Juan Zheng

Resveratrol attenuates high-fat diet–induced insulin resistance by influencing skeletal muscle lipid transport and subsarcolemmal mitochondrial β-oxidation

Although resveratrol (RES) is implicated in the regulation of insulin sensitivity in rodents, the exact mechanism underlying this effect remains unclear. Therefore, we sought to investigate how RES affects skeletal muscle lipid transportation and lipid oxidation of subsarcolemmal (SS) and intermyofibrillar (IMF) mitochondrial populations in high-fat diet (HFD)-induced insulin resistance (IR) rats. Systemic and skeletal muscle insulin sensitivity together with expressions of several genes related to mitochondrial biogenesis and skeletal muscle lipid transportation was studied in rats fed a normal diet, an HFD, and an HFD with intervention of RES for 8 weeks. Citrate synthase (CS), electron transport chain (ETC) activities, and several enzymes for mitochondrial β-oxidation were assessed in SS and IMF mitochondria from tibialis anterior muscle. The HFD-fed rats exhibited obvious systemic and skeletal muscle IR as well as intramuscular lipid accumulation. SIRT1 activity and expression of genes related to mitochondrial biogenesis were greatly declined, whereas the gene for lipid transportation, FAT/CD36, was upregulated (P < .05). Subsarcolemmal but not IMF mitochondria displayed lower CS, ETC, and β-oxidation activities. By contrast, RES treatment protected rats against diet-induced intramuscular lipid accumulation and IR, increased SIRT1 activity and mitochondrial biogenesis, and reverted the decline in SS mitochondrial CS and ETC activities. Importantly, although expression of FAT/CD36 was increased (11%, P < .05), activities of SS mitochondrial β-oxidation enzymes were largely enhanced (41%~67%, P < .05). This study suggests that RES ameliorates insulin sensitivity consistent with an improved balance between skeletal muscle lipid transportation and SS mitochondrial β-oxidation in HFD rats.

The protective effect of resveratrol on islet insulin secretion and morphology in mice on a high-fat diet

The aim of this study was to investigate the effect of resveratrol on beta cells in male C57BL/6J mice fed a high-fat diet and the possible mechanisms. Male C57BL/6J mice were randomly divided into three groups: normal control (NC) group, high-fat diet (HF) group and high-fat diet and resveratrol treatment (HFR) group (15 in each group). HFR group was fed with high fat diet for 8 weeks and then orally administered resveratrol at 400mg/kg daily. Twenty-four weeks later, the function of insulin secretion in vivo and in vitro was improved robustly in HFR group compared with HF group. The levels of glucose and lipid metabolism, beta cell mass, lipid content, and oxidative stress were lower in HFR group than in HF group. Simultaneously, resveratrol administration promoted the expression of SIRT1 in islets, while the expression of uncoupling protein 2 (UCP2) was restrained. Resveratrol, as well, also had a beneficial effect on the ratios of expressions of Bcl-2/Bax and levels of malondialdehyde/glutathione peroxidase. Resveratrol can protect islets from abnormal insulin secretion and morphological changes induced by a high-fat diet. The effect might be partly related to activated SIRT1 signal pathway, improved oxidative stress induced damage and incidence of apoptosis.

Resveratrol improves insulin resistance of catch-up growth by increasing mitochondrial complexes and antioxidant function in skeletal muscle

Caloric restriction followed by refeeding, a phenomenon known as catch-up growth (CUG), affects mitochondrial function and results in systemic insulin resistance (IR). We investigated the potential of resveratrol (RES) in CUG to prevent IR by increasing activity of the mitochondrial respiratory chain and antioxidant enzymes in skeletal muscle. Rats (8 weeks of age) were divided into 3 groups: normal chow, CUG, and CUG with RES intervention. Skeletal muscle and systemic IR were measured in each group after 4 and 8 weeks. Mitochondrial biogenesis and function, oxidative stress levels, and antioxidant enzyme activity in skeletal muscle were assessed. Catch-up growth-induced IR resulted in significant reductions in both average glucose infusion rate(60-120) at euglycemia and skeletal muscle glucose uptake. Mitochondrial citrate synthase activity was lower; and the activity of complexes I to IV in the intermyofibrillar and subsarcolemmal (SS) mitochondria were reduced by 20% to 40%, with the decrease being more pronounced in the SS fraction. Reactive oxygen species levels were significantly higher in intermyofibrillar and SS mitochondria, whereas activities of antioxidant enzymes were decreased. Oral administration of RES, however, increased silent information regulator 1 activity and improved mitochondrial number and insulin sensitivity. Resveratrol treatment decreased levels of reactive oxygen species and restored activities of antioxidant enzymes. This study demonstrates that RES protects insulin sensitivity of skeletal muscle by improving activities of mitochondrial complexes and antioxidant defense status in CUG rats. Thus, RES has therapeutic potential for preventing CUG-related metabolic disorders.

Methylation status of CpG sites in the MCP-1 promoter is correlated to serum MCP-1 in Type 2 diabetes.

Aim: Monocyte chemoattractant protein-1 (MCP-1) is a potent chemokine and plays an important role in atherosclerosis of Type 2 diabetes. The aim of this study was to investigate the methylation status of CpG sites in the MCP-1 promoter in Type 2 diabetic patients and its correlation to serum MCP-1 level, and blood glucose level. Methods: The 32 patients with Type 2 diabetes and 15 healthy controls were enrolled into the study. Body mass index, blood pressure, blood lipid, blood glucose, glycosylated hemoglobin (HbA1c), and serum MCP-1 were measured. Genomic DNA was isolated from the peripheral blood mononuclear cells (PBMC). Methylation status of CpG sites in the MCP-1 promoter was determined using methylation specific polymerase chain reaction. Results: The promoter region (2890–3050 bp) was predominantly methylated in PBMC from controls. Methylation of CpG motifs were less methylated in the patients than in the controls (25% vs 80%; p<0.001), while the level of MCP-1 in serum was higher in patients with Type 2 diabetes (193.95±74.96 vs 88.46±55.10; p<0.001). MCP-1 promoter methylation was significantly correlated to serum MCP-1, HbA1c, fasting blood glucose, and triglyceride. Conclusion: These data suggest that hypomethylation of CpG sites in the MCP-1 promoter region may be affected by blood glucose and TG, which then increase the serum MCP-1 level and may play a role in the vascular complications of Type 2 diabetes.

Relationship between Serum TSH Level with Obesity and NAFLD in Euthyroid Subjects

SummaryTo explore the relationship between serum thyroid stimulating hormone (TSH) level and obesity and nonalcoholic fatty liver disease (NAFLD) in euthyroid subjects, 1322 subjects were subjected to a questionnaire survey and physical examination. Fasting blood samples were collected to test serum TSH, plasma glucose and lipids. Fatty liver was diagnosed by type B ultrasonography. The relationship between serum TSH level and body mass index (BMI), percentage of body fat and NAFLD was analyzed. The results showed that serum TSH level was significantly higher in females than in males at the same group, and it was significantly higher in overweight group than in control group. Levels of body weight, BMI, waist circumference and percentage of body fat were increased in TSH >2.5 group compared to TSH ≤2.5 group in women. However, plasma lipids showed no significant differences. In males all the parameters showed no significant differences between two groups. Serum TSH was significantly correlated with body weight, BMI, waist circumference and percentage of body fat after adjustment for age in females. Multiple linear regression analysis revealed that percentage of body fat and BMI contributed significantly to the variance of TSH. Serum TSH level was significantly higher in nonalcoholic fatty liver group than in normal group in females. Multiple logistic regression analysis showed that TSH level was not the independent risk factor of NAFLD. Taken together the data suggest that serum TSH in normal range is significantly correlated with BMI and percentage of body fat in females. And the change of TSH level would not influence the prevalence of NAFLD.To explore the relationship between serum thyroid stimulating hormone (TSH) level and obesity and nonalcoholic fatty liver disease (NAFLD) in euthyroid subjects, 1322 subjects were subjected to a questionnaire survey and physical examination. Fasting blood samples were collected to test serum TSH, plasma glucose and lipids. Fatty liver was diagnosed by type B ultrasonography. The relationship between serum TSH level and body mass index (BMI), percentage of body fat and NAFLD was analyzed. The results showed that serum TSH level was significantly higher in females than in males at the same group, and it was significantly higher in overweight group than in control group. Levels of body weight, BMI, waist circumference and percentage of body fat were increased in TSH >2.5 group compared to TSH ≤2.5 group in women. However, plasma lipids showed no significant differences. In males all the parameters showed no significant differences between two groups. Serum TSH was significantly correlated with body weight, BMI, waist circumference and percentage of body fat after adjustment for age in females. Multiple linear regression analysis revealed that percentage of body fat and BMI contributed significantly to the variance of TSH. Serum TSH level was significantly higher in nonalcoholic fatty liver group than in normal group in females. Multiple logistic regression analysis showed that TSH level was not the independent risk factor of NAFLD. Taken together the data suggest that serum TSH in normal range is significantly correlated with BMI and percentage of body fat in females. And the change of TSH level would not influence the prevalence of NAFLD.

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.

Insulin improves β-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 β-cell apoptosis and proliferation in glucose-intolerant rats to explore the protective role of insulin on β-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 β-cell cell apoptosis and proliferation were detected by a propidium iodide cell death assay and immunofluorescence for proliferating cell nuclear antigen. Relative β-cell area was determined by immunohistochemistry for insulin, whereas insulin production in pancreas was assessed by reverse transcriptase polymerase chain reaction. Islet β-cell secreting function was assessed by the index ΔI30/ΔG30. Glucose-intolerant rats had higher pancreatic lipid content, more islet β-cell apoptosis, lower β-cell proliferation, and reduced β-cell area in pancreas when compared with controls. Insulin therapy reduced blood glucose, inhibited pancreatic lipid accumulation and islet β-cell apoptosis, and increased β-cell proliferation and β-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 β-cell function by protecting islets from glucotoxicity and lipotoxicity. It can also ameliorate β-cell area by enhancing β-cell proliferation and reducing β-cell apoptosis.

Effect of catch-up growth after food restriction on the entero-insular axis in rats

BackgroundCatch-up growth after food restriction (CUGFR) is characterized by a significant change in food intake which could theoretically lead to the change in glucagon-like peptide-1 (GLP-1) secretion that consequently results in altered functions of pancreatic islets.MethodsExperimental rats were divided into two groups. Rats in CUGFR group were put on food-restriction for 4 weeks, and then allowed full access to food for 0, 2, 4 weeks respectively while rats in the control group were offered ad libitum access to food. Plasma glucose, insulin and GLP-1 level during OGTT were measured in all the rats. Moreover, morphology of intestinal mucosa, number of L cells, beta cell mass, incretin effect and the expression of GLP-1 receptor (GLP-1R) gene in the islets were also determined.ResultsThe size of pancreatic islets, insulin concentration, plasma GLP-1 concentration, incretin effect, villus height-to-crypt depth ratio and L cells were all significantly decreased in CUGFR group at the end of a 4-week food-restriction period as compared with the controls. Insulin concentration and the villus height-to-crypt depth ratio were increased and finally exceeded the level of the control group over a 4-week catch-up period. Nevertheless, at the conclusion of the study, islet size, L cells number, plasma GLP-1 concentration and incretin effect increased but failed to reach the levels of the controls.ConclusionCUGFR decreases incretin effect and disturbs the entero-insular axis partially by decreasing GLP-1 concentration, which might be responsible for the increased risk of metabolic disorder during CUGFR.

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.

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.