Diabetes Mellitus, Type 2 ; drug therapy ; Humans ; Hypoglycemic Agents ; therapeutic use ; Non-alcoholic Fatty Liver Disease ; drug therapy

Objective To investigate the role played by fibroblast growth factor-21 (FGF-21) in glucoselipid metabolism in mice adipocyte and hepatocyte. Methods FGF-21 over-expressive vector and FGF-21-shRNA vector were transfected to Hepa1-6 hepatocyte and 3T3-L1 adipocyte, respectively. FGF-21 protein levels were evaluated by Western blotting, glucose uptake rate (GUR) was evaluated by radioimmunoassay. The mRNA expression of transcription factors was detected by real-time quantitative PCR. Results Transfection of pcDNAFGF21 significantly increased FGF-21 expression in both liver and fat cells (4.8 fold and 4.2 fold, both P<0.05). Moreover, FGF-21 expressions were down-regulated by 86. 3% and 77. 8% with pGenesil-FGF21,respectively (both P<0.05 ). The FGF-21 up-regulation markedly increased GUR and decreased intracellular triglycerides content in the 3T3-L1 adipocyte. Meanwhile, the up-regulation of glucose transporter-1, insulin receptor substrate-1 (IRS-1), PPARγ, adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL),and adipocyte fatty acid binding protein 2 ( ap2 ) mRNA expressions were also observed ( all P<0. 05 ). The reverse changes happened in FGF-21 deficient adipocyte except IRS-1. In hepatocyte, FGF-21 has no effect on GUR.FGF-21 over-expression reduced PPARγ, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR), and phosphoenolpyruvate carboxykinase (PEPCK) mRNA expressions, and increased low-density lipoprotein receptor expression (P<0.05). Conclusions FGF-21 regulates glucose homeostasis and accommodates intracellular fat content in adipocyte. In hepatocyte, FGF-21 plays an important role in gluconeogenesis and cholesterol metabolism.

Insulin-mediated glucose metabolism of peripheral tissue and liver was assessed by euglycemic hyperinsulinemia clamp technique in lipid-infused rats. There was a significant increase in plasma free fatty acids and a significant reduction in glucose infusion rates in the lipid-infused group. The suppressive effect of insulin on hepatic glucose production (HGP) was significantly blunted and the rate of glucose disappearance showed a slight decrease in the lipid-infused rats, suggesting that lipid impaired the abilities of insulin to suppress lipolysis, HGP and insulin-mediated glucose utilization in peripheral tissues.

Objective To investigate the effects of tumor necrosis factor-alpha (TNF-?) on insulin sensitivity and glucose-lipid metabolism in TNF-?-induced IR mice. Methods Male C57BL/6J mice were given an intraperitoneal injection of TNF-? (H group,6?g/kg; M group,3?g/kg; L group,1?g/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-? 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

Objective To investigate the effects of Liraglutide on plasma FGF-21 level in patients with type 2 diabetes mellitus (T2DM). Methods Enzyme linked immunosorbent assay (ELISA) was used to measure plasma FGF-21 level in patients with T2DM and normal controls (NGT). Relationship between plasma FGF-21level and BMI, WHR, HOMA-IR, HOMA-IS, FFA was analyzed. After Liraglutide treatment, plasma FGF-21level was observed in patients with T2DM. Results Fasting plasma FGF-21 level was higher in T2DM patients than that in normal control group ( 1.81 ±0.32 vs. 1.32 ±0.09 μg/L, P ＜0.01 ). After Liraglutide treatment, WHR, BMI, FPG, 2hPBG, HbA1c and FFA in T2DM patients significantly decreased ( P ＜0.05 or P ＜0. 01 ),HOMA-IS remarkably increased (P ＜ 0. 01 ), and FGF-21 had no change. Conclusion Liraglutide and FGF-21may have different roles in insulin resistance.

To evaluate the association of ealpain-10 gene UCSNP-43 polyorphism with type 2 diabetes in Chinese Han population.Meta-analysis showed that calpain-10 gene UCSNP-43 polymorphism may be associated with type 2 diabetes in Chinese Han population.Allele G and genotypo GG may be risk factors for type 2 diabetes,while allele A and genotype GA may be the protective factors.

The effect of RNA interference-mediated adiponectin gene silence on glucose-lipid metabolism in apolipoprotein E gene knock-out(ApoE~(-/-)) mice was studied. The plasma adiponectin level in ApoE~(-/-) mice with high-fat diet and adiponectin short hairpin RNA (shRNA) adenovirus injection (ADI group) was significantly lower than that in ApoE~(-/-)mice with high-fat diet(HF group), normal-chow(NF group)and naked adenovirus injection (GF, both P<0.01). Fasting blood glucose, fasting plasma insulin, free fatty acids, total cholesterol, triglycerides, low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), and body weight were significandy elevated in three high-fat diet groups compared with in NF group, (P<0.01). However, fasting plasma insulin, free fatty acids, total cholesterol, triglycerides, LDL-C, and HDL-C in ADI group were significantly higher than those in HF and GF groups(P<0.01 or P<0. 05). A typical clinical phenotype of glucose-lipid metabolism and insulin resistance in ApoE~(-/-) mice can be induced by high-fat feeding and adiponecting gene silencing.

Fasting plasma preptin level was assayed by RIA in the patients with different glucose tolerances. Regarding fasting plasma preptin levels, it was higher in females than in males. Fasting plasma preptin level was increased in patients with type 2 diabetes as compared with subjects of impaired glucose tolerance and normal controls, and there were positive correlations with diastolic blood pressure, blood triglyceride, total cholesterol, high-density lipoprotein-cholesterol, free fatty acids, 2 h plasma glucose after glucose load, HbA1C and HOMA-IR, suggesting a potential link between preptin and glucose-lipid metabolism and insulin resistance.

Objective To investigate the relationship of circulating zinc-α2-glycoprotein (ZAG) as well as adiponectin with adiposity and insulin resistance in humans.Methods Serum ZAG and adiponectin levels were determined by ELISA in 285 subjects with normal glucose tolerance (NGT),impaired glucose tolerance (IGT),and newly diagnosed cases with type 2 diabetes mellitus(T2DM).The relationships between circulating ZAG and insulin resistance or metabolic parameters were also explored.Results Circulating ZAG and adiponectin levels were all lower in T2 DM and IGT subjects than those in control subjects [ZAG:(37.14 ± 13.25 and 48.84 ± 18.74 vs 59.36 ± 16.20) mg/L,P＜0.05 or P＜0.01 ; adiponectin:(27.79 ± 11.23 and 33.00 ± 9.42 vs 41.81 ± 13.68) μg/L,P＜0.01].Circulating ZAG was correlated positively with high density lipoprotein-cholesterol and adiponectin (all P＜0.01),and inversely with body mass index,waist-hip ratio,FAT％,diastolic blood pressure,triglyceride,fasting blood glucose,fasting insulin,HbA1C,and homeostasis model assessment for insulin resistance(HOMA-IR,P＜0.05 or P＜0.01).By multivariate analysis,ZAG levels were independently associated with body mass index,HOMA-IR,diastolic blood pressure,and adiponectin (P＜0.05 or P＜0.01).Conclusions ZAG levels,associated with fat,insulin sensitivity,and adiponectin expression,are likely to play an important role in insulin resistance and energy homeostasis in humans.

AIM: To investigate the effects of milrinone (a selective phosphdiesterase III inhibitor PDE 3) on insulin secretion, blood glucose, plasma free fatty acids (FFA) and dose-response relationship, and assess possible effects of milrinone on glucose metabolism and insulin sensitivity in conscious rats. METHODS: The catheterized nonstressed rats were administered by the varying doses of milrinone (1, 5, 25 ?mol/kg) and were compared with controls. A hyperinsulinaemic- euglycaemic clamp was established in awake rats, and milrinone(25 ?mol/kg) and 25% dimethyl sulfoxide (DMSO, as a control) were given at 120 min during hyperinsulinaemic- euglycaemic clamp. Glucose turnover was decided by gas chromatograph mass spectrometer (GC-MS). RESULTS: After dosing, plasma FFA levels in 3 milrinone groups significantly increased compared with the controls and before dosing. The percentages of elevation of FFA by the different milrinone doses were very similar, 50%, 52%, 55% for 1, 5, 25 ?mol/kg respectively at 2 min after dosing. Plasma insulin levels were significantly elevated in the 5 and 25 ?mol/kg groups, and the effect of milrinone on glucose concentration was detectable only 25 ?mol/kg group. During hyperinsulinaemic clamp, there were significant increase in plasma FFA (from 173.1?15 2 to 633 8?87 3 ?Eq/L) and hepatic glucose production (HGP), and a significant decrease in glucose infusion rates (GIR) (to about 21%). CONCLUSION: These data suggest that milrinone impaires the abilities of insulin to suppress lipolysis and HGP, and insulin-mediated glucose utilization in peripheral tissue. Therefore, milrinone administration may induce an acute insulin resistance in vivo.