, GSK3β and Erk1/2 in insulin-resistant HepG2 cells, as well as the phosphorylation of IRβ, IRS-2, Akt in liver tissues of diabetic KKAy mice. These results showed that FU increased glucose uptake and improved insulin resistance by down-regulating the expression of PTP1B and activating the insulin signaling pathway, suggesting that it may possess antidiabetic properties. - Highlights: • Fumosorinone is a new PTP1B inhibitor isolated from insect pathogenic fungi. • Fumosorinone attenuated the insulin resistance both in vitro and in vivo. • Fumosorinone decreased the expression of PTP1B both in vitro and in vivo. • Fumosorinone activated the insulin signaling pathway both in vitro and in vivo.

Association between omentin levels and insulin resistance in pregnancy.

Science.gov (United States)

Aktas, G; Alcelik, A; Ozlu, T; Tosun, M; Tekce, B K; Savli, H; Tekce, H; Dikbas, O

2014-03-01

Omentin is a new adipokine secreted mainly from visceral adipose tissue. Serum omentin is found to be reduced in patients with impaired glucose tolerance, type 2 diabetes mellitus, obesity and insulin resistant states. Despite the fact that pregnancy is also characterized with hyperinsulinemia, literature is lacking about data of omentin levels and its association with insulin resistance in pregnant women. We aimed to evaluate the association of omentin levels and insulin resistance in pregnant women and to compare these levels with those of non-pregnant, non-diabetic women. Uncomplicated pregnant women who admit to our outpatient clinics for routine follow-up were included in the study group. Non-pregnant women without diabetes mellitus were served as control group. Fasting glucose, insulin, omentin levels and HOMA IR were recorded. SPSS 15.0 for Windows was used for statistical analysis. There were 36 pregnant women in the study group and 37 healthy, non-pregnant women in the control group. Serum omentin and fasting glucose levels were significantly decreased and fasting insulin was significantly increased in the study group compared to control group. Omentin might be an indicator of insulin resistance in pregnant women. Larger prospective studies are needed to claim whether omentin can have a clinical use for diagnosis of gestational diabetes mellitus. © J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York.

Insulin resistance and the mitochondrial link. Lessons from cultured human myotubes

DEFF Research Database (Denmark)

Gaster, Michael

2007-01-01

In order to better understand the impact of reduced mitochondrial function for the development of insulin resistance and cellular metabolism, human myotubes were established from lean, obese, and T2D subjects and exposed to mitochondrial inhibitors, either affecting the electron transport chain...... lipid uptake. The metabolic phenotype during respiratory uncoupling resembled the above picture, except for an increase in glucose and palmitate oxidation. Antimycin A and oligomycin treatment induced insulin resistance at the level of glucose and palmitate uptake in all three study groups while......, at the level of glycogen synthesis, insulin resistance was only seen in lean myotubes. Primary insulin resistance in diabetic myotubes was significantly worsened at the level of glucose and lipid uptake. The present study is the first convincing data linking functional mitochondrial impairment per se...

Suppression in growth hormone during overeating ameliorates the increase in insulin resistance and cardiovascular disease risk.

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Cornford, Andrea S; Barkan, Ariel L; Hinko, Alexander; Horowitz, Jeffrey F

2012-11-15

Previously, we reported that overeating for only a few days markedly suppressed the secretion of growth hormone (GH). The purpose of the present study was to determine the role of this reduction in GH concentration on key metabolic adaptations that occur during 2 wk of overeating. Nine nonobese, healthy adults were admitted to the hospital for 2 wk, during which time they ate ∼4,000 kcal/day (70 kcal·kg fat-free mass(-1)·day(-1); 50% carbohydrate, 35% fat, and 15% protein), and their plasma GH concentration was allowed to decline naturally (control). An additional eight subjects underwent the same overeating intervention and received exogenous GH treatment (GHT) administered in four daily injections to mimic physiological GH secretion throughout the 2-wk overeating period. We measured plasma insulin and glucose concentrations in the fasting and postprandial state as well as fasting lipolytic rate, proteolytic rate, and fractional synthetic rate (FSR) using stable-isotope tracer methods. GHT prevented the fall in plasma GH concentration, maintaining plasma GH concentration at baseline levels (1.2 ± 0.2 ng/ml), which increased fasting and postprandial assessments of insulin resistance (P overeating also blunted the increase in systemic proteolysis (P overeating. In conclusion, our main findings suggest that the suppression in GH secretion that naturally occurs during the early stages of overeating may help attenuate the insulin resistance and hyperlipidemia that typically accompany overeating.

Insulin resistance in obese children and adolescents

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Monica Cristina dos Santos Romualdo

2014-11-01

Conclusion: The results confirmed that insulin resistance is present in many obese children and adolescents, and that this condition is associated with alterations that represent an increased risk for developing metabolic disorders in adulthood.

The role of polycarbonate monomer bisphenol-A in insulin resistance.

Science.gov (United States)

Pjanic, Milos

2017-01-01

Bisphenol A (BPA) is a synthetic unit of polycarbonate polymers and epoxy resins, the types of plastics that could be found in essentially every human population and incorporated into almost every aspect of the modern human society. BPA polymers appear in a wide range of products, from liquid storages (plastic bottles, can and glass linings, water pipes and tanks) and food storages (plastics wraps and containers), to medical and dental devices. BPA polymers could be hydrolyzed spontaneously or in a photo- or temperature-catalyzed process, providing widespread environmental distribution and chronic exposure to the BPA monomer in contemporary human populations. Bisphenol A is also a xenoestrogen, an endocrine-disrupting chemical (EDC) that interferes with the endocrine system mimicking the effects of an estrogen and could potentially keep our endocrine system in a constant perturbation that parallels endocrine disruption arising during pregnancy, such as insulin resistance (IR). Gestational insulin resistance represents a natural biological phenomenon of higher insulin resistance in peripheral tissues of the pregnant females, when nutrients are increasingly being directed to the embryo instead of being stored in peripheral tissues. Gestational diabetes mellitus may appear in healthy non-diabetic females, due to gestational insulin resistance that leads to increased blood sugar levels and hyperinsulinemia (increased insulin production from the pancreatic beta cells). The hypothesis states that unnoticed and constant exposure to this environmental chemical might potentially lead to the formation of chronic low-level endocrine disruptive state that resembles gestational insulin resistance, which might contribute to the development of diabetes. The increasing body of evidence supports the major premises of this hypothesis, as exemplified by the numerous publications examining the association of BPA and insulin resistance, both epidemiological and mechanistic. However, to

Helicobacter pylori Infection and Insulin Resistance in Diabetic and Nondiabetic Population

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Jamshid Vafaeimanesh

2014-01-01

Full Text Available Helicobacter pylori (HP is a common worldwide infection with known gastrointestinal and nongastrointestinal complications. One of the gastrointestinal side effects posed for this organism is its role in diabetes and increased insulin resistance. The aim of this study was to evaluate the association between HP and insulin resistance in type 2 diabetic patients and nondiabetics. This cross-sectional study was carried out from May to December 2013 on 211 diabetic patients referred to diabetes clinic of Shahid Beheshti Hospital of Qom and 218 patients without diabetes. HP was evaluated using serology method and insulin resistance was calculated using HOMA-IR. The prevalence of H. pylori infection was 55.8% and 44.2% in diabetics and nondiabetics (P=0.001. The study population was divided into two HP positive and negative groups. Among nondiabetics, insulin resistance degree was 3.01±2.12 and 2.74±2.18 in HP+ and HP− patients, respectively P=0.704. Oppositely, insulin resistance was significantly higher in diabetic HP+ patients rather than seronegative ones (4.484±2.781 versus 3.160±2.327, P=0.013. In diabetic patients, in addition to higher prevalence of HP, it causes a higher degree of insulin resistance.

Nutritional Modulation of Insulin Resistance

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Martin O. Weickert

2012-01-01

Full Text Available Insulin resistance has been proposed as the strongest single predictor for the development of Type 2 Diabetes (T2DM. Chronic oversupply of energy from food, together with inadequate physical activity, have been recognized as the most relevant factors leading to overweight, abdominal adiposity, insulin resistance, and finally T2DM. Conversely, energy reduced diets almost invariably to facilitate weight loss and reduce abdominal fat mass and insulin resistance. However, sustained weight loss is generally difficult to achieve, and distinct metabolic characteristics in patients with T2DM further compromise success. Therefore, investigating the effects of modulating the macronutrient composition of isoenergetic diets is an interesting concept that may lead to additional important insights. Metabolic effects of various different dietary concepts and strategies have been claimed, but results from randomized controlled studies and particularly from longer-term-controlled interventions in humans are often lacking. However, some of these concepts are supported by recent research, at least in animal models and short-term studies in humans. This paper provides an update of the current literature regarding the role of nutrition in the modulation of insulin resistance, which includes the discussion of weight-loss-independent metabolic effects of commonly used dietary concepts.

Obesity genes and insulin resistance.

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Belkina, Anna C; Denis, Gerald V

2010-10-01

The exploding prevalence of insulin resistance and Type 2 diabetes (T2D) linked to obesity has become an alarming public health concern. Worldwide, approximately 171 million people suffer from obesity-induced diabetes and public health authorities expect this situation to deteriorate rapidly. An interesting clinical population of 'metabolically healthy but obese' (MHO) cases is relatively protected from T2D and its associated cardiovascular risk. The molecular basis for this protection is not well understood but is likely to involve reduced inflammatory responses. The inflammatory cells and pathways that respond to overnutrition are the primary subject matter for this review. The chance discovery of a genetic mutation in the Brd2 gene, which is located in the class II major histocompatibility complex and makes mice enormously fat but protects them from diabetes, offers revolutionary new insights into the cellular mechanisms that link obesity to insulin resistance and T2D. These Brd2-hypomorphic mice have reduced inflammation in fat that is normally associated with insulin resistance, and resemble MHO patients, suggesting novel therapeutic pathways for obese patients at risk for T2D. Deeper understanding of the functional links between genes that control inflammatory responses to diet-induced obesity is crucial to the development of therapies for obese, insulin-resistant patients.

Vitamin D Supplementation Does Not Impact Insulin Resistance in Black and White Children.

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Ferira, Ashley J; Laing, Emma M; Hausman, Dorothy B; Hall, Daniel B; McCabe, George P; Martin, Berdine R; Hill Gallant, Kathleen M; Warden, Stuart J; Weaver, Connie M; Peacock, Munro; Lewis, Richard D

2016-04-01

Vitamin D supplementation trials with diabetes-related outcomes have been conducted almost exclusively in adults and provide equivocal findings. The objective of this study was to determine the dose-response of vitamin D supplementation on fasting glucose, insulin, and a surrogate measure of insulin resistance in white and black children aged 9–13 years, who participated in the Georgia, Purdue, and Indiana University (or GAPI) trial: a 12-week multisite, randomized, triple-masked, dose-response, placebo-controlled vitamin D trial. Black and white children in the early stages of puberty (N = 323, 50% male, 51% black) were equally randomized to receive vitamin D3 (0, 400, 1000, 2000, or 4000 IU/day) for 12 weeks. Fasting serum 25-hydroxyvitamin D (25(OH)D), glucose and insulin were assessed at baseline and weeks 6 and 12. Homeostasis model assessment of insulin resistance was used as a surrogate measure of insulin resistance. Statistical analyses were conducted as intent-to-treat using a mixed effects model. Baseline serum 25(OH)D was inversely associated with insulin (r = −0.140, P = 0.017) and homeostasis model assessment of insulin resistance (r = −0.146, P = 0.012) after adjusting for race, sex, age, pubertal maturation, fat mass, and body mass index. Glucose, insulin, and insulin resistance increased (F > 5.79, P insulin resistance, vitamin D supplementation had no impact on fasting glucose, insulin, or a surrogate measure of insulin resistance over 12 weeks in apparently healthy children.

Effects of glucose, insulin, and insulin resistance on cerebral 18F-FDG distribution in cognitively normal older subjects

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Onishi, Airin; Fujiwara, Yoshinori; Ishiwata, Kiichi; Ishii, Kenji

2017-01-01

Background Increasing plasma glucose levels and insulin resistance can alter the distribution pattern of fluorine-18-labeled fluorodeoxyglucose (18F-FDG) in the brain and relatively reduce 18F-FDG uptake in Alzheimer's disease (AD)-related hypometabolic regions, leading to the appearance of an AD-like pattern. However, its relationship with plasma insulin levels is unclear. We aimed to compare the effects of plasma glucose levels, plasma insulin levels and insulin resistance on the appearance of the AD-like pattern in 18F-FDG images. Methods Fifty-nine cognitively normal older subjects (age = 75.7 ± 6.4 years) underwent 18F-FDG positron emission tomography along with measurement of plasma glucose and insulin levels. As an index of insulin resistance, the Homeostasis model assessment of Insulin Resistance (HOMA-IR) was calculated. Results Plasma glucose levels, plasma insulin levels, and HOMA-IR were 102.2 ± 8.1 mg/dL, 4.1 ± 1.9 μU/mL, and 1.0 ± 0.5, respectively. Whole-brain voxelwise analysis showed a negative correlation of 18F-FDG uptake with plasma glucose levels in the precuneus and lateral parietotemporal regions (cluster-corrected p < 0.05), and no correlation with plasma insulin levels or HOMA-IR. In the significant cluster, 18F-FDG uptake decreased by approximately 4–5% when plasma glucose levels increased by 20 mg/dL. In the precuneus region, volume-of-interest analysis confirmed a negative correlation of 18F-FDG uptake with plasma glucose levels (r = -0.376, p = 0.002), and no correlation with plasma insulin levels (r = 0.156, p = 0.12) or HOMA-IR (r = 0.096, p = 0.24). Conclusion This study suggests that, of the three parameters, plasma glucose levels have the greatest effect on the appearance of the AD-like pattern in 18F-FDG images. PMID:28715453

Effects of glucose, insulin, and insulin resistance on cerebral 18F-FDG distribution in cognitively normal older subjects.

Directory of Open Access Journals (Sweden)

Kenji Ishibashi

Full Text Available Increasing plasma glucose levels and insulin resistance can alter the distribution pattern of fluorine-18-labeled fluorodeoxyglucose (18F-FDG in the brain and relatively reduce 18F-FDG uptake in Alzheimer's disease (AD-related hypometabolic regions, leading to the appearance of an AD-like pattern. However, its relationship with plasma insulin levels is unclear. We aimed to compare the effects of plasma glucose levels, plasma insulin levels and insulin resistance on the appearance of the AD-like pattern in 18F-FDG images.Fifty-nine cognitively normal older subjects (age = 75.7 ± 6.4 years underwent 18F-FDG positron emission tomography along with measurement of plasma glucose and insulin levels. As an index of insulin resistance, the Homeostasis model assessment of Insulin Resistance (HOMA-IR was calculated.Plasma glucose levels, plasma insulin levels, and HOMA-IR were 102.2 ± 8.1 mg/dL, 4.1 ± 1.9 μU/mL, and 1.0 ± 0.5, respectively. Whole-brain voxelwise analysis showed a negative correlation of 18F-FDG uptake with plasma glucose levels in the precuneus and lateral parietotemporal regions (cluster-corrected p < 0.05, and no correlation with plasma insulin levels or HOMA-IR. In the significant cluster, 18F-FDG uptake decreased by approximately 4-5% when plasma glucose levels increased by 20 mg/dL. In the precuneus region, volume-of-interest analysis confirmed a negative correlation of 18F-FDG uptake with plasma glucose levels (r = -0.376, p = 0.002, and no correlation with plasma insulin levels (r = 0.156, p = 0.12 or HOMA-IR (r = 0.096, p = 0.24.This study suggests that, of the three parameters, plasma glucose levels have the greatest effect on the appearance of the AD-like pattern in 18F-FDG images.

Brain natriuretic peptide and insulin resistance in older adults.

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Kim, F; Biggs, M L; Kizer, J R; Brutsaert, E F; de Filippi, C; Newman, A B; Kronmal, R A; Tracy, R P; Gottdiener, J S; Djoussé, L; de Boer, I H; Psaty, B M; Siscovick, D S; Mukamal, K J

2017-02-01

Higher levels of brain natriuretic peptide (BNP) have been associated with a decreased risk of diabetes in adults, but whether BNP is related to insulin resistance in older adults has not been established. N-terminal of the pro hormone brain natriuretic peptide (NT-pro BNP) was measured among Cardiovascular Health Study participants at the 1989-1990, 1992-1993 and 1996-1997 examinations. We calculated measures of insulin resistance [homeostatic model assessment of insulin resistance (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), Gutt index, Matsuda index] from fasting and 2-h concentrations of glucose and insulin among 3318 individuals with at least one measure of NT-proBNP and free of heart failure, coronary heart disease and chronic kidney disease, and not taking diabetes medication. We used generalized estimating equations to assess the cross-sectional association of NT-proBNP with measures of insulin resistance. Instrumental variable analysis with an allele score derived from nine genetic variants (single nucleotide polymorphisms) within or near the NPPA and NPPB loci was used to estimate an un-confounded association of NT-proBNP levels on insulin resistance. Lower NT-proBNP levels were associated with higher insulin resistance even after adjustment for BMI, waist circumference and other risk factors (P insulin resistance (P = 0.38; P = 0.01 for comparison with the association of measured levels of NT-proBNP). In older adults, lower NT-proBNP is associated with higher insulin resistance, even after adjustment for traditional risk factors. Because related genetic variants were not associated with insulin resistance, the causal nature of this association will require future study. © 2016 Diabetes UK.

Central insulin-like growth factor-1 (IGF-1) restores whole-body insulin action in a model of age-related insulin resistance and IGF-1 decline.

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Huffman, Derek M; Farias Quipildor, Gabriela; Mao, Kai; Zhang, Xueying; Wan, Junxiang; Apontes, Pasha; Cohen, Pinchas; Barzilai, Nir

2016-02-01

Low insulin-like growth factor-1 (IGF-1) signaling is associated with improved longevity, but is paradoxically linked with several age-related diseases in humans. Insulin-like growth factor-1 has proven to be particularly beneficial to the brain, where it confers protection against features of neuronal and cognitive decline. While aging is characterized by central insulin resistance in the face of hyperinsulinemia, the somatotropic axis markedly declines in older humans. Thus, we hypothesized that increasing IGF-1 in the brain may prove to be a novel therapeutic alternative to overcome central insulin resistance and restore whole-body insulin action in aging. Utilizing hyperinsulinemic-euglycemic clamps, we show that old insulin-resistant rats with age-related declines in IGF-1 level demonstrate markedly improved whole-body insulin action, when treated with central IGF-1, as compared to central vehicle or insulin (P IGF-1, but not insulin, suppressed hepatic glucose production and increased glucose disposal rates in aging rats (P IGF-1 action in the brain and periphery provides a 'balance' between its beneficial and detrimental actions. Therefore, we propose that strategies aimed at 'tipping the balance' of IGF-1 action centrally are the optimal approach to achieve healthy aging and longevity in humans. © 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Insulin resistance, insulin sensitization and inflammation in polycystic ovarian syndrome

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Dhindsa G

2004-04-01

Full Text Available It is estimated that 5-10% of women of reproductive age have polycystic ovarian syndrome (PCOS. While insulin resistance is not part of the diagnostic criteria for PCOS, its importance in the pathogenesis of PCOS cannot be denied. PCOS is associated with insulin resistance independent of total or fat-free body mass. Post-receptor defects in the action of insulin have been described in PCOS which are similar to those found in obesity and type 2 diabetes. Treatment with insulin sensitizers, metformin and thiazolidinediones, improve both metabolic and hormonal patterns and also improve ovulation in PCOS. Recent studies have shown that PCOS women have higher circulating levels of inflammatory mediators like C-reactive protein, tumour necrosis factor- , tissue plasminogen activator and plasminogen activator inhibitor-1 (PAI-1 . It is possible that the beneficial effect of insulin sensitizers in PCOS may be partly due to a decrease in inflammation.

Hepatic Insulin Resistance Following Chronic Activation of the CREB Coactivator CRTC2

DEFF Research Database (Denmark)

Hogan, Meghan F; Ravnskjaer, Kim; Matsumura, Shigenobu

2015-01-01

and dephosphorylation of the cAMP regulated CREB coactivators CRTC2 and CRTC3. In parallel, decreases in circulating insulin also increase gluconeogenic gene expression via the de-phosphorylation and activation of the forkhead transcription factor FOXO1. Hepatic gluconeogenesis is increased in insulin resistance where...... increased gluconeogenic gene expression under fasting as well as feeding conditions. Circulating glucose concentrations were constitutively elevated in CRTC2S171,275A expressing mice, leading to compensatory increases in circulating insulin concentrations that enhance FOXO1 phosphorylation. Despite...... accompanying decreases in FOXO1 activity, hepatic gluconeogenic gene expression remained elevated in CRTC2S171,275A mice demonstrating that chronic increases in CRTC2 activity in the liver are indeed sufficient to promote hepatic insulin resistance and to disrupt glucose homeostasis....

Role of sialic acid in insulin action and the insulin resistance of diabetes mellitus

International Nuclear Information System (INIS)

Salhanick, A.I.; Amatruda, J.M.

1988-01-01

Adipocytes treated with neuraminidase show markedly reduced responsiveness to insulin without any alteration in insulin binding. In addition, several studies have separately demonstrated both insulin resistance and decreases in membrane sialic acid content and associated biosynthetic enzymes in diabetes mellitus. In the present study, the authors investigated the role that sialic acid residues may play in insulin action and in the hepatic insulin resistance associated with nonketotic diabetes. Primary cultures of hepatocytes from normal rats treated with neuraminidase demonstrated a dose-dependent decrease in insulin-stimulated lipogenesis. At a concentration of neuraminidase that decreases insulin action by 50%, 23% of total cellular sialic acid content was released. Neuraminidase-releasable sialic acid was significantly decreased in hepatocytes from diabetic rats and this was associated with significant insulin resistance. Treatment of hepatocytes from diabetic rats with cytidine 5'-monophospho-N-acetylneuraminic acid (CMP-NANA) enhanced insulin responsiveness 39%. The enhanced insulin responsiveness induced by CMP-NANA was blocked by cytidine 5'-monophosphate (CMP) suggesting that the CMP-NANA effect was catalyzed by a cell surface sialyl-transferase. CMP reduced neuraminidase-releasable [ 14 C]sialic acid incorporation into hepatocytes by 43%. The data demonstrate a role for cell surface sialic acid residues in hepatic insulin action and support a role for decreased cell surface sialic acid residues in the insulin resistance of diabetes mellitus

The proteomic signature of insulin-resistant human skeletal muscle reveals increased glycolytic and decreased mitochondrial enzymes

DEFF Research Database (Denmark)

Giebelstein, J; Poschmann, G; Højlund, K

2012-01-01

The molecular mechanisms underlying insulin resistance in skeletal muscle are incompletely understood. Here, we aimed to obtain a global picture of changes in protein abundance in skeletal muscle in obesity and type 2 diabetes, and those associated with whole-body measures of insulin action....

BPN, a marine-derived PTP1B inhibitor, activates insulin signaling and improves insulin resistance in C2C12 myotubes.

Science.gov (United States)

Xu, Qi; Luo, Jiao; Wu, Ning; Zhang, Renshuai; Shi, Dayong

2018-01-01

Insulin resistance is a key feature of type 2 diabetes mellitus (T2DM) and is characterized by defects in insulin signaling. Protein tyrosine phosphatase 1B (PTP1B) is a major negative regulator of insulin signaling cascade and has attracted intensive investigation in recent T2DM therapy study. BPN, a marine-derived bromophenol compound, was isolated from the red alga Rhodomela confervoides. This study investigated the effects of BPN on the insulin signaling pathway in insulin-resistant C2C12 myotubes by inhibiting PTP1B. Molecular docking study and analysis of small- molecule interaction with PTP1B all showed BPN inhibited PTP1B activity via binding to the catalytic site through hydrogen bonds. We then found that BPN permeated into C2C12 myotubes, on the one hand, activated insulin signaling in an insulin-independent manner in C2C12 cells; on the other hand, ameliorated palmitate-induced insulin resistance through augmenting insulin sensitivity. Moreover, our studies also showed that PTP1B inhibition by BPN increased glucose uptake in normal and insulin-resistant C2C12 myotubes through glucose transporter 4 (GLUT4) translocation. Taken together, BPN activates insulin signaling and alleviates insulin resistance and represents a potential candidate for further development as an antidiabetic agent. Copyright © 2017 Elsevier B.V. All rights reserved.

Homeostatic model assessment for insulin resistance (homa-ir): a better marker for evaluating insulin resistance than fasting insulin in women with polycystic ovarian syndrome

International Nuclear Information System (INIS)

Majid, H.; Khan, A.H.; Masood, Q.

2017-01-01

To assess the utility of HOMA-IR in assessing insulin resistance in patients with polycystic ovary syndrome (PCOS) and compare it with fasting insulin for assessing insulin resistance (IR). Study Design: Observational study. Place and Duration of Study: Section of Clinical Chemistry, Department of Pathology and Laboratory Medicine, The Aga Khan University Hospital, Karachi, from January 2009 to September 2012. Methodology: Medical chart review of all women diagnosed with PCOS was performed. Of the 400 PCOS women reviewed, 91 met the inclusion criteria. Insulin resistance was assessed by calculating HOMA-IR using the formula (fasting glucose x fasting insulin)/405, taking normal value =12 micro IU/ml. Results: A total of 91 premenopausal women diagnosed with PCOS were included. Mean age was 30 +-5.5 years. Mean HOMA-IR of women was 3.1 +-1.7, respectively with IR in 69% (n=63) women, while hyperinsulinemia was present in 60% (n=55) women (fasting Insulin 18.5 +-5.8 micro IU/ml). Hyperandrogenism was present in 53.8% (n=49), whereas 38.5% (n=35) women had primary infertility or subfertility, while 65.9% (n=60) had menstrual irregularities; and higher frequencies were observed in women with IR. Eight subjects with IR and endocrine abnormalities were missed by fasting insulin. Conclusion: Insulin resistance is common in PCOS and it is likely a pathogenic factor for development of PCOS. HOMA-IR model performed better than hyperinsulinemia alone for diagnosing IR. (author)

Insulin resistance in obesity as the underlying cause for the metabolic syndrome.

Science.gov (United States)

Gallagher, Emily J; Leroith, Derek; Karnieli, Eddy

2010-01-01

The metabolic syndrome affects more than a third of the US population, predisposing to the development of type 2 diabetes and cardiovascular disease. The 2009 consensus statement from the International Diabetes Federation, American Heart Association, World Heart Federation, International Atherosclerosis Society, International Association for the Study of Obesity, and the National Heart, Lung, and Blood Institute defines the metabolic syndrome as 3 of the following elements: abdominal obesity, elevated blood pressure, elevated triglycerides, low high-density lipoprotein cholesterol, and hyperglycemia. Many factors contribute to this syndrome, including decreased physical activity, genetic predisposition, chronic inflammation, free fatty acids, and mitochondrial dysfunction. Insulin resistance appears to be the common link between these elements, obesity and the metabolic syndrome. In normal circumstances, insulin stimulates glucose uptake into skeletal muscle, inhibits hepatic gluconeogenesis, and decreases adipose-tissue lipolysis and hepatic production of very-low-density lipoproteins. Insulin signaling in the brain decreases appetite and prevents glucose production by the liver through neuronal signals from the hypothalamus. Insulin resistance, in contrast, leads to the release of free fatty acids from adipose tissue, increased hepatic production of very-low-density lipoproteins and decreased high-density lipoproteins. Increased production of free fatty acids, inflammatory cytokines, and adipokines and mitochondrial dysfunction contribute to impaired insulin signaling, decreased skeletal muscle glucose uptake, increased hepatic gluconeogenesis, and β cell dysfunction, leading to hyperglycemia. In addition, insulin resistance leads to the development of hypertension by impairing vasodilation induced by nitric oxide. In this review, we discuss normal insulin signaling and the mechanisms by which insulin resistance contributes to the development of the metabolic

The origins and drivers of insulin resistance.

Science.gov (United States)

Johnson, Andrew M F; Olefsky, Jerrold M

2013-02-14

Obesity-induced insulin resistance is the major determinant of metabolic syndrome, which precedes the development of type 2 diabetes mellitus and is thus the driving force behind the emerging diabetes epidemic. The precise causes of insulin resistance are varied, and the relative importance of each is a matter of ongoing research. Here, we offer a Perspective on the heterogeneous etiology of insulin resistance, focusing in particular on the role of inflammation, lipid metabolism, and the gastrointestinal microbiota. Copyright © 2013 Elsevier Inc. All rights reserved.

Insulin resistance and neurodegeneration: Roles of obesity, type 2 diabetes mellitus and non-alcoholic steatohepatitis

OpenAIRE

de la Monte, Suzanne M; Longato, Lisa; Tong, Ming; Wands, Jack R

2009-01-01

Recent studies have linked obesity, type 2 diabetes mellitus (T2DM) or non-alcoholic steatohepatitis (NASH) to insulin resistance in the brain, cognitive impairment and neurodegeneration. Insulin resistance compromises cell survival, metabolism and neuronal plasticity, and increases oxidative stress, cytokine activation and apoptosis. T2DM/NASH has been demonstrated to be associated with increased ceramide generation, suggesting a mechanistic link between peripheral insulin resistance and neu...

Tribbles 3 Mediates Endoplasmic Reticulum Stress-Induced Insulin Resistance in Skeletal Muscle

Science.gov (United States)

Koh, Ho-Jin; Toyoda, Taro; Didesch, Michelle M.; Lee, Min-Young; Sleeman, Mark W.; Kulkarni, Rohit N.; Musi, Nicolas; Hirshman, Michael F.; Goodyear, Laurie J.

2013-01-01

Endoplasmic Reticulum (ER) stress has been linked to insulin resistance in multiple tissues but the role of ER stress in skeletal muscle has not been explored. ER stress has also been reported to increase tribbles 3 (TRB3) expression in multiple cell lines. Here, we report that high fat feeding in mice, and obesity and type 2 diabetes in humans significantly increases TRB3 and ER stress markers in skeletal muscle. Overexpression of TRB3 in C2C12 myotubes and mouse tibialis anterior muscles significantly impairs insulin signaling. Incubation of C2C12 cells and mouse skeletal muscle with ER stressors thapsigargin and tunicamycin increases TRB3 and impairs insulin signaling and glucose uptake, effects reversed in cells overexpressing RNAi for TRB3 and in muscles from TRB3 knockout mice. Furthermore, TRB3 knockout mice are protected from high fat diet-induced insulin resistance in skeletal muscle. These data demonstrate that TRB3 mediates ER stress-induced insulin resistance in skeletal muscle. PMID:23695665

Mitochondrial adaptations in insulin resistant muscle

NARCIS (Netherlands)

Broek, van den N.M.A.

2010-01-01

Diabetes has reached epidemic proportions worldwide. Type 2 diabetes (T2D) accounts for about 90% of all diabetes cases and is characterized by insulin resistance (IR) in major metabolic tissues. The dramatic rise in T2D is associated with the increased occurrence of obesity and excessive ectopic

The role of dietary fat in obesity-induced insulin resistance.

Science.gov (United States)

Lackey, Denise E; Lazaro, Raul G; Li, Pingping; Johnson, Andrew; Hernandez-Carretero, Angelina; Weber, Natalie; Vorobyova, Ivetta; Tsukomoto, Hidekazu; Osborn, Olivia

2016-12-01

Consumption of excess calories results in obesity and insulin resistance and has been intensively studied in mice and humans. The objective of this study was to determine the specific contribution of dietary fat rather than total caloric intake to the development of obesity-associated insulin resistance. We used an intragastric feeding method to overfeed excess calories from a low-fat diet (and an isocalorically matched high-fat diet) through a surgically implanted gastric feeding tube to generate obesity in wild-type mice followed by hyperinsulinemic-euglycemic clamp studies to assess the development of insulin resistance. We show that overfeeding a low-fat diet results in levels of obesity similar to high-fat diet feeding in mice. However, despite a similar body weight, obese high-fat diet-fed mice are more insulin resistant than mice fed an isocaloric low-fat diet. Therefore, increased proportion of calories from dietary fat further potentiates insulin resistance in the obese state. Furthermore, crossover diet studies revealed that reduction in dietary fat composition improves glucose tolerance in obesity. In the context of the current obesity and diabetes epidemic, it is particularly important to fully understand the role of dietary macronutrients in the potentiation and amelioration of disease. Copyright © 2016 the American Physiological Society.

Lifelong Physical Activity Prevents Aging-Associated Insulin Resistance in Human Skeletal Muscle Myotubes via Increased Glucose Transporter Expression

DEFF Research Database (Denmark)

Bunprajun, Tipwadee; Henriksen, Tora Ida; Scheele, Camilla

2013-01-01

, and significantly higher GLUT4 protein. It is likely that physical activity induces a number of stable adaptations, including increased GLUT4 expression that are retained in cells ex vivo and protect, or delay the onset of middle-aged-associated insulin resistance. Additionally, a sedentary lifestyle has an impact...

Trehalose prevents adipocyte hypertrophy and mitigates insulin resistance.

Science.gov (United States)

Arai, Chikako; Arai, Norie; Mizote, Akiko; Kohno, Keizo; Iwaki, Kanso; Hanaya, Toshiharu; Arai, Shigeyuki; Ushio, Simpei; Fukuda, Shigeharu

2010-12-01

Trehalose has been shown to evoke lower insulin secretion than glucose in oral saccharide tolerance tests in humans. Given this hypoinsulinemic effect of trehalose, we hypothesized that trehalose suppresses adipocyte hypertrophy by reducing storage of triglyceride and mitigates insulin resistance in mice fed a high-fat diet (HFD). Mice were fed an HFD and given drinking water containing 2.5% saccharide (glucose [Glc], trehalose [Tre], maltose [Mal], high-fructose corn syrup, or fructose [Fru]) ad libitum. After 7 weeks of HFD and saccharide intake, fasting serum insulin levels in the Tre/HFD group were significantly lower than in the Mal/HFD and Glc/HFD groups (P fructose corn syrup/HFD, or Fru/HFD group. Analysis of gene expression in mesenteric adipocytes showed that no statistically significant difference in the expression of monocyte chemoattractant protein-1 (MCP-1) messenger RNA (mRNA) was observed between the Tre/HFD group and the distilled water/standard diet group, whereas a significant increase in the MCP-1 mRNA expression was observed in the Glc/HFD, Mal/HFD, Fru/HFD, and distilled water/HFD groups. Thus, our data indicate that trehalose prevents adipocyte hypertrophy and mitigates insulin resistance in HFD-fed mice by reducing insulin secretion and down-regulating mRNA expression of MCP-1. These findings further suggest that trehalose is a functional saccharide that mitigates insulin resistance. Copyright © 2010 Elsevier Inc. All rights reserved.

Effects of niacin supplementation on the insulin resistance in Holstein cows during early lactation

OpenAIRE

Talija Hristovska; Marko R. Cincović; Branislava Belić; Dragica Stojanović; Milanka Jezdimirović; Radojica Đoković; Bojan Toholj

2017-01-01

Insulin resistance in early lactation includes low glucose concentration, low insulin release and responsiveness and high lipolysis. Niacin is important antilipolytic agent and leads to increase glucose and insulin concentration. The objectives of this study were to determine the influence of niacin on the insulin resistance in cows during early lactation using the difference of value and regression analysis between blood non-esterified fatty acid (NEFA), glucose and insulin concentrations, r...

Vitamin C deficiency aggravates tumor necrosis factor α-induced insulin resistance.

Science.gov (United States)

Qing, Zhou; Xiao-Hui, Wu; Xi-Mei, Wu; Chao-Chun, Zou

2018-06-15

Chronic low-grade inflammation plays a major role in the development of insulin resistance. The potential role and underlying mechanism of vitamin C, an antioxidant and anti-inflammatory agent, was investigated in tumor necrosis factor-α (TNF-α)-induced insulin resistance. Gulonolactone oxidase knockout (Gulo -/- ) mice genetically unable to synthesize vitamin C were used to induce insulin resistance by continuously pumping small doses of TNF-α for seven days, and human liver hepatocellular carcinoma cells (HepG2 cells) were used to induce insulin resistance by treatment with TNF-α. Vitamin C deficiency aggravated TNF-α-induced insulin resistance in Gulo -/- mice, resulting in worse glucose tolerance test (GTT) results, higher fasting plasma insulin level, and the inactivation of the protein kinase B (AKT)/glycogen synthase kinase-3β (GSK3β) pathway in the liver. Vitamin C deficiency also worsened liver lipid accumulation and inflammation in TNF-α-treated Gulo -/- mice. In HepG2 cells, vitamin C reversed the TNF-α-induced reduction of glucose uptake and glycogen synthesis, which were mediated by increasing GLUT2 levels and the activation of the insulin receptor substrate (IRS-1)/AKT/GSK3β pathway. Furthermore, vitamin C inhibited the TNF-α-induced activation of not only the mitogen-activated protein kinase (MAPKs), but also nuclear factor-kappa B (NF-κB) signaling. Taken together, vitamin C is essential for preventing and improving insulin resistance, and the supplementing with vitamin C may be an effective therapeutic intervention for metabolic disorders. Copyright © 2018 Elsevier B.V. All rights reserved.

Suppression of Ghrelin Exacerbates HFCS-Induced Adiposity and Insulin Resistance.

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Ma, Xiaojun; Lin, Ligen; Yue, Jing; Wu, Chia-Shan; Guo, Cathy A; Wang, Ruitao; Yu, Kai-Jiang; Devaraj, Sridevi; Murano, Peter; Chen, Zheng; Sun, Yuxiang

2017-06-19

High fructose corn syrup (HFCS) is widely used as sweetener in processed foods and soft drinks in the United States, largely substituting sucrose (SUC). The orexigenic hormone ghrelin promotes obesity and insulin resistance; ghrelin responds differently to HFCS and SUC ingestion. Here we investigated the roles of ghrelin in HFCS- and SUC-induced adiposity and insulin resistance. To mimic soft drinks, 10-week-old male wild-type (WT) and ghrelin knockout ( Ghrelin -/- ) mice were subjected to ad lib. regular chow diet supplemented with either water (RD), 8% HFCS (HFCS), or 10% sucrose (SUC). We found that SUC-feeding induced more robust increases in body weight and body fat than HFCS-feeding. Comparing to SUC-fed mice, HFCS-fed mice showed lower body weight but higher circulating glucose and insulin levels. Interestingly, we also found that ghrelin deletion exacerbates HFCS-induced adiposity and inflammation in adipose tissues, as well as whole-body insulin resistance. Our findings suggest that HFCS and SUC have differential effects on lipid metabolism: while sucrose promotes obesogenesis, HFCS primarily enhances inflammation and insulin resistance, and ghrelin confers protective effects for these metabolic dysfunctions.

Suppression of Ghrelin Exacerbates HFCS-Induced Adiposity and Insulin Resistance

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Xiaojun Ma

2017-06-01

Full Text Available High fructose corn syrup (HFCS is widely used as sweetener in processed foods and soft drinks in the United States, largely substituting sucrose (SUC. The orexigenic hormone ghrelin promotes obesity and insulin resistance; ghrelin responds differently to HFCS and SUC ingestion. Here we investigated the roles of ghrelin in HFCS- and SUC-induced adiposity and insulin resistance. To mimic soft drinks, 10-week-old male wild-type (WT and ghrelin knockout (Ghrelin−/− mice were subjected to ad lib. regular chow diet supplemented with either water (RD, 8% HFCS (HFCS, or 10% sucrose (SUC. We found that SUC-feeding induced more robust increases in body weight and body fat than HFCS-feeding. Comparing to SUC-fed mice, HFCS-fed mice showed lower body weight but higher circulating glucose and insulin levels. Interestingly, we also found that ghrelin deletion exacerbates HFCS-induced adiposity and inflammation in adipose tissues, as well as whole-body insulin resistance. Our findings suggest that HFCS and SUC have differential effects on lipid metabolism: while sucrose promotes obesogenesis, HFCS primarily enhances inflammation and insulin resistance, and ghrelin confers protective effects for these metabolic dysfunctions.

Evidence for altered transport of insulin across the blood-brain barrier in insulin-resistant humans.

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Heni, Martin; Schöpfer, Patricia; Peter, Andreas; Sartorius, Tina; Fritsche, Andreas; Synofzik, Matthis; Häring, Hans-Ulrich; Maetzler, Walter; Hennige, Anita M

2014-08-01

Eating behavior, body weight regulation, peripheral glucose metabolism, and cognitive function depend on adequate insulin action in the brain, and recent studies in humans suggested that impaired insulin action in the brain emerges upon fat intake, obesity, and genetic variants. As insulin enters into the brain in a receptor-mediated fashion, we hypothesized that whole-body insulin sensitivity might affect the transport of insulin into the brain and contribute to the aversive effect of insulin resistance in the central nervous system. In this study, we aimed to determine the ratio of insulin in the cerebrospinal fluid and serum to whole-body insulin sensitivity. Healthy human subjects participated in an oral glucose tolerance test to determine whole-body insulin sensitivity and underwent lumbar puncture. Blood and CSF concentrations of insulin were significantly correlated. The CSF/serum ratio for insulin was significantly associated with whole body insulin sensitivity with reduced insulin transported into the CSF in insulin-resistant subjects. Together, our data suggest that transport of insulin into the CSF relates to peripheral insulin sensitivity and impairs insulin action in the brain. This underlines the need for sensitizing measures in insulin-resistant subjects.

Metabolic Profiles in Obese Children and Adolescents with Insulin Resistance

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Marko Kostovski

2018-03-01

CONCLUSION: Higher percentage of insulin-resistant participants was of female gender and was adolescents. In general, insulin resistant obese children and adolescents tend to have a worse metabolic profile in comparison to individuals without insulin resistance. It is of note that the highest insulin resistance was also linked with the highest concentrations of triglycerides.

Anesthesia with propofol induces insulin resistance systemically in skeletal and cardiac muscles and liver of rats

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Yasuda, Yoshikazu; Fukushima, Yuji; Kaneki, Masao [Department of Anaesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Shriners Hospitals for Children, Harvard Medical School, Boston, MA 02114 (United States); Martyn, J.A. Jeevendra, E-mail: jmartyn@partners.org [Department of Anaesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Shriners Hospitals for Children, Harvard Medical School, Boston, MA 02114 (United States)

2013-02-01

Highlights: ► Propofol, as a model anesthetic drug, induced whole body insulin resistance. ► Propofol anesthesia decreased glucose infusion rate to maintain euglycemia. ► Propofol decreased insulin-mediated glucose uptake in skeletal and cardiac muscles. ► Propofol increased hepatic glucose output confirming hepatic insulin resistance. -- Abstract: Hyperglycemia together with hepatic and muscle insulin resistance are common features in critically ill patients, and these changes are associated with enhanced inflammatory response, increased susceptibility to infection, muscle wasting, and worsened prognosis. Tight blood glucose control by intensive insulin treatment may reduce the morbidity and mortality in intensive care units. Although some anesthetics have been shown to cause insulin resistance, it remains unknown how and in which tissues insulin resistance is induced by anesthetics. Moreover, the effects of propofol, a clinically relevant intravenous anesthetic, also used in the intensive care unit for sedation, on insulin sensitivity have not yet been investigated. Euglycemic hyperinsulinemic clamp study was performed in rats anesthetized with propofol and conscious unrestrained rats. To evaluate glucose uptake in tissues and hepatic glucose output [{sup 3}H]glucose and 2-deoxy[{sup 14}C]glucose were infused during the clamp study. Anesthesia with propofol induced a marked whole-body insulin resistance compared with conscious rats, as reflected by significantly decreased glucose infusion rate to maintain euglycemia. Insulin-stimulated tissue glucose uptake was decreased in skeletal muscle and heart, and hepatic glucose output was increased in propofol anesthetized rats. Anesthesia with propofol induces systemic insulin resistance along with decreases in insulin-stimulated glucose uptake in skeletal and heart muscle and attenuation of the insulin-mediated suppression of hepatic glucose output in rats.

Anesthesia with propofol induces insulin resistance systemically in skeletal and cardiac muscles and liver of rats

International Nuclear Information System (INIS)

Yasuda, Yoshikazu; Fukushima, Yuji; Kaneki, Masao; Martyn, J.A. Jeevendra

2013-01-01

Highlights: ► Propofol, as a model anesthetic drug, induced whole body insulin resistance. ► Propofol anesthesia decreased glucose infusion rate to maintain euglycemia. ► Propofol decreased insulin-mediated glucose uptake in skeletal and cardiac muscles. ► Propofol increased hepatic glucose output confirming hepatic insulin resistance. -- Abstract: Hyperglycemia together with hepatic and muscle insulin resistance are common features in critically ill patients, and these changes are associated with enhanced inflammatory response, increased susceptibility to infection, muscle wasting, and worsened prognosis. Tight blood glucose control by intensive insulin treatment may reduce the morbidity and mortality in intensive care units. Although some anesthetics have been shown to cause insulin resistance, it remains unknown how and in which tissues insulin resistance is induced by anesthetics. Moreover, the effects of propofol, a clinically relevant intravenous anesthetic, also used in the intensive care unit for sedation, on insulin sensitivity have not yet been investigated. Euglycemic hyperinsulinemic clamp study was performed in rats anesthetized with propofol and conscious unrestrained rats. To evaluate glucose uptake in tissues and hepatic glucose output [ 3 H]glucose and 2-deoxy[ 14 C]glucose were infused during the clamp study. Anesthesia with propofol induced a marked whole-body insulin resistance compared with conscious rats, as reflected by significantly decreased glucose infusion rate to maintain euglycemia. Insulin-stimulated tissue glucose uptake was decreased in skeletal muscle and heart, and hepatic glucose output was increased in propofol anesthetized rats. Anesthesia with propofol induces systemic insulin resistance along with decreases in insulin-stimulated glucose uptake in skeletal and heart muscle and attenuation of the insulin-mediated suppression of hepatic glucose output in rats

The Emerging Role of Branched-Chain Amino Acids in Insulin Resistance and Metabolism

OpenAIRE

Yoon, Mee-Sup

2016-01-01

Insulin is required for maintenance of glucose homeostasis. Despite the importance of insulin sensitivity to metabolic health, the mechanisms that induce insulin resistance remain unclear. Branched-chain amino acids (BCAAs) belong to the essential amino acids, which are both direct and indirect nutrient signals. Even though BCAAs have been reported to improve metabolic health, an increased BCAA plasma level is associated with a high risk of metabolic disorder and future insulin resistance, or...

High-fat diet-induced insulin resistance does not increase plasma anandamide levels or potentiate anandamide insulinotropic effect in isolated canine islets.

Science.gov (United States)

Woolcott, Orison O; Richey, Joyce M; Kabir, Morvarid; Chow, Robert H; Iyer, Malini S; Kirkman, Erlinda L; Stefanovski, Darko; Lottati, Maya; Kim, Stella P; Harrison, L Nicole; Ionut, Viorica; Zheng, Dan; Hsu, Isabel R; Catalano, Karyn J; Chiu, Jenny D; Bradshaw, Heather; Wu, Qiang; Kolka, Cathryn M; Bergman, Richard N

2015-01-01

Obesity has been associated with elevated plasma anandamide levels. In addition, anandamide has been shown to stimulate insulin secretion in vitro, suggesting that anandamide might be linked to hyperinsulinemia. To determine whether high-fat diet-induced insulin resistance increases anandamide levels and potentiates the insulinotropic effect of anandamide in isolated pancreatic islets. Dogs were fed a high-fat diet (n = 9) for 22 weeks. Abdominal fat depot was quantified by MRI. Insulin sensitivity was assessed by the euglycemic-hyperinsulinemic clamp. Fasting plasma endocannabinoid levels were analyzed by liquid chromatography-mass spectrometry. All metabolic assessments were performed before and after fat diet regimen. At the end of the study, pancreatic islets were isolated prior to euthanasia to test the in vitro effect of anandamide on islet hormones. mRNA expression of cannabinoid receptors was determined in intact islets. The findings in vitro were compared with those from animals fed a control diet (n = 7). Prolonged fat feeding increased abdominal fat content by 81.3±21.6% (mean±S.E.M, Pcanines, high-fat diet-induced insulin resistance does not alter plasma anandamide levels or further potentiate the insulinotropic effect of anandamide in vitro.

Cardiac Development and Transcription Factors: Insulin Signalling, Insulin Resistance, and Intrauterine Nutritional Programming of Cardiovascular Disease

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Govindsamy, Annelene; Naidoo, Strinivasen

2018-01-01

Programming with an insult or stimulus during critical developmental life stages shapes metabolic disease through divergent mechanisms. Cardiovascular disease increasingly contributes to global morbidity and mortality, and the heart as an insulin-sensitive organ may become insulin resistant, which manifests as micro- and/or macrovascular complications due to diabetic complications. Cardiogenesis is a sequential process during which the heart develops into a mature organ and is regulated by several cardiac-specific transcription factors. Disrupted cardiac insulin signalling contributes to cardiac insulin resistance. Intrauterine under- or overnutrition alters offspring cardiac structure and function, notably cardiac hypertrophy, systolic and diastolic dysfunction, and hypertension that precede the onset of cardiovascular disease. Optimal intrauterine nutrition and oxygen saturation are required for normal cardiac development in offspring and the maintenance of their cardiovascular physiology. PMID:29484207

Effects of pomegranate seed oil followed by resistance exercise on insulin resistance and lipid profile in non-athletic men

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Fereshteh Shahidi

2017-08-01

Full Text Available Background: Although some studies have reported the health-related benefits for the pomegranate seed oil (PSO, there is not enough information on its combined effect with exercise. Therefore, in this study the effect of supplementation with pomegranate seed oil followed by resistance exercise on insulin resistance and lipid profile was considered in non-athletes men. Materials and Methods: In this semi-experimental double-blind randomized study non-athletic male (n=14 were divided into two groups: Exercise+Supplementation (n=7 and Exercise +Placebo (n=7. Both groups performed resistance training for 4 weeks (3 sessions per week. The experimental group consumed 2 capsules of pomegranate seed oil (400 mg and the control group received 2 placebo capsules daily. Glucose, fasting insulin, total cholesterol, triglycerides, LDL-C, HDL-C, were measured at the beginning and end of the study. Insulin resistance was estimated using homeostasis formula (HOMA-IR. Results: While the average concentration of HDL-C in Supplement+Exercise group was significantly increased compared to pre-test, no significant increase was seen compared to Placebo + Exercise group (P<0.05. Between and within group comparison for the changes in total cholesterol, triglycerides, LDL-C, glucose, fasting insulin and insulin resistance was not significant. Conclusion: According to the results, it can be concluded that 4 weeks of resistance training followed by PSO supplementation, except for HDL-C, has no significant effect on the other lipid profiles and insulin resistance in healthy non-athlete men.

Plasma Asprosin Concentrations Are Increased in Individuals with Glucose Dysregulation and Correlated with Insulin Resistance and First-Phase Insulin Secretion

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Yuren Wang

2018-01-01

Full Text Available Background. Adipokines are reported to participate in many common pathologic processes of glucose dysregulation, such as insulin resistance, β-cell dysfunction, and chronic inflammation. Objective. To detect the concentrations of plasma asprosin in subjects with impaired glucose regulation (IGR and newly diagnosed type 2 diabetes (nT2DM and its relationship to parameters of glucose and lipid metabolism, insulin resistance, and pancreatic β-cell function. Methods. 143 eligible participants were included and were divided into three groups including normal glucose regulation (NGR, n=52, IGR (n=40, and nT2DM group (n=51. The intravenous glucose tolerance test (IVGTT and clinical and biochemical parameters were measured in all participants. Results. Plasma asprosin levels were higher in IGR (82.40 ± 91.06 ng/mL, P<0.001 and nT2DM (73.25 ± 91.69 ng/mL, P<0.001 groups compared with those in the NGR (16.22 ± 9.27 ng/mL group, especially in IGR subjects. Correlation analysis showed that plasma asprosin levels were positively correlated with waist circumference (Wc, fasting plasma glucose (FPG, postchallenge plasma glucose (2hPG, HbA1c, triglyceride (TG, and homeostasis model assessment for insulin resistance (HOMA-IR and negatively correlated with homeostasis model assessment for β-cell function (HOMA-β, area under the curve of the first-phase (0–10 min insulin secretion (AUC, acute insulin response (AIR, and glucose disposition index (GDI (all P<0.05. Multiple logistical regression analyses revealed that plasma asprosin concentrations were significantly correlated with IGR and nT2DM after controlling for age, sex, BMI, and WHR. Conclusions. Circulating asprosin might be a predictor of early diagnosis in DM and might be a potential therapeutic target for prediabetes and T2DM.

In nondiabetic, human immunodeficiency virus-infected patients with lipodystrophy, hepatic insulin extraction and posthepatic insulin clearance rate are decreased in proportion to insulin resistance

DEFF Research Database (Denmark)

Haugaard, Steen B; Andersen, Ove; Hansen, Birgitte R

2005-01-01

In healthy, nondiabetic individuals with insulin resistance, fasting insulin is inversely correlated to the posthepatic insulin clearance rate (MCRi) and the hepatic insulin extraction (HEXi). We investigated whether similar early mechanisms to facilitate glucose homeostasis exist in nondiabetic...... endogenous insulin secretion, which was estimated by deconvolution of C-peptide concentrations. Hepatic extraction of insulin was calculated as 1 minus the ratio of fasting posthepatic insulin delivery rate to fasting endogenous insulin secretion rate. Compared with controls, LIPO displayed increased fasting...... insulin (130%, P Hepatic extraction of insulin was similar between groups (LIPO, 55%; controls, 57%; P > .8). In LIPO, HEXi and MCRi correlated inversely with fasting insulin (r = -0.56, P

Insulin resistance and mitochondrial function in skeletal muscle

DEFF Research Database (Denmark)

Dela, Flemming; Helge, Jørn Wulff

2013-01-01

are used in the attempt to resolve the mechanisms of insulin resistance. In this context, a dysfunction of mitochondria in the skeletal muscle has been suggested to play a pivotal role. It has been postulated that a decrease in the content of mitochondria in the skeletal muscle can explain the insulin...... resistance. Complementary to this also specific defects of components in the respiratory chain in the mitochondria have been suggested to play a role in insulin resistance. A key element in these mechanistic suggestions is inability to handle substrate fluxes and subsequently an accumulation of ectopic...... intramyocellular lipids, interfering with insulin signaling. In this review we will present the prevailing view-points and argue for the unlikelihood of this scenario being instrumental in human insulin resistance. This article is part of a Directed Issue entitled: Bioenergetic dysfunction....

Testosterone treatment increases androgen receptor and aromatase gene expression in myotubes from patients with PCOS and controls, but does not induce insulin resistance.

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Eriksen, Mette Brandt; Glintborg, Dorte; Nielsen, Michael Friberg Bruun; Jakobsen, Marianne Antonius; Brusgaard, Klaus; Tan, Qihua; Gaster, Michael

2014-09-05

Polycystic ovary syndrome (PCOS) is associated with insulin resistance and increased risk of type 2 diabetes. Skeletal muscle is the major site of insulin mediated glucose disposal and the skeletal muscle tissue is capable to synthesize, convert and degrade androgens. Insulin sensitivity is conserved in cultured myotubes (in vitro) from patients with PCOS, but the effect of testosterone on this insulin sensitivity is unknown. We investigated the effect of 7days testosterone treatment (100nmol/l) on glucose transport and gene expression levels of hormone receptors and enzymes involved in the synthesis and conversion of testosterone (HSD17B1, HSD17B2, CYP19A1, SRD5A1-2, AR, ER-α, HSD17B6 and AKR1-3) in myotubes from ten patients with PCOS and ten matched controls. Testosterone treatment significantly increased aromatase and androgen receptor gene expression levels in patients and controls. Glucose transport in myotubes was comparable in patients with PCOS vs. controls and was unchanged by testosterone treatment (p=0.21 PCOS vs. controls). These results suggest that testosterone treatment of myotubes increases the aromatase and androgen receptor gene expression without affecting insulin sensitivity and if testosterone is implicated in muscular insulin resistance in PCOS, this is by and indirect mechanism. Copyright © 2014 Elsevier Inc. All rights reserved.

Association between insulin resistance and c-reactive protein among Peruvian adults

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Gelaye Bizu

2010-05-01

Full Text Available Abstract Objective Insulin resistance (IR, a reduced physiological response of peripheral tissues to the action of insulin, is one of the major causes of type 2 diabetes. We sought to evaluate the relationship between serum C-reactive protein (CRP, a marker of systemic inflammation, and prevalence of IR among Peruvian adults. Methods This population based study of 1,525 individuals (569 men and 956 women; mean age 39 years old was conducted among residents in Lima and Callao, Peru. Fasting plasma glucose, insulin, and CRP concentrations were measured using standard approaches. Insulin resistance was assessed using the homeostasis model (HOMA-IR. Categories of CRP were defined by the following tertiles: 2.53 mg/l. Logistic regression procedures were employed to estimate odds ratios (OR and 95% confidence intervals (CI. Results Elevated CRP were significantly associated with increased mean fasting insulin and mean HOMA-IR concentrations (p 2.53 mg/l (upper tertile had a 2.18-fold increased risk of IR (OR = 2.18 95% CI 1.51-3.16 as compared with those in the lowest tertile ( Conclusion Our observations among Peruvians suggest that chronic systemic inflammation, as evidenced by elevated CRP, may be of etiologic importance in insulin resistance and diabetes.

Body fat and insulin resistance independently predict increased serum C-reactive protein in hyperandrogenic women with polycystic ovary syndrome.

Science.gov (United States)

Tosi, Flavia; Dorizzi, Romolo; Castello, Roberto; Maffeis, Claudio; Spiazzi, Giovanna; Zoppini, Giacomo; Muggeo, Michele; Moghetti, Paolo

2009-11-01

Increased serum C-reactive protein (CRP), an independent predictor of coronary heart disease, was reported in women with polycystic ovary syndrome (PCOS). It remains unclear whether this finding is due to the association between PCOS and either insulin resistance, obesity, or androgen excess, which are all common features of this condition. The aims of this study were to assess whether increased serum CRP is a specific feature of PCOS and to investigate the mechanisms underlying this association. Serum high-sensitivity CRP (hs-CRP) was measured in 86 hyperandrogenic women (age 21.6+/-4.2 years, body mass index (BMI) 23.6+/-3.5 kg/m2), 50 with PCOS and 36 with idiopathic hyperandrogenism (HA). Thirty-five BMI-matched healthy women were also studied as controls. In these subjects, endocrine and metabolic profiles were assessed. In all hyperandrogenic subjects and 14 controls, insulin sensitivity was measured by the glucose clamp technique. Body fat was measured by bioelectrical impedance. Hs-CRP concentrations were higher in PCOS women (3.43+/-2.01 mg/l) than in HA subjects and healthy women (2.43+/-1.04, PPCOS). In multiple regression analyses, increased serum hs-CRP was independently predicted by higher body fat and lower insulin sensitivity. However, in lean women, serum-free testosterone was an additional, negative, predictive variable. PCOS is accompanied by a low-grade chronic inflammation. Body fat appears the main determining factor of this finding, which is only partly explained by insulin resistance. At least in lean women, androgen excess per se seems to play an additional, possibly protective, role in this association.

Insulin resistance in human subjects having impaired glucose regulation

International Nuclear Information System (INIS)

Khan, S.H.; Khan, F.A.; Ijaz, A.

2007-01-01

To determine insulin resistance in human subjects having impaired glucose regulation (IGR) by Homeostasis Model Assessment for Insulin Resistance (HOMA-IR). A total of 100 subjects with impaired glucose regulation were selected for evaluation of metabolic syndrome as per the criteria of National Cholesterol Education Program, Adult Treatment Panel III (NCEP, ATP III), along with 47 healthy age and gender-matched controls. Physical examination to determine blood pressure and waist circumference was carried out and so was sampling for plasma glucose, serum triglycerides, HDL-cholesterol and insulin. Insulin resistance was calculated by the HOMA-IR. Finally, subjects with and without metabolic syndrome were compared with controls (n=47), using one-way ANOVA for studying insulin resistance between groups, with Tukey's post-hoc comparison. The frequency of finding metabolic syndrome in cases of IGR remained 47%. The insulin resistance demonstrated stepwise worsening from control population (mean=1.54, 95 % CI: 1.77 - 2.37) to subjects suffering from only IGR (mean=2.07, 95 % CI: 1.77- 2.37) to metabolic syndrome (mean=2.67, 95 %, CI: 2.34 - 3.00) (p < 0.001). Patients with impaired glucose regulation may have significant insulin resistance. It is, thus, recommended that a vigorous search be made to measure insulin resistance in all cases diagnosed to have impaired glucose regulation. (author)

Retinol binding protein 4, obesity, and insulin resistance in adolescents

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Ronaldi Noor

2017-02-01

Full Text Available Background Obesity is a global problem. Even in poor and developing countries, obesity has reached alarming levels. In childhood, obesity may lead to insulin resistance. Retinol binding protein (RBP4, secreted primarily by liver and adipose tissues, was recently proposed as a link between obesity and insulin resistance. The role of RBP4 in pediatric obesity and its relationship with insulin resistance have not been well elucidated. Objective To compare RBP4 levels in obese and lean adolescents and to assess for a relationship between RBP4 levels and insulin resistance. Method This cross-sectional study was conducted in three senior high schools in Padang, West Sumatera, Indonesia. Subjects were adolescents aged 14-18 years, who were obese or normal weight (n=56. We measured subjects’ body mass index (BMI and serum RBP4 concentrations. Insulin resistance was assessed using the homeostasis model assessment of insulin resistance (HOMA-IR index. Results Similar RBP4 levels were found in the obese and normoweight groups (P>0.05. Higher RBP4 levels were found in the insulin resistant compared to the non-insulin resistant group, but the difference was not significant (P > 0.05. Conclusion There is no significant difference in mean RBP4 levels in obese adolescents compared to normoweight adolescents. Nor are mean RBP4 levels significantly different between obese adolescents with and without insulin resistance.

Insulin Resistance, Metabolic Syndrome, and Polycystic Ovary Syndrome in Obese Youth.

Science.gov (United States)

Platt, Adrienne M

2015-07-01

School nurses are well aware of the childhood obesity epidemic in the United States, as one in three youth are overweight or obese. Co-morbidities found in overweight or obese adults were not commonly found in youth three decades ago but are now increasingly "normal" as the obesity epidemic continues to evolve. This article is the second of six related articles discussing the co-morbidities of childhood obesity and discusses the complex association between obesity and insulin resistance, metabolic syndrome, and polycystic ovary syndrome. Insulin resistance increases up to 50% during puberty, which may help to explain why youth are more likely to develop co-morbidities as teens. Treatment of these disorders is focused on changing lifestyle habits, as a child cannot change his or her pubertal progression, ethnicity, or family history. School nurses and other personnel can assist youth with insulin resistance, metabolic syndrome, and polycystic ovary syndrome by supporting their efforts to make changes, reinforcing that insulin resistance is not necessarily type 2 diabetes even if the child is taking medication, and intervening with negative peer pressure. © 2015 The Author(s).

Relationship between insulin resistance and plasma endothelin in hypertension patients

International Nuclear Information System (INIS)

Duan Yongqiang; Wang Zuobing; Yu Hui; Cao Wei; Wang Jing; Li Xiaoqin

2011-01-01

To explore the relationship between plasma endothelin and hypertension insulin resistance, and the improvement of insulin resistance in hypertension patients treated with captopril and l-amlodipine, 25 patients with primary hypertension and impaired glucose tolerance were selected and treated by captopril and l-amlodipine. Systolic pressure, diastolic pressure, fasting blood glucose, insulin and insulin antibody were measured before and after treatment and compared with healthy controls. The results showed that the plasma ET-1 level in hypertension group was significantly higher than that of healthy controls (P<0.01), and he plasma ET-1 level was positively correlated with FPG, FINS, Anti-INS, HOMA-IR. The systolic pressure, diastolic pressure, fasting blood glucose, insulin, insulin antibody and insulin resistance index in hypertension patients were decreased significantly after treatment (P<0.05). There is a good correlation between endothelin and insulin resistance index in hypertension patients. Captopril and l-amlodipine had obvious improvement effect on insulin resistance in hypertension patients. (authors)

[Severe type A insulin resistance syndrome due to a mutation in the insulin receptor gene].

Science.gov (United States)

Ros, P; Colino-Alcol, E; Grasso, V; Barbetti, F; Argente, J

2015-01-01

Insulin resistance syndromes without lipodystrophy are an infrequent and heterogeneous group of disorders with variable clinical phenotypes, associated with hyperglycemia and hyperinsulinemia. The three conditions related to mutations in the insulin receptor gene are leprechaunism or Donohue syndrome, Rabson-Mendenhall syndrome, and Type A syndrome. A case is presented on a patient diagnosed with type A insulin resistance, defined by the triad of extreme insulin resistance, acanthosis nigricans, and hyperandrogenism, carrying a heterozygous mutation in exon 19 of the insulin receptor gene coding for its tyrosine kinase domain that is crucial for the catalytic activity of the receptor. The molecular basis of the syndrome is reviewed, focusing on the structure-function relationships of the insulin receptor, knowing that the criteria for survival are linked to residual insulin receptor function. It is also pointed out that, although type A insulin resistance appears to represent a somewhat less severe condition, these patients have a high morbidity and their treatment is still unsatisfactory. Copyright © 2014 Asociación Española de Pediatría. Published by Elsevier Espana. All rights reserved.

Insulin receptor internalization defect in an insulin-resistant mouse melanoma cell line

International Nuclear Information System (INIS)

Androlewicz, M.J.; Straus, D.S.; Brandenburg, D.F.

1989-01-01

Previous studies from this laboratory demonstrated that the PG19 mouse melanoma cell line does not exhibit a biological response to insulin, whereas melanoma x mouse embryo fibroblast hybrids do respond to insulin. To investigate the molecular basis of the insulin resistance of the PG19 melanoma cells, insulin receptors from the insulin-resistant melanoma cells and insulin-sensitive fibroblast x melanoma hybrid cells were analyzed by the technique of photoaffinity labeling using the photoprobe 125 I-NAPA-DP-insulin. Photolabeled insulin receptors from the two cell types have identical molecular weights as determined by SDS gel electrophoresis under reducing and nonreducing conditions, indicating that the receptors on the two cell lines are structurally similar. Insulin receptor internalization studies revealed that the hybrid cells internalize receptors to a high degree at 37 degree C, whereas the melanoma cells internalize receptors to a very low degree or not at all. The correlation between ability to internalize insulin receptors and sensitivity to insulin action in this system suggests that uptake of the insulin-receptor complex may be required for insulin action in these cells. Insulin receptors from the two cell lines autophosphorylate in a similar insulin-dependent manner both in vitro and in intact cells, indicating that insulin receptors on the melanoma and hybrid cells have functional tyrosine protein kinase activity. Therefore, the block in insulin action in the PG19 melanoma cells appears to reside at a step beyond insulin-stimulated receptor autophosphorylation

Uric acid concentrations are associated with insulin resistance and birthweight in normotensive pregnant women.

Science.gov (United States)

Laughon, S Katherine; Catov, Janet; Roberts, James M

2009-12-01

We sought to investigate whether uric acid concentrations are increased in pregnant women with insulin resistance and to correlate both with fetal growth. Uric acid, glucose, and insulin were measured in plasma at 20.4 (+/-2.0) weeks' gestation in 263 women. The association between uric acid and insulin resistance, as estimated using the homeostasis model assessment (HOMA), was analyzed and related to birthweights. In 212 (80.6%) women who remained normotensive throughout pregnancy, HOMA increased 1.23 U per 1-mg/dL increase in uric acid (95% confidence interval, 1.07-1.42; P=.003). Infants born to normotensive women in the upper quartile of uric acid and lowest HOMA quartile weighed 435.6 g less than infants of women with highest uric acid and HOMA quartiles (Pinsulin resistance in midpregnancy. Hyperuricemia was associated with lower birthweight in normotensive women, and this effect was attenuated by insulin resistance.

Fructose, insulin resistance, and metabolic dyslipidemia

Directory of Open Access Journals (Sweden)

Adeli Khosrow

2005-02-01

Full Text Available Abstract Obesity and type 2 diabetes are occurring at epidemic rates in the United States and many parts of the world. The "obesity epidemic" appears to have emerged largely from changes in our diet and reduced physical activity. An important but not well-appreciated dietary change has been the substantial increase in the amount of dietary fructose consumption from high intake of sucrose and high fructose corn syrup, a common sweetener used in the food industry. A high flux of fructose to the liver, the main organ capable of metabolizing this simple carbohydrate, perturbs glucose metabolism and glucose uptake pathways, and leads to a significantly enhanced rate of de novo lipogenesis and triglyceride (TG synthesis, driven by the high flux of glycerol and acyl portions of TG molecules from fructose catabolism. These metabolic disturbances appear to underlie the induction of insulin resistance commonly observed with high fructose feeding in both humans and animal models. Fructose-induced insulin resistant states are commonly characterized by a profound metabolic dyslipidemia, which appears to result from hepatic and intestinal overproduction of atherogenic lipoprotein particles. Thus, emerging evidence from recent epidemiological and biochemical studies clearly suggests that the high dietary intake of fructose has rapidly become an important causative factor in the development of the metabolic syndrome. There is an urgent need for increased public awareness of the risks associated with high fructose consumption and greater efforts should be made to curb the supplementation of packaged foods with high fructose additives. The present review will discuss the trends in fructose consumption, the metabolic consequences of increased fructose intake, and the molecular mechanisms leading to fructose-induced lipogenesis, insulin resistance and metabolic dyslipidemia.

Dissociation of hepatic steatosis and insulin resistance in mice overexpressing DGAT in the liver.

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Monetti, Mara; Levin, Malin C; Watt, Matthew J; Sajan, Mini P; Marmor, Stephen; Hubbard, Brian K; Stevens, Robert D; Bain, James R; Newgard, Christopher B; Farese, Robert V; Hevener, Andrea L; Farese, Robert V

2007-07-01

Hepatic steatosis, the accumulation of lipids in the liver, is widely believed to result in insulin resistance. To test the causal relationship between hepatic steatosis and insulin resistance, we generated mice that overexpress acyl-CoA:diacylglycerol acyltransferase 2 (DGAT2), which catalyzes the final step of triacylglycerol (TG) biosynthesis, in the liver (Liv-DGAT2 mice). Liv-DGAT2 mice developed hepatic steatosis, with increased amounts of TG, diacylglycerol, ceramides, and unsaturated long-chain fatty acyl-CoAs in the liver. However, they had no abnormalities in plasma glucose and insulin levels, glucose and insulin tolerance, rates of glucose infusion and hepatic glucose production during hyperinsulinemic-euglycemic clamp studies, or activities of insulin-stimulated signaling proteins in the liver. DGAT1 overexpression in the liver also failed to induce glucose or insulin intolerance. Our results indicate that DGAT-mediated lipid accumulation in the liver is insufficient to cause insulin resistance and show that hepatic steatosis can occur independently of insulin resistance.

Increased serum chemerin concentrations in patients with polycystic ovary syndrome: Relationship between insulin resistance and ovarian volume.

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Huang, Rong; Yue, Jiang; Sun, Yun; Zheng, Jun; Tao, Tao; Li, Shengxian; Liu, Wei

2015-10-23

Chemerin has been linked to adiposity, and insulin resistance (IR) which are the common characteristics of polycystic ovary syndrome (PCOS). Chemerin also shows inhibitory action on follicular steroidogenesis. We investigated the associations between chemerin and IR or polycystic ovary morphology in patients with PCOS. A total of 148 women with newly diagnosed PCOS using Rotterdam criteria and 88 healthy individuals were enrolled. The recruited patients with PCOS were further stratified by tertiles of serum chemerin concentrations as follows: Group 1 ( 30.27 ng/ml). Compared to controls, women with PCOS in each tertile had higher serum chemerin concentrations. By linear regression analysis, homeostasis model assessment-insulin resistance and ovarian volume showed significant associations with chemerin after adjusting for confounding factors (β = 0.257, P = 0.028; β = 0.276, P = 0.005, respectively). The odds ratios (ORs) for ovarian volume excess gradually increased across increasing tertiles of chemerin in the adjusted model [Group 1: reference; Group 2: OR 1.602; 95% confidence interval (CI): 1.170–2.194; Group 3: OR 1.857; 95% CI: 1.335-2.583]. Patients with PCOS showed increased serum chemerin concentrations as compared to healthy women. Individuals with higher chemerin tended to have higher risk for ovarian volume excess in patients with PCOS, regardless of adiposity.

Targeted Overexpression of Inducible 6-Phosphofructo-2-kinase in Adipose Tissue Increases Fat Deposition but Protects against Diet-induced Insulin Resistance and Inflammatory Responses*

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Huo, Yuqing; Guo, Xin; Li, Honggui; Xu, Hang; Halim, Vera; Zhang, Weiyu; Wang, Huan; Fan, Yang-Yi; Ong, Kuok Teong; Woo, Shih-Lung; Chapkin, Robert S.; Mashek, Douglas G.; Chen, Yanming; Dong, Hui; Lu, Fuer; Wei, Lai; Wu, Chaodong

2012-01-01

Increasing evidence demonstrates the dissociation of fat deposition, the inflammatory response, and insulin resistance in the development of obesity-related metabolic diseases. As a regulatory enzyme of glycolysis, inducible 6-phosphofructo-2-kinase (iPFK2, encoded by PFKFB3) protects against diet-induced adipose tissue inflammatory response and systemic insulin resistance independently of adiposity. Using aP2-PFKFB3 transgenic (Tg) mice, we explored the ability of targeted adipocyte PFKFB3/iPFK2 overexpression to modulate diet-induced inflammatory responses and insulin resistance arising from fat deposition in both adipose and liver tissues. Compared with wild-type littermates (controls) on a high fat diet (HFD), Tg mice exhibited increased adiposity, decreased adipose inflammatory response, and improved insulin sensitivity. In a parallel pattern, HFD-fed Tg mice showed increased hepatic steatosis, decreased liver inflammatory response, and improved liver insulin sensitivity compared with controls. In both adipose and liver tissues, increased fat deposition was associated with lipid profile alterations characterized by an increase in palmitoleate. Additionally, plasma lipid profiles also displayed an increase in palmitoleate in HFD-Tg mice compared with controls. In cultured 3T3-L1 adipocytes, overexpression of PFKFB3/iPFK2 recapitulated metabolic and inflammatory changes observed in adipose tissue of Tg mice. Upon treatment with conditioned medium from iPFK2-overexpressing adipocytes, mouse primary hepatocytes displayed metabolic and inflammatory responses that were similar to those observed in livers of Tg mice. Together, these data demonstrate a unique role for PFKFB3/iPFK2 in adipocytes with regard to diet-induced inflammatory responses in both adipose and liver tissues. PMID:22556414

Linking mitochondrial bioenergetics to insulin resistance via redox biology

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Fisher-Wellman, Kelsey H.; Neufer, P. Darrell

2012-01-01

Chronic overnutrition and physical inactivity are major risk factors for insulin resistance and type 2 diabetes. Recent research indicates that overnutrition generates an increase in hydrogen peroxide (H2O2) emission from mitochondria, serving as a release valve to relieve the reducing pressure created by fuel overload, as well as a primary signal to ultimately decrease insulin sensitivity. H2O2 is a major input to cellular redox circuits that link to cysteine residues throughout the entire proteome to regulate cell function. Here we review the principles of mitochondrial bioenergetics and redox systems biology and offer new insight as to how H2O2 emission may be linked via redox biology to the etiology of insulin resistance. PMID:22305519

Attenuation of insulin-evoked responses in brain networks controlling appetite and reward in insulin resistance: the cerebral basis for impaired control of food intake in metabolic syndrome?

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Anthony, Karen; Reed, Laurence J; Dunn, Joel T; Bingham, Emma; Hopkins, David; Marsden, Paul K; Amiel, Stephanie A

2006-11-01

The rising prevalence of obesity and type 2 diabetes is a global challenge. A possible mechanism linking insulin resistance and weight gain would be attenuation of insulin-evoked responses in brain areas relevant to eating in systemic insulin resistance. We measured brain glucose metabolism, using [(18)F]fluorodeoxyglucose positron emission tomography, in seven insulin-sensitive (homeostasis model assessment of insulin resistance [HOMA-IR] = 1.3) and seven insulin-resistant (HOMA-IR = 6.3) men, during suppression of endogenous insulin by somatostatin, with and without an insulin infusion that elevated insulin to 24.6 +/- 5.2 and 23.2 +/- 5.8 mU/l (P = 0.76), concentrations similar to fasting levels of the resistant subjects and approximately threefold above those of the insulin-sensitive subjects. Insulin-evoked change in global cerebral metabolic rate for glucose was reduced in insulin resistance (+7 vs. +17.4%, P = 0.033). Insulin was associated with increased metabolism in ventral striatum and prefrontal cortex and with decreased metabolism in right amygdala/hippocampus and cerebellar vermis (P reward. Diminishing the link be-tween control of food intake and energy balance may contribute to development of obesity in insulin resistance.

Retinol-Binding Protein 4 and Insulin Resistance in Polycystic Ovary Syndrome

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Hutchison, Samantha K.; Harrison, Cheryce; Stepto, Nigel; Meyer, Caroline; Teede, Helena J.

2008-01-01

OBJECTIVE?Polycystic ovary syndrome (PCOS) is an insulin-resistant state with insulin resistance being an established therapeutic target; however, measurement of insulin resistance remains challenging. We aimed to 1) determine serum retinol-binding protein 4 (RBP4) levels (purported to reflect insulin resistance) in women with PCOS and control subjects, 2) examine the relationship of RBP4 to conventional markers of insulin resistance, and 3) examine RBP4 changes with interventions modulating ...

Odontella aurita-enriched diet prevents high fat diet-induced liver insulin resistance.

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Amine, Hamza; Benomar, Yacir; Haimeur, Adil; Messaouri, Hafida; Meskini, Nadia; Taouis, Mohammed

2016-01-01

The beneficial effect of polyunsaturated omega-3 fatty acid (w-3 FA) consumption regarding cardiovascular diseases, insulin resistance and inflammation has been widely reported. Fish oil is considered as the main source of commercialized w-3 FAs, and other alternative sources have been reported such as linseed or microalgae. However, despite numerous reports, the underlying mechanisms of action of w-3 FAs on insulin resistance are still not clearly established, especially those from microalgae. Here, we report that Odontella aurita, a microalga rich in w-3 FAs eicosapentaenoic acid, prevents high fat diet-induced insulin resistance and inflammation in the liver of Wistar rats. Indeed, a high fat diet (HFD) increased plasma insulin levels associated with the impairment of insulin receptor signaling and the up-regulation of toll-like receptor 4 (TLR4) expressions. Importantly, Odontella aurita-enriched HFD (HFOA) reduces body weight and plasma insulin levels and maintains normal insulin receptor expression and responsiveness. Furthermore, HFOA decreased TLR4 expression, JNK/p38 phosphorylation and pro-inflammatory factors. In conclusion, we demonstrate for the first time, to our knowledge, that diet supplementation with whole Ondontella aurita overcomes HFD-induced insulin resistance through the inhibition of TLR4/JNK/p38 MAP kinase signaling pathways. © 2016 Society for Endocrinology.

Insulin resistance induced by antiretroviral drugs: Current ...

African Journals Online (AJOL)

Treatment with highly active antiretroviral therapy (HAART) has improved the prognosis of patients with AIDS, but it has also increased the incidence of various metabolic disorders, in particular insulin resistance accompanied by dyslipidaemia, hyperglycaemia and lipodystrophy. This is often accompanied by frank type 2 ...

Metabolic Syndrome and Insulin Resistance: Underlying Causes and Modification by Exercise Training

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Roberts, Christian K.; Hevener, Andrea L.; Barnard, R. James

2014-01-01

Metabolic syndrome (MS) is a collection of cardiometabolic risk factors that includes obesity, insulin resistance, hypertension, and dyslipidemia. Although there has been significant debate regarding the criteria and concept of the syndrome, this clustering of risk factors is unequivocally linked to an increased risk of developing type 2 diabetes and cardiovascular disease. Regardless of the true definition, based on current population estimates, nearly 100 million have MS. It is often characterized by insulin resistance, which some have suggested is a major underpinning link between physical inactivity and MS. The purpose of this review is to: (i) provide an overview of the history, causes and clinical aspects of MS, (ii) review the molecular mechanisms of insulin action and the causes of insulin resistance, and (iii) discuss the epidemiological and intervention data on the effects of exercise on MS and insulin sensitivity. PMID:23720280

The effect of different doses of vitamin D supplementation on insulin resistance during pregnancy.

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Soheilykhah, Sedigheh; Mojibian, Mahdieh; Moghadam, Maryam Jannati; Shojaoddiny-Ardekani, Ahmad

2013-04-01

Low serum vitamin D levels are correlated with insulin resistance during pregnancy. We have assessed the effects of different doses of vitamin D on insulin resistance during pregnancy. A randomized clinical trial was done on 120 women with a gestational age of less than 12 weeks. The women were divided into three groups randomly. Group A received 200 IU vitamin D daily, group B 50,000 IU vitamin D monthly and group C 50,000 IU vitamin D every 2 weeks from 12 weeks of pregnancy until delivery. The serum levels of fasting blood sugar (FBS), insulin, calcium and 25-hydroxyvitamin D were measured before and after intervention. We used the homeostatic model assessment of insulin resistance (HOMA-IR) as a surrogate measure of insulin resistance. The mean ± standard deviation of serum 25-hydroxyvitamin D increased in group C from 7.3 ± 5.9 to 34.1 ± 11.5 ng/ml and in group B it increased from 7.3 ± 5.3 to 27.23 ± 10.7 ng/ml, but the level of vitamin D in group A increased from 8.3 ± 7.8 to 17.7 ± 9.3 ng/ml (p insulin and HOMA-IR before and after intervention in groups A and C were significant (p = 0.01, p = 0.02). This study has shown that supplementation of pregnant women with 50 000 IU vitamin D every 2 weeks improved insulin resistance significantly.

Celastrol Protects against Antimycin A-Induced Insulin Resistance in Human Skeletal Muscle Cells

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Mohamad Hafizi Abu Bakar

2015-05-01

Full Text Available Mitochondrial dysfunction and inflammation are widely accepted as key hallmarks of obesity-induced skeletal muscle insulin resistance. The aim of the present study was to evaluate the functional roles of an anti-inflammatory compound, celastrol, in mitochondrial dysfunction and insulin resistance induced by antimycin A (AMA in human skeletal muscle cells. We found that celastrol treatment improved insulin-stimulated glucose uptake activity of AMA-treated cells, apparently via PI3K/Akt pathways, with significant enhancement of mitochondrial activities. Furthermore, celastrol prevented increased levels of cellular oxidative damage where the production of several pro-inflammatory cytokines in cultures cells was greatly reduced. Celastrol significantly increased protein phosphorylation of insulin signaling cascades with amplified expression of AMPK protein and attenuated NF-κB and PKC θ activation in human skeletal muscle treated with AMA. The improvement of insulin signaling pathways by celastrol was also accompanied by augmented GLUT4 protein expression. Taken together, these results suggest that celastrol may be advocated for use as a potential therapeutic molecule to protect against mitochondrial dysfunction-induced insulin resistance in human skeletal muscle cells.

Investigation of pancreas indocrine function in order to reveal subclinical insulin resistence in women with acne

OpenAIRE

Filippova, T.; Rudykh, N.; Shevchuk, A.

2008-01-01

Changed glycemic curves and indices of insulin resistance, the increase of insulin basal level in comparison with healthy persons, presence of antibodies to insulin antigen, decrease of level sex hormone bilding globulin were revealed in patients with acne. It can be considered as sign of formation of subclinical insulin resistance.

Partial ablation of adult Drosophila insulin-producing neurons modulates glucose homeostasis and extends life span without insulin resistance.

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Haselton, Aaron; Sharmin, Effat; Schrader, Janel; Sah, Megha; Poon, Peter; Fridell, Yih-Woei C

2010-08-01

In Drosophila melanogaster (D. melanogaster), neurosecretory insulin-like peptide-producing cells (IPCs), analogous to mammalian pancreatic beta cells are involved in glucose homeostasis. Extending those findings, we have developed in the adult fly an oral glucose tolerance test and demonstrated that IPCs indeed are responsible for executing an acute glucose clearance response. To further develop D. melanogaster as a relevant system for studying age-associated metabolic disorders, we set out to determine the impact of adult-specific partial ablation of IPCs (IPC knockdown) on insulin-like peptide (ILP) action, metabolic outcomes and longevity. Interestingly, while IPC knockdown flies are hyperglycemic and glucose intolerant, these flies remain insulin sensitive as measured by peripheral glucose disposal upon insulin injection and serine phosphorylation of a key insulin-signaling molecule, Akt. Significant increases in stored glycogen and triglyceride levels as well as an elevated level of circulating lipid measured in adult IPC knockdown flies suggest profound modulation in energy metabolism. Additional physiological outcomes measured in those flies include increased resistance to starvation and impaired female fecundity. Finally, increased life span and decreased mortality rates measured in IPC knockdown flies demonstrate that it is possible to modulate ILP action in adult flies to achieve life span extension without insulin resistance. Taken together, we have established and validated an invertebrate genetic system to further investigate insulin action, metabolic homeostasis and regulation of aging regulated by adult IPCs.

Fatty Acids, Obesity and Insulin Resistance

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Peter Arner

2015-04-01

Full Text Available Objective: Although elevated free fatty acid (FFA levels in obesity have been considered to be of importance for insulin resistance, a recent meta-analysis suggested normal FFA levels in obese subjects. We investigated fasting circulating FFA and glycerol levels in a large cohort of non-obese and obese subjects. Methods: Subjects recruited for a study on obesity genetics were investigated in the morning after an overnight fast (n = 3,888. Serum FFA (n = 3,306, plasma glycerol (n = 3,776, and insulin sensitivity index (HOMA-IR,n = 3,469 were determined. Obesity was defined as BMI ≥ 30 kg/m2 and insulin resistance as HOMA-IR ≥ 2.21. Results: In obese subjects, circulating FFA and glycerol levels were higher than in non-obese individuals (by 26% and 47%, respectively; both p Conclusion: Circulating FFA and glycerol levels are markedly elevated in obesity but only marginally influenced by insulin resistance and type 2 diabetes. Whether these differences persist during diurnal variations in circulating FFA/glycerol, remains to be established.

Effect of cholecalciferol and levo carnitine on plasma glucose, plasma insulin and insulin resistance in type 2 diabetic rats

International Nuclear Information System (INIS)

Anwar, M. K.; Hussain, M. M.; Khan, M. A.; Ahmad, T.

2013-01-01

Objective: To compare the effects of combined and individual supplementation of cholecalciferol and levo carnitine on plasma glucose, plasma insulin and insulin resistance in type 2 diabetic rats. Methods: The randomised controlled trial was conducted at the Department of Physiology, Army Medical College, Rawalpindi, between October 2010 and April 2011. It comprised 80 healthy Sprague Dawley rats who were divided into four groups (n = 20 each). Rats were fed high-fat diet for 2 weeks followed by an intraperitoneal injection of streptozocin to induce type 2 diabetes mellitus. Group I served as diabetic control; group II was given cholecalciferol; group III; levo carnitine; and group IV was administered cholecalciferol and levo carnitine together. After 6 days of supplementation, terminal intracardiac blood extraction was done and samples were analysed for fasting plasma glucose and plasma insulin. Insulin resistance was calculated by homeostatic model assessment for insulin resistance. SPSS 17.0 was used for statistical analysis. Results: Fasting plasma glucose levels were significantly decreased (p <0.001) in the combined supplementation group compared to the diabetic control and individual supplementation groups. Combined supplementation showed a significant increase in fasting plasma insulin levels when compared with diabetic control and levo carnitine groups (p <0.001), and the effect of combined supplementation on ameliorating insulin resistance was significantly better (p <0.001) as compared to the individual supplementation of cholecalciferol and levo carnitine. Conclusions: The combined supplementation of cholecalciferol and levo carnitine for 6 days markedly improved the glycaemic control, insulin secretion and insulin resistance in type 2 diabetic rats on high-fat diet. A prolonged supplementation by both the compounds along with caloric restriction may yield a more promising outcome. (author)

Polychlorinated biphenyls exposure-induced insulin resistance is mediated by lipid droplet enlargement through Fsp27.

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Kim, Hye Young; Kwon, Woo Young; Kim, Yeon A; Oh, Yoo Jin; Yoo, Seung Hee; Lee, Mi Hwa; Bae, Ju Yong; Kim, Jong-Min; Yoo, Young Hyun

2017-06-01

Although epidemiological and experimental studies demonstrated that polychlorinated biphenyls (PCBs) lead to insulin resistance, the mechanism underlying PCBs-induced insulin resistance has remained unsolved. In this study, we examined in vitro and in vivo effects of PCB-118 (dioxin-like PCB) and PCB-138 (non-dioxin-like PCB) on adipocyte differentiation, lipid droplet growth, and insulin action. 3T3-L1 adipocytes were incubated with PCB-118 or PCB-138 during adipocyte differentiation. For in vivo studies, C57BL/6 mice were administered PCB-118 or PCB-138 (37.5 mg/kg) by intraperitoneal injection and we examined adiposity and whole-body insulin action. PCB-118 and PCB-138 significantly promoted adipocyte differentiation and increased the lipid droplet (LD) size in 3T3-L1 adipocytes. In mice, both PCBs increased adipose mass and adipocyte size. Furthermore, both PCBs induced insulin resistance in vitro and in vivo. Expression of fat-specific protein 27 (Fsp27), which is localized to LD contact sites, was increased in PCB-treated 3T3-L1 adipocytes and mice. Depletion of Fsp27 by siRNA resulted in the inhibition of LD enlargement and attenuation of insulin resistance in PCB-treated 3T3-L1 adipocytes. An anti-diabetic drug, metformin, attenuated insulin resistance in PCB-treated 3T3-L1 adipocytes through the reduced expression of Fsp27 protein and LD size. This study suggests that PCB exposure-induced insulin resistance is mediated by LD enlargement through Fsp27.

The etiology of oxidative stress in insulin resistance

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Samantha Hurrle

2017-10-01

Full Text Available Insulin resistance is a prevalent syndrome in developed as well as developing countries. It is the predisposing factor for type 2 diabetes mellitus, the most common end stage development of metabolic syndrome in the United States. Previously, studies investigating type 2 diabetes have focused on beta cell dysfunction in the pancreas and insulin resistance, and developing ways to correct these dysfunctions. However, in recent years, there has been a profound interest in the role that oxidative stress in the peripheral tissues plays to induce insulin resistance. The objective of this review is to focus on the mechanism of oxidative species generation and its direct correlation to insulin resistance, to discuss the role of obesity in the pathophysiology of this phenomenon, and to explore the potential of antioxidants as treatments for metabolic dysfunction.

Nutritional Modulation of Non-Alcoholic Fatty Liver Disease and Insulin Resistance

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Hannele Yki-Järvinen

2015-11-01

Full Text Available Non-alcoholic fatty liver disease (NAFLD covers a spectrum of disorders ranging from simple steatosis (non-alcoholic fatty liver, NAFL to non-alcoholic steatohepatitis (NASH and cirrhosis. NAFL increases the risk of liver fibrosis. If the liver is fatty due to causes of insulin resistance such as obesity and physical inactivity, it overproduces glucose and triglycerides leading to hyperinsulinemia and a low high-density lipoprotein (HDL cholesterol concentration. The latter features predispose to type 2 diabetes and cardiovascular disease (CVD. Understanding the impact of nutritional modulation of liver fat content and insulin resistance is therefore of interest for prevention and treatment of NAFLD. Hypocaloric, especially low carbohydrate ketogenic diets rapidly decrease liver fat content and associated metabolic abnormalities. However, any type of caloric restriction seems effective long-term. Isocaloric diets containing 16%–23% fat and 57%–65% carbohydrate lower liver fat compared to diets with 43%–55% fat and 27%–38% carbohydrate. Diets rich in saturated (SFA as compared to monounsaturated (MUFA or polyunsaturated (PUFA fatty acids appear particularly harmful as they increase both liver fat and insulin resistance. Overfeeding either saturated fat or carbohydrate increases liver fat content. Vitamin E supplementation decreases liver fat content as well as fibrosis but has no effect on features of insulin resistance.

Inverse association between soya food consumption and insulin resistance in Japanese adults.

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Nakamoto, Mariko; Uemura, Hirokazu; Sakai, Tohru; Katsuura-Kamano, Sakurako; Yamaguchi, Miwa; Hiyoshi, Mineyoshi; Arisawa, Kokichi

2015-08-01

The purpose of the present study was to examine the association between soya food consumption and insulin resistance using baseline data of the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study in Tokushima, Japan. This cross-sectional study included 1274 subjects, aged 34-70 years at baseline, living in Tokushima Prefecture between 2008 and 2013. Fasting blood samples were collected and information on lifestyle characteristics including soya food intake and medical history were obtained using a structured self-administered questionnaire. The homeostasis model assessment of insulin resistance (HOMA-IR) was measured and those with HOMA-IR ≥ 2.5 were defined as having insulin resistance. Multiple logistic regression models were used to analyse the association between soya product intake and the prevalence of insulin resistance. Rural communities located in Tokushima Prefecture, Japan, between 2008 and 2013. A total of 1148 adults (565 men and 583 women), aged 34-70 years. The frequency of intake of miso soup, total non-fried soya products and total soya products showed significant inverse dose-response relationships with insulin resistance, after adjustments for potential confounders. When soya product intake was calculated as soya protein and isoflavone, the odds ratios of insulin resistance decreased significantly as the estimated intake of soya protein increased. Furthermore, significant inverse dose-response relationships were observed for total non-fried soya products and total soya products, after adjustment for total vegetable or total fibre consumption. The present results indicate that the intake of soya products and non-fried soya products is associated with reduced insulin resistance in the Japanese population.

Acute insulin resistance mediated by advanced glycation endproducts in severely burned rats.

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Zhang, Xing; Xu, Jie; Cai, Xiaoqing; Ji, Lele; Li, Jia; Cao, Bing; Li, Jun; Hu, Dahai; Li, Yan; Wang, Haichang; Xiong, Lize; Xiao, Ruiping; Gao, Feng

2014-06-01

Hyperglycemia often occurs in severe burns; however, the underlying mechanisms and importance of managing postburn hyperglycemia are not well recognized. This study was designed to investigate the dynamic changes of postburn hyperglycemia and the underlying mechanisms and to evaluate whether early glycemic control is beneficial in severe burns. Prospective, randomized experimental study. Animal research laboratory. Sprague-Dawley rats. Anesthetized rats were subjected to a full-thickness burn injury comprising 40% of the total body surface area and were randomized to receive vehicle, insulin, and a soluble form of receptor for advanced glycation endproducts treatments. An in vitro study was performed on cultured H9C2 cells subjected to vehicle or carboxymethyllysine treatment. We found that blood glucose change presented a distinct pattern with two occurrences of hyperglycemia at 0.5- and 3-hour postburn, respectively. Acute insulin resistance evidenced by impaired insulin signaling and glucose uptake occurred at 3-hour postburn, which was associated with the second hyperglycemia and positively correlated with mortality. Mechanistically, we found that serum carboxymethyllysine, a dominant species of advanced glycation endproducts, increased within 1-hour postburn, preceding the occurrence of insulin resistance. More importantly, treatment of animals with soluble form of receptor for advanced glycation endproducts, blockade of advanced glycation endproducts signaling, alleviated severe burn-induced insulin resistance. In addition, early hyperglycemic control with insulin not only reduced serum carboxymethyllysine but also blunted postburn insulin resistance and reduced mortality. These findings suggest that severe burn-induced insulin resistance is partly at least mediated by serum advanced glycation endproducts and positively correlated with mortality. Early glycemic control with insulin or inhibition of advanced glycation endproducts with soluble form of receptor

Intramuscular Lipid Metabolism in the Insulin Resistance of Smoking

OpenAIRE

Bergman, Bryan C.; Perreault, Leigh; Hunerdosse, Devon M.; Koehler, Mary C.; Samek, Ali M.; Eckel, Robert H.

2009-01-01

OBJECTIVE Smoking decreases insulin action and increases the risk of type 2 diabetes in humans. Mechanisms responsible for smoking-induced insulin resistance are unclear. We hypothesized smokers would have increased intramuscular triglyceride (IMTG) and diacylglycerol (DAG) concentration and decreased fractional synthesis rate (FSR) compared with nonsmokers. RESEARCH DESIGN AND METHODS Nonsmokers (n = 18, aged 20 ± 0.5 years, BMI 22 ± 0.4 kg/m2, body fat 20 ± 2%, 0 cigarettes per day) and smo...

Skeletal Muscle Insulin Resistance in Endocrine Disease

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Melpomeni Peppa

2010-01-01

Full Text Available We summarize the existing literature data concerning the involvement of skeletal muscle (SM in whole body glucose homeostasis and the contribution of SM insulin resistance (IR to the metabolic derangements observed in several endocrine disorders, including polycystic ovary syndrome (PCOS, adrenal disorders and thyroid function abnormalities. IR in PCOS is associated with a unique postbinding defect in insulin receptor signaling in general and in SM in particular, due to a complex interaction between genetic and environmental factors. Adrenal hormone excess is also associated with disrupted insulin action in peripheral tissues, such as SM. Furthermore, both hyper- and hypothyroidism are thought to be insulin resistant states, due to insulin receptor and postreceptor defects. Further studies are definitely needed in order to unravel the underlying pathogenetic mechanisms. In summary, the principal mechanisms involved in muscle IR in the endocrine diseases reviewed herein include abnormal phosphorylation of insulin signaling proteins, altered muscle fiber composition, reduced transcapillary insulin delivery, decreased glycogen synthesis, and impaired mitochondrial oxidative metabolism.

Empagliflozin decreases remnant-like particle cholesterol in type 2 diabetes patients with insulin resistance.

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Hattori, Sachiko

2017-11-28

Remnant lipoproteins are thought to be atherogenic. Remnant-like particle cholesterol (RLP-C), which reflects the levels of various kinds of remnant lipoproteins in the blood, has a significant correlation with insulin resistance. In the present study, we measured the effect of empagliflozin (EMPA) on the levels of RLP-C, and investigated whether EMPA-mediated change in RLP-C is associated with a change in insulin resistance in type 2 diabetes patients who have insulin resistance. Patients were allocated to receive a placebo (n = 51) or EMPA (n = 58) as an add-on treatment. Fasting blood samples were collected before and 12 weeks after this intervention. EMPA significantly decreased glycated hemoglobin, bodyweight, systolic blood pressure, plasma triglycerides, liver transaminases and estimated glomerular filtration rate, and increased high-density lipoprotein cholesterol. Furthermore, EMPA decreased RLP-C and homeostatic model assessment of insulin resistance. In the placebo group, there were no significant changes in these factors except for slight increases in liver transaminases. Multiple regression analysis showed that the change in homeostatic model assessment of insulin resistance (P = 0.0102) and the change in alanine aminotransferase (P = 0.0301) were significantly associated with the change in RLP-C in the EMPA group. The change in RLP-C significantly correlated with the change in homeostatic model assessment of insulin resistance (Pearson correlation coefficient 0.503, 95% confidence interval 0.199-0.719; P = 0.00241). EMPA decreases RLP-C levels, which is closely associated with amelioration of insulin sensitivity in diabetes patients who have insulin resistance. © 2017 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.

Implication of low level inflammation in the insulin resistance of adipose tissue at late pregnancy.

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de Castro, J; Sevillano, J; Marciniak, J; Rodriguez, R; González-Martín, C; Viana, M; Eun-suk, O H; de Mouzon, S Hauguel; Herrera, E; Ramos, M P

2011-11-01

Insulin resistance is a characteristic of late pregnancy, and adipose tissue is one of the tissues that most actively contributes to the reduced maternal insulin sensitivity. There is evidence that pregnancy is a condition of moderate inflammation, although the physiological role of this low-grade inflammation remains unclear. The present study was designed to validate whether low-grade inflammation plays a role in the development of insulin resistance in adipose tissue during late pregnancy. To this end, we analyzed proinflammatory adipokines and kinases in lumbar adipose tissue of nonpregnant and late pregnant rats at d 18 and 20 of gestation. We found that circulating and tissue levels of adipokines, such as IL-1β, plasminogen activator inhibitor-1, and TNF-α, were increased at late pregnancy, which correlated with insulin resistance. The observed increase in adipokines coincided with an enhanced activation of p38 MAPK in adipose tissue. Treatment of pregnant rats with the p38 MAPK inhibitor SB 202190 increased insulin-stimulated tyrosine phosphorylation of the insulin receptor (IR) and IR substrate-1 in adipose tissue, which was paralleled by a reduction of IR substrate-1 serine phosphorylation and an enhancement of the metabolic actions of insulin. These results indicate that activation of p38 MAPK in adipose tissue contributes to adipose tissue insulin resistance at late pregnancy. Furthermore, the results of the present study support the hypothesis that physiological low-grade inflammation in the maternal organism is relevant to the development of pregnancy-associated insulin resistance.

Detecting insulin resistance in polycystic ovary syndrome: purposes and pitfalls.

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Legro, Richard S; Castracane, V Daniel; Kauffman, Robert P

2004-02-01

Approximately 50% to 70% of all women with polycystic ovary syndrome (PCOS) have some degree of insulin resistance, and this hormone insensitivity probably contributes to the hyperandrogenism that is responsible for the signs and symptoms of PCOS. Although uncertainty exists, early detection and treatment of insulin resistance in this population could ultimately reduce the incidence or severity of diabetes mellitus, dyslipidemia, hypertension, and cardiovascular disease. Even if that proves to be the case, there are still several problems with our current approach to insulin sensitivity assessment in PCOS, including the apparent lack of consensus on what defines PCOS and "normal" insulin sensitivity, ethnic and genetic variability, the presence of other factors contributing to insulin resistance such as obesity, stress, and aging, and concern about whether simplified models of insulin sensitivity have the precision to predict treatment needs, responses, and future morbidity. Although the hyperinsulinemic-euglycemic clamp technique is the gold standard for measuring insulin sensitivity, it is too expensive, time-consuming, and labor-intensive to be of practical use in an office setting. Homeostatic measurements (fasting glucose/insulin ratio or homeostatic model assessment [HOMA] value) and minimal model tests (particularly the oral glucose tolerance test [OGTT]) represent the easiest office-based assessments of insulin resistance in the PCOS patient. The OGTT is probably the best simple, office-based method to assess women with PCOS because it provides information about both insulin resistance and glucose intolerance. The diagnosis of glucose intolerance holds greater prognostic and treatment implications. All obese women with PCOS should be screened for the presence of insulin resistance by looking for other stigmata of the insulin resistance syndrome such as hypertension, dyslipidemia, central obesity, and glucose intolerance.

High serum resistin is associated with an increase in adiposity but not a worsening of insulin resistance in Pima Indians

DEFF Research Database (Denmark)

de Courten, Barbora; Degawa-Yamauchi, Mikako; Considine, Robert V

2004-01-01

Resistin is an adipokine with putative prodiabetogenic properties. Like other hormones secreted by adipose tissue, resistin is being investigated as a possible etiologic link between excessive adiposity and insulin resistance. Although there is growing evidence that circulating levels...... of this adipokine are proportional to the degree of adiposity, an effect on insulin resistance in humans remains unproven. To evaluate the relations among resistin, obesity, and insulin resistance, we measured fasting serum resistin levels in 113 nondiabetic (75-g oral glucose tolerance test) Pima Indians (ages 29...... +/- 7 years, body fat 31 +/- 8%, resistin 3.7 +/- 1.1 ng/ml [means +/- SD]), who were characterized for body composition (assessed by hydrodensitometry or dual-energy X-ray absorptiometry), whole-body insulin sensitivity (M; assessed by hyperinsulinemic clamp), basal hepatic glucose output (BHGO...

Endoplasmic reticulum stress regulates inflammation and insulin resistance in skeletal muscle from pregnant women.

Science.gov (United States)

Liong, Stella; Lappas, Martha

2016-04-15

Sterile inflammation and infection are key mediators of inflammation and peripheral insulin resistance associated with gestational diabetes mellitus (GDM). Studies have shown endoplasmic reticulum (ER) stress to induce inflammation and insulin resistance associated with obesity and type 2 diabetes, however is paucity of studies investigating the effects of ER stress in skeletal muscle on inflammation and insulin resistance associated with GDM. ER stress proteins IRE1α, GRP78 and XBP-1s were upregulated in skeletal muscle of obese pregnant women, whereas IRE1α was increased in GDM women. Suppression of ER stress, using ER stress inhibitor tauroursodeoxycholic acid (TUDCA) or siRNA knockdown of IRE1α and GRP78, significantly downregulated LPS-, poly(I:C)- or IL-1β-induced production of IL-6, IL-8, IL-1β and MCP-1. Furthermore, LPS-, poly(I:C)- or TNF-α-induced insulin resistance was improved following suppression of ER stress, by increasing insulin-stimulated phosphorylation of IR-β, IRS-1, GLUT-4 expression and glucose uptake. In summary, our inducible obesity and GDM-like models suggests that the development of GDM may be involved in activating ER stress-induced inflammation and insulin resistance in human skeletal muscle. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Bilirubin Increases Insulin Sensitivity by Regulating Cholesterol Metabolism, Adipokines and PPARγ Levels

Science.gov (United States)

Liu, Jinfeng; Dong, Huansheng; Zhang, Yong; Cao, Mingjun; Song, Lili; Pan, Qingjie; Bulmer, Andrew; Adams, David B.; Dong, Xiao; Wang, Hongjun

2015-01-01

Obesity can cause insulin resistance and type 2 diabetes. Moderate elevations in bilirubin levels have anti-diabetic effects. This study is aimed at determining the mechanisms by which bilirubin treatment reduces obesity and insulin resistance in a diet-induced obesity (DIO) mouse model. DIO mice were treated with bilirubin or vehicle for 14 days. Body weights, plasma glucose, and insulin tolerance tests were performed prior to, immediately, and 7 weeks post-treatment. Serum lipid, leptin, adiponectin, insulin, total and direct bilirubin levels were measured. Expression of factors involved in adipose metabolism including sterol regulatory element-binding protein (SREBP-1), insulin receptor (IR), and PPARγ in liver were measured by RT-PCR and Western blot. Compared to controls, bilirubin-treated mice exhibited reductions in body weight, blood glucose levels, total cholesterol (TC), leptin, total and direct bilirubin, and increases in adiponectin and expression of SREBP-1, IR, and PPARγ mRNA. The improved metabolic control achieved by bilirubin-treated mice was persistent: at two months after treatment termination, bilirubin-treated DIO mice remained insulin sensitive with lower leptin and higher adiponectin levels, together with increased PPARγ expression. These results indicate that bilirubin regulates cholesterol metabolism, adipokines and PPARγ levels, which likely contribute to increased insulin sensitivity and glucose tolerance in DIO mice. PMID:26017184

Induced Pluripotent Stem Cell-Derived Endothelial Cells in Insulin Resistance and Metabolic Syndrome.

Science.gov (United States)

Carcamo-Orive, Ivan; Huang, Ngan F; Quertermous, Thomas; Knowles, Joshua W

2017-11-01

Insulin resistance leads to a number of metabolic and cellular abnormalities including endothelial dysfunction that increase the risk of vascular disease. Although it has been particularly challenging to study the genetic determinants that predispose to abnormal function of the endothelium in insulin-resistant states, the possibility of deriving endothelial cells from induced pluripotent stem cells generated from individuals with detailed clinical phenotyping, including accurate measurements of insulin resistance accompanied by multilevel omic data (eg, genetic and genomic characterization), has opened new avenues to study this relationship. Unfortunately, several technical barriers have hampered these efforts. In the present review, we summarize the current status of induced pluripotent stem cell-derived endothelial cells for modeling endothelial dysfunction associated with insulin resistance and discuss the challenges to overcoming these limitations. © 2017 American Heart Association, Inc.

Novel adiponectin-resistin (AR and insulin resistance (IRAR indexes are useful integrated diagnostic biomarkers for insulin resistance, type 2 diabetes and metabolic syndrome: a case control study

Directory of Open Access Journals (Sweden)

Muniandy Sekaran

2011-01-01

Full Text Available Abstract Background Adiponectin and resistin are adipokines which modulate insulin action, energy, glucose and lipid homeostasis. Meta-analyses showed that hypoadiponectinemia and hyperresistinemia are strongly associated with increased risk of insulin resistance, type 2 diabetes (T2DM, metabolic syndrome (MS and cardiovascular disease. The aim of this study was to propose a novel adiponectin-resistin (AR index by taking into account both adiponectin and resistin levels to povide a better indicator of the metabolic homeostasis and metabolic disorders. In addition, a novel insulin resistance (IRAR index was proposed by integration of the AR index into an existing insulin resistance index to provide an improved diagnostic biomarker of insulin sensitivity. Methods In this case control study, anthropometric clinical and metabolic parameters including fasting serum total adiponectin and resistin levels were determined in 809 Malaysian men (208 controls, 174 MS without T2DM, 171 T2DM without MS, 256 T2DM with MS whose ages ranged between 40-70 years old. Significant differences in continuous variables among subject groups were confirmed by ANCOVA or MANCOVA test using 1,000 stratified bootstrap samples with bias corrected and accelerated (BCa 95% CI. Spearman's rho rank correlation test was used to test the correlation between two variables. Results The AR index was formulated as 1+log10(R0-log10(A0. The AR index was more strongly associated with increased risk of T2DM and MS than hypoadiponectinemia and hyperresistinemia alone. The AR index was more strongly correlated with the insulin resistance indexes and key metabolic endpoints of T2DM and MS than adiponectin and resistin levels alone. The AR index was also correlated with a higher number of MS components than adiponectin and resistin levels alone. The IRAR index was formulated as log10(I0G0+log10(I0G0log10(R0/A0. The normal reference range of the IRAR index for insulin sensitive individuals was

Obesogenic memory can confer long-term increases in adipose tissue but not liver inflammation and insulin resistance after weight loss.

Science.gov (United States)

Schmitz, J; Evers, N; Awazawa, M; Nicholls, H T; Brönneke, H S; Dietrich, A; Mauer, J; Blüher, M; Brüning, J C

2016-05-01

Obesity represents a major risk factor for the development of type 2 diabetes mellitus, atherosclerosis and certain cancer entities. Treatment of obesity is hindered by the long-term maintenance of initially reduced body weight, and it remains unclear whether all pathologies associated with obesity are fully reversible even upon successfully maintained weight loss. We compared high fat diet-fed, weight reduced and lean mice in terms of body weight development, adipose tissue and liver insulin sensitivity as well as inflammatory gene expression. Moreover, we assessed similar parameters in a human cohort before and after bariatric surgery. Compared to lean animals, mice that demonstrated successful weight reduction showed increased weight gain following exposure to ad libitum control diet. However, pair-feeding weight-reduced mice with lean controls efficiently stabilized body weight, indicating that hyperphagia was the predominant cause for the observed weight regain. Additionally, whereas glucose tolerance improved rapidly after weight loss, systemic insulin resistance was retained and ameliorated only upon prolonged pair-feeding. Weight loss enhanced insulin action and resolved pro-inflammatory gene expression exclusively in the liver, whereas visceral adipose tissue displayed no significant improvement of metabolic and inflammatory parameters compared to obese mice. Similarly, bariatric surgery in humans (n = 55) resulted in massive weight reduction, improved hepatic inflammation and systemic glucose homeostasis, while adipose tissue inflammation remained unaffected and adipocyte-autonomous insulin action only exhibit minor improvements in a subgroup of patients (42%). These results demonstrate that although sustained weight loss improves systemic glucose homeostasis, primarily through improved inflammation and insulin action in liver, a remarkable obesogenic memory can confer long-term increases in adipose tissue inflammation and insulin resistance in mice as

Elevated TCA cycle function in the pathology of diet-induced hepatic insulin resistance and fatty liver.

Science.gov (United States)

Satapati, Santhosh; Sunny, Nishanth E; Kucejova, Blanka; Fu, Xiaorong; He, Tian Teng; Méndez-Lucas, Andrés; Shelton, John M; Perales, Jose C; Browning, Jeffrey D; Burgess, Shawn C

2012-06-01

The manner in which insulin resistance impinges on hepatic mitochondrial function is complex. Although liver insulin resistance is associated with respiratory dysfunction, the effect on fat oxidation remains controversial, and biosynthetic pathways that traverse mitochondria are actually increased. The tricarboxylic acid (TCA) cycle is the site of terminal fat oxidation, chief source of electrons for respiration, and a metabolic progenitor of gluconeogenesis. Therefore, we tested whether insulin resistance promotes hepatic TCA cycle flux in mice progressing to insulin resistance and fatty liver on a high-fat diet (HFD) for 32 weeks using standard biomolecular and in vivo (2)H/(13)C tracer methods. Relative mitochondrial content increased, but respiratory efficiency declined by 32 weeks of HFD. Fasting ketogenesis became unresponsive to feeding or insulin clamp, indicating blunted but constitutively active mitochondrial β-oxidation. Impaired insulin signaling was marked by elevated in vivo gluconeogenesis and anaplerotic and oxidative TCA cycle flux. The induction of TCA cycle function corresponded to the development of mitochondrial respiratory dysfunction, hepatic oxidative stress, and inflammation. Thus, the hepatic TCA cycle appears to enable mitochondrial dysfunction during insulin resistance by increasing electron deposition into an inefficient respiratory chain prone to reactive oxygen species production and by providing mitochondria-derived substrate for elevated gluconeogenesis.

Insulin receptor degradation is accelerated in cultured lymphocytes from patients with genetic syndromes of extreme insulin resistance

International Nuclear Information System (INIS)

McElduff, A.; Hedo, J.A.; Taylor, S.I.; Roth, J.; Gorden, P.

1984-01-01

The insulin receptor degradation rate was examined in B lymphocytes that were obtained from peripheral blood of normal subjects and patients with several syndromes of extreme insulin resistance. The insulin receptors were surface labeled using Na 125 I/lactoperoxidase and the cells were returned to incubate in growth media. After varying periods of incubation, aliquots of cells were solubilized and the cell content of labeled receptor subunits were measured by immunoprecipitation with anti-receptor antibodies and NaDodSO4/polyacrylamide gel electrophoresis. In cell lines from four patients in whom the number of insulin receptors was reduced by greater than 90%, the rate of receptor loss was greater than normal (t1/2 equals 3.8 +/- 0.9 h vs. 6.5 +/- 1.2 h; mean +/- SD, P less than 0.01). However, a similar acceleration in receptor degradation was seen in cells from five patients with extreme insulin resistance but low-normal insulin receptor concentration (t1/2 equals 4.4 +/- 0.9 h). Thus, all the patients with genetic syndromes of insulin resistance had accelerated receptor degradation, regardless of their receptor concentration. By contrast, insulin receptors on cultured lymphocytes that were obtained from patients with extreme insulin resistance secondary to autoantibodies to the insulin receptor had normal receptor degradation (t1/2 equals 6.1 +/- 1.9 h). We conclude that (a) accelerated insulin receptor degradation is an additional feature of cells from patients with genetic forms of insulin resistance; (b) that accelerated insulin receptor degradation may explain the low-normal receptor concentrations that were seen in some patients with extreme insulin resistance; and (c) that accelerated degradation does not explain the decreased receptor concentration in patients with very low insulin receptor binding and, therefore, by inference, a defect in receptor synthesis must be present in this subgroup

Effect of cigarette smoking on insulin resistance risk.

Science.gov (United States)

Haj Mouhamed, D; Ezzaher, A; Neffati, F; Douki, W; Gaha, L; Najjar, M F

2016-02-01

Smoking is one of the main risk factors for cardiovascular disease (CVD). The mechanism(s) of the effects of smoking on CVD are not clearly understood; however, a number of atherogenic characteristics, such as insulin resistance have been reported. We aim to investigate the effects of cigarette smoking on insulin resistance and to determine the correlation between this parameter with smoking status characteristics. This study was conducted on 138 non-smokers and 162 smokers aged respectively 35.6±16.0 and 38.5±21.9 years. All subjects are not diabetic. Fasting glucose was determined by enzymatic methods and insulin by chemiluminescence method. Insulin resistance (IR) was estimated using the Homeostasis Model of Assessment equation: HOMA-IR=[fasting insulin (mU/L)×fasting glucose (mmol/L)]/22.5. IR was defined as the upper quartile of HOMA-IR. Values above 2.5 were taken as abnormal and reflect insulin resistance. Compared to non-smokers, smokers had significantly higher levels of fasting glucose, fasting insulin and HOMA-IR index. These associations remained significant after adjustment for confounding factors (age, gender, BMI and alcohol consumption). A statistically significant association was noted between the smoking status parameters, including both the number of cigarettes smoked/day and the duration of smoking, and fasting insulin levels as well for HOMA-IR index. Among smokers, we noted a positive correlation between HOMA-IR index and both plasma thiocyanates and urinary cotinine. Our results show that smokers have a high risk to developing an insulin resistance and hyperinsulinemia, compared with a matched group of non-smokers, and may help to explain the high risk of cardiovascular diseases in smokers. Copyright © 2015. Published by Elsevier SAS.

Hematopoietic-Derived Galectin-3 Causes Cellular and Systemic Insulin Resistance.

Science.gov (United States)

Li, Pingping; Liu, Shuainan; Lu, Min; Bandyopadhyay, Gautum; Oh, Dayoung; Imamura, Takeshi; Johnson, Andrew M F; Sears, Dorothy; Shen, Zhufang; Cui, Bing; Kong, Lijuan; Hou, Shaocong; Liang, Xiao; Iovino, Salvatore; Watkins, Steven M; Ying, Wei; Osborn, Olivia; Wollam, Joshua; Brenner, Martin; Olefsky, Jerrold M

2016-11-03

In obesity, macrophages and other immune cells accumulate in insulin target tissues, promoting a chronic inflammatory state and insulin resistance. Galectin-3 (Gal3), a lectin mainly secreted by macrophages, is elevated in both obese subjects and mice. Administration of Gal3 to mice causes insulin resistance and glucose intolerance, whereas inhibition of Gal3, through either genetic or pharmacologic loss of function, improved insulin sensitivity in obese mice. In vitro treatment with Gal3 directly enhanced macrophage chemotaxis, reduced insulin-stimulated glucose uptake in myocytes and 3T3-L1 adipocytes and impaired insulin-mediated suppression of glucose output in primary mouse hepatocytes. Importantly, we found that Gal3 can bind directly to the insulin receptor (IR) and inhibit downstream IR signaling. These observations elucidate a novel role for Gal3 in hepatocyte, adipocyte, and myocyte insulin resistance, suggesting that Gal3 can link inflammation to decreased insulin sensitivity. Inhibition of Gal3 could be a new approach to treat insulin resistance. Copyright © 2016 Elsevier Inc. All rights reserved.

Direct Evidence that Myocardial Insulin Resistance following Myocardial Ischemia Contributes to Post-Ischemic Heart Failure

Science.gov (United States)

Fu, Feng; Zhao, Kun; Li, Jia; Xu, Jie; Zhang, Yuan; Liu, Chengfeng; Yang, Weidong; Gao, Chao; Li, Jun; Zhang, Haifeng; Li, Yan; Cui, Qin; Wang, Haichang; Tao, Ling; Wang, Jing; Quon, Michael J; Gao, Feng

2015-01-01

A close link between heart failure (HF) and systemic insulin resistance has been well documented, whereas myocardial insulin resistance and its association with HF are inadequately investigated. This study aims to determine the role of myocardial insulin resistance in ischemic HF and its underlying mechanisms. Male Sprague-Dawley rats subjected to myocardial infarction (MI) developed progressive left ventricular dilation with dysfunction and HF at 4 wk post-MI. Of note, myocardial insulin sensitivity was decreased as early as 1 wk after MI, which was accompanied by increased production of myocardial TNF-α. Overexpression of TNF-α in heart mimicked impaired insulin signaling and cardiac dysfunction leading to HF observed after MI. Treatment of rats with a specific TNF-α inhibitor improved myocardial insulin signaling post-MI. Insulin treatment given immediately following MI suppressed myocardial TNF-α production and improved cardiac insulin sensitivity and opposed cardiac dysfunction/remodeling. Moreover, tamoxifen-induced cardiomyocyte-specific insulin receptor knockout mice exhibited aggravated post-ischemic ventricular remodeling and dysfunction compared with controls. In conclusion, MI induces myocardial insulin resistance (without systemic insulin resistance) mediated partly by ischemia-induced myocardial TNF-α overproduction and promotes the development of HF. Our findings underscore the direct and essential role of myocardial insulin signaling in protection against post-ischemic HF. PMID:26659007

Fluoxetine increases insulin action in obese type II (non-insulin dependent) diabetic patients

NARCIS (Netherlands)

Potter van Loon, B. J.; Radder, J. K.; Froelich, M.; Krans, H. Michiel J.; Zwinderman, A. H.; Meinders, A. E.

1992-01-01

Insulin resistance contributes to the metabolic defects in non-insulin dependent diabetes mellitus (NIDDM). Anorectic agents have been shown to improve insulin action in NIDDM, irrespective of weight reduction. In a double-blind placebo-controlled cross-over study, we examined hepatic and peripheral

Studies on insulin secretion and insulin resistance in non-insulin-dependent diabetes in young Indians

International Nuclear Information System (INIS)

Naidoo, C.

1986-01-01

Patients with Non-insulin-dependent diabetes mellitus (NIDDM) have defects in insulin secretion and insulin action. In the discrete genetic syndrome of NIDDY (non-insulin-dependent diabetes in the young), the situation is less clear and these aspects is the subject of this thesis. This study included Indian pasients with three generation transmission of NIDDM via one parent. The insulin and C-peptide responses to oral and intravenous glucose in patients with NIDDY were studied. The insulin and glucose responses to non-glucose secretogogues glucagon, tolbutamide and arginine, in NIDDY were also investigated. The following aspects with regard to insulin resistance in NIDDY were examined: glucose and free fatty acid response to intravenous insulin administration, insulin binding to circulating erythrocytes and monocytes, 125 I-insulin binding to the solubilized erythrocyte membrane receptor and 125 I-insulin binding to fibroblasts in culture

Studies on insulin secretion and insulin resistance in non-insulin-dependent diabetes in young Indians

Energy Technology Data Exchange (ETDEWEB)

Naidoo, C

1986-01-01

Patients with Non-insulin-dependent diabetes mellitus (NIDDM) have defects in insulin secretion and insulin action. In the discrete genetic syndrome of NIDDY (non-insulin-dependent diabetes in the young), the situation is less clear and these aspects is the subject of this thesis. This study included Indian pasients with three generation transmission of NIDDM via one parent. The insulin and C-peptide responses to oral and intravenous glucose in patients with NIDDY were studied. The insulin and glucose responses to non-glucose secretogogues glucagon, tolbutamide and arginine, in NIDDY were also investigated. The following aspects with regard to insulin resistance in NIDDY were examined: glucose and free fatty acid response to intravenous insulin administration, insulin binding to circulating erythrocytes and monocytes, /sup 125/I-insulin binding to the solubilized erythrocyte membrane receptor and /sup 125/I-insulin binding to fibroblasts in culture.

Molecular mechanisms of insulin resistance | Pillay | South African ...

African Journals Online (AJOL)

This review discusses recent advances in understanding of the structure and function of the insulin receptor and insulin action, and how these relate to the clinical aspects of insulin resistance associated with non-insulin-dependent diabetes and other disorders. Improved understanding of the molecular basis of insulin ...

Biochemical adaptations of mammalian hibernation: exploring squirrels as a perspective model for naturally induced reversible insulin resistance

Energy Technology Data Exchange (ETDEWEB)

Wu, C-W.; Biggar, K.K.; Storey, K.B. [Carleton University, Department of Biology, Institute of Biochemistry, Ottawa, ON (Canada)

2013-01-28

An important disease among human metabolic disorders is type 2 diabetes mellitus. This disorder involves multiple physiological defects that result from high blood glucose content and eventually lead to the onset of insulin resistance. The combination of insulin resistance, increased glucose production, and decreased insulin secretion creates a diabetic metabolic environment that leads to a lifetime of management. Appropriate models are critical for the success of research. As such, a unique model providing insight into the mechanisms of reversible insulin resistance is mammalian hibernation. Hibernators, such as ground squirrels and bats, are excellent examples of animals exhibiting reversible insulin resistance, for which a rapid increase in body weight is required prior to entry into dormancy. Hibernator studies have shown differential regulation of specific molecular pathways involved in reversible resistance to insulin. The present review focuses on this growing area of research and the molecular mechanisms that regulate glucose homeostasis, and explores the roles of the Akt signaling pathway during hibernation. Here, we propose a link between hibernation, a well-documented response to periods of environmental stress, and reversible insulin resistance, potentially facilitated by key alterations in the Akt signaling network, PPAR-γ/PGC-1α regulation, and non-coding RNA expression. Coincidentally, many of the same pathways are frequently found to be dysregulated during insulin resistance in human type 2 diabetes. Hence, the molecular networks that may regulate reversible insulin resistance in hibernating mammals represent a novel approach by providing insight into medical treatment of insulin resistance in humans.

Biochemical adaptations of mammalian hibernation: exploring squirrels as a perspective model for naturally induced reversible insulin resistance

International Nuclear Information System (INIS)

Wu, C-W.; Biggar, K.K.; Storey, K.B.

2013-01-01

An important disease among human metabolic disorders is type 2 diabetes mellitus. This disorder involves multiple physiological defects that result from high blood glucose content and eventually lead to the onset of insulin resistance. The combination of insulin resistance, increased glucose production, and decreased insulin secretion creates a diabetic metabolic environment that leads to a lifetime of management. Appropriate models are critical for the success of research. As such, a unique model providing insight into the mechanisms of reversible insulin resistance is mammalian hibernation. Hibernators, such as ground squirrels and bats, are excellent examples of animals exhibiting reversible insulin resistance, for which a rapid increase in body weight is required prior to entry into dormancy. Hibernator studies have shown differential regulation of specific molecular pathways involved in reversible resistance to insulin. The present review focuses on this growing area of research and the molecular mechanisms that regulate glucose homeostasis, and explores the roles of the Akt signaling pathway during hibernation. Here, we propose a link between hibernation, a well-documented response to periods of environmental stress, and reversible insulin resistance, potentially facilitated by key alterations in the Akt signaling network, PPAR-γ/PGC-1α regulation, and non-coding RNA expression. Coincidentally, many of the same pathways are frequently found to be dysregulated during insulin resistance in human type 2 diabetes. Hence, the molecular networks that may regulate reversible insulin resistance in hibernating mammals represent a novel approach by providing insight into medical treatment of insulin resistance in humans

Tetradecylthioacetic acid prevents high fat diet induced adiposity and insulin resistance

DEFF Research Database (Denmark)

Madsen, Lise; Guerre-Millo, Michéle; Flindt, Esben N

2002-01-01

Tetradecylthioacetic acid (TTA) is a non-beta-oxidizable fatty acid analog, which potently regulates lipid homeostasis. Here we evaluate the ability of TTA to prevent diet-induced and genetically determined adiposity and insulin resistance. In Wistar rats fed a high fat diet, TTA administration...... completely prevented diet-induced insulin resistance and adiposity. In genetically obese Zucker (fa/fa) rats TTA treatment reduced the epididymal adipose tissue mass and improved insulin sensitivity. All three rodent peroxisome proliferator-activated receptor (PPAR) subtypes were activated by TTA...... that a TTA-induced increase in hepatic fatty acid oxidation and ketogenesis drains fatty acids from blood and extrahepatic tissues and that this contributes significantly to the beneficial effects of TTA on fat mass accumulation and peripheral insulin sensitivity....

Adipokines mediate inflammation and insulin resistance

Directory of Open Access Journals (Sweden)

Jeffrey E. Pessin

2013-06-01

Full Text Available For many years, adipose tissue was considered as an inert energy storage organ that accumulates and stores triacylglycerols during energy excess and releases fatty acids in times of systemic energy need. However, over the last two decades adipose tissue depots have been established as highly active endocrine and metabolically important organs that modulate energy expenditure and glucose homeostasis. In rodents, brown adipose tissue plays an essential role in non-shivering thermogenesis and in energy dissipation that can serve to protect against diet-induced obesity. White adipose tissue collectively referred too as either subcutaneous or visceral adipose tissue is responsible for the secretion of an array of signaling molecules, termed adipokines. These adipokines function as classic circulating hormones to communicate with other organs including brain, liver, muscle, the immune system and adipose tissue itself. The dysregulation of adipokines has been implicated in obesity, type 2 diabetes and cardiovascular disease. Recently, inflammatory responses in adipose tissue have been shown as a major mechanism to induce peripheral tissue insulin resistance. Although leptin and adiponectin regulate feeding behavior and energy expenditure, these adipokines are also involved in the regulation of inflammatory responses. Adipose tissue secrete various pro- and anti-inflammatory adipokines to modulate inflammation and insulin resistance. In obese humans and rodent models, the expression of pro-inflammatory adipokines is enhanced to induce insulin resistance. Collectively, these findings have suggested that obesity-induced insulin resistance may result, at least in part, from an imbalance in the expression of pro- and anti-inflammatory adipokines. Thus we will review the recent progress regarding the physiological and molecular functions of adipokines in the obesity-induced inflammation and insulin resistance with perspectives on future directions.

Autophagy downregulation contributes to insulin resistance mediated injury in insulin receptor knockout podocytes in vitro

Directory of Open Access Journals (Sweden)

Ying Xu

2016-04-01

Full Text Available It is unknown whether autophagy activity is altered in insulin resistant podocytes and whether autophagy could be a therapeutic target for diabetic nephropathy (DN. Here we used shRNA transfection to knockdown the insulin receptor (IR gene in cultured human immortalized podocytes as an in vitro insulin resistant model. Autophagy related proteins LC3, Beclin, and p62 as well as nephrin, a podocyte injury marker, were assessed using western blot and immunofluorescence staining. Our results show that autophagy is suppressed when podocytes lose insulin sensitivity and that treatment of rapamycin, an mTOR specific inhibitor, could attenuate insulin resistance induced podocytes injury via autophagy activation. The present study deepens our understanding of the role of autophagy in the pathogenesis of DN.

Serum progranulin levels in relation to insulin resistance in childhood obesity.

Science.gov (United States)

Alissa, Eman M; Sutaih, Rima H; Kamfar, Hayat Z; Alagha, Abdulmoeen E; Marzouki, Zuhair M

2017-11-27

Progranulin is an adipokine that is involved in the inflammatory response, glucose metabolism, insulin resistance, and may therefore be involved in chronic subclinical inflammation associated with the pathogenesis of childhood obesity. We aimed to investigate the association of circulating progranulin levels with metabolic parameters in children and to assess the importance of progranulin as a biomarker for metabolic diseases. A total of 150 children were consecutively recruited from the Pediatric Nutrition Clinics at King Abdulaziz University Hospital in Jeddah, Saudi Arabia. Children were classified into four groups based on quartile for serum progranulin. Anthropometric variables were measured in all study subjects. Fasting blood samples were collected for measurement of blood glucose, insulin and lipid profile. Children within the upper quartile for serum progranulin concentration were heavier, more insulin resistant and had higher concentrations of serum total cholesterol, triglycerides, insulin and high sensitivity C reactive protein compared to those in the lower quartile. On correlation analysis, serum progranulin concentrations were significantly related to general and central adiposity, metabolic parameters, markers of inflammation and insulin resistance. Stepwise multiple regression showed that 26.6% of the variability in serum progranulin could be explained by measures of adiposity. The increased serum progranulin concentrations were closely related to measures of adiposity, metabolic parameters, inflammatory marker and insulin resistance indices, suggesting that progranulin may be an excellent biomarker for obesity in childhood.

Researching Effective Strategies to Improve Insulin Sensitivity in Children and Teenagers - RESIST. A randomised control trial investigating the effects of two different diets on insulin sensitivity in young people with insulin resistance and/or pre-diabetes.

Directory of Open Access Journals (Sweden)

De Sukanya

2010-09-01

Full Text Available Abstract Background Concomitant with the rise in childhood obesity there has been a significant increase in the number of adolescents with clinical features of insulin resistance and prediabetes. Clinical insulin resistance and prediabetes are likely to progress to type 2 diabetes and early atherosclerosis if not targeted for early intervention. There are no efficacy trials of lifestyle intervention in this group to inform clinical practice. The primary aim of this randomised control trial (RCT is to determine the efficacy and effectiveness of two different structured lifestyle interventions differing in diet composition on insulin sensitivity, in adolescents with clinical insulin resistance and/or prediabetes treated with metformin. Methods/design This study protocol describes the design of an ongoing RCT. We are recruiting 108 (54 each treatment arm 10 to 17 year olds with clinical features of insulin resistance and/or prediabetes, through physician referral, into a multi-centred RCT. All participants are prescribed metformin and participate in a diet and exercise program. The lifestyle program is the same for all participants except for diet composition. The diets are a high carbohydrate, low fat diet and a moderate carbohydrate, increased protein diet. The program commences with an intensive 3 month dietary intervention, implemented by trained dietitians, followed by a 3 month intensive gym and home based exercise program, supervised by certified physical trainers. To measure the longer term effectiveness, after the intensive intervention trial participants are managed by either their usual physician or study physician and followed up by the study dietitians for an additional 6 months. The primary outcome measure, change in insulin sensitivity, is measured at 3, 6 and 12 months. Discussion Clinical insulin resistance and prediabetes in the paediatric population are rapidly emerging clinical problems with serious health outcomes. With

Periparturient dairy cows do not exhibit hepatic insulin resistance, yet adipose-specific insulin resistance occurs in cows prone to high weight loss.

Science.gov (United States)

Zachut, M; Honig, H; Striem, S; Zick, Y; Boura-Halfon, S; Moallem, U

2013-09-01

The periparturient period in dairy cows is associated with alterations in insulin action in peripheral tissues; however, the molecular mechanism underlying this process is not completely understood. The objective was to examine the response to a glucose tolerance test (GTT) and to analyze insulin signaling in liver and adipose tissues in pre- and postpartum dairy cows. Liver and adipose tissue biopsies were taken before and after GTT, at 17d prepartum and again at 3 to 5d postpartum from 8 high-yielding Israeli Holstein dairy cows. Glucose clearance rate after GTT was similar pre- and postpartum. Basal insulin concentrations and the insulin response to GTT were approximately 4-fold higher prepartum than postpartum. In accordance, phosphorylation of the hepatic insulin receptor after GTT was higher prepartum than postpartum. Across periods, a positive correlation was observed between the basal and peak plasma insulin and phosphorylated insulin receptor after GTT in the liver. Hepatic phosphorylation of protein kinase B after GTT was elevated pre- and postpartum. Conversely, in adipose tissue, phosphorylation of protein kinase B after GTT pre- and postpartum was increased only in 4 out of 8 cows that lost less body weight postpartum. Our results demonstrate that hepatic insulin signaling is regulated by plasma insulin concentrations as part of the homeorhetic adjustments toward calving, and do not support a model of hepatic insulin resistance in periparturient cows. Nevertheless, we suggest that specific insulin resistance in adipose tissue occurs pre- and postpartum only in cows prone to high weight loss. The different responses among these cows imply that genetic background may affect insulin responsiveness in adipose tissue pre- and postpartum. Copyright © 2013 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Down-regulation of the miR-543 alleviates insulin resistance through targeting the SIRT1.

Science.gov (United States)

Hu, Xiaojing; Chi, Liyi; Zhang, Wentao; Bai, Tiao; Zhao, Wei; Feng, Zhanbin; Tian, Hongyan

2015-12-25

Insulin resistance plays an important role in the development of hypertension, which is seriously detrimental to human health. Recently, Sirtuin-1 (SIRT1) has been found to participate in regulation of insulin resistance. Therefore, further studies focused on the SIRT1 regulators might provide a potential approach for combating insulin resistance and hypertension. Interestingly, in this study, we found that SIRT1 was the target gene of the miR-543 by the Dual-Luciferase Reporter Assay. Moreover, the miR-543 expression notably increased in the insulin-resistant HepG2 cells induced by TNF-α. Further analysis showed that the overexpression of the miR-543 lowered the SIRT1 mRNA and protein levels, resulting in the insulin resistance in the HepG2 cells; the inhibition of miR-543, however, enhanced the mRNA and protein expression of the SIRT1, and alleviated the insulin resistance. Furthermore, the SIRT1 overexpression abrogated the effect of miR-543 on insulin resistance. In addition, the overexpression of the miR-543 by the lentivirus-mediated gene transfer markedly impaired the insulin signaling assessed by the Western blot analysis of the glycogen synthesis and the phosphorylation of Akt and GSK3β. In summary, our study suggested that the downregulation of the miR-543 could alleviate the insulin resistance via the modulation of the SIRT1 expression, which might be a potential new strategy for treating insulin resistance and a promising therapeutic method for hypertension. Copyright © 2015 Elsevier Inc. All rights reserved.

The Relationship among Smoking, Plasma Adiponectin, Leptin, Inflammatory Markers and Insulin Resistance

International Nuclear Information System (INIS)

Shousha, M.A.; Soliman, S.Et

2012-01-01

We aimed to study how smoking influences the relationship between fat mass ,soluble tumor necrosis factor-α, (TNF?) receptors 1 and 2 (sTNFR1 and sTNFR2),highly sensitive C-reactive protein(hs-CRP), adiponectin, leptin and insulin resistance.A total of 60 healthy men (age: 27-53 years, body mass index (BMI): 20-35 kg/m 2 ), 30 of whom were never-smokers and 30 smokers, matched for age, BMI and waist-to-hip ratio were included in this study. Those were subdivided into insulin resistant (IR) and insulin sensitive (IS) subgroups. Measures included circulating soluble fractions of the tumor necrosis factor α (TNF α) receptors (sTNFR1 and sTNFR2) and their relationship to fat mass, fasting plasma adiponectin, leptin, hs- CRP and insulin sensitivity index.Smokers had significantly lower fat mass, lower fasting glucose, insulin and leptin concentrations than nonsmokers. Despite lower fat mass, insulin and leptin, smokers showed significantly increased circulating sTNFR2 levels (3.7±0.8 vs. 2.9 ±0.8 ng/ml, π=0.03). Being either a smoker or having insulin resistance was independently associated with lower adiponectin concentrations (π = 0.046 and 0.001, respectively). No difference was detected in average hs- CRP concentrations between smokers and nonsmokers (π = 0.18) and between IR and IS subjects (π = 0.13).Both fat mass and smoking are related to increased activity of the TNFα axis. Plasma adiponectin concentrations are lower in smokers and IR subjects. These two mechanisms could be associated with increased cardiovascular risk in smokers

The Relationship among Smoking, Plasma Adiponectin, Leptin, Inflammatory Markers and Insulin Resistance

International Nuclear Information System (INIS)

Shousha, M.A.; Soliman, S.Et.

2011-01-01

The study aimed to investigate how smoking influences the relationship between fat mass, soluble tumor necrosis factor-α , (TNFα ) receptors 1 and 2 (sTNFR1 and sTNFR2), highly sensitive C-reactive protein (hs-CRP), adiponectin, leptin and insulin resistance. A total of 60 healthy men (age: 27-53 years, body mass index (BMI): 20-35 kg/m2), 30 of whom were never-smokers and 30 smokers, matched for age, BMI and waist-to-hip ratio were included in this study. Those were subdivided into insulin resistant (IR) and insulin sensitive (IS) subgroups. Measures included circulating soluble fractions of the tumor necrosis factor α (TNFα ) receptors (sTNFR1 and sTNFR2) and their relationship to fat mass, fasting plasma adiponectin, leptin, hs-CRP and insulin sensitivity index. Smokers had significantly lower fat mass, lower fasting glucose, insulin and leptin concentrations than nonsmokers. Despite lower fat mass, insulin and leptin, smokers showed significantly increased circulating sTNFR2 levels (3.7±0.8 vs. 2.9±0.8 ng/ml, P=0.03). Being either a smoker or having insulin resistance was independently associated with lower adiponectin concentrations (P = 0.046 and 0.001, respectively). No difference was detected in average hs- CRP concentrations between smokers and nonsmokers (P = 0.18) and between IR and IS subjects (P = 0.13).Both fat mass and smoking are related to increased activity of the TNFα axis. Plasma adiponectin concentrations are lower in smokers and IR subjects. These two mechanisms could be associated with increased cardiovascular risk in smokers

Insulin resistance enhances the mitogen-activated protein kinase signaling pathway in ovarian granulosa cells.

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Linghui Kong

Full Text Available The ovary is the main regulator of female fertility. Granulosa cell dysfunction may be involved in various reproductive endocrine disorders. Here we investigated the effect of insulin resistance on the metabolism and function of ovarian granulosa cells, and dissected the functional status of the mitogen-activated protein kinase signaling pathway in these cells. Our data showed that dexamethasone-induced insulin resistance in mouse granulosa cells reduced insulin sensitivity, accompanied with an increase in phosphorylation of p44/42 mitogen-activated protein kinase. Furthermore, up-regulation of cytochrome P450 subfamily 17 and testosterone and down-regulation of progesterone were observed in insulin-resistant mouse granulosa cells. Inhibition of p44/42 mitogen-activated protein kinase after induction of insulin resistance in mouse granulosa cells decreased phosphorylation of p44/42 mitogen-activated protein kinase, downregulated cytochrome P450 subfamily 17 and lowered progesterone production. This insulin resistance cell model can successfully demonstrate certain mechanisms such as hyperandrogenism, which may inspire a new strategy for treating reproductive endocrine disorders by regulating cell signaling pathways.

Assesment of propolis supplementation on insulin resistance in diabetic patients

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nazli samadi

2017-05-01

Full Text Available Introduction: Diabetes mellitus is a common endocrine disease . The number of people with diabetes over the last twenty years has doubled . Asia as a result of rapid economic growth , as the center of the epidemic in the world . Iran is among the countries with a high prevalence of diabetes mellitus . Use of medicinal plants as adjunctive therapy along with medication always been original . In recent years the tendency of patients to alternative therapies and traditional medicine has increased. Methods : Among patients referred to clinics of University of Medical Sciences, Yazd, Iran , 67 people were selected and randomly divided into two groups,intervention or placebo. Patients in the intervention group received 3 tablets of 300 mg bee propolis and in the control group received placebo . The study lasted 12 weeks . Serum insulin and insulin resistance index were evaluated at the beginning and end of the study. Results: 57 patients completed the study . The average demographic characteristics , anthropometric indices , serum insulin and insulin resistance index at the beginning and end of the study between the two groups showed no significant difference. Conclusion : In this study , supplementation with bee propolis for 12 weeks , on the serum insulin and indices of insulin resistance in patients with type II diabetes is not effective . Further studies are needed to make a final decision.

The Association Between IGF-I and Insulin Resistance

DEFF Research Database (Denmark)

Friedrich, Nele; Thuesen, Betina; Jørgensen, Torben

2012-01-01

OBJECTIVEIGF-I has an almost 50% amino acid sequence homology with insulin and elicits nearly the same hypoglycemic response. Studies showed that low and high IGF-I levels are related to impaired glucose tolerance and to a higher risk of type 2 diabetes. The aim of the current study was to evaluate...... the association between IGF-I level and insulin resistance in a Danish general population.RESEARCH DESIGN AND METHODSIncluded were 3,354 adults, aged 19-72 years, from the cross-sectional Health2006 study. The homeostasis model assessment of insulin resistance (HOMA-IR) was used as the index to estimate insulin...... with intermediate (Q3) IGF-I levels. These associations remained statistically significant after the exclusion of subjects with type 2 diabetes and by using the updated computer HOMA2-IR model.CONCLUSIONSLow- and high-normal IGF-I levels are both related to insulin resistance. The biological mechanism...

Short-Term Exercise Training Improves Insulin Sensitivity but Does Not Inhibit Inflammatory Pathways in Immune Cells from Insulin-Resistant Subjects

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Sara M. Reyna

2013-01-01

Full Text Available Background. Exercise has an anti-inflammatory effect against, and immune cells play critical roles in the development, of insulin resistance and atherosclerotic vascular disease (AVD. Thus, the goal of this study was to determine whether exercise improves insulin sensitivity in insulin-resistant subjects by downregulating proinflammatory signaling in immune cells. Methods. Seventeen lean, 8 obese nondiabetic, and 11 obese type 2 diabetic individuals underwent an aerobic exercise program for 15 days and an insulin clamp before and after exercise. Peripheral mononuclear cells (PMNC were obtained for determination of Toll-like receptor (TLR 2 and 4 protein content and mitogen-activated protein kinase phosphorylation. Results. Compared with that in lean individuals, TLR4 protein content was increased by 4.2-fold in diabetic subjects. This increase in TLR4 content was accompanied by a 3.0-fold increase in extracellular signal-regulated kinase (ERK phosphorylation. Exercise improved insulin sensitivity in the lean, obese, and type 2 diabetes groups. However, exercise did not affect TLR content or ERK phosphorylation. Conclusions. TLR4 content and ERK phosphorylation are increased in PMNC of type 2 diabetic individuals. While exercise improves insulin sensitivity, this effect is not related to changes in TLR2/TLR4 content or ERK phosphorylation in PMNC of type 2 diabetic individuals.

Short-term exercise training improves insulin sensitivity but does not inhibit inflammatory pathways in immune cells from insulin-resistant subjects.

Science.gov (United States)

Reyna, Sara M; Tantiwong, Puntip; Cersosimo, Eugenio; Defronzo, Ralph A; Sriwijitkamol, Apiradee; Musi, Nicolas

2013-01-01

Background. Exercise has an anti-inflammatory effect against, and immune cells play critical roles in the development, of insulin resistance and atherosclerotic vascular disease (AVD). Thus, the goal of this study was to determine whether exercise improves insulin sensitivity in insulin-resistant subjects by downregulating proinflammatory signaling in immune cells. Methods. Seventeen lean, 8 obese nondiabetic, and 11 obese type 2 diabetic individuals underwent an aerobic exercise program for 15 days and an insulin clamp before and after exercise. Peripheral mononuclear cells (PMNC) were obtained for determination of Toll-like receptor (TLR) 2 and 4 protein content and mitogen-activated protein kinase phosphorylation. Results. Compared with that in lean individuals, TLR4 protein content was increased by 4.2-fold in diabetic subjects. This increase in TLR4 content was accompanied by a 3.0-fold increase in extracellular signal-regulated kinase (ERK) phosphorylation. Exercise improved insulin sensitivity in the lean, obese, and type 2 diabetes groups. However, exercise did not affect TLR content or ERK phosphorylation. Conclusions. TLR4 content and ERK phosphorylation are increased in PMNC of type 2 diabetic individuals. While exercise improves insulin sensitivity, this effect is not related to changes in TLR2/TLR4 content or ERK phosphorylation in PMNC of type 2 diabetic individuals.

Insulin Resistance and the Polycystic Ovary Syndrome Revisited: An Update on Mechanisms and Implications

Science.gov (United States)

Diamanti-Kandarakis, Evanthia

2012-01-01

Polycystic ovary syndrome (PCOS) is now recognized as an important metabolic as well as reproductive disorder conferring substantially increased risk for type 2 diabetes. Affected women have marked insulin resistance, independent of obesity. This article summarizes the state of the science since we last reviewed the field in the Endocrine Reviews in 1997. There is general agreement that obese women with PCOS are insulin resistant, but some groups of lean affected women may have normal insulin sensitivity. There is a post-binding defect in receptor signaling likely due to increased receptor and insulin receptor substrate-1 serine phosphorylation that selectively affects metabolic but not mitogenic pathways in classic insulin target tissues and in the ovary. Constitutive activation of serine kinases in the MAPK-ERK pathway may contribute to resistance to insulin's metabolic actions in skeletal muscle. Insulin functions as a co-gonadotropin through its cognate receptor to modulate ovarian steroidogenesis. Genetic disruption of insulin signaling in the brain has indicated that this pathway is important for ovulation and body weight regulation. These insights have been directly translated into a novel therapy for PCOS with insulin-sensitizing drugs. Furthermore, androgens contribute to insulin resistance in PCOS. PCOS may also have developmental origins due to androgen exposure at critical periods or to intrauterine growth restriction. PCOS is a complex genetic disease, and first-degree relatives have reproductive and metabolic phenotypes. Several PCOS genetic susceptibility loci have been mapped and replicated. Some of the same susceptibility genes contribute to disease risk in Chinese and European PCOS populations, suggesting that PCOS is an ancient trait. PMID:23065822

Insulin resistance as a predictor of incident asthma-like symptoms in adults

DEFF Research Database (Denmark)

Thuesen, B H; Husemoen, L L N; Hersoug, L-G

2009-01-01

BACKGROUND: There is accumulating evidence that obesity is associated with an increased risk of asthma. It has been hypothesized that insulin resistance may be involved in obesity-induced asthma, but till date there is no prospective data on this issue. OBJECTIVE: To investigate the association...... of obesity and insulin resistance with the incidence of asthma-like symptoms in adults. METHODS: Out of a random sample of 12 934 persons from a general population, 6784 (52.5%) were included and participated in a health examination in 1999-2001. After 5 years they were re-invited and 4516 (66.......6%) participated at follow-up. At baseline three obesity measures were considered: body mass index, waist circumference, and waist-to-hip ratio. In addition, fasting glucose and insulin were measured for determination of insulin resistance. Information on asthma-like symptoms at baseline and follow-up were...

Method for preventing and/or treating insulin resistance

NARCIS (Netherlands)

Nieuwdorp, M.; Vos, de W.M.

2013-01-01

The present invention describes use of Eubacterium hallii et rel. and/or Alcaligenes faecalis et rel., as well as pharmaceutical, food, or feed compositions comprising these bacteria, as a medicament, in particular for preventing and/or treating insulin resistance and/or insulin resistance-related

The study of Insulin Resistance in the Off Springs of Diabetics and Non Diabetic Patients

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Ganesh Manoorkar

2017-12-01

Full Text Available Introduction: Insulin resistance is one of the main cause in the pathogenesis of the development of type- 2 diabetes mellitus. Elevated insulin levels and insulin resistance may be present several years prior to the development of hyperglycaemia. Hence the diagnosis of insulin resistance at the initial stages in risk group people could be used as an effective measure to prevent type 2 diabetes mellitus and its outcome, including reduction in morbidity and mortality. Though type 2 diabetes mellitus has multifactorial aetiology, genetic factor plays an important role in the development of diabetes mellitus. So we have tried to establish relation between genetic factor and insulin resistance by studying the insulin resistance in off springs of diabetics and non diabetics patients. Aims and objectives: Estimation of insulin levels in the off springs (non diabetics of diabetics and non diabetics patients. Comparision of insulin resistance in the off springs (non diabetics of diabetics and non diabetics. To find the relation between insulin resistance and genetic factor. Material and method: This study was carried out in the department of Biochemistry Grant Government Medical College Mumbai. Total 100 non diabetic people were included in the study of age above 30 years. These are divided into two groups as- Group-I includes 50 off springs (Ist degree relatives of non diabetic people. Group-II includes 50 off springs (Ist degree relatives of diabetic people. The fasting plasma glucose and serum insulin levels are estimated in the above two groups. The insulin resistance was calculated by using HOMA-IR model. Result: Fasting plasma glucose, serum insulin level and insulin resistance is significantly increased in group-II people as compared to group-I people. Conclusion: There is a strong relation between genetic factor and insulin resistance which exist prior to the development of diabetes mellitus. The people of group-II are susceptible for the

Total body fat, pro-inflammatory cytokines and insulin resistance in Indian subjects

Energy Technology Data Exchange (ETDEWEB)

Yajnik, C S [Diabetes Unit, KEM Hospital Research Centre, Pune (India); Yudkin, J S [Whittington Hospital, University College of London, London (United Kingdom); Shetty, P S [London School of Hygiene and Tropical Medicine, London (United Kingdom); Kurpad, A [St. John' s Medical College, Bangalore (India)

1999-07-01

There is a growing epidemic of insulin resistance syndrome (IRS) in Indians. We postulate that increased susceptibility of the urban Indians to insulin resistance is a result of a tendency to increased fat deposition from the time of intrauterine life (thrifty phenotype), exaggerated in the urban environment by a positive energy balance. The pro-inflammatory cytokines secreted by the inflammatory cells as well by the adipose tissue could aggravate insulin resistance and endothelial damage and therefore, increase the susceptibility to type 2 diabetes and coronary heart disease (CHD) independent of the previously proposed glucose fatty acid cycle mechanism. In a preliminary study, we propose to make detailed measurements of the proposed mechanisms in a selected population from 3 geographical locations in and near the city of Pune, India and also validate simple 'epidemiologic' measurements of body composition with 'reference' measurements. One hundred men (30 to 50y) each from the three geographical locations (rural, urban slum-dwellers and urban middle class in Pune) will be studied for: (i) Body composition: Anthropometric and bioimpedance measurement of total body fat (to be calibrated against deuterated water in 30 subjects from each location), and muscle mass by anthropometry and urinary creatinine excretion; (ii) Body fat distribution by subscapular- triceps ratio, waist-hip ratio; (iii) Metabolic: Glucose tolerance and insulin resistance variables (insulin, lipids, NEFA) and leptin; (iv) Endothelial markers: e-Selectin and von Willebrand Factor (vWF); (v) Inflammatory markers and pro-inflammatory cytokines: C-reactive protein (CRP), Interleukin-6 (IL-6) and tumour necrosis factor (TNF- {alpha}); (vi) Energy Balance: Assessment of nutritional intake (calories, carbohydrates, proteins and fats, n3 and n6 fatty acids) and physical activity by a questionnaire. Insulin resistance variables, endothelial markers, cytokines and obesity parameters will be compared in

Total body fat, pro-inflammatory cytokines and insulin resistance in Indian subjects

International Nuclear Information System (INIS)

Yajnik, C.S.; Yudkin, J.S.; Shetty, P.S.; Kurpad, A.

1999-01-01

There is a growing epidemic of insulin resistance syndrome (IRS) in Indians. We postulate that increased susceptibility of the urban Indians to insulin resistance is a result of a tendency to increased fat deposition from the time of intrauterine life (thrifty phenotype), exaggerated in the urban environment by a positive energy balance. The pro-inflammatory cytokines secreted by the inflammatory cells as well by the adipose tissue could aggravate insulin resistance and endothelial damage and therefore, increase the susceptibility to type 2 diabetes and coronary heart disease (CHD) independent of the previously proposed glucose fatty acid cycle mechanism. In a preliminary study, we propose to make detailed measurements of the proposed mechanisms in a selected population from 3 geographical locations in and near the city of Pune, India and also validate simple 'epidemiologic' measurements of body composition with 'reference' measurements. One hundred men (30 to 50y) each from the three geographical locations (rural, urban slum-dwellers and urban middle class in Pune) will be studied for: (i) Body composition: Anthropometric and bioimpedance measurement of total body fat (to be calibrated against deuterated water in 30 subjects from each location), and muscle mass by anthropometry and urinary creatinine excretion; (ii) Body fat distribution by subscapular- triceps ratio, waist-hip ratio; (iii) Metabolic: Glucose tolerance and insulin resistance variables (insulin, lipids, NEFA) and leptin; (iv) Endothelial markers: e-Selectin and von Willebrand Factor (vWF); (v) Inflammatory markers and pro-inflammatory cytokines: C-reactive protein (CRP), Interleukin-6 (IL-6) and tumour necrosis factor (TNF- α); (vi) Energy Balance: Assessment of nutritional intake (calories, carbohydrates, proteins and fats, n3 and n6 fatty acids) and physical activity by a questionnaire. Insulin resistance variables, endothelial markers, cytokines and obesity parameters will be compared in the 3

Insulin resistance in type 1 diabetes: what is ?double diabetes? and what are the risks?

OpenAIRE

Cleland, S. J.; Fisher, B. M.; Colhoun, H. M.; Sattar, N.; Petrie, J. R.

2013-01-01

In this review, we explore the concept of ‘double diabetes’, a combination of type 1 diabetes with features of insulin resistance and type 2 diabetes. After considering whether double diabetes is a useful concept, we discuss potential mechanisms of increased insulin resistance in type 1 diabetes before examining the extent to which double diabetes might increase the risk of cardiovascular disease (CVD). We then go on to consider the proposal that weight gain from intensive insulin regimens ma...

11beta-hydroxysteroid dehydrogenase type 1 regulates glucocorticoid-induced insulin resistance in skeletal muscle.

LENUS (Irish Health Repository)

Morgan, Stuart A

2009-11-01

Glucocorticoid excess is characterized by increased adiposity, skeletal myopathy, and insulin resistance, but the precise molecular mechanisms are unknown. Within skeletal muscle, 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) converts cortisone (11-dehydrocorticosterone in rodents) to active cortisol (corticosterone in rodents). We aimed to determine the mechanisms underpinning glucocorticoid-induced insulin resistance in skeletal muscle and indentify how 11beta-HSD1 inhibitors improve insulin sensitivity.

Effects of Hormone Replacement Therapy on Insulin Resistance in Postmenopausal Diabetic Women

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Iskra Bitoska

2016-02-01

CONCLUSION: HRT was associated with statistically signifficant increase of insulin sensitivity. Larger clinical trials will be necessary to understand whether HRT may improve insulin resistance and glucose homeostasis in women with diabetes, especially when given shortly after entering menopause.

Studies of insulin resistance in congenital generalized lipodystrophy

DEFF Research Database (Denmark)

Søvik, O; Vestergaard, H; Trygstad, O

1996-01-01

suppressed lipid oxidation in the controls. It is concluded that patients with congenital generalized lipodystrophy may present severe insulin resistance with regard to hepatic glucose production as well as muscle glycogen synthesis and lipid oxidation. The results suggest a postreceptor defect in the action......, immunoreactive protein and mRNA levels. The patients had fasting hyperinsulinaemia, and the rate of total glucose disposal was severely impaired, primarily due to a decreased non-oxidative glucose metabolism. In the patient studied with muscle biopsy, the expected activation of glycogen synthase by insulin did...... not occur. In both patients there was severely increased hepatic glucose output in the basal state, suggesting a failure of insulin to suppress hepatic gluconeogenesis. During insulin infusion a substantially elevated rate of lipid oxidation remained in the patients, in contrast to the almost completely...

Elevated toll-like receptor 4 expression and signaling in muscle from insulin-resistant subjects.

Science.gov (United States)

Reyna, Sara M; Ghosh, Sangeeta; Tantiwong, Puntip; Meka, C S Reddy; Eagan, Phyllis; Jenkinson, Christopher P; Cersosimo, Eugenio; Defronzo, Ralph A; Coletta, Dawn K; Sriwijitkamol, Apiradee; Musi, Nicolas

2008-10-01

OBJECTIVE- Tall-like receptor (TLR)4 has been implicated in the pathogenesis of free fatty acid (FFA)-induced insulin resistance by activating inflammatory pathways, including inhibitor of kappaB (IkappaB)/nuclear factor kappaB (NFkappaB). However, it is not known whether insulin-resistant subjects have abnormal TLR4 signaling. We examined whether insulin-resistant subjects have abnormal TLR4 expression and TLR4-driven (IkappaB/NFkappaB) signaling in skeletal muscle. RESEARCH DESIGN AND METHODS- TLR4 gene expression and protein content were measured in muscle biopsies in 7 lean, 8 obese, and 14 type 2 diabetic subjects. A primary human myotube culture system was used to examine whether FFAs stimulate IkappaB/NFkappaB via TLR4 and whether FFAs increase TLR4 expression/content in muscle. RESULTS- Obese and type 2 diabetic subjects had significantly elevated TLR4 gene expression and protein content in muscle. TLR4 muscle protein content correlated with the severity of insulin resistance. Obese and type 2 diabetic subjects also had lower IkappaBalpha content, an indication of elevated IkappaB/NFkappaB signaling. The increase in TLR4 and NFkappaB signaling was accompanied by elevated expression of the NFkappaB-regulated genes interleukin (IL)-6 and superoxide dismutase (SOD)2. In primary human myotubes, acute palmitate treatment stimulated IkappaB/NFkappaB, and blockade of TLR4 prevented the ability of palmitate to stimulate the IkappaB/NFkappaB pathway. Increased TLR4 content and gene expression observed in muscle from insulin-resistant subjects were reproduced by treating myotubes from lean, normal-glucose-tolerant subjects with palmitate. Palmitate also increased IL-6 and SOD2 gene expression, and this effect was prevented by inhibiting NFkappaB. CONCLUSIONS- Abnormal TLR4 expression and signaling, possibly caused by elevated plasma FFA levels, may contribute to the pathogenesis of insulin resistance in humans.

Curcumin reverses the depressive-like behavior and insulin resistance induced by chronic mild stress.

Science.gov (United States)

Shen, Ji-Duo; Wei, Yu; Li, Yu-Jie; Qiao, Jing-Yi; Li, Yu-Cheng

2017-08-01

Increasing evidence has demonstrated that patients with depression have a higher risk of developing type 2 diabetes. Insulin resistance has been identified as the key mechanism linking depression and diabetes. The present study established a rat model of depression complicated by insulin resistance using a 12-week exposure to chronic mild stress (CMS) and investigated the therapeutic effects of curcumin. Sucrose intake tests were used to evaluate depressive-like behaviors, and oral glucose tolerance tests (OGTT) and intraperitoneal insulin tolerance tests (IPITT) were performed to evaluate insulin sensitivity. Serum parameters were detected using commercial kits. Real-time quantitative PCR was used to examine mRNA expression. CMS rats exhibited reduced sucrose consumption, increased serum glucose, insulin, triglyceride (TG), low density lipoprotein-cholesterol (LDL-C), non-esterified fatty acid (NEFA), glucagon, leptin, and corticosterone levels, as well as impaired insulin sensitivity. Curcumin upregulated the phosphorylation of insulin receptor substrate (IRS)-1 and protein kinase B (Akt) in the liver, enhanced insulin sensitivity, and reversed the metabolic abnormalities and depressive-like behaviors mentioned above. Moreover, curcumin increased the hepatic glycogen content by inhibiting glycogen synthase kinase (GSK)-3β and prevented gluconeogenesis by inhibiting phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase). These results suggest that curcumin not only exerted antidepressant-like effects, but also reversed the insulin resistance and metabolic abnormalities induced by CMS. These data may provide evidence to support the potential use of curcumin against depression and/or metabolic disorders.

Glucagon-Like Peptide 1 Recruits Muscle Microvasculature and Improves Insulin’s Metabolic Action in the Presence of Insulin Resistance

Science.gov (United States)

Chai, Weidong; Zhang, Xingxing; Barrett, Eugene J.

2014-01-01

Glucagon-like peptide 1 (GLP-1) acutely recruits muscle microvasculature, increases muscle delivery of insulin, and enhances muscle use of glucose, independent of its effect on insulin secretion. To examine whether GLP-1 modulates muscle microvascular and metabolic insulin responses in the setting of insulin resistance, we assessed muscle microvascular blood volume (MBV), flow velocity, and blood flow in control insulin-sensitive rats and rats made insulin-resistant acutely (systemic lipid infusion) or chronically (high-fat diet [HFD]) before and after a euglycemic-hyperinsulinemic clamp (3 mU/kg/min) with or without superimposed systemic GLP-1 infusion. Insulin significantly recruited muscle microvasculature and addition of GLP-1 further expanded muscle MBV and increased insulin-mediated glucose disposal. GLP-1 infusion potently recruited muscle microvasculature in the presence of either acute or chronic insulin resistance by increasing muscle MBV. This was associated with an increased muscle delivery of insulin and muscle interstitial oxygen saturation. Muscle insulin sensitivity was completely restored in the presence of systemic lipid infusion and significantly improved in rats fed an HFD. We conclude that GLP-1 infusion potently expands muscle microvascular surface area and improves insulin’s metabolic action in the insulin-resistant states. This may contribute to improved glycemic control seen in diabetic patients receiving incretin-based therapy. PMID:24658303

Acceptance of insulin therapy: a long shot? Psychological insulin resistance in primary care

NARCIS (Netherlands)

Woudenberg, Y. J. C.; Lucas, C.; Latour, C.; Scholte Op Reimer, W. J. M.

2012-01-01

Diabet. Med. 29, 796802 (2012) Abstract Aim To explore which factors are associated with psychological insulin resistance in insulin-naive patients with Type 2 diabetes in primary care. Methods A sample of 101 insulin-naive patients with Type 2 diabetes completed self-administered questionnaires

Prevalence of impaired glucose tolerance and insulin resistance among obese children and adolescents

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Robabeh Ghergherechi

2010-07-01

Full Text Available Robabeh Ghergherechi1, Ali Tabrizi21Department of Pediatrics Endocrinology, Tabriz University of Medical Sciences, Tabriz, Iran; 2Students’ Research Committee, Tabriz University of Medical Sciences, Tabriz, IranPurpose: Obesity is one of the most important nutritional disorders in the world which has an obvious relationship with the incidence of metabolic diseases. Obesity prevalence has increased among children and adolescents during recent decades, leading to a rise in Type 2 diabetes mellitus (DM II prevalence in these two age brackets. Hence, the aim of this study was to assess impaired glucose tolerance and insulin resistance, and gather metabolic findings in obese children and adolescents.Methods and materials: We studied 110 obese children and adolescents (body mass index > 95th percentile for age and gender 4–18 years of age referred to the endocrine clinic of the Children’s Hospital at Tabriz University in a descriptive cross-sectional study. ­Fasting glucose, insulin, and lipid profile in all subjects were determined. Oral glucose tolerance test after eating 75 g/kg glucose was performed. Homeostatic model assessment was used to ­estimate insulin resistance.Results: Impaired glucose tolerance and insulin resistance prevalence in 68 obese adolescents was 14.7% and 31.8%, respectively. Impaired glucose tolerance and insulin resistance was not seen in 23.8% of 42 obese children. No case of DM II was seen. There was a significant statistical difference in glucose (P = 0.003 and insulin (P < 0.001 level at minute 120 in individuals with impaired glucose tolerance compared to obese children and adolescents without impaired glucose tolerance. Rate of insulin resistance in patients with impaired glucose tolerance was greater and had a significant statistical difference (P = 0.03.Conclusion: Obesity has a close relationship with increased risk of impaired glucose tolerance and insulin resistance in children and adolescents. Oral glucose

Fasting insulin, insulin resistance and risk of hypertension in the general population: A meta-analysis.

Science.gov (United States)

Wang, Feng; Han, Lili; Hu, Dayi

2017-01-01

Studies on the association of fasting insulin concentrations or insulin resistance with subsequent risk of hypertension have yielded conflicting results. To quantitatively assess the association of fasting insulin concentrations or homeostasis model assessment insulin resistance (HOMA-IR) with incident hypertension in a general population by performing a meta-analysis. We searched the PubMed and Embase databases until August 31, 2016 for prospective observational studies investigating the elevated fasting insulin concentrations or HOMA-IR with subsequent risk of hypertension in the general population. Pooled risk ratio (RR) and 95% confidence interval (CI) of hypertension was calculated for the highest versus the lowest category of fasting insulin or HOMA-IR. Eleven studies involving 10,230 hypertension cases were identified from 55,059 participants. Meta-analysis showed that the pooled adjusted RR of hypertension was 1.54 (95% CI 1.34-1.76) for fasting insulin concentrations and 1.43 (95% CI 1.27-1.62) for HOMA-IR comparing the highest to the lowest category. Subgroup analysis results showed that the association of fasting insulin concentrations with subsequent risk of hypertension seemed more pronounced in women (RR 2.07; 95% CI 1.19-3.60) than in men (RR 1.48; 95% CI 1.17-1.88). This meta-analysis suggests that elevated fasting insulin concentrations or insulin resistance as estimated by homeostasis model assessment is independently associated with an exacerbated risk of hypertension in the general population. Early intervention of hyperinsulinemia or insulin resistance may help clinicians to identify the high risk of hypertensive population. Copyright © 2016 Elsevier B.V. All rights reserved.

Molecular Mechanisms of Insulin Resistance Development

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Vsevolod Arsen'evich Tkachuk

2014-05-01

Full Text Available Insulin resistance (IR is a phenomenon associated with an impaired ability of insulin to stimulate glucose uptake by target cells and to reduce the blood glucose level. A response increase in insulin secretion by the pancreas and hyperinsulinemia are compensatory reactions of the body. The development of IR leads to the inability of target cells to respond to insulin that results in developing type 2 diabetes mellitus (T2DM and metabolic syndrome. For this reason, the metabolic syndrome is defined in practice as a combination of IR with one or more pathologies such as T2DM, arterial hypertension, dyslipidemia, abdominal obesity, non-alcoholic fatty liver disease, and some others. However, a combination of high blood glucose and insulin levels always serves as its physiological criterion.IR should be considered as a systemic failure of the endocrine regulation in the body. Physiological causes of IR are diverse. The main ones are nutritional overload and accumulation of certain lipids and their metabolites in cells, low physical activity, chronic inflammation and stress of various nature, including oxidative and endoplasmic reticulum stress (impairment of damaged protein degradation in the cell. Recent studies have demonstrated that these physiological mechanisms likely act through a single intracellular scenario. This is the impairment of signal transduction from the insulin receptor to its targets via the negative feedback mechanism in intracellular insulin-dependent signaling cascades.This review describes the physiological and intracellular mechanisms of insulin action and focuses on their abnormalities upon IR development. Finally, feasible trends in early molecular diagnosis and therapy of IR are discussed.

Insulin resistance and delayed clearance of peptide hormones in cirrhotic rat liver

International Nuclear Information System (INIS)

Shankar, T.P.; Drake, S.; Solomon, S.S.

1987-01-01

Clearance of porcine insulin, glucagon, and human growth hormone was measured in intact perfused cirrhotic and normal rat livers. Binding and degradation of 125 I-insulin by hepatocytes isolated from cirrhotic and normal livers were also studied. The half-lives (t/sub 1/2/) of immunoreactive insulin and glucagon were 14.0 +/- 3.1 and 9.6 +/- 2.1 min in normal livers and 26.0 +/- 6.1 and 25.0 +/- 7.1 min in cirrhotic livers. Insulin binding and degradation by hepatocytes from control and cirrhotic livers showed no significant differences. Intraportal insulin infusion in perfusion studies suppressed glucagon-stimulated increases in glucose output from control livers but failed to suppress glucose production by cirrhotic livers, suggesting the presence of hepatic insulin resistance in cirrhosis. Impaired clearance of insulin and glucagon by the intact cirrhotic liver and normal binding and degradation of insulin by isolated hepatocytes suggest that factors such as intrahepatic fibrosis and shunting and postbinding defects may be responsible for the impaired hormone clearance and hepatic insulin resistance

[Molecular mechanism for ET-1-induced insulin resistance in skeletal muscle cells].

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Horinouchi, Takahiro; Mazaki, Yuichi; Terada, Koji; Miwa, Soichi

2018-01-01

Insulin resistance is a condition where the sensitivity to insulin of the tissues expressing insulin receptor (InsR) is decreased due to a functional disturbance of InsR-mediated intracellular signaling. Insulin promotes the entry of glucose into the tissues and skeletal muscle is the most important tissue responsible for the insulin's action of decreasing blood glucose levels. Endothelin-1 (ET-1), a potent vasoconstrictor and pro-inflammatory peptide, induces insulin resistance through a direct action on skeletal muscle. However, the signaling pathways of ET-1-induced insulin resistance in skeletal muscle remain unclear. Here we show molecular mechanism underlying the inhibitory effect of ET-1 on insulin-stimulated Akt phosphorylation and glucose uptake in myotubes of rat L6 skeletal muscle cell line. mRNA expression levels of differentiation marker genes, MyoD and myogenin, were increased during L6 myoblasts differentiation into myotubes. Some of myotubes possessed the ability to spontaneously contract. In myotubes, insulin promoted Akt phosphorylation at Thr 308 and Ser 473 , and [ 3 H]-labelled 2-deoxy-D-glucose ([ 3 H]2-DG) uptake. The insulin-facilitated Akt phosphorylation and [ 3 H]2-DG uptake were inhibited by ET-1. The inhibitory effect of ET-1 was counteracted by blockade of ET type A receptor (ET A R), inhibition of G q/11 protein, and siRNA knockdown of G protein-coupled receptor kinase 2 (GRK2). The exogenously overexpressed GRK2 directly bound to endogenous Akt and their association was facilitated by ET-1. In summary, activation of ET A R with ET-1 inhibits insulin-induced Akt phosphorylation and [ 3 H]2-DG uptake in a G q/11 protein- and GRK2-dependent manner in skeletal muscle. These findings indicate that ET A R and GRK2 are potential targets for insulin resistance.

Effects of clenbuterol on insulin resistance in conscious obese Zucker rats.

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Pan, S J; Hancock, J; Ding, Z; Fogt, D; Lee, M; Ivy, J L

2001-04-01

The present study was conducted to determine the effect of chronic administration of the long-acting beta(2)-adrenergic agonist clenbuterol on rats that are genetically prone to insulin resistance and impaired glucose tolerance. Obese Zucker rats (fa/fa) were given 1 mg/kg of clenbuterol by oral intubation daily for 5 wk. Controls received an equivalent volume of water according to the same schedule. At the end of the treatment, rats were catheterized for euglycemic-hyperinsulinemic (15 mU insulin. kg(-1). min(-1)) clamping. Clenbuterol did not change body weight compared with the control group but caused a redistribution of body weight: leg muscle weights increased, and abdominal fat weight decreased. The glucose infusion rate needed to maintain euglycemia and the rate of glucose disappearance were greater in the clenbuterol-treated rats. Furthermore, plasma insulin levels were decreased, and the rate of glucose uptake into hindlimb muscles and abdominal fat was increased in the clenbuterol-treated rats. This increased rate of glucose uptake was accompanied by a parallel increase in the rate of glycogen synthesis. The increase in muscle glucose uptake could not be ascribed to an increase in the glucose transport protein GLUT-4 in clenbuterol-treated rats. We conclude that chronic clenbuterol treatment reduces the insulin resistance of the obese Zucker rat by increasing insulin-stimulated muscle and adipose tissue glucose uptake. The improvements noted may be related to the repartitioning of body weight between tissues.

Elevated TCA cycle function in the pathology of diet-induced hepatic insulin resistance and fatty liver[S

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Satapati, Santhosh; Sunny, Nishanth E.; Kucejova, Blanka; Fu, Xiaorong; He, Tian Teng; Méndez-Lucas, Andrés; Shelton, John M.; Perales, Jose C.; Browning, Jeffrey D.; Burgess, Shawn C.

2012-01-01

The manner in which insulin resistance impinges on hepatic mitochondrial function is complex. Although liver insulin resistance is associated with respiratory dysfunction, the effect on fat oxidation remains controversial, and biosynthetic pathways that traverse mitochondria are actually increased. The tricarboxylic acid (TCA) cycle is the site of terminal fat oxidation, chief source of electrons for respiration, and a metabolic progenitor of gluconeogenesis. Therefore, we tested whether insulin resistance promotes hepatic TCA cycle flux in mice progressing to insulin resistance and fatty liver on a high-fat diet (HFD) for 32 weeks using standard biomolecular and in vivo 2H/13C tracer methods. Relative mitochondrial content increased, but respiratory efficiency declined by 32 weeks of HFD. Fasting ketogenesis became unresponsive to feeding or insulin clamp, indicating blunted but constitutively active mitochondrial β-oxidation. Impaired insulin signaling was marked by elevated in vivo gluconeogenesis and anaplerotic and oxidative TCA cycle flux. The induction of TCA cycle function corresponded to the development of mitochondrial respiratory dysfunction, hepatic oxidative stress, and inflammation. Thus, the hepatic TCA cycle appears to enable mitochondrial dysfunction during insulin resistance by increasing electron deposition into an inefficient respiratory chain prone to reactive oxygen species production and by providing mitochondria-derived substrate for elevated gluconeogenesis. PMID:22493093

Streptozotocin diabetes and insulin resistance impairment of ...

African Journals Online (AJOL)

... insulin resistance impairment of spermatogenesis in adult rat testis: Central Vs local ... Summary: Mammalian reproduction is dynamically regulated by the pituitary ... Group 3 > Streptozotocin-insulin treated group; received a single dose IP ...

Insulin resistance and protein energy metabolism in patients with advanced chronic kidney disease.

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Siew, Edward D; Ikizler, Talat Alp

2010-01-01

Insulin resistance (IR), the reciprocal of insulin sensitivity is a known complication of advanced chronic kidney disease (CKD) and is associated with a number of metabolic derangements. The complex metabolic abnormalities observed in CKD such as vitamin D deficiency, obesity, metabolic acidosis, inflammation, and accumulation of "uremic toxins" are believed to contribute to the etiology of IR and acquired defects in the insulin-receptor signaling pathway in this patient population. Only a few investigations have explored the validity of commonly used assessment methods in comparison to gold standard hyperinsulinemic hyperglycemic clamp technique in CKD patients. An important consequence of insulin resistance is its role in the pathogenesis of protein energy wasting, a state of metabolic derangement characterized by loss of somatic and visceral protein stores not entirely accounted for by inadequate nutrient intake. In the general population, insulin resistance has been associated with accelerated protein catabolism. Among end-stage renal disease (ESRD) patients, enhanced muscle protein breakdown has been observed in patients with Type II diabetes compared to ESRD patients without diabetes. In the absence of diabetes mellitus (DM) or severe obesity, insulin resistance is detectable in dialysis patients and strongly associated with increased muscle protein breakdown, primarily mediated by the ubiquitin-proteasome pathway. Recent epidemiological data indicate a survival advantage and better nutritional status in insulin-free Type II DM patients treated with insulin sensitizer thiazolidinediones. Given the high prevalence of protein energy wasting in ESRD and its unequivocal association with adverse clinical outcomes, insulin resistance may represent an important modifiable target for intervention in the ESRD population.

Reduction of insulinotropic properties of GLP-1 and GIP after glucocorticoid-induced insulin resistance

DEFF Research Database (Denmark)

Eriksen, Marie; Jensen, David H; Tribler, Siri

2015-01-01

. In addition, first-phase insulin responses were determined at 7 mmol/l and 15 mmol/l and second-phase insulin responses at 7 mmol/l. RESULTS: After dexamethasone treatment, all 19 participants had increased insulin resistance (HOMA-IR and insulin sensitivity index [M/I] values) and 2 h plasma glucose...

Gut microbiota is a key modulator of insulin resistance in TLR 2 knockout mice.

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Andréa M Caricilli

2011-12-01

Full Text Available Environmental factors and host genetics interact to control the gut microbiota, which may have a role in the development of obesity and insulin resistance. TLR2-deficient mice, under germ-free conditions, are protected from diet-induced insulin resistance. It is possible that the presence of gut microbiota could reverse the phenotype of an animal, inducing insulin resistance in an animal genetically determined to have increased insulin sensitivity, such as the TLR2 KO mice. In the present study, we investigated the influence of gut microbiota on metabolic parameters, glucose tolerance, insulin sensitivity, and signaling of TLR2-deficient mice. We investigated the gut microbiota (by metagenomics, the metabolic characteristics, and insulin signaling in TLR2 knockout (KO mice in a non-germ free facility. Results showed that the loss of TLR2 in conventionalized mice results in a phenotype reminiscent of metabolic syndrome, characterized by differences in the gut microbiota, with a 3-fold increase in Firmicutes and a slight increase in Bacteroidetes compared with controls. These changes in gut microbiota were accompanied by an increase in LPS absorption, subclinical inflammation, insulin resistance, glucose intolerance, and later, obesity. In addition, this sequence of events was reproduced in WT mice by microbiota transplantation and was also reversed by antibiotics. At the molecular level the mechanism was unique, with activation of TLR4 associated with ER stress and JNK activation, but no activation of the IKKβ-IκB-NFκB pathway. Our data also showed that in TLR2 KO mice there was a reduction in regulatory T cell in visceral fat, suggesting that this modulation may also contribute to the insulin resistance of these animals. Our results emphasize the role of microbiota in the complex network of molecular and cellular interactions that link genotype to phenotype and have potential implications for common human disorders involving obesity, diabetes

Prenatal Testosterone Programming of Insulin Resistance in the Female Sheep.

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Puttabyatappa, Muraly; Padmanabhan, Vasantha

2017-01-01

Insulin resistance, a common feature of metabolic disorders such as obesity, nonalcoholic fatty liver disease, metabolic syndrome, and polycystic ovary syndrome, is a risk factor for development of diabetes. Because sex hormones orchestrate the establishment of sex-specific behavioral, reproductive, and metabolic differences, a role for them in the developmental origin of insulin resistance is also to be expected. Female sheep exposed to male levels of testosterone during fetal life serve as an excellent translational model for delineating programming of insulin resistance. This chapter summarizes the ontogeny of insulin resistance, the tissue-specific changes in insulin sensitivity, and the various factors that are involved in the programming and maintenance of the insulin resistance in adult female sheep that were developmentally exposed to fetal male levels of testosterone during the sexual-differentiation window.

Is Insulin Resistance an Intrinsic Defect in Asian Polycystic Ovary Syndrome?

OpenAIRE

Lee, Hyejin; Oh, Jee-Young; Sung, Yeon-Ah; Chung, Hyewon

2013-01-01

Purpose Approximately 50% to 70% of women with polycystic ovary syndrome (PCOS) have some degree of insulin resistance, and obesity is known to worsen insulin resistance. Many metabolic consequences of PCOS are similar to those of obesity; therefore, defining the cause of insulin resistance in women can be difficult. Our objective was to clarify the factors contributing to insulin resistance in PCOS. Materials and Methods We consecutively recruited 144 women with PCOS [age: 26?5 yr, body mass...

Insulin resistance is associated with the aggressiveness of pancreatic ductal carcinoma.

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Dugnani, Erica; Balzano, Gianpaolo; Pasquale, Valentina; Scavini, Marina; Aleotti, Francesca; Liberati, Daniela; Di Terlizzi, Gaetano; Gandolfi, Alessandra; Petrella, Giovanna; Reni, Michele; Doglioni, Claudio; Bosi, Emanuele; Falconi, Massimo; Piemonti, Lorenzo

2016-12-01

To study whether insulin resistance accelerates the development and/or the progression of pancreatic adenocarcinoma (PDAC), we hypothesized that patients with insulin resistance, compared with those without insulin resistance, show: (1) a younger age and more advanced PDAC stage at diagnosis and (2) a shorter disease-free and overall survival after PDAC diagnosis. Prospective observational study of patients admitted to a referral center for pancreatic disease. Insulin resistance was defined as a HOMA-IR value greater than the 66th percentile value of the patients included in this study. Survival was estimated according to Kaplan-Meier and by Cox regression. Of 296 patients with PDAC, 99 (33 %) met criteria for being classified as insulin resistant at diagnosis. Median follow-up time after diagnosis was 5.27 ± 0.23 years. Patients with insulin resistance received a diagnosis of PDAC at a similar age compared to patients without insulin resistance (67.1 ± 9 vs. 66.8 ± 10 years, p = 0.68), but were more likely to have a cancer stage ≥3 (23.2 vs. 14.2 %, p = 0.053) and a residual disease after surgery (R1 56.4 vs. 38 %; p = 0.007). The median overall survival was 1.3 ± 0.14 and 1.79 ± 0.11 years for the patients with and without insulin resistance, respectively (p = 0.016). Results did not change when patients with diabetes at PDAC diagnosis were excluded from the analysis. Multivariate analysis showed that insulin resistance was independently associated with overall survival. Insulin resistance is associated with the aggressiveness of PDAC.