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Background: Diabetes is a metabolic disorder characterized by an imbalance in insulin synthesis or utilization, resulting in elevated blood glucose levels. Type 2 diabetes (T2D) is characterized by high blood glucose levels, which are primarily caused by insulin resistance, resulting in a variety of complications and a significant impact on vital organs. The primary function of protein tyrosine phosphatase 1B (PTP1B) is to regulate the signaling pathways of insulin and leptin, both of which are involved in cellular metabolism and glucose homeostasis. PTP1B catalyzes the de-phosphorylation of active insulin receptors and insulin receptor substrates, resulting in insulin signaling downregulation. Methods: In this study, natural compounds from the ZINC database were screened against the PTP1B protein using the PyRx 0.8 tool. The physicochemical and drug-likeness characteristics of the top five screened compounds were investigated using the SwissADME web tool. Results: The compounds ZINC899884, ZINC56981, ZINC252509722, ZINC1843029, and ZINC21789 interacted and bound with PTP1B protein strongly, and their binding energies were higher than those of the control compounds. Furthermore, these compounds have good druglike properties. Conclusion: This study suggests that these compounds can be used as PTP1B inhibitors for diabetes management. However, additional experimental studies are needed to optimize them as PTP1B inhibitors. [ABSTRACT FROM AUTHOR]

Gestational diabetes mellitus (GDM) is characterized by glucose intolerance in pregnant women without a previous diagnosis of diabetes. While the etiology of GDM remains elusive, the close association of GDM with increased maternal adiposity and advanced gestational age implicates insulin resistance as a culpable factor for the pathogenesis of GDM. Pregnancy is accompanied by the physiological induction of insulin resistance in the mother secondary to maternal weight gain. This effect serves to spare blood glucose for the fetus. To overcome insulin resistance, maternal β-cells are conditioned to release more insulin into the blood. Such an adaptive response, termed β-cell compensation, is essential for maintaining normal maternal metabolism. β-cell compensation culminates in the expansion of β-cell mass and augmentation of β-cell function, accounting for increased insulin synthesis and secretion. As a result, a vast majority of mothers are protected from developing GDM during pregnancy. In at-risk pregnant women, β-cells fail to compensate for maternal insulin resistance, contributing to insulin insufficiency and GDM. However, gestational β-cell compensation ensues in early pregnancy, prior to the establishment of insulin resistance in late pregnancy. How β-cells compensate for pregnancy and what causes β-cell failure in GDM are subjects of investigation. In this mini-review, we will provide clinical and preclinical evidence that β-cell compensation is pivotal for overriding maternal insulin resistance to protect against GDM. We will highlight key molecules whose functions are critical for integrating gestational hormones to β-cell compensation for pregnancy. We will provide mechanistic insights into β-cell decompensation in the etiology of GDM. [ABSTRACT FROM AUTHOR]

Glycyrrhetinic acid (GA) is found in the roots and rhizomes of the legume licorice genus. The sweetness of GA is 250 times of sucrose. GA has a variety of biological activities. To develop new functional additive with hypoglycemic properties, the GA was modified with amino acids. The carboxyl group in C-30 of GA was modified with glycine, aspartic acid and arginine, respectively, to successfully prepare three amino acid amide derivatives of GA. The total yields of N-glycyrrhetinylglycine, N-glycyrrhetinyl aspartic acid and N-glycyrrhetinylarginine were 43.60%, 39.33% and 35.10%, respectively. The modification of C-30 of GA was modified with amino acid can significantly reduce the log P value and promote the hydrophilicity of GA. The N-glycyrrhetinylarginine had effective inhibition on α-glucosidase and is superior to GA. The inhibition on α-glucosidase by GA and N-Glycyrrhetinyl amino acid were reversible and mixed type. The GA and N-glycyrrhetinylarginine can effectively increase glucose consumption and glycogen synthesis to regulate insulin resistance. The GA and N-glycyrrhetinylarginine can regulate the insulin resistance in HepG2-IR cells via PI3K/Akt signaling pathway. [Display omitted] • Glycyrrhetinic acid was successfully modified by glycine, aspartic acid and arginine. • The modifications by amino acid promoted the hydrophilicity of glycyrrhetinic acid. • The modification by arginine enhanced the inhibition on α-glucosidase. • The N-glycyrrhetinylarginine regulated insulin resistance in HepG2-IR cells. • The regulation of N-glycyrrhetinylarginine in HepG2-IR cells via PI3K/Akt pathway. [ABSTRACT FROM AUTHOR]

Polycystic ovary syndrome (PCOS) is a disease with endocrine and metabolic disorders. The main symptoms are hyperandrogenemia (HA), insulin resistance (IR), and ovulation disorder. However, the pathogenesis and pathophysiological process of these major symptoms in PCOS are still not well defined. In recent studies, the chronic low‐grade inflammatory state has become one of the factors affecting PCOS. Some alterable immune factors in PCOS, such as interleukin‐15 and interleukin‐1, have been identified to be related to androgen synthesis and insulin resistance in PCOS. In addition, a disturbed immune microenvironment in the ovary leads to impaired follicular growth and ovulation. Previous studies have roughly reviewed the relationship between immunity and PCOS. However, the link between the different clinical manifestations of PCOS and immunity has not been well explored and analyzed. The clinical presentation of each patient is diverse, and symptomatic treatment is mainly used. Therefore, this article reviews several representative immunological factors that affect these three symptoms to explore the underlying mechanism, which will be beneficial for developing new treatment strategies. [ABSTRACT FROM AUTHOR]

Dysregulation of insulin signaling in the Alzheimer's disease (AD) brain has been extensively reported. Serine racemase (SR) modulates insulin secretion in pancreatic islets. This study aimed to examine whether SR regulates insulin synthesis and secretion in neurons, thereby modulating insulin signaling in the AD brain. Srr‐knockout (Srr−/−) mice generated with the CRISPR/Cas9 technique were used. Using immunofluorescence and fluorescence in situ hybridization, levels of insulin protein and insulin(ins2) mRNA were significantly increased in the hippocampal but not in hypothalamic sections of Srr−/− mice compared with WT mice. Real‐time quantitative PCR revealed that ins2 mRNA from primary hippocampal neuronal cultures of Srr−/− mice was significantly increased compared with that from cultured neurons of WT mice. Notably, the secretion of proinsulin C‐peptide was increased in Srr−/− neurons relative to WT neurons. By examining membrane fractional proteins with immunoblotting, Srr−/− neurons retained ATP‐dependent potassium channels on plasmalemma and correspondingly contained higher levels of p‐AMPK. After treatment with Aβ42, the phosphorylation levels of insulin receptor substrate at serine 616 636 (p‐IRS1ser616,636) were significantly lower, whereas p‐AKT308 and p‐AKT473 were higher in Srr−/− neurons than in WT neurons, respectively. The phosphorylated form of c‐Jun N‐terminal kinase decreased in the cultured Srr−/− neurons relative to the WT neurons upon Aβ42 treatment. In contrast, phosphorylated protein kinase R remained at the same levels. Further, reactive oxygen species were reduced in cultured Srr−/− neurons under Aβ42 treatment relative to the WT neurons. Collectively, our study indicated that Srr deletion promoted insulin synthesis and secretion of proinsulin C‐peptide, thereby reversing insulin resistance by Aβ42. This study suggests that targeting the neuronal SR may be utilized to enhance insulin signaling which is inhibited at the early stage of the AD brain. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common type of dementia. The evolution and aggregation of amyloid beta (β) oligomers is linked to insulin resistance in AD, which is also the major characteristic of type 2 diabetes (T2D). Being physically inactive can contribute to the development of AD and/or T2D. Aerobic exercise training (AET), a type of physical exercise, can be useful in preventing or treating the negative outcomes of AD and T2D. AD, T2D and AET can regulate the expression of microRNAs (miRNAs). Here, we review some of the changes in miRNAs expression regulated by AET, AD and T2D. MiRNAs play an important role in the gene regulation of key signaling pathways in both pathologies, AD and T2D. MiRNA dysregulation is evident in AD and has been associated with several neuropathological alterations, such as the development of a reactive gliosis. Expression of miRNAs are associated with many pathophysiological mechanisms involved in T2D like insulin synthesis, insulin resistance, glucose intolerance, hyperglycemia, intracellular signaling, and lipid profile. AET regulates miRNAs levels. We identified 5 miRNAs (miR-21, miR-29a/b, miR-103, miR-107, and miR-195) that regulate gene expression and are modulated by AET on AD and T2D. The identified miRNAs are potential targets to treat the symptoms of AD and T2D. Thus, AET is a non-pharmacological tool that can be used to prevent and fight the negative outcomes in AD and T2D. [ABSTRACT FROM AUTHOR]

Introduction. Chronic inflammation and oxidative stress conditions have been reported in women with polycystic ovary syndrome (PCOS). Peroxiredoxin 4 (Prx4) is a related antioxidant in insulin synthesis. We hypothesized that insulin resistance in these women is associated with total oxidant status (TOS) and inflammatory factors. Materials and Methods. Two hundred three people including 104 PCOS patients and 99 healthy women, who were matched for age and body mass index (BMI), entered the study. Waist circumference of the participants was measured; serum glucose, lipid profile, insulin, Prx4, TOS, hs-CRP, and TNF-α were also evaluated. Results. The Prx4 level was significantly lower in PCOS than in the control group. In addition, marked increase was observed in the concentration of TOS, hs-CRP, and TNF-α in PCOS, compared to the healthy women. There was a positive correlation of TOS with hs-CRP, TNF-α, and HOMA-IR. The risk of PCOS for subjects with high hs-CRP was 60 times greater than those who had low serum hs-CRP concentration; after performing multiple logistic regression analyses with the backward method, TNF-α was considered as an effective biomarker to predict PCOS β = 49.087 (all p < 0.05). Conclusion. This study identified increased oxidative stress and inflammation in PCOS; this may be due to decrease in the antioxidants, such as Prx4. [ABSTRACT FROM AUTHOR]

BACKGROUND: miRNAs have been shown to be closely related to obesity and diabetes, which can be potential biomarkers for the diagnosis and prognosis of diabetes. OBJECTIVE: To review the roles of miRNAs in promoting insulin sensitivity, controlling insulin synthesis and regulating insulin resistance in hypoxic exercise, and to explore the mechanism of hypoxic exercise-mediated miRNAs in regulating glucose metabolism. METHODS: Relevant studies on hypoxic exercise glucose metabolism and miRNAs in PubMed, CNKI, WanFang databases were searched. The keywords were “miRNAs, low oxygen movement, hypoxic exercise, hypoxia-mediated, sugar metabolism, glucose metabolism” in English and Chinese, respectively. Relevant literatures published from 2007 to 2019 were searched and screened according to inclusion and exclusion criteria. RESULTS AND CONCLUSION: miRNAs have the potential to regulate the expression of major protein cascades in the insulin signaling pathway by regulating the expression of target genes and thereby affecting the homeostasis of glucose metabolism. miRNAs can also be used as single molecules or in combination therapy. There is an urgent need to integrate miRNAs into insulin signaling pathways and develop new miRNAs-related diagnostic and therapeutic approaches in hopes of addressing type 2 diabetes in the future. Studying the mechanism of the effects of miRNAs on glucose metabolism in hypoxic exercise can not only provide a theoretical basis for scientific hypoglycemic and body mass control, but also can be used as an intervention for the prevention and control of diseases related to glucose metabolism disorders. Diseases caused by abnormal glucose metabolism provide new therapeutic approaches. [ABSTRACT FROM AUTHOR]

Gestational diabetes mellitus (GDM) is often accompanied by the development of hyperinsulinemia as an adaptation to increased insulin demand, but this subsequently causes insulin resistance. Loss of function in pancreatic β-cells further aggravates the development of GDM. The level of serum platelet-derived growth factor (PDGF) reportedly increases in GDM patients. The present study investigated whether enhanced PDGF signaling directly causes β-cell dysfunction during gestation. Serum PDGF levels were negatively correlated with β-cell function in GDM patients. Administration of PDGF-BB disrupted glucose tolerance and β-cell function without inducing apoptosis in gestational mice but had no similar effect in non-gestational mice. The β-cell-specific genes encoding insulin synthesis proteins were decreased in the islets of PDGF-BB-treated gestational mice. In vitro experiments using INS1 insulinoma cells showed that PDGF-BB promoted cell proliferation, whereas it downregulated β-cell-specific genes. Taken together, these findings suggested that PDGF reduces β-cell function during gestation possibly through β-cell dedifferentiation. • Enhanced PDGF signal causes pancreatic β-cell dysfunction during gestation. • Exogenous PDGF disrupted glucose profile in gestational mice. • Increased PDGF level induces dedifferentiation of β-cells during gestation. [ABSTRACT FROM AUTHOR]

This Editorial highlights an interesting study in the current issue of the Journal of Neurochemistry in which Zhou et al. report new data showing that the ablation of serine racemase increases local insulin production in neurons of the hippocampus. The authors explored some of the possible mechanisms mediating the interaction between dampening production of D‐serine and the local synthesis of insulin, and they further propose that stimulating insulin production could counteract hippocampal insulin resistance in Alzheimer's disease (AD). Most importantly, they leave open a number of questions that need to be experimentally addressed to ascertain whether D‐serine modulation of neuronal insulin expression can effectively improve insulin sensitivity in AD, as well as in metabolic disease with neurological impact. [ABSTRACT FROM AUTHOR]

Hydrogels with an increased content of fine pores are synthesized via the copolymerization of acrylamide with N-(2-D-glucose) acrylamide and N,N-methylenebis(acrylamide) in the presence of concanavalin A and mercaptoacetic acid. Insulin introduced into the hydrogels is spontaneously released in response to increase in the concentration of glucose in the environment via a two-step mechanism similar to that in the case of the pancreas and the maximum rate is observed at the first stage. [ABSTRACT FROM AUTHOR]

Low-grade inflammation is seen with obesity and is suggested to be a mediator of insulin resistance. The eliciting factor of low-grade inflammation is unknown but increased permeability of gut bacteria-derived lipopolysaccharides (LPS) resulting in endotoxemia could be a candidate. Here we test the effect of LPS and the anti-inflammatory compound resveratrol on glucose homeostasis, insulin levels and inflammation. Mice were subcutaneously implanted with osmotic mini pumps infusing either low-dose LPS or saline for 28 days. Half of the mice were treated with resveratrol delivered through the diet. LPS caused increased inflammation of the liver and adipose tissue (epididymal and subcutaneous) together with enlarged spleens and increased number of leukocytes in the blood. Resveratrol specifically reduced the inflammatory status in epididymal fat (reduced expression of TNFa and Il1b, whereas the increased macrophage infiltration was unaltered) without affecting the other tissues investigated. By LC-MS, we were able to quantitate resveratrol metabolites in epididymal but not subcutaneous adipose tissue. LPS induced insulin resistance as the glucose-stimulated insulin secretion during an oral glucose tolerance test was increased despite similar plasma glucose level resulting in an increase in the insulinogenic index (IGI; delta0-15insulin / delta0-15glucose) from 13.73 to 22.40 pmol/mmol (P < 0.001). This aberration in insulin and glucose homeostasis was normalized by resveratrol. In conclusion: Low-dose LPS enhanced the glucose-stimulated insulin secretion without affecting the blood glucose suggesting increased insulin resistance. Resveratrol restored LPS-induced alteration of the insulin secretion and demonstrated anti-inflammatory effects specifically in epididymal adipose tissue possibly due to preferential accumulation of resveratrol metabolites pointing towards a possible important involvement of this tissue for the effects on insulin resistance and insulin secretion. [ABSTRACT FROM AUTHOR]

Background: The goal of the present study was to explore the correlations of 1,5-anhydroglucitol (l,5-AG), glycated hemoglobin (HbA1c), and glycated albumin (GA) with insulin sensitivity and secretion. Subjects and Methods: In total, 302 patients with newly diagnosed type 2 diabetes mellitus (166 men, 136 women) were enrolled in this study. The homeostasis model assessment for insulin resistance (HOMA-IR) and homeostasis model assessment for β-cell function (HOMA-β) were calculated to determine the basal insulin sensitivity and secretion. The insulinogenic index (IGI) was used to evaluate early-phase insulin secretion. 1,5-AG and GA were assayed via the enzymatic method, and HbA1c was detected by high-pressure liquid chromatography. Results: Among all 302 subjects, the serum 1,5-AG level was 13.1±7.2 μg/mL, and the HbA1c and GA levels [median (interquartile range)] were 6.7% (6.2-7.3%) and 17.7% (16.0-19.5%), respectively. Increased 1,5-AG quartiles were accompanied by trends toward a decreased HOMA-IR and an increased HOMA-β and IGI (for all trends, P<0.001). 1,5-AG was negatively associated with HOMA-IR ( r=−0.200, P<0.001) and positively associated with HOMA-β and IGI ( r=0.210 and 0.413, respectively; both P<0.001). 1,5-AG was independently related to HOMA-IR and HOMA-β and exhibited an independent positive association with IGI (standardized β=0.242, P<0.001). Additionally, both HbA1c and GA were independently correlated with HOMA-IR and HOMA-β. Conclusions: 1,5-AG is not only correlated with basal insulin sensitivity and secretion, but also closely associated with early-phase insulin secretion in Chinese patients with newly diagnosed type 2 diabetes mellitus. [ABSTRACT FROM AUTHOR]

Background: Increasing evidence indicates that long noncoding RNAs (IncRNAs) perform specific biological functions in diverse processes. Recent studies have reported that IncRNAs may be involved in β cell function. The aim of this study was to characterize the role of IncRNA TUG1 in mouse pancreatic β cell functioning both in vitro and in vivo. Methods: qRT-PCR analyses were performed to detect the expression of lncRNA TUG1 in different tissues. RNAi, MTT, TUNEL and Annexin V-FITC assays and western blot, GSIS, ELISA and immunochemistry analyses were performed to detect the effect of lncRNA TUG1 on cell apoptosis and insulin secretion in vitro and in vivo. Results: lncRNA TUG1 was highly expressed in pancreatic tissue compared with other organ tissues, and expression was dynamically regulated by glucose in Nit-1 cells. Knockdown of lncRNA TUG1 expression resulted in an increased apoptosis ratio and decreased insulin secretion in β cells both in vitro and in vivo . Immunochemistry analyses suggested decreased relative islet area after treatment with lncRNA TUG1 siRNA. Conclusion: Downregulation of lncRNA TUG1 expression affected apoptosis and insulin secretion in pancreatic β cells in vitro and in vivo. lncRNA TUG1 may represent a factor that regulates the function of pancreatic β cells. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Summary Background Posttraumatic stress disorder (PTSD) is associated with a 2–4 fold increased risk of developing Type 2 diabetes mellitus. However, detailed assessments of glucose metabolism and insulin secretion in a study designed to minimize confounders are lacking. Furthermore, few studies examine potential mechanisms involved. We analyzed data from a case–control study of medically healthy, medication-free adults to determine whether individuals with PTSD had abnormal glucose or insulin response to oral glucose tolerance test (OGTT) compared to controls. Secondarily, we assessed potential mediators such as sleep, cortisol and adiponectin. Methods Data was analyzed from 92 age and gender-matched subjects (44 PTSD, 48 controls). Chronic PTSD was diagnosed using the Structured Clinical Interview for DSM-IV and Clinician Administered PTSD Scale. Subjects underwent 75-g OGTT, actigraphy and sleep diary (to quantify sleep duration), polysomnography (to assess slow wave sleep [SWS] and delta power), and overnight blood sampling (for cortisol and adiponectin). Results At baseline, individuals with PTSD had mildly increased insulin levels (by 19%, compared to controls, p = 0.048) that was mediated primarily by weight. In response to OGTT, the PTSD group had higher levels of insulin at 120 min (by 44%, p = 0.03) and insulin AUC (by 43%, p = 0.015) compared to controls, after adjusting for confounders. Glucose levels were similar in the two groups. Although self-reported sleep duration, SWS, and delta power differed between PTSD subjects and controls, they did not mediate the effects of PTSD status on insulin response. Conclusion In this case–control study, individuals with PTSD had a hyperinsulinemic response to oral glucose challenge compared to controls, suggestive of insulin resistance. [ABSTRACT FROM AUTHOR]

We have previously shown that insulin plays an important role in the nutrient-induced insulin resistance. In this study, we tested the hypothesis that chronic exposure to excess long-acting insulin (glargine) can cause typical type 2 diabetes mellitus (T2DM) in normal mice fed on a chow diet. C57BL/6 mice were treated with glargine once a day for 8 weeks, followed by evaluations of food intake, body weight, blood levels of glucose, insulin, lipids, and cytokines, insulin signaling, histology of pancreas, ectopic fat accumulation, oxidative stress level, and cholesterol content in mitochondria in tissues. Cholesterol content in mitochondria and its association with oxidative stress in cultured hepatocytes and b-cells were also examined. Results show that chronic exposure to glargine caused insulin resistance, hyperinsulinemia, and relative insulin deficiency (T2DM). Treatment with excess glargine led to loss of pancreatic islets, ectopic fat accumulation in liver, oxidative stress in liver and pancreas, and increased cholesterol content in mitochondria of liver and pancreas. Prolonged exposure of cultured primary hepatocytes and HIT-TI5 β-cells to insulin induced oxidative stress in a cholesterol synthesis-dependent manner. Together, our results show that chronic exposure to excess insulin can induce typical T2DM in normal mice fed on a chow diet. [ABSTRACT FROM AUTHOR]

Aim: This randomized, double-blind, placebo-controlled parallel-group study assessed the effects of sodium glucose cotransporter 2 inhibition by dapagliflozin on insulin sensitivity and secretion in subjects with type 2 diabetes mellitus (T2DM), who had inadequate glycemic control with metformin (with or without an insulin secretagogue). Subjects and Methods: Forty-four subjects were randomized to receive dapagliflozin 5 mg or matching placebo once daily for 12 weeks. Subjects continued stable doses of background antidiabetes medication throughout the study. Insulin sensitivity was assessed by measuring the glucose disappearance rate (GDR) during the last 40 min of a 5-h hyperinsulinemic, euglycemic clamp. Insulin secretion was determined as the acute insulin response to glucose (AIRg) during the first 10 min of a frequently sampled intravenous glucose tolerance test. Where noted, data were adjusted for baseline values and background antidiabetes medication. Results: An adjusted mean increase from baseline in GDR (last observation carried forward), at Week 12, was observed with dapagliflozin (7.98%) versus a decrease with placebo (−9.99%). The 19.97% (95% confidence interval 5.75-36.10) difference in GDR versus placebo was statistically significant ( P=0.0059). A change from baseline in adjusted mean AIRg of 15.39 mU/L min was observed with dapagliflozin at Week 12, versus −12.73 mU/L min with placebo ( P=0.0598). Over 12 weeks, numerical reductions from baseline in glycosylated hemoglobin (HbA1c), fasting plasma glucose, and body weight were observed with dapagliflozin (−0.38%, −0.39 mmol/L, and −1.58%, respectively) versus slight numerical increases with placebo (0.03%, 0.26 mmol/L, and 0.62%, respectively). Conclusions: In patients with T2DM and inadequate glycemic control, dapagliflozin treatment improved insulin sensitivity in the setting of reductions in HbA1c and weight. [ABSTRACT FROM AUTHOR]

Growth arrest and DNA damage-inducible 45β (GADD45β) belongs to the GADD45 family which is small acidic proteins in response to cellular stress. GADD45β has already been reported to have excellent capabilities against cancer, innate immunity and neurological diseases. However, there is little information regard GADD45β and non-alcoholic fatty liver disease (NAFLD). In the current work, we found that the expression of GADD45β was markedly decreased in the livers of NAFLD patients via analyzing Gene Expression Omnibus (GEO) dataset and in mouse model through detecting its mRNA in high-fat-high-fructose diet (HFHFr)-fed mice. Moreover, the results from in vivo experiment demonstrated that overexpression of GADD45β by AAV8-mediated gene transfer in HFHFr-fed mouse model could reduce the level of serum and hepatic triglyceride (TG), and alleviate insulin resistance. Subsequently, by combining immunoprecipitation (IP) and mass spectrometry, we identified that HSP72 directly interacted with GADD45β to prevent GADD45β from being degraded by the proteasome pathway. Finally, the benefits of GADD45β in regulating key factors of TG synthesis and insulin signaling pathway were abolished after HSP72 knockdown. In conclusion, GADD45β stabilized by the interaction with HSP72 could alleviate the NAFLD-related pathologies, suggested it might be a potential target for the treatment of NAFLD. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among premenopausal women, who often develop insulin resistance. We tested the hypothesis that insulin resistance in skeletal muscle of patients with polycystic ovary syndrome (PCOS) is an intrinsic defect, by investigating the metabolic characteristics and gene expression of in vitro differentiated myotubes established from well characterized PCOS subjects. Methods: Using radiotracer techniques, RT-PCR and enzyme kinetic analysis we examined myotubes established from PCOS subjects with or without pioglitazone treatment, versus healthy control subjects who had been extensively metabolically characterized in vivo. Results Myotubes established from PCOS and matched control subjects comprehensively expressed all insulin-sensitive biomarkers; glucose uptake and oxidation, glycogen synthesis and lipid uptake. There were no significant differences between groups either at baseline or during acute insulin stimulation, although in vivo skeletal muscle was insulin resistant. In particular, we found no evidence for defects in insulin-stimulated glycogen synthase activity between groups. Myotubes established from PCOS patients with or without pioglitazone treatment also showed no significant differences between groups, neither at baseline nor during acute insulin stimulation, although in vivo pioglitazone treatment significantly improved insulin sensitivity. Consistently, the myotube cultures failed to show differences in mRNA levels of genes previously demonstrated to differ in PCOS patients with or without pioglitazone treatment (PLEK, SLC22A16, and TTBK). Conclusion: These results suggest that the mechanisms governing insulin resistance in skeletal muscle of PCOS patients in vivo are not primary, but rather adaptive. Trial Registration: ClinicalTrials.gov NCT00145340 [ABSTRACT FROM AUTHOR]

Abstract: Recent evidence indicates that decreased oxidative capacity, lipotoxicity, and mitochondrial aberrations contribute to the development of insulin resistance and type 2 diabetes. The goal of this study was to investigate the effects of peroxisome proliferator-activated receptor δ (PPARδ) activation on lipid oxidation, mitochondrial function, and insulin secretion in pancreatic β-cells. After HIT-T15 cells (a β-cell line) were exposed to high concentrations of palmitate and GW501516 (GW; a selective agonist of PPARδ), we found that administration of GW increased the expression of PPARδ mRNA. GW-induced activation of PPARδ up-regulated carnitine palmitoyltransferase 1 (CPT1), long-chain acyl-CoA dehydrogenase (LCAD), pyruvate dehydrogenase kinase 4 (PDK4), and uncoupling protein 2 (UCP2); alleviated mitochondrial swelling; attenuated apoptosis; and reduced basal insulin secretion induced by increased palmitate in HIT cells. These results suggest that activation of PPARδ plays an important role in protecting pancreatic β-cells against aberrations caused by lipotoxicity in metabolic syndrome and diabetes. [Copyright &y& Elsevier]

OBJECTIVE -- The Indian Diabetes Prevention Programme-1 (IDPP-1) showed that lifestyle modification (LSM) and metformin were effective for primary prevention of diabetes in subjects with impaired glucose tolerance (IGT). Among subjects followed up for 3 years (n = 502), risk reductions versus those for the control group were 28.5, 26.4, and 28.2% in LSM, metformin (MET), and LSM plus MET groups, respectively. In this analysis, the roles of changes in secretion and action of insulin in improving the outcome were studied. RESEARCH DESIGN AND METHODS-- For this analysis, 437 subjects (93 subjects with normoglycemia [NGT], 150 subjects with IGT, and 194 subjects with diabetes) were included. Measurements of anthropometry, plasma glucose, and plasma insulin at baseline and at follow-up were available for all of them. Indexes of insulin resistance (homeostasis model assessment of insulin resistance) and β-cell function (insulinogenic index [ΔI/G]: 30-min fasting insulin divided by 30-min glucose) were also analyzed in relation to the outcome. RESULTS -- Subjects with IGT showed a deterioration in R-cell function with time. Individuals with higher insulin resistance and/or low β-cell function at baseline had poor outcome on follow-up. In relation to no abnormalities, the highest incidence of diabetes occurred when both abnormalities coexisted (54.9 vs. 33.7%, χ² = 7.53, P = 0.006). Individuals having abnormal insulin resistance (41.1%) or abnormal ΔI/G (51.2%, χ² = 4.87, P = 0.027 vs. no abnormalities) had lower incidence. Normal β-cell function with improved insulin sensitivity facilitated reversal to NGT, whereas deterioration in both resulted in diabetes. The beneficial changes were better with intervention than in the control group. Intervention groups had higher rates of NGT and lower rates of diabetes. CONCLUSIONS-- In the IDPP-1 subjects, beneficial outcomes occurred because of improved insulin action and sensitivity caused by the intervention strategies. [ABSTRACT FROM AUTHOR]

In addition to its primary role in regulating glucose production from the liver, glucagon has many other actions, reflected by the wide tissue distribution of the glucagon receptor (Gcgr). To investigate the role of glucagon in the regulation of insulin secretion and whole body glucose homeostasis in vivo, we generated mice overexpressing the Gcgr specifically on pancreatic β-cells (RIP-Gcgr). In vivo and in vitro insulin secretion in response to glucagon and glucose was increased 1.7- to 3.9-fold in RIP-Gcgr mice compared with controls. Consistent with the observed increase in insulin release in response to glucagon and glucose, the glucose excursion resulting from both a glucagon challenge and intraperitoneal glucose tolerance test (IPGTT) was significantly reduced in RIP-Gcgr mice compared with controls. However, RIP-Gcgr mice display similar glucose responses to an insulin challenge. β-Cell mass and pancreatic insulin content were also increased (20 and 50%, respectively) in RIP-Gcgr mice compared with controls. When fed a high-fat diet (HFD), both control and RIP-Gcgr mice developed similar degrees of obesity and insulin resistance. However, the severity of both fasting hyperglycemia and impaired glucose tolerance (lOT) were reduced in RIP-Gcgr mice compared with controls. Furthermore, the insulin response of RIPGcgr mice to an TPGTT was twice that of controls when fed the HFD. These data indicate that increased pancreatic β-cell expression of the Ocgr increased insulin secretion, pancreatic insulin content, β-cell mass, and, when mice were fed a HFD, partially protected against hyperglycemia and IGT. [ABSTRACT FROM AUTHOR]

Abstract: Uncoupling protein 2 (UCP2) was reported to be involved in insulin–glucose homeostasis, based on well established event that inhibition of UCP2 stimulates insulin secretion in pancreatic β-cells. However, the role of UCP2 on insulin-stimulated glucose uptake in adipose tissue, which is an indispensable process in insulin–glucose homeostasis, remains unknown. In this study, UCP2 was inhibited by genipin in 3T3-L1 adipocytes, which increased mitochondrial membrane potential, intracellular ATP level and production of reactive oxygen species (ROS). Importantly, insulin-stimulated glucose uptake in 3T3-L1 adipocytes was largely impaired in the presence of genipin, and recovered by CCCP, a mitochondrial uncoupler. Furthermore, genipin leaded to suppression of insulin signal transduction through hyperactivation of c-Jun N-terminal kinase (JNK) and subsequent serine phosphorylation of insulin receptor substrate-1 (IRS-1). These results suggest that mitochondrial uncoupling in adipocytes positively regulates insulin-stimulated glucose uptake in adipocytes, and UCP2 may play an important role in insulin resistance. [Copyright &y& Elsevier]

Recent data have shown that individuals with low insulin sensitivity (SO also have reduced whole body maximal oxygen uptake. The objectives of this study were to determine 1) whether muscle mitochondrial function was independently related to SI after being adjusted for known determinants of SI and 2) whether lower SI among African-American (AA) vs. Caucasian-American (CA) women was due to lower muscle mitochondrial function among AA women. Subjects were 37 CA and 22 AA premenopausal women (age: 33.6 ± 6.3 yr). Mitochondrial function [time constant of ADP (ADPtc)] was assessed during a 90-s unilateral isometric contraction using 31p magnetic resonance spectroscopy, S1 with an intravenous glucose tolerance test, body composition by dual-energy X-ray absorptiometry, and visceral adipose tissue (VAT) with computed tomography. ANOVA was used to compare AA and CA groups, and multiple linear regression modeling was used to identify independent predictors of SI. Between-race comparisons indicated that muscle oxidative capacity was lower among AAs vs. CAs (ADPtc: 25.6 ± 9.8 vs. 21.4 ± 9.9 s). Multiple linear regression models for the dependent variable S1 contained 1) VAT and race and 2) VAT, race, and ADPtc. Significant independent effects for all predictor variables were observed in both the first (r² = 0.345) and second (r² = 0.410) models. The partial correlation for race was lower in the second model (-0.404 vs. -0.300), suggesting that muscle mitochondrial function contributed to the racial difference in SI. Lower muscle mitochondrial function among AAs may in part explain lower SI among them. [ABSTRACT FROM AUTHOR]

Background: Impaired insulin secretion (IS) and insulin resistance (IR) play an essential role in the pathogenesis of type 2 diabetes mellitus. Several simplifying indices were developed that calculate IS and/or IR from venous insulin and glucose concentrations. The aim of the present study was to compare these indices with each other and with regard to their efficiency to differentiate between non-diseased and diabetic glucose tolerance states. Methods: Oral glucose tolerance tests were performed in 301 subjects. The study group was divided into five groups according to WHO/American Diabetes Association (ADA) cut-off values: apparently normotolerant, diabetic, isolated 2-h post-challenge hyperglycemic, isolated fasting hyperglycemic and intermediate groups. The minimal error rate (diagnostic non-efficiency) indicating a misclassification of a diabetic tolerance state was determined for 12 indices. Results: The error rate was lower than 15% for the index of Cederholm and Wibell and for the indices of Stumvoll et al. The misclassification rates for the other indices (index of Matsuda and de Fronzo, index of Myllynen et al., HOMA IR, HOMA β-cell, FIRI, QUICKI, index of McAuley and insulinogenic index) were 20–27%; however, the diagnostic sensitivity was close to a 1:1 chance of a correct decision. The hypothesis that isolated post-prandial hyperglycemia (IPH) and isolated fasting hyperglycemia (IFH) differ in their insulin sensitivity and insulin response could not be supported by the present results. Conclusions: The indices of Cederholm and Wibell and of Stumvoll et al. were found to be appropriate as diagnostic indicators of the pathogenesis of diabetic glucose tolerance and were more closely related to the glucose tolerance state than the other indices. Clin Chem Lab Med 2006;44:817–23. [ABSTRACT FROM AUTHOR]

Protein targeting to glycogen (PTG) is a scaffolding protein that targets protein phosphatase 1alpha (PP1alpha) to glycogen, and links it to enzymes involved in glycogen synthesis and degradation. We generated mice that possess a heterozygous deletion of the PTG gene. These mice have reduced glycogen stores in adipose tissue, liver, heart, and skeletal muscle, corresponding with decreased glycogen synthase activity and glycogen synthesis rate. Although young PTG heterozygous mice initially demonstrate normal glucose tolerance, progressive glucose intolerance, hyperinsulinemia, and insulin resistance develop with aging. Insulin resistance in older PTG heterozygous mice correlates with a significant increase in muscle triglyceride content, with a corresponding attenuation of insulin receptor signaling. These data suggest that PTG plays a critical role in glycogen synthesis and is necessary to maintain the appropriate metabolic balance for the partitioning of fuel substrates between glycogen and lipid. [ABSTRACT FROM AUTHOR]

The expression of 47 genes involved in the biosynthesis and secretion of insulin, apoptosis, and cellular stress was evaluated in isolated human islets using cDNA probes arrayed on nitrocellulose membranes. Isolated human islets were cultured for four days, or one month, with glucose present at a concentration of either 5.5 or 16.7 mmol/L. Extracted islet total RNA was used to generate [32P]dATP-labelled complex cDNA targets and hybridised with immobilised cDNA arrays. The positive expression of 45 mRNA transcripts in isolated human islets was documented. The coefficient of variance for relative levels of expression of transcripts was <25% for 9, 25–50% for 22, and 50–100% for 10, indicating good reproducibility between islet preparations from five different human pancreas donors. This study demonstrates the utility of nitrocellulose-based cDNA arrays for a focused reproducible analysis of gene expression changes in human islets of Langerhans. [Copyright &y& Elsevier]

Type 2 Diabetes Mellitus (T2DM), one of the most common metabolic disorders, is caused by a combination of two primary factors: defective insulin secretion by pancreatic β-cells and the inability of insulin-sensitive tissues to respond appropriately to insulin. Because insulin release and activity are essential processes for glucose homeostasis, the molecular mechanisms involved in the synthesis and release of insulin, as well as in its detection are tightly regulated. Defects in any of the mechanisms involved in these processes can lead to a metabolic imbalance responsible for the development of the disease. This review analyzes the key aspects of T2DM, as well as the molecular mechanisms and pathways implicated in insulin metabolism leading to T2DM and insulin resistance. For that purpose, we summarize the data gathered up until now, focusing especially on insulin synthesis, insulin release, insulin sensing and on the downstream effects on individual insulin-sensitive organs. The review also covers the pathological conditions perpetuating T2DM such as nutritional factors, physical activity, gut dysbiosis and metabolic memory. Additionally, because T2DM is associated with accelerated atherosclerosis development, we review here some of the molecular mechanisms that link T2DM and insulin resistance (IR) as well as cardiovascular risk as one of the most important complications in T2DM. [ABSTRACT FROM AUTHOR]

Background:Insulin-resistance is commonly found in adrenal incidentaloma (AI) patients. However, little is known about beta-cell secretion in AI, because comparisons are difficult, since beta–cell-function varies with altered insulin-sensitivity. Objectives:To retrospectively analyze beta–cell function in non-diabetic AI, compared to healthy controls (CON). Methods:AI (n=217, 34%males, 57±1years, body-mass-index:27.7±0.3kg/m2) and CON [n=25, 32%males, 56±1years, 26.7±0.8kg/m2] with comparable anthropometry (p≥0.31) underwent oral-glucose-tolerance-tests (OGTTs) with glucose, insulin, and C–peptide measurements. 1mg-dexamethasone-suppression-tests were performed in AI. AI were divided according to post–dexamethasone-suppression–test cortisol-thresholds of 1.8 and 5µg/dL into 3subgroups: pDexa<1.8µg/dL, pDexa1.8-5µg/dL and pDexa>5µg/dL. Using mathematical modeling, whole-body insulin-sensitivity [Clamp-like-Index (CLIX)], insulinogenic Index, Disposition Index, Adaptation Index, and hepatic insulin extraction were calculated. Results:CLIX was lower in AI combined (4.9±0.2mg·kg-1·min-1), pDexa<1.8µg/dL (4.9±0.3) and pDexa1.8-5µg/dL (4.7±0.3, p<0.04 vs.CON:6.7±0.4). Insulinogenic and Disposition Indexes were 35%–97% higher in AI and each subgroup (p<0.008 vs.CON), whereas C–peptide–derived Adaptation Index, compensating for insulin-resistance, was comparable between AI, subgroups, and CON. Mathematical estimation of insulin–derived (insulinogenic and Disposition) Indexes from associations to insulin-sensitivity in CON revealed that AI-subgroups had ~19%-32% higher insulin-secretion than expectable. These insulin-secretion-index differences negatively (r=-0.45, p<0.001) correlated with hepatic insulin extraction, which was 13-16% lower in AI and subgroups (p<0.003 vs.CON). Conclusions:AI-patients show insulin-resistance, but adequately adapted insulin secretion with higher insulin concentrations during an OGTT, because of decreased hepatic insulin extraction; this finding affects all AI-patients, regardless of dexamethasone-suppression-test outcome. [ABSTRACT FROM AUTHOR]