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Abnormal glucose homeostasis is linked to a variety of metabolic syndromes, such as insulin resistance, obesity, type-2 diabetes mellitus, hypertension and cardiovascular diseases. Maintenance of normal glucose homeostasis is important for the body to keep normal biological functions. As the major bioactive ingredient in chili peppers responsible for the pungent flavor, capsaicin has been reported to effectively improve glucose homeostasis with low cytotoxicity. In this review, the modulating effects of capsaicin on glucose homeostasis in cell models, animal models and human trials are summarized through both TRPV1 dependent and TRPV1 independent pathways. The relevant molecular mechanisms underlying its regulatory effects are also evaluated. Understanding the effects and mechanisms of capsaicin on glucose metabolism could provide theoretical evidence for its application in the food and pharmaceutical industries.

Purpose Increasing evidence shows that many metabolic factors are involved in the progression of benign prostatic hyperplasia (BPH). We aimed to assess the relationship between the status of glucose homeostasis and prostate size in aging Chinese males undergoing transurethral resection of the prostate (TURP) for BPH. Methods A total of 1006 medical records of BPH patients undergoing TURP were reviewed. Prostate size was measured by transrectal ultrasound. Annual total prostate (TP) and transitional zone (TZ) growth rates were calculated. According to the American Diabetes Association criteria, the patients were categorized as normoglycemic, prediabetic, or diabetic. Levels of glucose homeostasis and other variables were considered independent variables in an effort to evaluate any potential correlations using non-adjusted and multivariate-adjusted regression models. Results A total of 659 individuals were included in the study. BPH patients Conclusions Among patients undergoing TURP, the prostate volume and growth rate were affected by different status of glucose homeostasis. Hyperglycemia may play an important role in prostate growth.

Physiologic adaptations in the postnatal period, along with gradual establishment of enteral feeding, help maintain plasma glucose concentrations in the neonatal period. The definition of normal plasma glucose in the neonatal period has been a subject of debate because of a lack of evidence linking a set plasma or blood glucose concentration to clinical symptoms or predictors of short- and long-term outcomes. However, there is consensus that maintaining plasma glucose in the normal range for age is important to prevent immediate and long-term neurodevelopmental consequences of hypoglycemia or hyperglycemia. The specific management strategy for abnormal glucose levels in neonates depends on the underlying etiology, and interventions could include nutritional changes, medications, hormone therapy, or even surgery. Here, we will review the physiological processes that help maintain plasma glucose in newborns and discuss the approach to a newborn with disordered glucose homeostasis, with an emphasis on the endocrine basis of abnormal glucose homeostasis.

Purpose: To determine the prevalence and underlying pathology of abnormal glucose homeostasis in Chinese patients with non-transfusion-dependent thalassemia (NTDT). Patients and methods: In this study, we enrolled 211 patients aged 4-63 years with NTDT, including 79 β thalassemia intermedia patients, 114 Hb H disease patients and 18 Hb E/β thalassemia patients. All had oral glucose tolerance test, serum ferritin (SF), homeostasis model assessment (HOMA) and liver iron concentration (LIC) measurement. One hundred and twenty healthy age-matched controls were also used for the comparative purpose. Iron load was assessed by using SF and hepatic load by LIC using validated MRI techniques. Results: The 211 patients were divided into three groups according to their fasting and 2 hrs postprandial blood glucose levels: hypoglycemic, normal glucose tolerance (NGT) and hyperglycemic groups. In this study, 149 patients had NGT, 33 had hypoglycemia, 4 had diabetes and 25 had impaired glucose tolerance (IGT). None had impaired fasting glucose. There was a significant correlation between 2 hrs postprandial blood glucose levels and age, PINS120, HOMA-IR, alanine aminotransferase and LIC (P

Findings of observational studies that investigated the relationship between vitamin D deficiency and abnormal glucose homeostasis were contradictory. This meta-analysis of epidemiologic studies evaluated the association of vitamin D status and risk of type-2 diabetes (T2D) and prediabetes in adults. A systematic search was conducted on all published articles in five electronic databases (including MEDLINE/PubMed, EMBASE, Institute for Scientific Information, Scopus and Google scholar), up to August 2020. Twenty-eight prospective cohort and nested case-control studies and 83 cross-sectional and case-control investigations that reported relative risks (RRs) or odds ratios (ORs) with 95% confidence intervals (CIs) for abnormal glucose homeostasis in relation to serum vitamin D levels in adults were included in the analysis. In prospective studies, high versus low level of vitamin D was respectively associated with significant 35%, 30% and 51% decrease in risk of T2D (RR:0.65; 95%CI: 0.55–0.76; 27 effect sizes), combined T2D and pre-diabetes (RR:0.70; 95%CI: 0.52–0.95; 9 effect sizes) and pre-diabetes (RR:0.49; 95%CI: 0.26–0.93; 2 effect sizes). These inverse associations were significant in almost all subgroups. Dose–response analysis in prospective studies showed that each 10 ng/ml increase in serum vitamin D levels resulted in 12% and 11% reduced risk of T2D (RR:0.88; 95%CI: 0.83–0.94) and combined T2D and prediabetes (RR:0.89; 95%CI: 0.87–0.92), respectively. In cross-sectional and case-control studies, highest versus lowest level of serum vitamin D was linked to reduced odds of T2D (OR:0.64; 95%CI: 0.57–0.72; 42 effect sizes) and combined T2D and pre-diabetes (OR:0.79; 95%CI: 0.74–0.85; 59 effect sizes); but not pre-diabetes (OR:0.64; 95%CI: 0.17–2.37; 11 effect sizes). This meta-analysis of epidemiologic studies disclosed that serum vitamin D level was reversely associated with the risk of T2D and combined T2D and prediabetes in adults, in a dose–response manner. However, the association was not remarkable for pre-diabetes.

Purpose of review Individuals with type 2 diabetes (T2D) are at increased risk of fracture, often despite normal bone density. This observation suggests deficits in bone quality in the setting of abnormal glucose homeostasis. The goal of this article is to review recent developments in our understanding of how advanced glycation end products (AGEs) are incorporated into the skeleton with resultant deleterious effects on bone health and structural integrity in patients with T2D. Recent findings The adverse effects of skeletal AGE accumulation on bone remodeling and the ability of the bone to deform and absorb energy prior to fracture have been demonstrated both at the bench as well as in small human studies; however, questions remain as to how these findings might be better explored in large, population-based investigations. Summary Hyperglycemia drives systemic, circulating AGE formation with subsequent accumulation in the bone tissue. In those with T2D, studies suggest that AGEs diminish fracture resistance, though larger clinical studies are needed to better define the direct role of longstanding AGE accumulation on bone strength in humans as well as to motivate potential interventions to reverse or disrupt skeletal AGE deposition with the goal of fracture prevention.

on the level of inflammatory cytokines following vitamin D supplementation among individuals with abnormal glucose homeostasis (AGH) are controversial. Therefore, the present study was conducted on AGH patients to assess the impact of vitamin D on inflammatory cytokines such as CRP, TNF-α and IL-6. A systematic search up to September 2020 was performed through PubMed and Scopus databases. All clinical studies which evaluated the effect of oral vitamin D supplementation on inflammation in patients with AGH were included. The random-effects model was applied to obtain pooled results. For dose-response analysis, we used a fractional polynomial model. Overall, 38 studies, with 46 effect sizes, were included in this study. Combining effect sizes, we found that vitamin D considerably decrease serum concentrations of CRP (weight mean difference (WMD): - 0.67 mg/l; 95%CI: - 0.92, - 0.43; P 0.001), IL-6 (WMD: -1.93 pg/mL; 95%CI: -2.80, -1.07; P 0.001) and TNF-α (WMD: -0.81 pg/mL; 95%CI: -1.59, -0.03; P = 0.04). In the dose-response analysis, we failed to find any correlation between dosage of supplements and inflammatory biomarkers concentrations. Summarizing earlier studies, we demonstrated that circulating concentrations of inflammatory cytokines such as CRP, TNF-α, and IL-6 might be decreased following vitamin D supplementation among individuals with AGH.

Hyperglycaemia first detected during pregnancy is either gestational diabetes mellitus (GDM) or previous undiagnosed diabetes. We aimed to study if there were a first trimester fasting glycaemia (FTG) and a glycated haemoglobin (HbA1c) cut-off values associated with type 2 diabetes mellitus (T2DM) or abnormal glucose homeostasis (AGH) at the post-partum oral glucose tolerance test (OGTT) reclassification. We retrospectively studied a group of pregnant women from the Portuguese National Registry of GDM. Receiver-operating characteristic (ROC) curves were used to determine the best FTG and HbA1c cut-offs to predict T2DM and AGH. We studied 4068 women. The area under the ROC curves (AUC) for the association with T2DM was 0.85 (0.80–0.90) for FTG and 0.85 (0.80–0.91) for HbA1c. The best FTG cut-off for association with T2DM was 99 mg/dL: sensitivity 77.4%, specificity 74.3%, positive predictive value (PPV) 4.8%, and negative predictive value (NPV) 99.5%. The best HbA1c cut-off for association with T2DM was 5.4%: sensitivity 79.0%, specificity 80.1%, PPV 5.7%, and NPV 99.6%. The AUC for the association of FTG and HbA1c with AGH were 0.73 (0.70–0.76) and 0.71 (0.67–0.74), respectively. The best FTG cut-off for predicting AGH was 99 mg/dL: sensitivity 59.4%, specificity 76.2%, PPV 17.0%, and NPV 95.8%. The best HbA1c cut-off was 5.4%: sensitivity 48.7%, specificity 81.5%, PPV 17.8%, and NPV 95.1%. We suggest an FTG of 99 mg/dL and an HbA1c of 5.4% as the best cut-offs below which T2DM is unlikely to be present. Almost all patients with FTG

Background Humans are widely exposed to environmental perfluoroalkyl substances (PFAS), which may affect glucose homeostasis. However, research linking PFAS exposure to glucose homeostasis during pregnancy is limited and the results were inconsistent. We aimed to investigate the association between PFAS exposure and glucose homeostasis in pregnancy in a large prospective cohort. Methods A total of 2747 pregnant women who participated in the Shanghai Birth Cohort, had blood samples in early pregnancy and completed a 75 g oral glucose tolerance test (OGTT) at 24–28 gestational weeks were included. 10 PFAS were determined by high-performance liquid chromatography/tandem mass spectrometry (HPLC/MS-MS) in the plasma samples in early pregnancy. Logistic regression was used to explore the associations between PFAS concentrations and gestational diabetes mellitus (GDM), while multiple linear regression was used to model the associations between PFAS and OGTT fasting, 1-h and 2-h glucose levels. Potential confounders were adjusted. Bayesian kernel machine regression (BKMR) and a quantile-based g-computation approach (qgcomp) were employed to explore the joint and independent effects of PFAS on glucose homeostasis. Results The incidence of GDM was 11.8%. One log-unit increment in plasma concentrations in early pregnancy was associated with an increased risk of GDM for perfluorobutane sulfonate (PFBS) (adjusted odd ratio (aOR) = 1.23, 95% confidence interval (95% CI): 1.05, 1.44) and perfluoroheptanoic acid (PFHpA) (aOR = 1.25, 95% CI: 1.07, 1.46). Perfluorooctane sulfonic acid (PFOS), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluorohexanesulfonate (PFHxS) and PFHpA were positively correlated with 1-h and 2-h glucose levels. Results of the mixed exposure model showed that the joint effects of PFAS were significantly associated with abnormal glucose homeostasis; In the BKMR model, PFAS mixture exposure was positively associated with the GDM incidence, 1-h and 2-h glucose levels and negatively correlated with FBG level. A similar trend could be observed in qgcomp and the positive correlation between PFAS and 2-h glucose level was significant (β = 0.12, 95% CI: 0.04, 0.20). PFOS, PFNA and PFHpA may be the main contributors after controlling for other PFAS congeners. PFOS was significantly correlated with GDM incidence and 2-h glucose level, and PFHpA was significantly associated with FBG and 2-h glucose levels. The above associations were more prominent among women with a normal prepregnant BMI. Conclusions Environmental exposure to PFAS may affect glucose homeostasis in pregnancy and increase the risk of GDM, especially in normal weight women.

Adiposopathy is a pathological adipose tissue (AT) response to overfeeding characterized by reduced AT expandability due to impaired adipogenesis, which favors inflammation, insulin resistance (IR), and abnormal glucose regulation. However, it is unclear whether defective adipogenesis causes metabolic derangement also independently of an increased demand for fat storage. As galectin-3 has been implicated in both adipocyte differentiation and glucose homeostasis, we tested this hypothesis in galectin-3 knockout (Lgal3−/−) mice fed a standard chow. In vitro, Lgal3−/− adipocyte precursors showed impaired terminal differentiation (maturation). Two-month-old Lgal3−/− mice showed impaired AT maturation, with reduced adipocyte size and expression of adipogenic genes, but unchanged fat mass and no sign of adipocyte degeneration/death or ectopic fat accumulation. AT immaturity was associated with AT and whole-body inflammation and IR, glucose intolerance, and hyperglycemia. Five-month-old Lgal3−/− mice exhibited a more mature AT phenotype, with no difference in insulin sensitivity and expression of inflammatory cytokines versus WT animals, though abnormal glucose homeostasis persisted and was associated with reduced β-cell function. These data show that adipogenesis capacity per se affects AT function, insulin sensitivity, and glucose homeostasis independently of increased fat intake, accumulation and redistribution, thus uncovering a direct link between defective adipogenesis, IR and susceptibility to diabetes.

The link between metabolic disorders during pregnancy and high risk of developing chronic noncommunicable diseases in later life has been well established. However, why the fetuses exposed to GDM have a higher risk of abnormal glucose homeostasis in later life, is still not fully understood. Exosomes have been well characterised in maternal circulation in normal and gestational diabetes pregnancies, however, the little is known about the profile of exosomes in fetal circulation. In this study, we isolated exosomes from cord-blood from women with normal tolerance glucose (NGT, n=35) and GDM (n=40) at the time of delivery. The miRNA content of exosomes was determined using a small RNA sequencing. The levels of circulating exosomes were significantly higher in GDM compared to NGT (p Disclosure V. Ormazabal: None. S. Nair: None. D. Guanzon: None. F. Zuniga: None. D. McIntyre: Other Relationship; Self; Novo Nordisk A/S. M. Lappas: None. C. Salomon: None. Funding Diabetes Australia; Fondo Nacional de Desarrollo Científico y Tecnológico (1170809, 1190522)

BACKGROUND: Cystic fibrosis related diabetes (CFRD) is associated with increased morbidity in CF. Variability in physiological systems is associated with dysfunctional homeostasis. We examined whether fluctuation in glucose is a marker of CFRD or "pre-diabetes". METHODS: Using a machine learning approach, we compared glucose IQR to current diagnostic criteria in a review of continuous glucose monitoring data. RESULTS: Analysis was performed on 248 studies from 142 children. Calculated IQR (cIQR) was increased between children with CFRD, normal glucose homeostasis and indeterminate status (p

Glucose utilization is reduced in vulnerable brain regions affected by neurological disorders, especially Alzheimer's disease (AD), but the basis for abnormal glucose homeostasis is unknown. Studies of brain-bank human tissue have made major contributions to understanding complex aspects of neurological, psychiatric, and neurodegenerative diseases, but they are not appropriate for metabolomic analysis of labile metabolites because postmortem intervals between death and tissue freezing are much too long. Recent reports of postmortem brain glucose levels led to suggestions that AD patients may be hyperglycemic and that elevated brain glucose levels along with reduced glycolytic activity reveal abnormal glucose homeostasis before clinical symptoms become manifest. These conclusions are, however, questioned because virtually all brain glucose is consumed within minutes after death, followed by progressive increases in glucose and amino acid levels, presumably due to autolytic changes. To illustrate pitfalls in use of autopsy material for metabolomic assays of labile metabolites, data from living human brain are compared with those from autopsy samples, and metabolism at the onset of postmortem ischemia is compared with calculated glycolytic enzyme activities. Postmortem glucose levels range from extremely low to unrealistically high, precluding their extrapolation to living brain. Indirect evaluation of glycolytic enzyme activities in postmortem AD brain is not valid because the glucose and amino acid concentrations used in the calculations are not stable after death, and reported values are unrealistically high. Specific recommendations are provided for non-invasive longitudinal monitoring of brain metabolism and metabolite levels in patients with neurological diseases.

Diabetes mellitus (DM) has become a public health problem worldwide, and it has large implications for cardiovascular disease (CVD). In this article, we discuss the etiology and pathophysiology of CVD in DM including the effects of abnormal glucose homeostasis, genetic factors, epigenetics, apoptosis, common pathophysiological mechanisms shared by both DM and CVD, and contributions of other comorbidities. We then cover the pathogenesis of both atherosclerotic disease and cardiomyopathy in relation to DM. Finally, we discuss the prevention of heart disease in DM with a focus on hypertension and dyslipidemia management, weight loss, lifestyle changes, antiplatelet therapy, and glycemic control.

Aims Glucagon-like peptide-1 (GLP-1) contributes to insulin secretion after meals. Though Hispanics have increased risk for type 2 diabetes mellitus, it is unknown if impaired GLP-1 secretion contributes to this risk. We therefore studied plasma GLP-1 secretion and action in Hispanic adults. Methods Hispanic (H; n = 31) and non-Hispanic (nH; n = 15) participants underwent an oral glucose tolerance test (OGTT). All participants were categorized by glucose tolerance into four groups: normal glucose tolerant non-Hispanic (NGT-nH; n = 15), normal glucose tolerant Hispanic (NGT-H; n = 12), impaired glucose tolerant Hispanic (IGT-H; n = 11), or newly diagnosed type 2 diabetes mellitus, Hispanic (T2D-H; n = 8). Results Glucose-induced increments in plasma GLP-1 (Δ-GLP-1) were not different in NGT-H and NGT-nH (p = .38), nor amongst Hispanic subgroups with varying degrees of glucose homeostasis (p = .6). In contrast, the insulinogenic index in T2D-H group was lower than the other groups (p = .016). Subjects with abnormal glucose homeostasis (AGH), i.e., T2D-H plus IGT-H, had a diminished glucagon suppression index compared to patients with normal glucose homeostasis (NGT-H plus NGT-nH) (p = .035). Conclusions GLP-1 responses to glucose were similar in Hispanic and Non-Hispanic NGT. Despite similar glucose-induced Δ-GLP-1, insulin and glucagon responses were abnormal in T2D-H and AGH, respectively. Thus, impaired GLP-1 secretion is unlikely to play a role in islet dysfunction in T2D. Although GLP-1 therapeutics enhance insulin secretion and glucagon suppression, it is likely due to pharmacological amplification of the GLP-1 pathways rather than treatment of hormonal deficiency.

Objective To determine accuracy of venous plasma glucose (VPG) and capillary blood glucose (CBG) in Gestational diabetes (GD) detection using Diabetes in Pregnancy Study Group India criteria. Methods It was a prospective single arm intervention study. One thousand thirty pregnant women, in second and third trimesters, recruited between June 2014 to March 2015 were included in the study. Seventy-five gram oral glucose was given, irrespective of last meal; venous and capillary blood samples were collected at 2h. Using World Health Organization (WHO) criteria, 2h VPG level ≥140mg/dl but Result Mean maternal age was 25.8±5.2 years, mean gestational age was 28.9±4.4 weeks and mean body mass index was 25.8±5.1kg/m 2 . By WHO criteria, 78 (7.6%) had GD, 14 (1.4%) had DM. Pearson's correlation between VPG and CBG was 0.761 ( p Conclusion Non fasting CBG is useful for screening of abnormal glucose homeostasis in pregnancy.

Background: Obese is risk factor for abnormal glucose homeostasis and causes oxidative stress that can decrease insulin sensitivity resulting in hyperglycemia and hyperinsulinemia. Black soy bean contains anthocyanins and isoflavones, it is expected to reduce oxidative stress. Objective: Determine the effect of various dosage of black soybean extract (Glycine soja.) on blood glucose, insulin levels, and HOMA - IR in obese Sprague Dawley (SD) rats. Methods: True experimental study with randomized controlled pre test-post test design in male SD rats. Twenty four samples divided into 4 groups: control (K), 500 (P1), 750 (P2), and 1000 mg/kgBW (P3). Rats were induced to become obese with High Fat Sucrose Diet (HFSD) for 4 weeks then black soybean extracts were given for 2 weeks.. Results: There was no difference in blood glucose before and after treatment (p> 0.05). There were differences on insulin levels in 500 (p = 0.012) and 750mg/kgBW (p = 0.020) doseges. There were differences on HOMA-IR in 500 (p = 0 . 043) and 750mg/kgBW (p = 0.028) dosages. There was difference in insulin levels’s difference (p = 0.009) between groups. Conclusion: There are differences on insulin levels and HOMA – IR in 500 and 750 mg/kgBW dosages groups. However, there is no difference on blood glucose before and after black soybean extract treatment. The most decreased levels of blood glucose, insulin and HOMA- IR were in 750mg/kgBW dosage.

Background: Humans are widely exposed to environmental perfluoroalkyl substances ( PFAS ), which may alter glucose homeostasis . However, research linking PFAS exposure to glucose tolerance during pregnancy is limited and the results were inconsistent. We aimed to investigate the association between PFAS exposure and glucose homeostasis in pregnancy in a large prospective cohort. Methods: A total of 2747 pregnant women who participated in the Shanghai Birth Cohort, had blood samples in early pregnancy and completed a 75 g oral glucose tolerance test (OGTT) at 24-28 gestational weeks were included. 10 PFAS were determined by high-performance liquid chromatography/tandem mass spectrometry (HPLC/MS-MS) in the plasma samples in early pregnancy. Logistic regression was used to explore the associations between PFAS concentrations and gestational diabetes mellitus (GDM), while multiple linear regression was used to model the associations between PFAS and OGTT fasting, 1-h and 2-h glucose levels. Potential confounders were adjusted. Bayesian kernel machine regression (BKMR) and a quantile-based g-computation approach were employed to explore the joint and independent effects of PFAS on glucose homeostasis. Findings: The incidence of GDM was 11·8%. One log-unit increment in plasma concentrations in early pregnancy was associated with an increased risk of GDM for perfluorobutane sulfonate (PFBS) [adjusted odd ratio (aOR)=1·23, 95% confidence interval (95% CI): 1·05,1·44] and perfluoroheptanoic acid (PFHpA) (aOR=1·25, 95% CI: 1·07,1·46). Perfluorooctane sulfonic acid (PFOS), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluorohexanesulfonate (PFHxS) and PFHpA were positively correlated with 1-h and 2-h glucose levels. Results of the mixed exposure model showed that the joint effects of PFAS were significantly associated with abnormal glucose homeostasis; PFOS, PFNA and PFHpA may be the main contributors. The above associations were more prominent among women with a normal prepregnant BMI. Interpretation: Environmental exposure to PFAS may affect glucose homeostasis in pregnancy and increase the risk of GDM, especially in normal weight women. Funding Statement: This study was funded by the National Nature Science Foundation of China (41991314 and 81530086) and the Collaborative Innovation Program of the Shanghai Municipal Health Commission (2020CXJQ01), the Ministry of Science and Technology of China (2019YFA0802501), and supported in part by the National Human Genetic Resources Sharing Service Platform (2005DKA21300). Declaration of Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Ethics Approval Statement: This project was approved by the Research Ethics Committees of Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine.

Aim To estimate the proportion of type 2 diabetes mellitus and abnormal glucose homeostasis in childhood obesity and assess the predictive role of HbA1c as a diagnostic marker compared with oral glucose tolerance testing (OGTT). Methods A retrospective study in a tertiary paediatric hospital. Data were collected on all overweight or obese children who underwent routine OGTT between 2012 and 2016. Ethnicity, anthropometry, comorbidities and other risk factors associated with diabetes were recorded systematically. Fasting venous glucose, insulin and HbA1c values, along with 120-min venous glucose were recorded. Receiver operating characteristic (ROC) curve analysis was performed to derive optimum thresholds of HbA1c for detection of type 2 diabetes, impaired fasting glucose (IFG) and impaired glucose tolerance (IGT). Predictive HbA1c thresholds for the detection of abnormal glucose homeostasis in children with obesity were calculated. Results Of 156 children, 13 (8%, 10 female, 10 Asian) had type 2 diabetes, 95 (61%) had normal glucose tolerance, 18 (12%) had isolated IFG, 19 (12%) had isolated IGT, and another 11 (7%) had both IFG and IGT. The proportion of abnormal glucose homeostasis was 39%. ROC curve analysis demonstrated that HbA1c ≥ 42 mmol/mol (6.0%) predicted type 2 diabetes (specificity 95%, sensitivity 85%) but performed moderately for IFG (specificity 46%, sensitivity 78%) and IGT (specificity 78%, sensitivity 55%). Conclusion Despite HbA1c being a less-sensitive diagnostic tool compared with OGTT for children with IFG and IGT, it is reliable in detecting type 2 diabetes in asymptomatic children with obesity, instead of the labour- and cost-intensive OGTT.

Abnormal Ca homeostasis has been associated with impaired glucose metabolism. However, the epidemiological evidence is controversial. We aimed to assess the association between circulating Ca levels and the risk of type 2 diabetes mellitus (T2DM) or abnormal glucose homeostasis through conducting a systematic review and meta-analysis. Eligible studies were identified by searching electronic database (PubMed, Embase and Google Scholar) and related references withde novoresults from primary studies up to December 2018. A random-effects meta-analysis was performed to estimate the weighted relative risks (RR) and 95 % CI for the associations. The search yielded twenty eligible publications with eight cohort studies identified for the meta-analysis, which included a total of 89 165 participants. Comparing the highest with the lowest category of albumin-adjusted serum Ca, the pooled RR was 1·14 (95 % CI 1·05, 1·24) for T2DM (n51 489). Similarly, serum total Ca was associated with incident T2DM (RR 1·25; 95 % CI 1·10, 1·42) (n64 502). Additionally, the adjusted RR for 1 mg/dl increments in albumin-adjusted serum Ca or serum total Ca levels was 1·16 (95 % CI 1·07, 1·27) and 1·19 (95 % CI 1·11, 1·28), respectively. The observed associations remained with the inclusion of a cohort study with ionised Ca as the exposure. However, data pooled from neither case–control (n4) nor cross-sectional (n8) studies manifested a significant correlation between circulating Ca and glucose homeostasis. In conclusion, accumulated data from the cohort studies suggest that higher circulating Ca levels are associated with an augmented risk of T2DM.

The neurohypophysial endocrine system is identified here as a potential target for therapeutic interventions toward improving obesity-related metabolic dysfunction, given its coinciding pleiotropic effects on psychological, neurological and metabolic systems that are disrupted in obesity. Copeptin, the C-terminal portion of the precursor of arginine-vasopressin, is positively associated with body mass index and risk of type 2 diabetes. Plasma oxytocin is decreased in obesity and several other conditions of abnormal glucose homeostasis. Recent data also show non-classical tissues, such as myocytes, hepatocytes and β-cells, exhibit responses to oxytocin and vasopressin receptor binding that may contribute to alterations in metabolic function. The modulation of anorexigenic and orexigenic pathways appears to be the dominant mechanism underlying the effects of oxytocin and vasopressin on body weight regulation; however, there are apparent limitations associated with their use in direct pharmacological applications. A clearer picture of their wider physiological effects is needed before either system can be considered for therapeutic use.

Purpose Chronic inflammation increases the risks for cardiovascular disease, type 2 diabetes, and cancer. Recently, the antiinflammatory effects of statins, as cholesterol-lowering medications, have been considered. This study systematically reviewed and summarized earlier findings from randomized clinical trials about the effects of statins on serum concentrations of C-reactive protein (CRP) and interleukin (IL)-6 in patients with abnormal glucose homeostasis. Methods Relevant articles published through October 2019 were searched using suitable key words on the PubMed/MEDLINE, SCOPUS, EMBASE, and Google Scholar databases. RCTs were included if they compared the effects of statins on serum concentrations of CRP and IL-6 in adults with abnormal glucose homeostasis. The effect sizes were represented as weighted mean differences (WMDs) and 95% CI s using a random-effects model. Subgroup analysis was performed to find possible sources of heterogeneity. Findings Overall, 17 publications with 21 effect sizes and which enrolled 3766 subjects (1895 participants in intervention and 1871 in control groups) were included. Combining 13 effect sizes from 10 studies, a significant reduction in serum CRP concentration following the administration of atorvastatin was found (WMD, −0.35; 95% CI, −0.54 to −0.17; I2 = 90.6%). Based on 5 effect sizes from 4 studies, we found a statistically significant reduction in serum IL-6 concentration after atorvastatin therapy (WMD, −0.44; 95% CI, −0.65 to −0.22; I2 = 93.9%). Pooling 6 effect sizes from 5 studies revealed a significantly reduced serum concentration of CRP after simvastatin therapy (WMD, −0.66; 95% CI, −0.79 to −0.54; I2 = 97.6%). Implications The administration of atorvastatin or simvastatin in patients with abnormal glucose hemostasis was associated with a reduced serum CRP concentration. Atorvastatin therapy might also help to decrease serum IL-6 concentration in these patients.

SMA is a rare autosomal recessive neuromuscular disorder affecting 4-10/100,000 live births. Fasting hyperglycemia, hyperglucagonemia, and glucose resistance attributed to a decrease in pancreatic β cells and an increase in α cells have been reported in mice and humans with SMA(1). Rare cases of DKA and T1DM have been reported in humans. We report a case of DKA in the setting of SMA with restoration of euglycemia off insulin following the resolution of DKA. A 22-year-old man with genetically-confirmed SMA type 2 and no history of diabetes presented with nausea, vomiting, polyuria, and polydipsia. Weight is 38kg and BMI 16.2. Family history is negative for diabetes. On admission, labs were consistent with DKA: venous BG of 289 mg/dL, anion gap of 23 (n=4-12), lactate of 1.1 mmol/L (n=0.6-1.9 mmol/L), WBC of 35.7 (n=4.3-10.0 thous/microL), bicarbonate of 7 mEq/L (n=23-27 mEq/L), beta-hydroxybutyrate of 8.99 mmol/L (n

Chronic inflammation is a driving force for the development of metabolic disease including diabetes and obesity. However, the functional characteristics of T-cell senescence in the abnormal glucose homeostasis are not fully understood. We studied the patients visiting a hospital for routine health check-ups, who were divided into two groups: normal controls and people with prediabetes. Gene expression profiling of peripheral blood mononuclear cells from normal controls and patients with type 2 diabetes was undertaken using microarray analysis. We also investigated the immunometabolic characteristics of peripheral and hepatic senescent T cells in the normal subjects and patients with prediabetes. Moreover, murine senescent T cells were tested functionally in the liver of normal or mice with metabolic deterioration caused by diet-induced obesity. Human senescent (CD28−CD57+) CD8+ T cells are increased in the development of diabetes and proinflammatory cytokines and cytotoxic molecules are highly expressed in senescent T cells from patients with prediabetes. Moreover, we demonstrate that patients with prediabetes have higher concentrations of reactive oxygen species (ROS) in their senescent CD8+ T cells via enhancing capacity to use glycolysis. These functional properties of senescent CD8+ T cells contribute to the impairment of hepatic insulin sensitivity in humans. Furthermore, we found an increase of hepatic senescent T cells in mouse models of aging and diet-induced obesity. Adoptive transfer of senescent CD8+ T cells also led to a significant deterioration in systemic abnormal glucose homeostasis, which is improved by ROS scavengers in mice. This study defines a new clinically relevant concept of T-cell senescence-mediated inflammatory responses in the pathophysiology of abnormal glucose homeostasis. We also found that T-cell senescence is associated with systemic inflammation and alters hepatic glucose homeostasis. The rational modulation of T-cell senescence would be a promising avenue for the treatment or prevention of diabetes.

The authors assessed the frequency of glucose homeostasis abnormalities among 839 Cameroonians with newly diagnosed hypertension (mean age: 50.8±11 years; 49.9% female) in a cross‐sectional survey conducted at the Douala General Hospital, Douala, Cameroon. In all participants, blood pressure, fasting plasma glucose (FPG), and lipids were recorded. Impaired fasting glycemia was described as an FPG level between 100 and 125 mg/dL and provisional diabetes as an FPG level ≥126 mg/dL. The FPG was 101±30 mg/dL. The overall proportion of abnormal glucose homeostasis was 38.3%, while 7.7% of patients (n=65) had known diabetes. A total of 23.7% (n=199) had impaired fasting glycemia and 6.8% (n=57) had provisional diabetes. Multivariable logistic regression revealed that male sex (odds ratio [OR], 1.53; 95% confidence interval [CI], 1.15–2.06), age older than 55 years (OR, 1.55; 95% CI, 1.15–2.09), and low‐density lipoprotein cholesterol >1 g/L (OR, 1.34; 95% CI, 1.00–1.82) were independently associated with abnormal glucose homeostasis (all P

Background: The link among perfluoroalkyl and polyfluoroalkyl substances (PFASs), abnormal glucose homeostasis and the risk of diabetes has been intensively debated with conflicting evidence. Objectives: We evaluated the associations among PFASs, oral glucose tolerance testing (OGTT) curves and diabetes prevalence in 571 working-aged Taiwanese participants. Methods: Exposure measures included serum perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), perfluorononanoic acid (PFNA), and perfluoroundecanoic acid (PFUA). Outcomes were OGTT curves and prevalent diabetes defined by fasting blood glucose (FBG) ≥126 mg/dL, 2-h glucose ≥200 mg/dL, or glycated hemoglobin ≥6.5%. Analyses were performed with multiple logistic regression and functional data analysis. Results: A total of 39 participants (6.8%) had diabetes in this study. After full adjustment, the increase in the geometric means of FBG, 2-h glucose concentrations, and area under the OGTT curve (AUC120) with a doubling increase in PFOS was 3% (95% CI 1–4), 8% (5–12), and 6% (4–9), respectively. Compared to the lowest-quartile of PFOS concentrations (4.8 ng/ml) and the vertical shifting of the mean curve for each PFOS quartile showed a dose–response pattern. The adjusted odds ratio for diabetes comparing the highest to lowest quartile was 3.37 (95% CI 1.18–9.65). For PFOA, PFNA, and PFUA, the opposite pattern of OGTT trajectory and the opposite risk profile for diabetes were observed. Conclusions: Chronic PFOS exposure was associated with impaired glucose homeostasis and the increased prevalence of diabetes. However, PFOA, PFNA, and PFUA showed a potential protective effect against glucose intolerance and the risk of diabetes. Future research focusing on clarifying possible differential effects of different species of PFASs on glucose homeostasis and establishing the prospective associations between PFASs and diabetes is needed. Keywords: Perfluorinated chemicals, Oral glucose tolerance testing, Diabetes, Glucose homeostasis

Intrauterine growth restricted offspring suffer from abnormal glucose homeostasis and β cell dysfunction. In this study, we observed the dynamic changes of glucose metabolic phenotype, pancreatic morphology, and insulin synthesis in prenatal ethanol exposure (PEE) male offspring rats, and to explore the potential intrauterine programming mechanism of the glucocorticoid-insulin-like growth factor 1 (GC-IGF1) axis. Ethanol (4 g/kg·d) was administered through oral gavage during gestational day (GD) 9-20. Serum glucose and insulin levels, pancreatic β cell mass, and expression of glucocorticoid receptor (GR), IGF1 and insulin were determined on GD20, postnatal week (PW) 6, PW12 with/without chronic stress (CS), and PW24, respectively. Both intraperitoneal glucose and insulin tolerance tests were conducted at PW12 and PW24. Results showed that the serum glucose and insulin levels as well as pancreatic β cell mass were reduced on GD20 in PEE males compared with the controls, while pancreatic GR expression was enhanced but IGF1 and INS1/2 expression were suppressed. After birth, compared with the controls, β cell mass in the PEE males was initially decreased at PW6 and gradually recovered from PW12 to PW24, which was accompanied by increased serum glucose/insulin levels and insulin resistance index (IRI) at PW6 and decreased serum glucose contents at PW12, as well as unchanged serum glucose/insulin concentrations at PW24. In addition, both improved glucose tolerance and impaired insulin sensitivity of the PEE males at PW12 were inversed at PW24. Moreover, at PW6 and PW12, pancreatic GR expression in the PEE group was decreased, while IGF1 expression was reversely increased, resulting in a compensatory increase of insulin expression. Moreover, CS induced pancreatic GR activation and inhibited IGF1 expression, resulting in impaired insulin biosynthesis. Conclusively, the above changes were associated with age and the intrauterine programming alteration of GC-IGF1 axis may be involved in prenatal and postnatal pancreatic dysplasia and impaired insulin biosynthesis in PEE male offspring.

There will be 642 million people worldwide by 2040 suffering from diabetes mellitus. Long-term multidrug therapy aims to achieve normal glycemia and minimize complications, and avoid severe hypoglycemic events. The appreciation of the drug-metabolizing enzymes and drug transporters as critical players in the treatment of diabetes has attracted much attention regarding their potential alterations in the pathogenesis of the disease. This review discusses pharmacokinetics-based alterations of cytochrome P450 enzymes, phase-II metabolizing enzymes, and membrane transporter proteins, as well as the potential mechanisms underlying these alterations. We also discuss the potential influences of altered enzymes and transporters on the disposition of commonly prescribed glucose-lowering medicines. Future studies should delve into the impact of altered drug-metabolizing enzymes and transporters on the progression toward abnormal glucose homeostasis.

The present study investigated the efficacy of the hepatoprotective drug matrine (Mtr) for its new application for hepatosteatosis and associated disorders in glucose homeostasis. The study was performed in two nutritional models of hepatosteatosis in mice with various abnormal glucose homeostasis: (1) high-fructose diet (HFru) induced hepatosteatosis and glucose intolerance from hepatic, and (2) hepatosteatosis and hyperglycemia induced by high-fat (HF) diet in combination with low doses of streptozotocin (STZ). Administration of Mtr (100 mg/kg every day in diet for 4 weeks) abolished HFru-induced hepatosteatosis and glucose intolerance. These effects were associated with the inhibition of HFru-stimulated de novo lipogenesis (DNL) without altering hepatic fatty acid oxidation. Further investigation revealed that HFru-induced endoplasmic reticulum (ER) stress was inhibited, whereas heat-shock protein 72 (an inducible chaperon protein) was increased by Mtr. In a type 2 diabetic model induced by HF-STZ, Mtr reduced hepatosteatosis and improved attenuated hyperglycemia. The hepatoprotective drug Mtr may be repurposed for the treatment of hepatosteatosis and associated disorders in glucose homeostasis. The inhibition of ER stress associated DNL and fatty acid influx appears to play an important role in these metabolic effects.

Background Exposure to ambient fine particulate matter (PM2.5) correlates with abnormal glucose homeostasis, but the underlying biological mechanism has not been fully understood. The gut microbiota is an emerging crucial player in the homeostatic regulation of glucose metabolism. Few studies have investigated its role in the PM2.5 exposure-induced abnormalities in glucose homeostasis. Methods C57Bl/6J mice were exposed to filtered air (FA) or concentrated ambient PM2.5 (CAP) for 12 months using a versatile aerosol concentration enrichment system (VACES) that was modified for long-term whole-body exposures. Their glucose homeostasis and gut microbiota were examined and analysed by correlation and mediation analysis. Results Intraperitoneal glucose tolerance test (IPGTT) and insulin tolerance test (ITT) showed that CAP exposure markedly impaired their glucose and insulin tolerance. Faecal microbiota analysis demonstrated that the impairment in glucose homeostasis was coincided with decreased faecal bacterial ACE and Chao-1 estimators (the indexes of community richness), while there was no significant change in all faecal fungal alpha diversity estimators. The Pearson’s correlation analyses showed that the bacterial richness estimators were correlated with glucose and insulin tolerance, and the mediation analyses displayed a significant mediation of CAP exposure-induced glucose intolerance by the alteration in the bacterial Chao-1 estimator. LEfSe analyses revealed 24 bacterial and 21 fungal taxa differential between CAP- and FA-exposed animals. Of these, 14 and 20 bacterial taxa were correlated with IPGTT AUC and ITT AUC, respectively, and 5 fungal taxa were correlated with abnormalities in glucose metabolism. Conclusions Chronic exposure to PM2.5 causes gut dysbiosis and may subsequently contribute to the development of abnormalities in glucose metabolism.

In patients with TM, uncontrolled iron overload has serious clinical consequences with considerable morbidity and mortality. Complications include liver damage, cardiac disease and endocrine dysfunction. Diabetes is an important complication of TM. The mechanisms of abnormal glucose homeostasis are complex and multifactorial. This review updates the current knowledge about glycemic abnormalities in TM patients and directs the attention to an early diagnosis and proper management.

Aims Diabetes mellitus (DM) is considered to be one of the important risk factors for cardiac diseases. Frank diabetes is usually preceded by long term abnormality in glucose homeostasis which is called pre-diabetes. The hypothesis that diabetic patients have greater risk and worse prognosis of Acute Myocardial Infarction (AMI) than pre-diabetics is controversial. Considering that India has been declared as a diabetic capital of the world, the study aimed to assess the load of pre diabetics, diabetics and non-diabetics landing in myocardial infarction. Materials and methods The study consisted of through physiological and biochemical evaluation of 200 patients of newly diagnosed AMI and evaluating the load of non-diabetics, pre-diabetics and diabetics among them. Result It was found that the total non-diabetic population (normoglycaemic and pre-diabetic) formed the bulk of AMI patient (69%) in our study. The degree of biochemical alterations seen among the three groups suggests that abnormal glucose homeostasis is not the sole determinant of the severity of AMI. The study data also suggests that glycaemic status, which poses a risk for AMI, differs in male and female individuals. Males even with normal glucose level are at increased risk to develop MI. Conclusion The study concludes that both males and females with their blood glucose in pre-diabetic range are seen to be vulnerable to develop AMI. Thus all individuals irrespective of their glycaemic status around the age of forty should be screened and individuals with fasting sugar in pre-diabetic range should take extra precaution in terms of healthy diet, life style and regular check up

Aim To compare the performance of HbA1c with established glucose criteria during an oral glucose tolerance test (OGTT) and to assess HbA1c as a screening test for undiagnosed diabetes and pre-diabetes after gestational diabetes mellitus (GDM). Methods Glucose homeostasis was re-evaluated 1–5 years after delivery in 140 women with previous GDM, by means of OGTT and simultaneous HbA1c measurement. Glucose tolerance was defined according to World Health Organisation criteria. HbA1c ≥6.5% (≥48 mmol/mol) was used for diabetes diagnosis and HbA1c ≥5.7% (≥39 mmol/mol) to define abnormal glucose homeostasis. Results HbA1c had low sensitivity (14.3%) and high specificity (99.1%) in diabetes diagnosis. Sensitivity and specificity of HbA1c to detect abnormal glucose tolerance were 29.5% and 95.2%, respectively. The consistency in classifying abnormal glucose tolerance between HbA1c and OGTT criteria was 59% (κ = 0.227) and the area under the receiver operating characteristic curve was 0.708. The combined use of HbA1c and fasting glucose criteria showed similar performance to that of fasting glucose criteria alone. The latter identified 63% of the women with pre-diabetes or diabetes in the study cohort. However, by lowering the cut-point of HbA1c to ≥5.0% (≥31 mmol/mol), an additional proportion (27%) with isolated post-glucose load hyperglycaemia was identified. Conclusion Proposed thresholds of HbA1c had low diagnostic sensitivity. Combined with a fasting glucose test, the performance was no better than with using a fasting glucose test alone. Combining a fasting glucose test with a lower HbA1c cut-point may be an alternative approach for selection of women for an OGTT., Highlights • We compare the performance of HbA1c with established glucose criteria during an oral glucose tolerance test (OGTT). • We also assess HbA1c as a screening test for undiagnosed diabetes and pre-diabetes after gestational diabetes mellitus. • Proposed thresholds of HbA1c had low diagnostic sensitivity relative to OGTT. • Combining HbA1c with a fasting glucose test the performance was no better than using a fasting glucose test alone. • Combining a fasting glucose test with a lower HbA1c cut-point may be an option for selection of women for an OGTT.

Background: Insulin resistance (IR) is one of the important causes of abnormal glucose homeostasis in CKD even in the absence of overt diabetes mellitus. Retinol-binding protein 4 (RBP4) is a lipocalin superfamily molecule that is synthesized primarily by hepatocytes and adipocytes. CKD may contribute to the increased survival and retention of RBP4 in the circulation. RBP has recently been proposed as a novel adipokine involved in the metabolism of glucose. Objective: To evaluate Retinol Binding Protein 4 in stage 5 Chronic kidney disease patients on regular hemodialysis and its contribution to insulin resistance in those patients. Patients &Methods: The patients divided into 2 groups: Group I: Patients group consist of 50 ESRD patients on regular hemodialysis; they were 20 females (40.0%) and 30 males (60.0%) with age ranged from 19 years to 52 years and with mean±SD (38.08±7.1 years). Group II: Control group consists of 50 normal subjects; 26 females (52%) and 24 males (48%) with age ranged from 21 years to 51 years and with mean±SD (35.38±8.77 years). Results: comparison between group I and group II show that there was highly significant increase in RBP4 (p 0.000) while no statistically significant difference found between the two studied groups regarding HOMA (p 0.260). Conclusion:no correlation betweenRBP4 and HOMA in hemodialysis patients.

Proopiomelanocortin (POMC) neurons are critical sensors of nutrient availability implicated in energy balance and glucose metabolism control. However, the precise mechanisms underlying nutrient sensing in POMC neurons remain incompletely understood. We show that mitochondrial dynamics mediated by Mitofusin 1 (MFN1) in POMC neurons couple nutrient sensing with systemic glucose metabolism. Mice lacking MFN1 in POMC neurons exhibited defective mitochondrial architecture remodeling and attenuated hypothalamic gene expression programs during the fast-to-fed transition. This loss of mitochondrial flexibility in POMC neurons bidirectionally altered glucose sensing, causing abnormal glucose homeostasis due to defective insulin secretion by pancreatic β cells. Fed mice lacking MFN1 in POMC neurons displayed enhanced hypothalamic mitochondrial oxygen flux and reactive oxygen species generation. Central delivery of antioxidants was able to normalize the phenotype. Collectively, our data posit MFN1-mediated mitochondrial dynamics in POMC neurons as an intrinsic nutrient-sensing mechanism and unveil an unrecognized link between this subset of neurons and insulin release.

Excessive production of glucose by the liver contributes to fasting and postprandial hyperglycaemia, hallmarks of type 2 diabetes. A central feature of this pathologic response is insufficient hepatic insulin action, due to a combination of insulin resistance and impaired β-cell function. However, a case can be made that glucagon also plays a role in dysregulated hepatic glucose production and abnormal glucose homeostasis. Plasma glucagon concentrations are inappropriately elevated in diabetic individuals, and α-cell suppression by hyperglycaemia is blunted. Experimental evidence suggests that this contributes to greater rates of hepatic glucose production in the fasting state and attenuated reduction after meals. Recent studies in animal models indicate that reduction of glucagon action can have profound effects to mitigate hyperglycaemia even in the face of severe hypoinsulinaemia. While there are no specific treatments for diabetic patients yet available that act specifically on the glucagon signalling pathway, newer agents including glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors reduce plasma glucagon and this is thought to contribute to their action to lower blood glucose. The α-cell and glucagon receptor remain tempting targets for novel diabetes treatments, but it is important to understand the magnitude of benefit new strategies would provide as preclinical models suggest that chronic interference with glucagon action could entail adverse effects as well.

Summary Reasons for performing study: The use of plasma fructosamine concentration ([fructosamine]) as a marker of abnormal glucose homeostasis in laminitic horses has not been investigated. Hypothesis: Plasma fructosamine concentration may be higher amongst laminitic horses than normal horses; this might relate to underlying insulin resistance. Objectives: 1) To compare [fructosamine] between laminitic and normal horses. 2) To investigate associations between [fructosamine] at presentation in laminitic horses with a) single sample markers of insulin resistance and b) outcome. Methods: Plasma fructosamine concentration, fasting serum insulin concentration (insulin) and fasting plasma glucose concentration (glucose) were measured in 30 horses that presented with laminitis. Clinical details and follow-up data were recorded. Plasma fructosamine concentration was also measured in 19 nonlaminitic control horses. Results: Laminitic horses had significantly higher mean [fructosamine] than normal horses (P

Context and Objective: Obesity is associated with activation of the TNF-α system, increased inflammatory markers, and insulin resistance. Although studies in rodents suggest that attenuation of TNF activity improves glucose homeostasis, the effect of prolonged inhibition of TNF-α with etanercept on inflammation and glucose homeostasis in a human model of obesity is not known. Design and Participants: Forty obese subjects with features of metabolic syndrome were randomized to etanercept or placebo, 50 mg twice weekly for 3 months, followed by 50 mg once weekly for 3 months. Outcome Measures: Subjects underwent oral glucose tolerance testing and measurement of serum inflammatory biomarkers and adipokines. Subcutaneous fat biopsy was performed in a subset for measurement of adipokine and TNF-α mRNA expression. Results: Visceral adiposity was significantly associated with serum concentrations of TNF receptor 1 (TNFR1), TNFR2, and vascular cell adhesion molecule-1 and adipose tissue expression of TNF-α and SOCS-3 (all P < 0.05). Insulin resistance as assessed by homeostasis model assessment was significantly associated with TNFR1, C-reactive protein, IL-6, and soluble intracellular adhesion molecule-1 (sICAM-1) (all P < 0.05). Etanercept significantly improved fasting glucose (treatment effect vs. placebo over 6 months, −10.8 ± 4.4%, P = 0.02). Etanercept also increased the ratio of high molecular weight adiponectin to total adiponectin (+22.1 ± 9.2% vs. placebo, P = 0.02), and decreased levels of sICAM-1 (−11 ± 2% vs. placebo, P < 0.0001). In contrast, body composition, lipids, C-reactive protein, and IL-6 were unchanged after 6 months. Conclusions: Prolonged therapy with etanercept improved fasting glucose, increased the ratio of high molecular weight to total adiponectin, and decreased sICAM-1 in obese subjects with abnormal glucose homeostasis and significant subclinical inflammation.

Eukaryotic cells sense extracellular glucose concentrations via diverse mechanisms to regulate the expression of genes involved in metabolic control. One such example is the tight correlation between the expression of thioredoxin-interacting protein (Txnip) and extracellular glucose levels. In this report, we show that the transcription of the Txnip gene is induced by adenosine-containing molecules, of which an intact adenosine moiety is necessary and sufficient. Txnip promoter contains a carbohydrate response element, which mediates the induction of Txnip expression by these molecules in a glucose-dependent manner. Max-like protein X and MondoA are transcription factors previously shown to stimulate glucose-dependent Txnip expression and are shown here to convey stimulatory signals from extracellular adenosine-containing molecules to the Txnip promoter. The regulatory role of these molecules may be exerted via amplifying glucose signaling. Hence, this revelation may pave the way for interventions aimed toward metabolic disorders resulting from abnormal glucose homeostasis.

OBJECTIVE—The purpose of this study was to test the hypothesis that any degree of abnormal glucose homeostasis detected on antepartum screening for gestational diabetes mellitus (GDM) should be associated with an increased risk of postpartum pre-diabetes or diabetes. RESEARCH DESIGN AND METHODS—In this prospective cohort study, 487 women underwent 1) antepartum GDM screening by a glucose challenge test (GCT) and a diagnostic oral glucose tolerance test (OGTT) and 2) postpartum metabolic characterization by OGTT at 3 months after delivery. Four baseline glucose tolerance groups were defined on the basis of the antepartum GCT/OGTT: 1) GDM (n = 137); 2) gestational impaired glucose tolerance (GIGT) (n = 91); 3) abnormal GCT with normal glucose tolerance on an OGTT (abnormal GCT NGT) (n = 166); and 4) normal GCT with NGT on an OGTT (normal GCT NGT) (n = 93). RESULTS—The prevalence of postpartum glucose intolerance (pre-diabetes or diabetes) increased across the groups from normal GCT NGT (3.2%) to abnormal GCT NGT (10.2%) to GIGT (16.5%) to GDM (32.8%) (Ptrend < 0.0001). On logistic regression analysis, all three categories of abnormal glucose homeostasis in pregnancy independently predicted postpartum glucose intolerance: abnormal GCT NGT odds ratio (OR) 3.6 (95% CI 1.01–12.9); GIGT OR 5.7 (1.6–21.1); and GDM OR 14.3 (4.2–49.1). Furthermore, both in pregnancy and at 3 months postpartum, insulin sensitivity (ISOGTT) and pancreatic β-cell function (insulinogenic index/homeostasis model assessment of insulin resistance) progressively decreased across the groups from normal GCT NGT to abnormal GCT NGT to GIGT to GDM (all Ptrend < 0.0001). CONCLUSIONS—Any degree of abnormal glucose homeostasis in pregnancy independently predicts an increased risk of glucose intolerance postpartum.

ObjectiveTo look into the relation between parathyroid hormone and abnormal glucose homeostasis in chronic renal failure patients on regular hemodialysis.Methods41 subjects, with chronic renal failure, and on regular hemodialysis (28 male, 13 female; age range 19–64 years). Full history and clinical examination were taken for every patient. In addition, ten age and sex matched healthy persons were selected randomly as control group. Informed consent was obtained. All patients were investigated to determine serum creatinine, calcium, phosphorus, alkaline phosphatase, parathyroid hormone, fasting glucose, and fasting insulin. Homeostasis module assessment of insulin resistance was calculated as a measure of insulin resistance, Homeostasis module assessment of beta cell was calculated as a measure of pancreatic beta cell function. The uremic patients were classified into two groups: group A included 24 patients with plasma parathyroid hormone levels < 450pg/ ml and group B included 17 patients with plasma parathyroid hormone level >450pg/ml.ResultsThere is a marked increase in fasting insulin level in all patients versus control associated with increased homeostasis module assessment of insulin resistance, an index for insulin resistance. Significant negative correlation is found between parathyroid hormone and fasting insulin and homeostasis module assessment of insulin resistance in uremic patients. Patients with severe hyperparathyroidism have relatively more impaired pancreatic beta cell function in comparison to those with mild hyperparathyroidism. The pulsed dose of intravenous 1-cholecalciferol is associated with low parathormone level and high serum calcium.ConclusionInsulin resistance is a constant feature of chronic renal failure patients under hemodialysis therapy, while secondary hyperparathyroidism is linked negatively to beta cell function. Intermittent pulsed intravenous alphacalcidol is an effective method of lowering high serum parathyroid hormone and is associated with improvement of beta cell function without significant effect on insulin resistance.

Exocytosis of insulin vesicles in the pancreatic beta-cell involves a sequence of regulated events, whose normal function and efficient adaptation to increased demand are essential for the maintenance of glucose homeostasis. These exocytotic events comprise the trafficking and docking of vesicles to the plasma membrane, followed by fusion triggered by Ca(2+). Recent studies have unravelled post-docking steps mediated by novel factors, which, by their interactions with soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE)- and SNARE-associated proteins, confer the docked vesicles fusion competence. These priming steps define the releasable pool of insulin vesicles, which accounts for the first phase of insulin secretion, and controls the rate at which vesicles are replenished for the second phase of secretion. This article aims to summarize what is currently known about the mechanisms that underlie the priming activity of these proteins, focusing on Munc13, a topic to which we have made some recent contributions. Abnormal glucose homeostasis in type 2 diabetes is because of the failure of islet beta-cells to augment insulin secretion sufficiently to compensate for reduced insulin sensitivity. A better understanding of the priming steps may help develop novel approaches to increase insulin secretory capacity and thereby prevent the progression to type 2 diabetes.

Fanconi-Bickel syndrome (FBS) is a rare disorder of glucose transport caused by autosomal recessive mutations in GLUT2. Clinically, FBS results in growth failure, hepatomegaly, renal Fanconi syndrome, and abnormal glucose homeostasis. We report a 23 month old female with FBS characterized by more severe and refractory hypoglycemia than typically seen in this disorder. Although previous reports indicate that FBS patients have diminished insulin secretion, our patient showed evidence of hyperinsulinism (HI). Sequence analysis showed that the patient was homozygous for a known null mutation in GLUT2, confirming the clinical diagnosis of FBS. Parental genotyping showed that the mother was heterozygous for the GLUT2 mutation, while the father was wild type. Tandem repeat marker analysis showed that the patient inherited the GLUT2 mutation via maternal isodisomy of chromosome 3. Further molecular testing showed that the patient was heterozygous for a mutation in ABCC8, a known cause of congenital HI. We discuss the patient's biochemical responses in light of the molecular findings.

Adverse events during pregnancy, including prenatal ethanol (EtOH) exposure, are associated with insulin-resistant diabetes in male rat offspring, but it is unclear whether this is true for female offspring. We investigated whether prenatal EtOH exposure alters glucose metabolism in adult female rat offspring and whether this is associated with reduced in vivo insulin signaling in skeletal muscle. Female Sprague-Dawley rats were given EtOH, 4 g·kg−1·day−1by gavage throughout pregnancy. Glucose tolerance test and hyperinsulinemic euglycemic clamp were performed, and insulin signaling was investigated in skeletal muscle, in adult female offspring. We gave insulin intravenously to these rats and determined the association of glucose transporter-4 with plasma membranes, as well as the phosphorylation of phosphoinositide-dependent protein kinase-1 (PDK1), Akt, and PKCζ. Although EtOH offspring had normal birth weight, they were overweight as adults and had fasting hyperglycemia, hyperinsulinemia, and reduced insulin-stimulated glucose uptake. After insulin treatment, EtOH-exposed rats had decreased membrane glucose transporter-4, PDK1, Akt, and PKCζ in the gastrocnemius muscle, compared with control rats. Insulin stimulation of PDK1, Akt, and PKCζ phosphorylation was also reduced. In addition, the expression of the protein tribbles-3 and the phosphatase enzyme activity of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), which prevent Akt activation, were increased in muscle from EtOH-exposed rats. Female rat offspring exposed to EtOH in utero develop insulin-resistant diabetes in association with excessive PTEN and tribbles-3 signaling downstream of the phosphatidylinositol 3-kinase pathway in skeletal muscle, which may be a mechanism for the abnormal glucose tolerance.

OBJECTIVE—We sought to determine the clinical phenotype of adolescent/adult patients with cystic fibrosis, according to heterozygosity or homozygosity for cystic fibrosis transmembrane regulator (CFTR) ΔF508 mutation, and to analyze their characteristics according to glucose tolerance status. RESEARCH DESIGN AND METHODS—A total of 76 cystic fibrosis patients with CFTR ΔF508 mutation (33 heterozygous and 43 homozygous) stratified according to normal glucose tolerance (NGT) (n = 51) or abnormal glucose homeostasis (AGH) (impaired fasting glucose, impaired glucose tolerance, or diabetes; n = 25) had their homeostasis model assessment (HOMA) of β-cell function and of insulin sensitivity and hyperbolic product (β-cell function × insulin sensitivity [B × S]) measured. Pancreatic exocrine insufficiency was inferred from pancreatine requirements. Clinical effects of insulin therapy on weight and lung function were recorded. RESULTS—AGH was observed in 24 and 40% of heterozygous and homozygous subjects, respectively. AGH patients were older than NGT patients (mean ± SD age 29 ± 10 vs. 23 ± 8 years, P = 0.006), and their β-cell function was lower (93 ± 49 vs. 125 ± 51%, P = 0.011). Insulin sensitivity values were comparable in NGT and AGH patients. A lower B × S product was observed in AGH, although it was nonsignificant when adjusted for error propagation. Pancreatic insufficiency was observed in 52 and 100% of heterozygous and homozygous patients (P = 0.001). CONCLUSIONS—Pre-diabetes and diabetes represent frequent comorbidities in CFTR ΔF508 mutation in the homozygous or heterozygous states. Impairment of insulin secretion, as shown by HOMA, is an important determinant when compared with the magnitude of compensation from insulin sensitivity. Given the high prevalence of abnormal glucose tolerance, screening for (pre-)diabetes is mandatory. Insulin supplementation in diabetic subjects with CFTR ΔF508 mutation seems a rational therapy for consideration, although this does not preclude that therapy directed toward insulin resistance could also interact.

Available data suggest a possible link between abnormal vitamin D level and abnormal glucose homeostasis, two of the most common chronic medical conditions. Both conditions are associated with inflammation, and the exact mechanism for role of either on the other is not well clear. Literature investigating the link between vitamin D and either pre-diabetic states or diabetes is reviewed. Vitamin D deficiency is detrimental to insulin synthesis and secretion in animal and human studies. In humans, it has been shown by majority of observational studies, that vitamin D is positively correlated with insulin sensitivity and its role is mediated both by direct mechanism through the availability of vitamin D receptors in several tissues and indirectly through the changes in calcium levels. Large number of, but not all, variable samples cross sectional human trials have demonstrated an inverse relation between vitamin D status and impaired glucose tolerance, insulin resistance or diabetes. To compliment this conclusively, evidence from intervention studies is critically warranted before we can frankly state that vitamin D plays a role in diabetes prevention or treatment. Absence of both sizable prospective observational trials utilizing 25(OH)D as the main variable and the non-availability of randomized studies specifically designed to assess the effects of vitamin D on pre-diabetes and diabetes states, are the main obstacles to draw solid and conclusive relationships.

Insulin resistance after burn is associated with alterations in postreceptor insulin signaling and abnormal glucose homeostasis. The renin-angiotensin system (RAS) exerts a largely inhibitory role on insulin action and is activated after burn injury. We hypothesized that upregulation of RAS is involved in the development of insulin resistance in burned rats. We examined the possibility that an angiotensin II type 1 (AT1) receptor blocker, losartan, enhances insulin sensitivity and thereby increases glucose tolerance in thermally injured rats. A 30% body surface area burn was induced by immersion of the dorsum into water with a temperature level of 95 degrees C for 15 s. Sham-burned rats were immersed in water with a temperature level of 23 degrees C. Losartan (30 mg/kg per day) or placebo (water) was given by gavage immediately after the burn injury and daily for 3 days postburn injury, resulting in sham-burned, burn placebo, and burn losartan groups. Plasma angiotensin II levels between burn placebo and sham-burned groups were not different 3 days after burn injury. However, losartan significantly increased plasma angiotensin II levels (P0.05), suggesting blockade of the AT1 receptor. An oral glucose tolerance test was performed 3 days postburn injury. There was an increase in the area under the curve for insulin and the glucose insulin index in burn placebo group as compared with sham-burned group, indicating insulin resistance. Losartan treatment abolished the insulin resistance in burn as evidenced by an area under the curve for insulin and glucose insulin index lower than that in the burn placebo group and similar to that in the sham-burned group. This suggests that insulin resistance and glucose intolerance associated with burn injury is, in part, caused by RAS.

The prevalence and mechanisms of diabetes in hereditary haemochromatosis are not known. We therefore measured glucose tolerance, insulin secretory capacity and insulin sensitivity in adults with haemochromatosis.Subjects recruited from referrals to a haemochromatosis clinic underwent OGTT and frequently sampled IVGTT. A chart review of former clinic patients was also performed.The prevalence of diabetes (23%) and IGT (30%) was increased in haemochromatosis compared with matched control subjects (0% diabetes and 14% IGT). Subjects with haemochromatosis and diabetes were overweight (14%) or obese (86%). The prevalence of diabetes, as determined by chart review of fasting glucose values, in subjects who had haemochromatosis and were in the 40-79 years age range was 26%. Overall, patients with haemochromatosis and control subjects had similar values for acute insulin response to glucose and insulin sensitivity. However, patients with haemochromatosis and IGT had a 68% decrease in acute insulin response to glucose (p0.02) compared with those with NGT. They were not insulin-resistant, exhibiting instead a 62% increase in insulin sensitivity (NS). Haemochromatosis subjects with diabetes exhibited further declines in acute insulin response to glucose, insulin resistance, or both.Diabetes and IGT are common in haemochromatosis, justifying screening for diabetes and therapeutic phlebotomy. The major abnormality associated with IGT is decreased insulin secretory capacity. Diabetes is usually associated with obesity and concomitant insulin resistance.