Comparative analysis of long non­coding RNA expression profiles induced by resveratrol and metformin treatment for hepatic insulin resistance.

Resveratrol (RSV) and metformin (MET) play a role in the treatment of diabetes; however, the mechanisms through which they mediate insulin resistance by regulating long non­coding RNAs (lncRNAs) remain unknown. The present study was conducted to determine whether RSV and MET can improve insulin resistance in the livers of high­fat diet (HFD)­fed mice by regulating lncRNAs. C57BL/6J mice were fed a HFD for 8 weeks to establish a model of insulin resistance. The mice were subsequently treated with RSV or MET for 8 weeks and liver tissue samples were then collected. High­throughput sequencing was utilized to analyze mouse liver tissue samples to obtain differential lncRNA expression profiles. RSV or MET both reduced the blood glucose levels, the insulin index and the area under the curve in HFD­fed mice. Treatment also improved liver structure and decreased lipid deposition in liver tissues, as shown by H&E and Oil Red O staining. Compared with the MET group, there were 55 lncRNAs and 19 mRNAs with a differential expression. In total, eight lncRNAs were randomly selected and evaluated by reverse transcription­quantitative PCR (RT­qPCR). The results of seven lncRNAs corresponded to those of the sequencing analysis. Pathway analysis revealed that the PI3K/Akt signaling pathway had the highest enrichment score. In addition, the results of western blot analysis and RT­qPCR revealed that the expression levels of forkhead box O1, glucose­6­phosphatase catalytic subunit 1 and phosphoenolpyruvate carboxykinase 1 in the RSV and MET groups were significantly decreased compared with those in the HFD group. NONMMUT034936.2 and G6PC target genes exhibited similar expression patterns, indicating that RSV and MET may affect the PI3K/Akt signaling pathway through NONMMUT034936.2 to attenuate insulin resistance. On the whole, the present study provides novel biomarkers or contemporary perspectives for the use of RSV and MET in the treatment of insulin resistance and diabetes.

Resveratrol Ameliorates High-Fat-Diet-Induced Abnormalities in Hepatic Glucose Metabolism in Mice via the AMP-Activated Protein Kinase Pathway.

Diabetes mellitus is highly prevalent worldwide. High-fat-diet (HFD) consumption can lead to liver fat accumulation, impair hepatic glycometabolism, and cause insulin resistance and the development of diabetes. Resveratrol has been shown to improve the blood glucose concentration of diabetic mice, but its effect on the abnormal hepatic glycometabolism induced by HFD-feeding and the mechanism involved are unknown. In this study, we determined the effects of resveratrol on the insulin resistance of high-fat-diet-fed mice and a hepatocyte model by measuring serum biochemical indexes, key indicators of glycometabolism, glucose uptake, and glycogen synthesis in hepatocytes. We found that resveratrol treatment significantly ameliorated the HFD-induced abnormalities in glucose metabolism in mice, increased glucose absorption and glycogen synthesis, downregulated protein phosphatase 2A (PP2A) and activated Ca2+/CaM-dependent protein kinase kinase ß (CaMKKß), and increased the phosphorylation of AMP-activated protein kinase (AMPK). In insulin-resistant HepG2 cells, the administration of a PP2A activator or CaMKKß inhibitor attenuated the effects of resveratrol, but the administration of an AMPK inhibitor abolished the effects of resveratrol. Resveratrol significantly ameliorates abnormalities in glycometabolism induced by HFD-feeding and increases glucose uptake and glycogen synthesis in hepatocytes. These effects are mediated through the activation of AMPK by PP2A and CaMKKß.

Research on polycystic ovary syndrome: a bibliometric analysis from 2009 to 2019.

Polycystic ovary syndrome (PCOS) is a common reproductive and endocrine disease. However, there have not been any bibliometric studies on the latest scientific results and research trends of PCOS. This study aimed to review the state of research in PCOS worldwide. Publications on PCOS from 2009 to 2019 were identified and evaluated from the database Web of Science. A total of 7814 articles were retrieved. Shanghai Jiao Tong University published the most articles, with 218 publications. Gynecol Endocrinol had the greatest number of publications (n = 541). J Clin Endocr Metab was cited the most, with a total of 32,207 times. An article written by March et al. in 2010 had the most global citations (737 times) and local citations (463 times). From 2009 to 2019, the number of PCOS global publications gradually increased. Gynecol Endocrinol and Endocr Metab were popular journals for PCOS research. Research trends gradually shifted from treatment and methodology to genetics and basic research. The terms 'microrna,' 'rt qpcr,' 'lncrna,' and 'histological examination' may be hotspots that should be focused on in PCOS research.

Long non-coding RNA expression profiling following treatment with resveratrol to improve insulin resistance.

Resveratrol (RSV) and long non­coding RNAs (lncRNAs) play a role in the treatment of diabetes; however, the mechanism by which resveratrol regulates insulin resistance via lncRNAs is currently unknown. The present study aimed to determine the lncRNA expression level profile in mice following resveratrol treatment to improve insulin resistance using high­throughput sequencing technology. C57BL/6J mice were fed a high­fat diet for 8 weeks to develop an insulin resistance model, followed by treatment with or without RSV for 6 weeks before high­throughput sequencing. Following RSV treatment, 28 and 30 lncRNAs were up­ and downregulated, respectively; eight lncRNAs were randomly selected and evaluated using reverse transcription­quantitative PCR, which showed results consistent with the sequencing analysis. Pathway analysis demonstrated that the insulin signaling pathway enrichment score was the highest, and identified two lncRNAs, NONMMUT058999.2 and NONMMUT051901.2, consistent with the protein­encoding genes SOCS3 and G6PC, respectively. Similar expression level patterns were observed for SOCS3 and G6PC, suggesting that RSV improves insulin resistance by modulating lncRNAs. RSV decreased the expression levels of SOCS3, FOXO1, G6PC and PEPCK in mice. The same results were observed following knockdown of NONMMUT058999.2 in cells. The present study provides a new biomarker or intervention target for RSV in the treatment of diabetes, and a new perspective for understanding the hypoglycemic mechanism of RSV.

Effect of resveratrol on intestinal tight junction proteins and the gut microbiome in high-fat diet-fed insulin resistant mice.

High-fat diet (HFD)-feeding induces changes in the microbiome and increases intestinal permeability by impairing tight junction (TJ) protein function, which may explain the insulin resistance (IR) and associated pathologies. We aimed to determine the effects of resveratrol (RES) on the gut microbiome and intestinal TJ proteins. Results showed that RES administration improved the lipid profile, and ameliorated the endotoxemia, inflammation, intestinal barrier defect and glucose intolerance in the HFD-fed mice. Furthermore, it modified the gut microbial composition, reducing the proportion of Firmicutes and the Firmicutes-to-Bacteroidetes ratio. Moreover, Verrucomicrobia and Akkermansia were much more abundant in the HFD + RES group. RES also significantly reduced the abundance of Bilophila and Ruminococcus. These findings suggest that RES may be useful for the treatment of IR and associated metabolic diseases.

Resveratrol Upregulates mmu-miR-363-3p via the PI3K-Akt Pathway to Improve Insulin Resistance Induced by a High-Fat Diet in Mice.

PURPOSE: This study aimed to investigate how resveratrol (RSV) improves high-fat diet (HFD)-induced hepatic insulin resistance in mice via microRNA (miRNA) mmu-miR-363-3p in vitro and in vivo. MATERIALS AND METHODS: C57BL/6J mice were fed a HFD for 8 weeks to establish an insulin resistance model. The model mice were treated or not with RSV for 6 weeks. Differential miRNA expression in mouse liver tissues was analyzed by high-throughput sequencing. Mouse HepG2 cells were treated with palmitic acid (PA) to establish a cell model of insulin resistance. HepG2 cells were transfected with mmu-miR-363-3p inhibitor or mimic, and the expression of PI3K-Akt signaling pathway-related proteins was analyzed. RESULTS: Based on the high-throughput sequencing analysis, mmu-miR-363-3p was identified as a major miRNA involved in the action of RSV on insulin resistance. Based on KEGG pathway enrichment analysis, PI3K-Akt signaling was found to be significantly enriched among differentially expressed miRNAs, and this pathway is closely related to insulin resistance. RSV treatment reduced the expression of FOXO1 and G6PC, which are downstream of the PI3K-Akt pathway. In the cell model, mmu-miR-363-3p inhibitor significantly suppressed p-Akt and p-PI3K levels, but enhanced those of FOXO1 and G6PC. In contrast, mmu-miR-363-3p mimic significantly enhanced the p-Akt and p-PI3K levels, but suppressed FOXO1 and G6PC expression, which was similar to the effect of RSV. CONCLUSION: RSV improves insulin resistance by upregulating miRNA mmu-miR-363-3p via the PI3K-Akt pathway.

Association of the Triglyceride to High-Density Lipoprotein Ratio and the Visceral Adiposity Index with Metabolic Syndrome in Diabetic Susceptible Population.

The aim of this study was to explore the association of the triglyceride to high-density lipoprotein ratio (TG/HDL) and the visceral adiposity index (VAI) with metabolic syndrome (Mets) in high-risk populations of diabetic patients. Patients were recruited from the Endocrinology Clinic of Hebei General Hospital from April 2018 to April 2019,according to the "Guidelines for the Prevention and Treatment of Type 2 Diabetes in China (2017 Edition)". A total of 824 patients participated in the study. The association between TG/HDL or VAI and Mets in these patients was assessed using a multivariate logistic regression model. Receiver operating characteristic (ROC) curve analysis was used to evaluate the ability of TG/HDL and VAI to predict Mets in the diabetic susceptible population. The prevalence of Mets gradually increased in males and females with advancing tertiles of TG/HDL or VAI. After adjusting for the relevant risk factors, TG/HDL and VAI were positively correlated with Mets in men and women. Both of them showed a better the area under the ROC curve (AUC) for Mets in females than body mass index, waist circumference, TG and homeostatic model assessment of insulin resistance. In females, the cut-off point of 1.67 for VAI showed a higher accuracy for Mets (sensitivity 0.756, specificity 0.705, Youden index 0.461), the same relationship not significant in men. TG/HDL and VAI provide a high predictive value for Mets in a diabetic susceptible population, especially in females.

Resveratrol improves high-fat diet-induced insulin resistance in mice by downregulating the lncRNA NONMMUT008655.2.

As essential players in the field of diabetes treatment, resveratrol (RSV) has received much attention in recent years. However, it is unclear whether it can improve insulin resistance by regulating the long-chain non-coding RNA (lncRNA). The objective of this study was to investigate whether RSV improves high-fat diet-induced insulin resistance in mice by regulating thelncRNANONMMUT008655.2 in vivo and in vitro. To this end, animal and cell insulin resistance models were developed. Specifically, C57BL/6J mice were fed a high-fat diet (HFD) and administered RSV for eight weeks. Additionally, mouse Hepa cells were treated with palmitic acid, transfected with siRNA NONMMUT008655.2, and treated with RSV. Treated mice and cells were then compared to normal controls that were not exposed to RSV. In the animal model, RSV was found to decrease the levels of fasting blood glucose, triglycerides, and low-density lipoprotein cholesterol, as well as the insulin index and area under the curve; while increasing the insulin sensitivity index. Besides, RSV decreased the expression levels of SOCS3, G6PC, and FOXO1 yet increased that of p-Akt and p-FOXO1 in mice. The same results were observed following knockdown of NONMMUT008655.2 in cells. Overall, our results suggest that RSV may improve hepatic insulin resistance and control blood glucose levels by downregulating lncRNA NONMMUT008655.2.

Difference Analysis Of Related Factors In Macrovascular And Microvascular Complications In Chinese Patients With Type 2 Diabetes Mellitus: A Case-Control Study Protocol.

INTRODUCTION: Despite the increasingly young age at diabetes onset and the increasing number of deaths caused by type 2 diabetes mellitus (T2DM), why some patients develop macrovascular complications but others develop microvascular complications remains controversial and unclear. Notably, some patients have good glucose control but still develop vascular complications, whereas some patients have retinopathy with neither nephropathy nor neuropathy. This study will be performed to explore the risk factors for T2DM complications in Chinese patients. METHODS AND ANALYSIS: Patients with T2DM and healthy people will be recruited from Hebei General Hospital from September 2019 to September 2020. The subjects will be grouped into a control group, T2DM without vascular complications group, T2DM with macrovascular complications group, and T2DM with microvascular complications group; they will then be further subgrouped. The following data will be collected after admission: demographic information such as age, sex, and education; relevant medical history such as duration of diabetes, family history of first-degree relatives with diabetes, and age at diagnosis of diabetes; and anthropometric and blood indicators such as weight, waist circumference, fasting blood glucose level, C-peptide level, total cholesterol level, and triglyceride level. The statistical analysis will be performed using SPSS 22.0 (IBM Corp., Armonk, NY, USA). A P value of <0.05 will be considered statistically significant. The χ2 test, one-way analysis of variance and the rank sum test will be used to analyze differences between the groups. Logistic regression will be used to analyze the risk factors for macrovascular and microvascular complications of T2DM.

Resveratrol reduces liver endoplasmic reticulum stress and improves insulin sensitivity in vivo and in vitro.

Purpose: The aim of the study was to examine the effects of resveratrol upon hepatic endoplasmic reticulum stress (ERS) and insulin sensitivity in vivo and in vitro. Material and methods: C57BL/6J mice were fed a high-fat diet (HFD) for 8 weeks, and insulin resistance was evaluated by the intraperitoneal glucose tolerance test (IPGTT). Mice were then treated with resveratrol for 12 weeks and blood and liver samples collected. Blood biochemical indicators were determined by kits, liver protein expression was determined by western blot, and morphological changes were observed by histological staining. Palmitic acid (PA)-induced insulin-resistant HepG2 cells were established. Cells were exposed to 100, 50 or 20 µM resveratrol for 24 hrs, and proliferation/cytotoxicity was determined. Cells were divided into five groups: control, PA, PA + Rev (100 µM), PA + Rev (50 µM) and PA + Rev (20 µM) groups. After 24 hrs of treatment, cellular proteins were analyzed the same way as animal tissues. Results: The IPGTT confirmed that the insulin resistance model was established successfully. After resveratrol treatment, fasting blood glucose and cholesterol levels declined and the quantitative insulin sensitivity check index increased. Western-blot results showed that resveratrol-treated HFD mice had reduced hepatic levels of p-PERK, ATF-4 and TRIB3, and increased the levels of ATF-6, p-AKT and p-GSK3ß. In the cell model, resveratrol with 100 and 50 µM enhanced ERS and insulin resistance, whereas 20 µM had beneficial effects, similar to the animal model. Conclusion: Resveratrol reduced hepatic ERS, thereby improving insulin sensitivity and glucose levels. However, high doses of resveratrol had harmful effects on cells, elevating ERS and insulin resistance. The safe dose of resveratrol needs further investigation.

Resveratrol affects hepatic gluconeogenesis via histone deacetylase 4.

PURPOSE: The aim of this study was to determine whether resveratrol (Rev) affects the expression, phosphorylation, and nuclear and cytoplasmic distribution of histone deacetylase 4 (HDAC4), which in turn affects gluconeogenesis in hepatocytes under an insulin-resistant state. MATERIALS AND METHODS: HepG2 cells were treated with 0.25 mmol/L palmitic acid (PA) to establish an insulin resistance model. The cells were divided into five groups: control, PA, PA + Rev 100 µM, PA + Rev 50 µM, and PA + Rev 20 µM. After treatment for 24 hours, mRNA and protein expression levels of gluconeogenesis pathway-related molecules and HDAC4 were examined. Next, HepG2 cells were transfected with siRNA-HDAC4. The cells were divided into control, PA, PA + Rev 20 µM, PA + Rev 20 µM +siRNA-HDAC4 negative control, and PA + Rev 20 µM +siRNA-HDAC4 knockdown groups to determine the expression of gluconeogenesis pathway proteins. RESULTS: Compared with the control group, the gluconeogenesis pathway-related molecules, glucose-6-phosphatase catalytic subunit (G6PC), phosphoenolpyruvate carboxykinase 1 (PCK1) and forkhead box protein O1 (FOXO1), were increased, and the phosphorylation of FOXO1 decreased after PA treatment. The p-HDAC4 level decreased with the increase in HDAC4 in the nucleus and the decrease in HDAC4 in the cytoplasm in the PA group. Treatment with Rev 20 µM suppressed gluconeogenesis and promoted HDAC4 shuttling into the cytoplasm from the nucleus. However, 100 and Rev 50 µM exerted the opposite effects. Finally, after HDAC4 knockdown, the expression levels of the key gluconeogenesis molecules, G6PC, PCK1, and FOXO1, were increased, and p-FOXO1 was decreased, indicating that gluconeogenesis was enhanced. CONCLUSION: A low concentration of Rev inhibited gluconeogenesis under insulin-resistance conditions via translocation of HDAC4 from the nucleus to the cytoplasm.

Effect of Resveratrol on Blood Lipid Levels in Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis.

OBJECTIVE: Few studies have considered the effect of resveratrol on blood lipid levels, and the results of these studies are inconsistent. In this study, the first meta-analysis on the effect of resveratrol on blood lipid levels in patients with type 2 diabetes was conducted. METHODS: This study used keywords such as type 2 diabetes, total cholesterol, triglyceride (TG), high-density lipoprotein, low-density lipoprotein, and resveratrol and their abbreviations, free words, and related words to search PubMed, Cochrane Library, and Embase. The Cochrane risk of bias tool was used to evaluate the risk of bias, and Review Manager 5.3 and Stata 13.0 were used for data merging and statistical analysis. RESULTS: Ten randomized controlled trials involving a total of 363 patients with type 2 diabetes were included in the analysis. The results show that longer resveratrol intervention time (≥6 months) can reduce TG levels. But resveratrol increased total cholesterol in patients within obesity range. In type 2 diabetes patients with obesity and in those who took lipid-lowering drugs, resveratrol increased low-density lipoprotein levels. CONCLUSIONS: Resveratrol can improve TG in patients with type 2 diabetes.