Elevated circulating Neuregulin4 level in patients with diabetes.

BACKGROUND: Neuregulin4 (Nrg4) is a novel adipokine expressed in adipose tissues, enriched in brown adipose tissue, and able to improve whole-body metabolism in rodent, thus having the potential to treat obesity-associated disorders such as diabetes. However, the association between serum Nrg4 levels and diabetes risk in human remains unclear. This study was designed to examine circulating Nrg4 levels in subjects with different glucose tolerance status. METHODS: Age-, sex-, and body mass index-matched subjects (n = 310: 83 normal glucose tolerance [NGT], 129 prediabetes, and 96 diabetes) from the Risk Evaluation of Cancers in Chinese Diabetic Individuals: A Longitudinal study (Reaction study) were included. Serum Nrg4 was measured via enzyme-linked immunosorbent assay. Basic anthropometric parameters, fasting plasma glucose and 2-hours postload plasma glucose, hemoglobin A1c , and serum lipid profile were also measured. RESULTS: The serum Nrg4 levels were higher in patients with diabetes than those with NGT and prediabetes (diabetes: 396.8[65.9, 709.4], NGT: 80.1[0, 554.1], prediabetes: 168.0[32.9, 463.9] pg/mL [median (interquartile range), both P < 0.05]). The Nrg4 concentration was correlated with fasting plasma glucose. When the top versus bottom quartiles of serum Nrg4 concentrations were compared with adjustment for age and sex, an odds ratio of 3.005 was observed in diabetes prevalence, which persisted after adjusting other potential confounding variables. Other nonglucose parameters as body mass index; waist, hip, and neck circumferences; alanine aminotransferase; triglyceride; high-density lipoprotein; uric acid; and estimated glomerular filtration rate were also correlated with serum Nrg4 (P < 0.05). CONCLUSIONS: The circulating Nrg4 level is elevated in the prediabetic and diabetic patients compared to control and is an independent risk factor associated with diabetes.

Predictive modeling the probability of suffering from metabolic syndrome using machine learning: A population-based study.

Background: There is an increasing trend of Metabolic syndrome (MetS) prevalence, which has been considered as an important contributor for cardiovascular disease (CVD), cancers and diabetes. However, there is often a long asymptomatic phase of MetS, resulting in not diagnosed and intervened so timely as needed. It would be very helpful to explore tools to predict the probability of suffering from MetS in daily life or routinely clinical practice. Objective: To develop models that predict individuals' probability of suffering from MetS timely with high efficacy in general population. Methods: The present study enrolled 8964 individuals aged 40-75 years without severe diseases, which was a part of the REACTION study from October 2011 to February 2012. We developed three prediction models for different scenarios in hospital (Model 1, 2) or at home (Model 3) based on LightGBM (LGBM) technique and corresponding logistic regression (LR) models were also constructed for comparison. Model 1 included variables of laboratory tests, lifestyles and anthropometric measurements while model 2 was built with components of MetS excluded based on model 1, and model 3 was constructed with blood biochemical indexes removed based on model 2. Additionally, we also investigated the strength of association between the predictive factors and MetS, as well as that between the predictors and each component of MetS. Results: In this study, 2714 (30.3%) participants suffer from MetS accordingly. The performances of the LGBM models in predicting the probability of suffering from MetS produced good results and were presented as follows: model 1 had an area under the curve (AUC) value of 0.993 while model 2 indicated an AUC value of 0.885. Model 3 had an AUC value of 0.859, which is close to that of model 2. The AUC values of LR model 1 and 2 for the scenario in hospital and model 3 at home were 0.938, 0.839 and 0.820 respectively, which seemed lower than that of their corresponding machine learning models, respectively. In both LGBM and logistic models, gender, height and resting pulse rate (RPR) were predictors for MetS. Women had higher risk of MetS than men (OR 8.84, CI: 6.70-11.66), and each 1-cm increase in height indicated 3.8% higher risk of suffering from MetS in people over 58 years, whereas each 1- Beat Per Minute (bpm) increase in RPR showed 1.0% higher risk in individuals younger than 62 years. Conclusion: The present study showed that the prediction models developed by machine learning demonstrated effective in evaluating the probability of suffering from MetS, and presented prominent predicting efficacies and accuracies. Additionally, we found that women showed a higher risk of MetS than men, and height in individuals over 58 years was important factor in predicting the probability of suffering from MetS while RPR was of vital importance in people aged 40-62 years.

Not performing an OGTT results in underdiagnosis, inadequate risk assessment and probable cost increases of (pre)diabetes in Han Chinese over 40 years: a population-based prospective cohort study.

OBJECTIVE: To explore the influence by not performing an oral glucose tolerance test (OGTT) in Han Chinese over 40 years. DESIGN: Overall, 6682 participants were included in the prospective cohort study and were followed up for 3 years. METHODS: Fasting plasma glucose (FPG), 2-h post-load plasma glucose (2h-PG), FPG and 2h-PG (OGTT), and HbA1c testing using World Health Organization (WHO) or American Diabetes Association (ADA) criteria were employed for strategy analysis. RESULTS: The prevalence of diabetes is 12.4% (95% CI: 11.6-13.3), while the prevalence of prediabetes is 34.1% (95% CI: 32.9-35.3) and 56.5% (95% CI: 55.2-57.8) using WHO and ADA criteria, respectively. 2h-PG determined more diabetes individuals than FPG and HbA1c. The testing cost per true positive case of OGTT is close to FPG and less than 2h-PG or HbA1c. FPG, 2h-PG and HbA1c strategies would increase costs from complications for false-positive (FP) or false-negative (FN) results compared with OGTT. Moreover, the least individuals identified as normal by OGTT at baseline developed (pre)diabetes, and the most prediabetes individuals identified by HbA1c or FPG using ADA criteria developed diabetes. CONCLUSIONS: The prevalence of isolated impaired glucose tolerance and isolated 2-h post-load diabetes were high, and the majority of individuals with (pre)diabetes were undetected in Chinese Han population. Not performing an OGTT results in underdiagnosis, inadequate developing risk assessment and probable cost increases of (pre)diabetes in Han Chinese over 40 years and great consideration should be given to OGTT in detecting (pre)diabetes in this population. Further population-based prospective cohort study of longer-term effects is necessary to investigate the risk assessment and cost of (pre)diabetes.

Non-high-density lipoprotein cholesterol: High-density lipoprotein cholesterol ratio is an independent risk factor for diabetes mellitus: Results from a population-based cohort study.

BACKGROUND: Dyslipidemia predicts the development and progression of diabetes. A higher non-high-density lipoprotein cholesterol (HDL-C): HDL-C ratio is reportedly associated with metabolic syndrome and insulin resistance, but its relationship with glycemic levels and diabetes remains unclear. METHODS: In all, 4882 subjects aged ≥40 years without diabetes and not using lipid-lowering drugs were enrolled in the study. The non-HDL-C: HDL-C ratio was log10 transformed to achieve normal distribution. Multivariate logistic regression was used to investigate the association between the log10 -transformed non-HDL-C: HDL-C ratio and diabetes. Stratified analyses of the association by age, gender, and body mass index (BMI) were also performed. RESULTS: After 3 years of follow-up, 704 participants developed diabetes. After adjustment for age, gender, current smoking, current drinking, physical activity, BMI, systolic blood pressure, and family history of diabetes, each 1-SD increase in the log(non-HDL-C: HDL-C ratio) was associated with higher fasting blood glucose (FPG) levels (ß = 0.1; 95% confidence interval [CI] 0.1-0.1), 2-h postload plasma glucose levels (2-h glucose; ß = 0.2; 95% CI 0.1-0.2), and risk of diabetes (odds ratio [OR] 1.1; 95% CI 1.0-1.2). In a multivariate model, subjects in the top quartile of non-HDL-C: HDL-C ratio had higher FPG (ß = 0.2; 95% CI 0.2-0.3), 2-h glucose (ß = 0.5; 95% CI 0.3-0.7) and HbA1c (ß = 0.1; 95% CI 0.1-0.2) levels, and a 40% increased risk of diabetes (OR 1.4; 95% CI 1.1-1.8) than participants in the bottom quartile. CONCLUSIONS: The non-HDL-C: HDL-C ratio was found to be an independent risk factor for diabetes.

Genetic Regulation of the Thymic Stromal Lymphopoietin (TSLP)/TSLP Receptor (TSLPR) Gene Expression and Influence of Epistatic Interactions Between IL-33 and the TSLP/TSLPR Axis on Risk of Coronary Artery Disease.

The thymic stromal lymphopoietin (TSLP)/TSLP receptor (TSLPR) axis is involved in multiple inflammatory immune diseases, including coronary artery disease (CAD). To explore the causal relationship between this axis and CAD, we performed a three-stage case-control association analysis with 3,628 CAD cases and 3,776 controls using common variants in the genes TSLP, interleukin 7 receptor (IL7R), and TSLPR. Three common variants in the TSLP/TSLPR axis were significantly associated with CAD in a Chinese Han population [rs3806933T in TSLP, Padj = 4.35 × 10-5, odds ratio (OR) = 1.18; rs6897932T in IL7R, Padj = 1.13 × 10-7, OR = 1.31; g.19646A>GA in TSLPR, Padj = 2.04 × 10-6, OR = 1.20]. Reporter gene analysis demonstrated that rs3806933 and rs6897932 could influence TSLP and IL7R expression, respectively. Furthermore, the "T" allele of rs3806933 might increase plasma TSLP levels (R2 = 0.175, P < 0.01). In a stepwise procedure, the risk for CAD increased by nearly fivefold compared with the maximum effect of any single variant (Padj = 6.99 × 10-4, OR = 4.85). In addition, the epistatic interaction between TSLP and IL33 produced a nearly threefold increase in the risk of CAD in the combined model of rs3806933TT-rs7025417TT (Padj = 3.67 × 10-4, OR = 2.98). Our study illustrates that the TSLP/TSLPR axis might be involved in the pathogenesis of CAD through upregulation of mRNA or protein expression of the referenced genes and might have additive effects on the CAD risk when combined with IL-33 signaling.

Alteration of FXR phosphorylation and sumoylation in liver in the development of adult catch-up growth.

Catch-up growth in adult, is increasingly recognized as an important causative factor for the extremely prevalent insulin resistance-related diseases especially in developing countries/territories. We aimed to investigate the alteration of bile acids level, phosphorylation and sumoylation of its interacting protein, bile acid receptor/farnesoid X receptor and their downstream signaling pathway, as well as insulin sensitivity and lipid profile in catch-up growth in adult rats. Male Sprague-Dawley rats were randomly allocated into four groups for two sampling points: caloric restriction group, catch-up growth in adult refed with normal chow and their normal chow controls for four or eight weeks (N4, N8 individually).We found that total serum bile acids and farnesoid X receptor phosphorylation increased without significant changes in farnesoid X receptor sumoylation and its downstream small heterodimer partner expression at the end of caloric restriction stage, while the visceral fat decreased and insulin resistance never occurred in these animals; After refeeding, total serum bile acids, farnesoid X receptor phosphorylation and sumoylation, as well as Cyp7a1, SREBP-1c mRNA levels were higher with significant decrease in small heterodimer partner expression, which is associated fat accumulation, and drastic insulin resistance in whole body and skeletal muscle. Our findings demonstrated that the fat accumulation and insulin resistance are associated with increases of bile acids, alteration of farnesoid X receptor phosphorylation, and sumoylation and its downstream signaling pathway. These changes of bile acids, farnesoid X receptor phosphorylation and sumoylation, as well as their downstream signaling might be of importance in the etiology of fat accumulation and insulin resistance in catch-up growth in adult.

Renoprotective effects of fenofibrate in diabetic rats are achieved by suppressing kidney plasminogen activator inhibitor-1.

To investigate mechanisms of protective effects of fenofibrate on the diabetic kidney, male Wistar rats were divided into control, untreated diabetes, and fenofibrate-treated (32 mg kg(-1) d(-1), 8 weeks) diabetes groups. Diabetes induced by streptozotocin (25 mg/kg) and a high-fat diet was characterized by the disorders of plasma glucose and lipids. In untreated diabetic rats, there were increases in glomerular volume, matrix content, expressions of laminin and urinary albumin excretion. These nephropathies were associated with the upregulations of plasminogen activator inhibitor 1 (PAI-1) mRNA expression and its protein activity in the renal cortex, and a significant increase in transforming growth factor beta1 (TGF-beta1) expression. Treatment with fenofibrate suppressed the expression of PAI-I mRNA and its protein activity, and inhibited TGF-beta1 overexpression. It also partially reversed metabolic disorders and pathophysiologic changes associated with diabetic nephropathy. Our results indicate that fenofibrate delays the progression of diabetic nephropathy in rats to some extent. These renoprotective effects are likely to be achieved through suppression of PAI-1 and TGF-beta1 in the renal cortex, and consequently less extracellular matrix deposition.

Liraglutide prevents fast weight gain and ß-cell dysfunction in male catch-up growth rats.

We reported recently that after a nutritional growth retardation, rats showed significant weight gain, central fat accumulation, dyslipidemia, and ß-cell dysfunction during a catch-up growth (CUG) phase. Here, we investigated whether glucagon-like peptide-1 (GLP-1) ameliorated the rapid weight gain, central fat deposition, and ß-cell dysfunction during the CUG in rats. Sixty-four male Sprague Dawley rats were stratified into four groups including normal control group, CUG group, catch-up growth with liraglutide treatment group, and catch-up growth with liraglutide and exendin 9-39 treatment group. Energy intake, body weight, and body length were monitored. Fat mass percentage was analyzed by dual energy X-ray absorptiometry scan. Plasma triglyceride and non-esterified fatty acid were measured. The ß-cell mass was analyzed by morphometric analysis and signaling molecules were examined by Western blot and real-time PCR. Insulin secretion capability was evaluated by hyperglycemic clamp test. Liraglutide prevented weight gain and improved lipid and glucose metabolism in rats under CUG conditions, which were associated with reduced fasting insulin levels and improved glucose-stimulated insulin secretion. Improved ß-cell function is found to be associated with increased ß-cell replication as determined by ß-cell density and insulin-Ki67 dual staining. Furthermore, liraglutide increased islet pancreatic duodenal homeobox-1 (Pdx-1) and B-cell lymphoma-2 transcript and protein expression, and reduced Procaspase-3 transcript and Caspase-3 p11 subunit protein expression, suggesting that expression of Pdx-1 and reduction of apoptosis may be the mechanisms involved. The therapeutic effects were attenuated in rats co-administered with exendin 9-39, suggesting a GLP-1 receptor-dependent mechanism. These studies revealed that incretin therapy effectively prevented fast weight gain and ß-cell dysfunction in rats under conditions of nutrition restriction followed by nutrition excess, which is in part due to enhanced functional ß-cell mass and insulin secretory capacity.

Increases in systemic and local stress: a probable mechanism of visceral fat accumulation and insulin resistance in adult catch-up growth rats?

Catch-up growth in adult (CUGA) is increasingly proposed as an important causative factor for the widespread insulin resistance (IR)-related diseases especially in developing countries/territories. We aimed to investigate the effects of CUGA to insulin sensitivity, lipid profile and stress in rats, as well as the probable relationship among them. Male Sprague-Dawley rats were randomly divided into six groups for two sampling points: caloric restriction group (R4) and normal chow controls for four weeks (NC4); CUGA re-fed with normal chow (RN4), CUGA re-fed with high-fat diet (RH4), normal chow controls (NC8) and high-fat diet controls (HF8) for eight weeks. Visceral fat accumulation (visceral adipose tissue [VAT] percentage), systemic (plasma corticosterone) and local (HSD11B1 mRNA expression in skeletal muscle [SkM] and VAT) stress, whole-body and peripheral insulin sensitivity were determined in this study. After four weeks of caloric restriction, R4 rats showed increases in systemic and local stress, decreases in visceral fat accumulation and no IR (whole-body or peripheral). Yet, after re-feeding, sustained systemic and local stress, remarkable visceral fat accumulation and IR (whole-body and peripheral) were found in RN4 compared with NC8, in RH4 compared with NC8 and HF8. Our findings demonstrated that CUGA rats were characterized by significant IR, visceral fat accumulation and stress. These changes were more severe in CUGA re-fed with high-fat diet. The interaction of sustained caloric restriction-induced stress and re-feeding might be of utmost importance in the etiology of visceral fat accumulation and IR in CUGA.

Influence of catch-up growth on islet function and possible mechanisms in rats.

OBJECTIVE: The purpose of this study was to examine how catch-up growth modulated islet function and what the detailed mechanisms were, especially at various stages and in different forms, of catch-up growth. METHODS: We examined the modulation of islet function during catch-up growth by employing an oral glucose tolerance test and gained some insight into the possible mechanisms involved by measuring general physiologic parameters, pancreatic morphometry, insulin content, and the state of chronic oxidative stress. Correlation analyses were used to assess the correlation of insulin/glucose incremental area ratio to other parameters. RESULTS: The catch-up growth groups resulted in damage to islet function as shown by an increased insulin/glucose incremental area ratio (P ≤ 0.05), smaller relative area of ß-cells (P ≤ 0.05), larger relative area of α-cells (P ≤ 0.05), lower insulin content (P ≤ 0.05), increased nitric oxide and malondialdehyde concentrations, and decreased superoxide dismutase concentration (P ≤ 0.05, respectively). With time these changes became increasingly unmarked. CONCLUSION: Catch-up growth in different stages and forms induces varying degrees of islet dysfunction, possibly by corresponding changes in general physiologic parameters, pancreatic morphometry, insulin content, and the state of chronic oxidative stress.

Insulin improves ß-cell function in glucose-intolerant rat models induced by feeding a high-fat diet.

Insulin therapy has been shown to contribute to extended glycemia remission in newly diagnosed patients with type 2 diabetes mellitus. This study investigated the effects of insulin treatment on pancreatic lipid content, and ß-cell apoptosis and proliferation in glucose-intolerant rats to explore the protective role of insulin on ß-cell function. A rat glucose-intolerant model was induced by streptozotocin and a high-fat diet. Plasma and pancreatic triglycerides, free fatty acids, and insulin were measured; and pancreatic ß-cell cell apoptosis and proliferation were detected by a propidium iodide cell death assay and immunofluorescence for proliferating cell nuclear antigen. Relative ß-cell area was determined by immunohistochemistry for insulin, whereas insulin production in pancreas was assessed by reverse transcriptase polymerase chain reaction. Islet ß-cell secreting function was assessed by the index ΔI30/ΔG30. Glucose-intolerant rats had higher pancreatic lipid content, more islet ß-cell apoptosis, lower ß-cell proliferation, and reduced ß-cell area in pancreas when compared with controls. Insulin therapy reduced blood glucose, inhibited pancreatic lipid accumulation and islet ß-cell apoptosis, and increased ß-cell proliferation and ß-cell area in glucose-intolerant rats. Furthermore, impaired insulin secretion and insulin production in glucose-intolerant rats were improved by insulin therapy. Insulin can preserve ß-cell function by protecting islets from glucotoxicity and lipotoxicity. It can also ameliorate ß-cell area by enhancing ß-cell proliferation and reducing ß-cell apoptosis.

Lipid overaccumulation and drastic insulin resistance in adult catch-up growth rats induced by nutrition promotion after undernutrition.

This study was designed to explore the metabolic changes resulting from catch-up growth in adult (CUGA) induced by varying degrees of nutrition promotion after undernutrition and to confirm whether these changes are transient or not. The CUGA models were developed on rats refed on intakes of normal chow or high-fat diet after a period of caloric restriction. The growth of the rats measured by body weight and length stagnated during caloric restriction and then rapidly accelerated following refeeding. Catch-up growth in adult resulted in an increase in intramuscular and intrahepatic lipid content, visceral fat deposition, and insulin resistance, which is consistent with a transient rise in food efficiency during the early stage of refeeding. In addition, ectopic lipid deposition, visceral fat accumulation, and insulin resistance were more severe in rats refed the high-fat diet than rats refed the normal chow. These findings suggest that CUGA induced by rapid nutrition promotion could result in persistent lipid overaccumulation (increased visceral fat and ectopic lipid deposition) and drastic systemic insulin resistance. The effects of CUGA on metabolic characteristics are dependent on the type of diet that is used for refeeding, especially on the amount of fat intake.

Increases in energy intake, insulin resistance and stress in rats before Wenchuan earthquake far from the epicenter.

The study of pre-earthquake (PE) behavior in animals has always been shrouded by controversy. There is very little scientific evidence showing that animals can sense the coming of an earthquake and that their organisms undergo physiological changes during the PE period. On the day of the Wenchuan earthquake, prior to the time of its actual occurrence, we were coincidentally able to measure the insulin sensitivity and stress level in rats that were originally part of another study. We detected defects in insulin signaling and a decrease in glucose uptake in skeletal muscle (SkM) and adipose tissue (AT), indicating impaired insulin sensitivity. These changes were associated with significantly increased plasma corticosterone concentration and elevated HSD11B1 mRNA expression in SkM and AT. The increase in insulin resistance (IR) could be attributed to elevated local (SkM and AT) and systemic stress. Interestingly, we also noticed that the food intake in rats showed a sudden increase two days before the earthquake and reached a peak on the day of the earthquake itself. Our observations suggest the possibility that the rats underwent PE physiological changes consisting of an increase in the stress level and consequently leading to an increase in food intake and IR.