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Objective To investigate the effects of liraglutide on glucose-lipid metabolism in ApoE-/-mice with RNAi-mediated adiponectin gene inhibition. Methods The dose-effective relationship of liraglutide was evaluated by intravenous glucose tolerance test (IVGTT), and the insulin sensitivity and glucose-lipid metabolism were assessed by the hyperinsulinemic-euglycemic clamp technique using 3-[3 H]-glucose as a tracer. Results In the IVGTT, blood glucose was significantly lower in the 1 mg/kg liraglutide group than that in other groups ( all P＜0. 01 ) at the points of 5, 15, and 30 min after glucose load. However, plasma insulin was significantly higher at the points of 5 and 15 min (all P＜0. 01 ). Fasting blood glucose (FBG), body weight, free fatty acids (FFA),total cholesterol, triglycerides, low-density lipoprotein-cholesterol ( LDL-C), and fasting plasma insulin in ApoE-/-mice with co-injection of liraglutide and adiponectin shRNA adenovirus ( HEA group ) were significantly lower than those in ApoE-/-mice with adiponectin shRNA adenovirus injection ( ADI group, P＜0. 05 or P＜0. 01 ). However,high-density lipoprotein-cholesterol (HDL-C) was significantly higher than the latter (P＜0. 05 ). During the steady-state of clamp, plasma insulin in ADI group was significantly higher than that in HEA group (P＜0. 01 ). Although FFA, total cholesterol, and triglycerides were suppressed in all groups, they were still higher in ADI group than those in HEA group (P＜0. 05). Glucose infusion rate (GIR) in HEA group were significantly higher than that in ADI group ( P ＜ 0. 01 ). At the end of clamp, glucose disappearance rate ( GRd ) was significantly lower, and hepatic glucose production significantly higher in ADI group than those in HEA group (P＜0.01 ). Conclusion Administration of liraglutide may ameliorate insulin resistance via increasing plasma adiponectin level in ApoE-/-mice with RNAi-mediated adiponectin gene inhibition.
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Objective To investgate the effects of exenatide on islet β-cell function, insulin sensitivity and glucose-lipid metabolism in insulin resistant rats induced by high-fat-chow. Methods High fat-fed rats were treated with exenatide for 6 weeks. The insulin sensitivity, islet β-cell function and glucose lipid metabolism in awake rats were evaluated by intravenous glucose tolerance test (IVGTT), insulin tolerance test (ITT) and hyperinsulinemic-euglycemic clamp technique combined with 3-[3H] glucose as a tracer. In addition, plasma adiponectin level was measured by ELISA. Results Lee′s index and levels of plasma free fatty acids (FFA), triglyceride and total cholesterol were significantly reduced in high fat-fed rats after exenatide treatment for 6 weeks (all P＜0.01). In these rats exenatide also improved IVGTT and ITT, and increased the level of insulin secretion, especially when a high dose was given. In addition, plasma adiponectin level was also significantly increased in the group with high dose exenatide (HFH, P＜0.01). During the clamp steady-state, there were significant increases in plasma FFA and insulin and significant decreases in glucose infusion rate (GIR), glucose disposal rate (GRd) in high-fat group (HF) compared to control group (NC, all P＜0.01). The suppressive effect of insulin on hepatic glucose production (HGP) was significantly blunted (only 26%) in HF group. In HFH group, plasma insulin and FFA levels were significantly decreased (both P＜0.01), GIR and GRd were significantly increased (both all P＜0.01), and HGP was suppressed by 72%. Conclusion It is possible that exenatide pretreatment ameliorates high-fat induced insulin resistance by promoting β-cell insulin secretion, elevating adiponectin level, and improving glucose-lipid metabolism.
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Objective To investigate the effects of visfatin gene overexpressian on insulin sensitivity and plasma fibroblast growth factor 21 (FGF-21) level in rats. Methods The recombinant visfatin plasmid was constructed and transfected into normal rats. The euglyeemic-hyperinsulinemie clamp experiments were performed to evaluate the change of insulin sensitivity before and after administration of the plasmid, and plasma FGF-21 level was determined by radioimmunoassay. Results Plasma visfatin levels and glucose infusion rates (GIR) were significantly increased [(1.49±0.06 vs 0.99±0.04) and (35.3±1.4 vs 27.6±1.7) mg·kg-1·min-1,respectively, all P<0.01]. Fasting insulin level was significantly decreased [(14.5±3.7 vs 24.4±6.2) mU/L,P<0.05], total cholesterol and high-density lipoprotein cholesterol were significantly decreased [(1.31±0.10 vs1.76±0.22) mmol/L and (0.59±0.04 vs 0.95±0.15) mmol/L, respectively, all P<0.05], and plasma FGF-21 level was also decreased [(2.25±0.19 vs 2.59±0.23)μg/L, P<0.05] after plasmid being injected 3 days compared with that before injection, but there were no significant differences in fasting glucose and adiponectin levels before and after administration. Conclusion The transfection of visfatin plasmid increases plasma visfatin level, decreases FGF-21 levels and improves insulin sensitivity in normal rats.
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Objective To evaluate the association of apM1 gene single nucleotide polymorphisms (SNP) with type 2 diabetes mellitus in Chinese population. Methods Odds ratios (OR) of apM1 gene SNP distribution were analyzed. The Meta-analysis software (RevMan 4.3.1) was employed for summarizing the studies,calculating the pooled OR and its 95% CI and testing the overall effects. Egger's test and fail-safe number for P=0.05 (Nfs<,0.05>) were performed for evaluating the publication bias. The sensitivity analysis by different effect models and sample sizes were employed for the reliability of Meta-analysis. Results Nine literatures were obtained, apM1 gene SNP45 showed remarkable heterogeneity among the studies (P<0.10). Sub-group analysis revealed that the discrepancy based on southern Chinese individuals was the main source of the total heterogeneity.The distribution frequencies of apM1 gene SNP45G, SNP45GG, SNP276G and SNP276GG were significantly higher in Chinese type 2 diabetes mellitus group than those in NGT group (P<0.05). Their pooled OR and 95% C/were 1.50[1.12,2.02], 2.15[1.53, 3.02],1.23[1.03, 1.46] and 1.26[1.00,1.59], respectively (all P<0.05). The distribution of apM1 gene SNP45TG and SNP276GT between type 2 diabetes mellitus and normal glucose tolerance group revealed no difference among these studies. The results of publication bias diagnostics and sensitivity analysis accounted for the reliability and stability of this Meta-analysis. Conclusion apM1 gene SNPs are strongly associated with type 2 diabetes mellitus in Chinese population. SNP45G and SNP276G seem to be risk factors for type 2 diabetes mellitus.
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Objective To investigate the effects of tumor necrosis factor-alpha (TNF-α) on insulin sensitivity and glucose-lipid metabolism in TNF-α-induced IR mice. Methods Male C57BL/6J mice were given an intraperitoneal injection of TNF-α (H group,6μg/kg; M group,3μg/kg; L group,1μg/kg;twice daily) and saline (NC group) for 7 days. The plasma glucose and insulin were assayed during intravenous glucose tolerance test (IVGTT) and hyperinsulinemic-euglycemic clamp combined with 3-[3H] glucose as a tracer was carried out. Results After TNF-α treatment,fasting blood glucose (FBG),plasma insulin and free fatty acids (FFA) were significantly elevated in H group compared with NC,L and M groups (P<0.01 and P<0.05,respectively). There was a lower glucose tolerance in H group versus other three groups during IVGTT. The insulin release by glucose stimulation was higher in H group versus NC and L groups (P<0.01 and P<0.05). Basal glucose disappearance rate (GDR) and hepatic glucose production (HGP) were significantly increased in H group compared with NC group (P<0.01). During the steady-state of clamp,plasma insulin levels were significantly increased in H group versus NC group (341.7±17.7 vs 84.7±5.5mU/L,P<0.01). The suppressive effect of insulin on FFA was significantly blunted in H group compared with NC group (0.82±0.03 vs 0.43±0.07mmol/L,P<0.01). Steady-state glucose infusion rate (GIR) was significantly decreased in H group compared with NC group (39.1±2.3 vs 54.2±2.2 mg·kg-1·min-1,P<0.01). Although GDR was increased in both group,but it was still lower in H group than in control group(47.9±0.8 vs 53.9±2.0 mg.kg-1.min-1,P<0.01).As compared with baseline,HGP in the controls was almost completely suppressed during steady state of clamp,but in H group suppressed by approximately 41%. Conclusions High-dose TNF-α treatment induces the abnormality of glucose-lipid metabolism and the insulin resistance of hepatic and peripheral tissue in mice
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Objective To investigate the effects of exendin-4 (exenatide) on insulin sensitivity and adipocytokine in high-fat-fed rats. Methods Rats were divided randomly into normal-chow group (NC), high-fat group (HF) and high-fat+exendin treated group (HE). HE rats were given exenatide (2 μg/kg) twice daily for 6 wk. The insulin sensitivity was evaluated by intravenous insulin tolerance test (IVITT). Insulin-stimulated changes in insulin signal transduction, visfatin and adiponectin mRNA expressions as well as their plasma levels were also observed in these rats. Results Plasma free fatty acids (FFA), triglyceride (TG), total cholesterol (TC) levels were significantly reduced after exenatide treatment (in HE rats all P<0.01). And IVITT parameters were also improved in these rats. Insulin-stimulated IRS-1 tyrosine phosphorylation was slightly increased in exenatide-treated rats as compared with HF rats (P<0.05). In addition,plasma visfatin level was significantly reduced in HF and HE groups as compared with controls (P<0.05 and P<0.01). The adiponectin mRNA expression in adipose tissues and circulating adiponectin level were significantly elevated in exenatide-treated rats as compared with untreated rats and controls (P<0.01). Conclusions Chronic exenatide treatment improves insulin resistance in high-fat-fed rats, and the changes of IRS-1 tyrosine phosphorylation and adiponectin may be related to the role of exenatide in elevating insulin sensitivity
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There is a large body of evidence which indicates that elevated plasma levels of FFA are a major cause of insulin resistance in skeletal muscle and liver. Normalizing plasma FFA levels is, therefore, proposed as a novel approach to reduce insulin resistance, the risk of Type 2 diabetes mellitus and atherosclerotic vascular disease.