Whole fresh fruit intake and risk of incident diabetes in different glycemic stages: a nationwide prospective cohort investigation.

PURPOSE: Fruit intake is beneficial to several chronic diseases, but controversial in diabetes. We aimed to investigate prospectively the associations of whole fresh fruit intake with risk of incident type 2 diabetes (T2D) in subjects with different glucose regulation capacities. METHODS: The present study included 79,922 non-diabetic participants aged ≥ 40 years from an ongoing nationwide prospective cohort in China. Baseline fruit intake information was collected by a validated food frequency questionnaire. Plasma HbA1c, fasting and 2 h post-loading glucose levels were measured at both baseline and follow-up examinations. Cox proportional hazards models were used to calculate hazard ratio (HR) and 95% confidence intervals (CI) for incident diabetes among participants with normal glucose tolerance (NGT) and prediabetes, after adjusted for multiple confounders. Restricted cubic spline analysis was applied for dose-response relation. RESULTS: During a median 3.8-year follow-up, 5886 (7.36%) participants developed diabetes. Overall, we identified a linear and dose-dependent inverse association between dietary whole fresh fruit intake and risk of incident T2D. Each 100 g/d higher fruit intake was associated with 2.8% lower risk of diabetes (HR 0.972, 95%CI [0.949-0.996], P = 0.0217), majorly benefiting NGT subjects with 15.2% lower risk (HR 0.848, 95%CI [0.766-0.940], P = 0.0017), while not significant in prediabetes (HR 0.981, 95%CI 0.957-4.005, P = 0.1268). Similarly, the inverse association was present in normoglycemia individuals with a 48.6% lower risk of diabetes when consuming fruits > 7 times/week comparing to those < 1 time/week (HR 0.514, 95% CI [0.368-0.948]), but not in prediabetes (HR 0.883, 95% CI [0.762-1.023]). CONCLUSION: These findings suggest that higher frequency and amount of fresh fruit intake may protect against incident T2D, especially in NGT, but not in prediabetes, highlighting the dietary recommendation of higher fresh fruit consumption to prevent T2D in normoglycemia population.

Diagnosis, treatment and genetic analysis of a case of skin hyperpigmentation as the only manifestation with X-linked adrenoleukodystrophy.

X-linked adrenoleukodystrophy (X-ALD) is an inherited disease caused by a mutation in the adenosine 5'-triphosphate binding cassette subfamily D member 1 (ABCD1) gene encoding a peroxisomal transmembrane protein, which has various clinical manifestations and a rapid progression from initial symptoms to fatal inflammatory demyelination. Therefore, identification of early clinical symptoms and further early diagnosis as well as treatment can effectively prevent disease development. In this study, we reported the laboratory and radiographic features in a rare case of X-ALD with 3-year skin hyperpigmentation as the only manifestation. And the ABCD1 gene was sequenced for the patient and his parents by a high-throughput sequencing method. The results of laboratory examination showed adrenocortical hypofunction and increased serum concentrations of very long-chain fatty acids. Brain MRI showed no obvious abnormal signal shadow. A hemizygous mutation of c.521A>C was detected in the ABCD1 gene of the patient, and his mother has the same site heterozygous mutation. Therefore, this patient was diagnosed as "X-linked adrenoleukodystrophy". During the follow-up, adrenocortical hypothyroidism did not improve, and brain MRI showed few high-FLAIR signals in the white matter of the right radial corona and left parietal lobe, suggesting possible brain injury. X-ALD patients with only skin manifestations but no neurological abnormalities are easily neglected, but early diagnosis and early intervention are important ways to delay the progression of this disease. Therefore, genetic testing for early X-ALD is recommended in all male children patients with skin pigmentation as the sole clinical presentation and subsequent diagnosis of adrenal hypofunction.

Diagnosis and genetic analysis of a case of Waardenburg syndrome type 2 with hypogonadotropic hypogonadism caused by SOX10 gene deletion.

Hypogonadotropic hypogonadism (HH) is a disease defined by dysfunction of the hypothalamic- pituitary-gonadal hormone axis, leading to low sex hormone levels and impaired fertility. HH with anosmia or hyposmia is known as Kallmann syndrome (KS). Waardenburg syndrome (WS) is a rare autosomal dominant genetic disorder characterized by sensorineural hearing loss and abnormal pigmentation. In this report, we collected the clinical data of a patient with hypogonadotropic hypogonadism and congenital hearing loss of unknown cause. The patient had no obvious secondary sexual characteristics development after puberty, and had a heterozygous deletion (at least 419 kb) in 22q13.1 region (Chr.22:38106433-38525560), which covered the SOX10 gene. The abnormalities were not found in gene sequencing analysis of both the parents and sister of the proband. By summarizing and analyzing the characteristics of this case, we further discussed the molecular biological etiological association between HH and WS type 2. This case also enriches the clinical data of subsequent genetic studies, and provides a reference for the diagnosis and treatment of such diseases.

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.

TLR4/AP-1-Targeted Anti-Inflammatory Intervention Attenuates Insulin Sensitivity and Liver Steatosis.

Insulin resistance has been shown to be the common pathogenesis of many metabolic diseases. Metainflammation is one of the important characteristics of insulin resistance. Macrophage polarization mediates the production and development of metainflammation. Toll-like receptor 4 (TLR4) mediates macrophage activity and is probably the intersection of immunity and metabolism, but the detailed mechanism is probably not fully understood. Activated protein 1 (AP1) signaling pathway is very important in macrophage activation-mediated inflammation. However, it is unclear whether AP1 signaling pathway mediates metabolic inflammation in the liver. We aimed to investigate the effects of macrophage TLR4-AP1 signaling pathway on hepatocyte metabolic inflammation, insulin sensitivity, and lipid deposition, as well as to explore the potential of TLR4-AP1 as new intervention targets of insulin resistance and liver steatosis. TLR4 and AP1 were silenced in the RAW264.7 cells by lentiviral siRNA transfection. In vivo transduction of lentivirus was administered in mice fed with high-fat diet. Insulin sensitivity and inflammation were evaluated in the treated cells or animals. Our results indicated that TLR4/AP-1 siRNA transfection alleviated high-fat diet-induced systemic and hepatic inflammation, obesity, and insulin resistance in mice. Additionally, TLR4/AP-1 siRNA transfection mitigated palmitic acid- (PA-) induced inflammation in RAW264.7 cells and metabolic abnormalities in cocultured AML hepatocytes. Herein, we propose that TLR4-AP1 signaling pathway activation plays a crucial role in high fat- or PA-induced metabolic inflammation and insulin resistance in hepatocytes. Intervention of the TLR4 expression regulates macrophage polarization and metabolic inflammation and further alleviates insulin resistance and lipid deposition in hepatocytes.

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.

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.

Thyroid Hormones, Autoantibodies, Ultrasonography, and Clinical Parameters for Predicting Thyroid Cancer.

Our objective was to evaluate thyroid nodule malignancy prediction using thyroid function tests, autoantibodies, ultrasonographic imaging, and clinical data. We conducted a retrospective cohort study in 1400 patients with nodular thyroid disease (NTD). The thyroid stimulating hormone (TSH) concentration was significantly higher in patients with differentiated thyroid cancer (DTC) versus benign thyroid nodular disease (BTND) (p = 0.004). The receiver operating characteristic curve of TSH showed an AUC of 0.58 (95% CI 0.53-0.62, p = 0.001), sensitivity of 74%, and specificity of 57% at a cut-off of 1.59 mIU/L. There was an incremental increase in TSH concentration along with the increasing tumor size (p < 0.001). Thyroglobulin antibody (TgAb) concentration was associated with an increased risk of malignancy (p = 0.029), but this association was lost when the effect of TSH was taken into account (p = 0.11). Thyroid ultrasonographic characteristics, including fewer than three nodules, hypoechoic appearance, solid component, poorly defined margin, intranodular or peripheral-intranodular flow, and punctate calcification, can be used to predict the risk of thyroid cancer. In conclusion, our study suggests that preoperative serum TSH concentration, age, and ultrasonographic features can be used to predict the risk of malignancy in patients with NTD.

Beneficial effect of farnesoid X receptor activation on metabolism in a diabetic rat model.

Farnesoid X receptor (FXR) is an important regulator of glucose and lipid homeostasis. However, the exact role of FXR in diabetes remains to be fully elucidated. The present study examined the effects of chenodeoxycholic acid (CDCA), an agonist of FXR, on metabolism profile in a rat model of type 2 diabetes mellitus (T2DM). Male Wistar rats (8­week­old; n=40) were randomized into the following four groups (n=10): Untreated control, CDCA­treated, T2DM, and CDCA­treated T2DM. To establish the T2DM model, the rats were fed a high­fat diet (HFD) for 4 weeks and received a single low­dose intraperitoneal injection of streptozotocin (30 mg/kg), followed by an additional 4 weeks of HFD feeding. CDCA was administrated (10 mg/kg/d) intraperitoneally for 10 days. Reverse transcription­quantitative polymerase chain reaction and western blotting assays were performed to determine the RNA and protein expression of FXR, phosphoenolpyruvate carboxykinase, G6Pase, proliferator­activated receptor­Î³ coactivator­1 and short heterodimer partner in rat liver tissue. The results revealed that FXR activation by CDCA did not reduce body weight, but it lowered the plasma levels of fasting glucose, insulin and triglycerides in the T2DM rats. CDCA administration reversed the downregulation of the mRNA and protein expression of FXR in the T2DM rat liver tissue samples. Furthermore, treatment with CDCA reduced the mRNA and protein expression levels of phosphoenolpyruvate carboxykinase, glucose 6­phosphatase and peroxisome proliferator­activated receptor­Î³ coactivator­1 in the liver tissue samples of the T2DM rats. By contrast, CDCA treatment increased the mRNA and protein expression levels of short heterodimer partner in the liver tissue samples of the T2DM rats. In conclusion, FXR agonist treatment induces beneficial effects on metabolism in the rat T2DM model. In conclusion, the present study indicated that the FXR agonist may be useful for the treatment of T2DM and hypertriglyceridemia.

Depletion of Kupffer cells attenuates systemic insulin resistance, inflammation and improves liver autophagy in high-fat diet fed mice.

The objective of this study was to reveal the exact role of Kupffer cells in the diet-induced insulin resistance, inflammation and liver autophagy. C57BL/6j male mice were fed with either chow diet or high-fat diet (HFD) for 12 weeks. Meanwhile, HFD feeding mice received an intraperitoneal injection of either 0.2% GdCl3 solution (20mg/kg) twice a week to deplete Kupffer cells or natural saline (5mL/kg) as control. The mRNA expressions of Kupffer cells markers (CD68 and F4/80), insulin sensitivity, TNF-α concentration and NF-κB activation and parameters of autophagy were assessed. Results demonstrated that CD68 and F4/80 mRNA expressions in the liver were up-regulated in HFD fed animals, while significantly reduced after GdCl3 administration. HFD feeding led to insulin resistance and TNF-α level and activation of NF-κB in insulin-sensitive tissues (liver, adipose tissue and skeletal muscle) were significantly elevated. Interestingly, alterations above were reversed by varying degrees but significantly after Kupffer cells depletion. Furthermore, western blot showed hepatic LC3-II as well as phosphorylation of AMPK in liver and skeletal muscle were significantly lower in mice fed HFD, and these changes dramatically ameliorated by GdCl3 treating. In conclusion, selective depletion of Kupffer cells significantly attenuated diet-induced insulin resistance, inflammation and promoted liver autophagy. Strategies targeting Kupffer cells function or autophagic processes could be a promising approach to counteract diet induced obesity and related metabolic disorders.

Resveratrol supplementation restores high-fat diet-induced insulin secretion dysfunction by increasing mitochondrial function in islet.

Resveratrol (RSV), a natural compound, is known for its effects on energy homeostasis. Here we investigated the effects of RSV and possible mechanism in insulin secretion of high-fat diet rats. Rats were randomly divided into three groups as follows: NC group (animals were fed ad libitum with normal chow for 8 weeks), HF group (animals were fed ad libitum with high-fat diet for 8 weeks), and HFR group (animals were treated with high-fat diet and administered with RSV for 8 weeks). Insulin secretion ability of rats was assessed by hyperglycemic clamp. Mitochondrial biogenesis genes, mitochondrial respiratory chain activities, reactive oxidative species (ROS), and several mitochondrial antioxidant enzyme activities were evaluated in islet. We found that HF group rats clearly showed low insulin secretion and mitochondrial complex dysfunction. Expression of silent mating type information regulation 2 homolog- 1 (SIRT1) and related mitochondrial biogenesis were significantly decreased. However, RSV administration group (HFR) showed a marked potentiation of glucose-stimulated insulin secretion. This effect was associated with elevated SIRT1 protein expression and antioxidant enzyme activities, resulting in increased mitochondrial respiratory chain activities and decreased ROS level. This study suggests that RSV may increase islet mitochondrial complex activities and antioxidant function to restore insulin secretion dysfunction induced by high-fat diet.

Coronary heart disease risk equivalence in diabetes and arterial diseases characterized by endothelial function and endothelial progenitor cell.

AIMS: Peripheral Arterial Disease (PAD), Carotid Artery Disease (CAD), and Type 2 Diabetes Mellitus (DM) were considered as "Coronary Heart Disease (CHD) risk equivalents". Vascular endothelial dysfunction was recognized as an early event in the development of atherosclerosis. Involved in neovasculogenesis and maintenance of vascular homeostasis, endothelial progenitor cell (EPC) has been considered as a biological marker of cardiovascular disease. The purpose of this study was to assess the CHD risk equivalents concept by investigating the endothelial function and circulating EPC number in patients with CHD, PAD, CAD and T2DM. METHODS: There were four groups in the study: CHD (n = 19), AD [PAD and CAD (n = 17)], DM (n = 21) and healthy controls (HC, n = 20). PAD and CAD were assessed by ultrasonography. Coronal artery angiography was used to identify CHD. The diagnosis of T2DM was based on oral glucose tolerance test and medical history. Vascular endothelial function was assessed by flow-mediated brachial artery dilatation (FMD). Circulating EPC was quantified by flow cytometry. RESULTS: The circulating EPC numbers in four groups were CHD, 973 ± 96; AD, 1048 ± 97; T2DM, 1210 ± 125; HC, 1649 ± 112 cells/ml. There were no significant differences in circulating EPC numbers between CHD and AD groups (P > 0.05). Compared with CHD or AD group, T2DM group was associated with a slight increase in circulating EPC numbers (P < 0.05). The results of FMD were almost similar to the circulating EPC numbers(CHD, 4.06 ± 0.54; AD, 3.90 ± 0.48; DM, 3.85 ± 0.57; HC, 5.52 ± 0.67%)except that there was no significant difference among the CHD, AD and T2DM groups (P > 0.05). Age, glycosylated hemoglobin, low density lipoprotein cholesterol, systolic blood pressure, body mass index (BMI) and medical history were the independent risk factors of circulating EPC number in all the patients (P < 0.05). Age, total cholesterol, BMI and medical history were the independent risk factors of FMD in all of the patients (P<0.05). CONCLUSIONS: The results of this study supported the equivalents hypothesis and revealed that "CHD risk equivalents" were characterized by the consistent physiological changes of blood vessels in angiogenesis, repairing ability and endothelial function.

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.

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.

Effects of gliclazide on endothelial function in patients with newly diagnosed type 2 diabetes.

Endothelial dysfunction is thought to be a critical event in the pathogenesis of vasculopathy in type 2 diabetes and oxidant stress is a major etiological factor. Gliclazide, a second generation sulfonylurea, contains an azabicyclo-octyl ring, which has been described to have antioxidant properties. However, the effect of gliclazide on endothelial function is unknown. Therefore, in this study, we examined the effect of gliclazide on endothelial function in patients with newly diagnosed type 2 diabetes (diabetic group; n=33). A control group of non-diabetic subjects was also enrolled (n=25). All of the diabetic patients were treated with gliclazide for 12 weeks. Endothelial function was evaluated by flow-mediated vasodilation (FMD) before and after treatment. We also determined the number of circulating endothelial progenitor cells (EPCs), which were defined by CD45(low)/CD34(+)/VEGFR2(+) and quantified by flow cytometry, because these cells may offer a new biomarker for circulatory diseases. Oxidative stress was evaluated in terms of the serum levels of malondialdehyde, superoxide dismutase and nitric oxide. FMD, circulating EPC count and superoxide dismutase activity were significantly lower in the diabetic group than in the control group at baseline (P<0.05), and improved significantly following gliclazide treatment (P<0.05). Malondialdehyde and nitric oxide levels were higher in the diabetic group than in the control group at baseline (P<0.05), and decreased following gliclazide treatment. These results suggest that gliclazide could improve endothelial function in diabetes, which may be related to its antioxidant properties.

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.

Effects of metformin plus gliclazide compared with metformin alone on circulating endothelial progenitor cell in type 2 diabetic patients.

Circulating endothelial progenitor cells (EPCs) play an important role in the development and progression of diabetic vascular complications. The aim of this study was to investigate the effects of gliclazide plus metformin (GLIMET) compared with metformin alone (MET) on number and function of circulating EPCs in T2DM patients. Patients with newly diagnosed T2DM were randomly divided into two groups, receiving the following treatments for 16 weeks: MET group (assuming metformin 500-2500 mg/day, n=24) and GLIMET group [assuming gliclazide (modified release, 30-60 mg/day)+metformin (250-1000 mg/day), n=23]. Circulating EPCs were quantified by flow cytometry, and the ability to uptake LDL and stain for lectin were used as another method of characterizing EPCs ex vivo. The functions of circulating EPCs were evaluated by colony-forming units (CFU) and migration. The status of oxidative stress was analyzed by serum-free malonaldehyde (MDA) and superoxide dismutase (SOD). There were no significant differences in clinical characteristics and number and function of circulating EPCs between two groups at baseline. Glycemic responses were similar after treatments. Compared with MET group, GLIMET group was associated with an increase in circulating EPCs number, DiLDL-lectin-positive EPCs, and migration. The mean improvements in MDA and SOD of GLIMET group were more strongly upregulated than those of MET group. This study demonstrated that both metformin mono-treatment and metformin plus gliclazide combination treatment provided with improvements in number and function of circulating EPCs. Compared with metformin mono-treatment, early use of combination therapy with gliclazide plus metformin made more effective improvements in circulating EPCs.

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.