Gangyi Yang

Exenatide prevents fat-induced insulin resistance and raises adiponectin expression and plasma levels

Background:  Exenatide (exendin‐4) can reduce blood glucose levels, increase insulin secretion and improve insulin sensitivity through mechanisms that are not completely understood.

Circulating Sfrp5 Is a Signature of Obesity-Related Metabolic Disorders and Is Regulated by Glucose and Liraglutide in Humans

CONTEXT Secreted frizzled-related protein-5 (Sfrp5) is a novel adipocyte-secreted hormone that has been shown to link obesity with diabetes. Studies in mice have revealed that Sfrp5 represents a potential target for the control of obesity-linked abnormalities in glucose homeostasis. OBJECTIVE Our objective was to gain insight into the physiological role of circulating Sfrp5 in humans. PATIENTS AND DESIGN We conducted a series of cross-sectional and interventional studies of the general population and outpatients of the Internal Medicine Department at the Second Affiliated Hospital, Chongqing Medical University, Chongqing, China. Subjects included 104 healthy subjects, 101 with impaired glucose tolerance, and 112 with newly diagnosed type 2 diabetes mellitus and, in a separate study, 30 healthy women, and 32 women with polycystic ovarian syndrome (PCOS). Oral glucose tolerance test and euglycemic-hyperinsulinemic clamp were performed to assess glucose tolerance and insulin sensitivity. RESULTS Circulating Sfrp5 was significantly lower in both impaired glucose intolerance and newly diagnosed type 2 diabetes mellitus than in individuals with normal glucose tolerance (P < 0.01). Overweight/obese subjects had significantly lower Sfrp5 levels than lean individuals (P < 0.01), but females had higher Sfrp5 levels than males (P < 0.05). In a separate study, Sfrp5 levels were lower in PCOS women than healthy women (P < 0.05). Moreover, circulating Sfrp5 correlated with markers of adiposity, including body mass index, waist-to-hip ratio, percent body fat, homeostasis model assessment of insulin resistance, lipid profile, and adiponectin. Hyperglycemia decreased circulating Sfrp5 levels, whereas liraglutide increased Sfrp5 levels. In the euglycemic-hyperinsulinemic state, circulating Sfrp5 was significantly decreased in healthy women but not in PCOS women. CONCLUSIONS We conclude that circulating Sfrp5 is likely to play a major role in insulin resistance in humans.

Nesfatin-1 Action in the Brain Increases Insulin Sensitivity Through Akt/AMPK/TORC2 Pathway in Diet-Induced Insulin Resistance

Nesfatin-1, derived from nucleobindin 2, was recently identified as an anorexigenic signal peptide. However, its neural role in glucose homeostasis and insulin sensitivity is unknown. To evaluate the metabolic impact and underlying mechanisms of central nesfatin-1 signaling, we infused nesfatin-1 in the third cerebral ventricle of high-fat diet (HFD)–fed rats. The effects of central nesfatin-1 on glucose metabolism and changes in transcription factors and signaling pathways were assessed during euglycemic-hyperinsulinemic clamping. The infusion of nesfatin-1 into the third cerebral ventricle markedly inhibited hepatic glucose production (HGP), promoted muscle glucose uptake, and was accompanied by decreases in hepatic mRNA and protein expression and enzymatic activity of PEPCK in both standard diet- and HFD-fed rats. In addition, central nesfatin-1 increased insulin receptor (InsR)/insulin receptor substrate-1 (IRS-1)/AMP-dependent protein kinase (AMPK)/Akt kinase (Akt)/target of rapamycin complex (TORC) 2 phosphorylation and resulted in an increase in Fos immunoreactivity in the hypothalamic nuclei that mediate glucose homeostasis. Taken together, these results reveal what we believe to be a novel site of action of nesfatin-1 on HGP and the PEPCK/InsR/IRS-1/AMPK/Akt/TORC2 pathway and suggest that hypothalamic nesfatin-1 action through a neural-mediated pathway can contribute to increased peripheral and hepatic insulin sensitivity by decreasing gluconeogenesis and promoting peripheral glucose uptake in vivo.

The adipose triglyceride lipase, adiponectin and visfatin are downregulated by tumor necrosis factor-α (TNF-α) in vivo

Inflammatory cytokines have been linked to obesity-related insulin resistance. To investigate the effect of TNF-alpha, an inflammatory cytokine, on insulin action, C57BL/6J mice were treated with TNF-alpha for 7 days after which we examined the in vivo effects of TNF-alpha on glucose tolerance and insulin sensitivity with IV glucose tolerance tests and hyperinsulinemic-euglycemic clamps. In addition, we analyzed the in vivo effect of TNF-alpha on several metabolism-related genes and adipocytokines implicated in the development of insulin resistance. TNF-alpha treatment resulted in markedly increased fasting blood glucose, insulin and free fatty acids (FFA) levels and reduced glucose tolerance. During the clamps, the rates insulin-stimulated whole body (G(Rd)) and skeletal muscle glucose uptake (MGU) and insulins ability to suppress hepatic glucose production (HGP) were decreased in TNF-alpha treated animals, indicating insulin resistance. In addition, both PPARgamma and ATGL mRNA expression in adipose tissues as well as ATGL protein levels in plasma were downregulated. Moreover, adipose mRNA expression and plasma protein levels of adiponectin and visfatin were significantly down-regulated. We conclude that the alterations of PPARgamma, ATGL, adiponectin and visfatin may contribute to the development of insulin resistance mediated by TNF-alpha.

Circulating obestatin levels in normal subjects and in patients with impaired glucose regulation and type 2 diabetes mellitus

Background  Obestatin is a novel hormone that is encoded by the Ghrelin gene and produced in the gut. Ghrelin is profoundly orexogenic and adipogenic, increasing food intake and body weight. This new ghrelin‐associated peptide behaves as a physiological opponent of ghrelin in rodent animals, but its pathophysiological role in humans remains unknown

Overexpression of visfatin/PBEF/Nampt alters whole-body insulin sensitivity and lipid profile in rats

Background. Visfatin/PBEF/Nampt is an adipose-derived hormone proposed to exert insulin-mimicking effects and play a positive role in attenuating insulin resistance. However, the precise mechanisms underlying the beneficial effects of visfatin/PBEF/Nampt on insulin sensitivity remain unknown. Method. Euglycemic-hyperinsulinemic clamps were used in the same groups of rats to study the in vivo effect of visfatin/PBEF/Nampt on insulin sensitivity and glucose/lipid metabolism before and after the overexpression of visfatin/PBEF/Nampt protein, which was carried out by injection of pcDNA3.1-visfatin plasmid. Results. On day 4 after plasmid injection, plasma visfatin/PBEF/Nampt protein levels were significantly increased and displayed a hypocholesterolemic effect in both normal-chow (NC) and high-fat diet (HT) animals with pcDNA3.1-visfatin treatment. A second glucose clamp also demonstrated increased insulin sensitivity in pcDNA3.1-visfatin animals. Consistent with the clamp data, the extent of insulin receptor substrate (IRS)-1 tyrosine phosphorylation in response to insulin was significantly enhanced in the liver and adipose tissues. In addition, the mRNA expression of peroxisome proliferator-activated receptor-γ (PPARγ) and sterol regulatory element-binding proteins 2 (SREBP-2) in the liver and adipose tissues was also significantly upregulated in these animals. Conclusion. These results demonstrate that visfatin/PBEF/Nampt improves insulin sensitivity and exerts its hypocholesterolemic effects at least partially through upregulation of the tyrosine phosphorylation of IRS-1 protein and the mRNA levels of PPARγ and SREBP-2.

Systematic Review of the Effectiveness of Hyperbaric Oxygenation Therapy in the Management of Chronic Diabetic Foot Ulcers

OBJECTIVE To assess the efficacy and safety of hyperbaric oxygenation (HBO) therapy as adjunctive treatment for diabetic foot ulcers with a systematic review and meta-analysis of the literature. METHODS MEDLINE, EMBASE, and the Cochrane Library were searched to find relevant articles published up to April 20, 2012, without restriction as to language or publication status. All controlled trials that evaluated adjunctive treatment with HBO therapy compared with treatment without HBO for chronic diabetic foot ulcers were selected. A meta-analysis was performed to assess the efficacy and safety of hyperbaric oxygen in managing foot ulcers. RESULTS Thirteen trials (a total of 624 patients), including 7 prospective randomized trials, performed between January 1, 1966, and April 20, 2012, were identified as eligible for inclusion in the study. Pooling analysis revealed that, compared with treatment without HBO, adjunctive treatment with HBO resulted in a significantly higher proportion of healed diabetic ulcers (relative risk, 2.33; 95% CI, 1.51-3.60). The analysis also revealed that treatment with HBO was associated with a significant reduction in the risk of major amputations (relative risk, 0.29; 95% CI, 0.19-0.44); however, the rate of minor amputations was not affected (P=.30). Adverse events associated with HBO treatment were rare and reversible and not more frequent than those occurring without HBO treatment (P=.37). CONCLUSIONS This meta-analysis reveals that treatment with HBO improved the rate of healing and reduced the risk of major amputations in patients with diabetic foot ulcers. On the basis of these effects, we believe that quality of life could be improved in selected patients treated with HBO.

Plasma FGF-21 levels in type 2 diabetic patients with ketosis.

FGF-21 has been recently characterized as a potent metabolic regulator, but its pathophysiologic role in human remains unknown. In this study we investigate whether plasma FGF-21 level is different in patients with new-onset type 2 diabetes mellitus (T2DM) and diabetic ketosis (T2DK). Sixty-eight patients with T2DM, 41 subjects with T2DK, and 52 sex- and age-matched normal controls participated in the study. Plasma FGF-21 levels were measured with a radioimmunoassay. The relationship between plasma FGF-21 levels and anthropometric and metabolic parameters was also analyzed. Plasma FGF-21 levels were higher in patients with T2DK and T2DM than in controls (4.05+/-0.18microg/L and 2.82+/-0.14microg/L vs. 2.28+/-0.16microg/L, P<0.01 and P<0.05, respectively). Fasting plasma FGF-21 was found to correlate positively and significantly with SBP, DBP, FBG, 2hPBG, HbA(1)c, HDL-C and FFA, but negatively with fasting plasma insulin, 2hIns and HOMA(IS). Multiple regression analysis showed that DBP, WHR, 2hIns, 2hPBG and FFA were independent to the factors influencing plasma FGF-21 levels. Increasing concentrations of FGF-21 were independently and significantly associated with T2DM and T2DK. The present work suggests that FGF-21 may play a role in the pathogenesis of T2DM and T2DK.

Zinc-α2-Glycoprotein Is Associated With Insulin Resistance in Humans and Is Regulated by Hyperglycemia, Hyperinsulinemia, or Liraglutide Administration: Cross-sectional and interventional studies in normal subjects, insulin-resistant subjects, and subjects with newly diagnosed diabetes

OBJECTIVE Zinc-α2-glycoprotein (ZAG) has been proposed to play a role in the pathogenesis of insulin resistance. Previous studies in humans and in rodents have produced conflicting results regarding the link between ZAG and insulin resistance. The objective of this study was to examine the relationships between ZAG and insulin resistance in cross-sectional and interventional studies. RESEARCH DESIGN AND METHODS Serum ZAG (determined with ELISA) was compared with various parameters related to insulin resistance in subjects with normal glucose tolerance, impaired glucose tolerance (IGT), and newly diagnosed type 2 diabetes mellitus (T2DM), and in women with or without polycystic ovary syndrome (PCOS). Euglycemic-hyperinsulinemic clamps were performed in healthy and PCOS women. Real-time RT-PCR and Western blotting were used to assess mRNA and protein expression of ZAG. The effect of a glucagon-like peptide-1 agonist on ZAG was studied in a 12-week liraglutide treatment trial. RESULTS Circulating ZAG was lower in patients with IGT and newly diagnosed T2DM than in controls. Circulating ZAG correlated positively with HDL cholesterol and adiponectin, and correlated inversely with BMI, waist-to-hip ratio, body fat percentage, triglycerides, fasting blood glucose, fasting insulin, HbA1c, and homeostasis model assessment of insulin resistance (HOMA-IR). On multivariate analysis, ZAG was independently associated with BMI, HOMA-IR, and adiponectin. ZAG mRNA and protein were decreased in adipose tissue of T2DM patients. Moreover, circulating ZAG levels were lower in women with PCOS than in women with high insulin sensitivity. Liraglutide treatment for 12 weeks significantly increased circulating ZAG levels. CONCLUSIONS We conclude that ZAG may be an adipokine associated with insulin resistance.

Efficacy and Safety of Traditional Chinese Medicine for Diabetes: A Double-Blind, Randomised, Controlled Trial

Background Treatment of diabetes mellitus with Traditional Chinese Medicine has a long history. The aim of this study is to establish the safety and efficacy of traditional Chinese medicine combined with glibenclamide to treat type 2 diabetes mellitus. Methods In a controlled, double blind, multicentre non-inferiority trial, 800 patients with unsatisfactory glycemic control (fasting glucose 7–13 mmol/L and HbA1c 7–11%) were randomly assigned to receive Xiaoke Pill, a compound of Chinese herbs combined with glibenclamide, or Glibenclamide in two study groups – drug naive group, and patients previously treated with metformin monotherapy (metformin group). Outcome measures at 48 weeks were the incidence and rate of hypoglycemia, mean difference in HbA1c, and proportion of patients with HbA1c<6.5%. Findings In drug naïve group, the total hypoglycemia rate and the mild hypoglycemic episode in the Xiaoke Pill arm were 38% (p = 0.024) and 41% (p = 0.002) less compared to Glibenclamide arm; in Metformin group, the average annual rate of hypoglycemia was 62% lower in Xiaoke Pill arm (p = 0.003). Respective mean changes in HbA1c from baseline were −0.70% and −0.66% for Xiaoke Pill and Glibenclamide, with a between-group difference (95% CI) of −0.04% (−0.20, 0.12) in the drug naïve group, and those in metformin group were −0.45% and −0.59%, 0.14% (−0.12, 0.39) respectively. The respective proportions of patients with a HbA1c level <6.5% were 26.6% and 23.4% in the drug naïve group and 20.1% and 18.9% in the metformin group. Interpretation In patients with type 2 diabetes and inadequate glycaemic control, treatment with Xiaoke Pill led to significant reduction in risk of hypoglycemia and similar improvements in glycemic control after 48 weeks compared to Glibenclamide. Trial Registration Chinese Clinical Trial Register number, ChiCTR-TRC-08000074