Adipose tissue glycogen synthase activation by in vivo insulin in spontaneously insulin-resistant and Type 2 (non-insulin-dependent) diabetic rhesus monkeys

Summary In skeletal muscle, a defect in the covalent activation of glycogen synthase by insulin has been identified in insulin resistance and in Type 2 (non-insulin-dependent) diabetes mellitus, but a similar defect in insulin action at the adipose tissue has not been demonstrated. We sought to determine whether this defect in insulin action in muscle was also present in the same pathway in adipose tissue. We examined the effect of in vivo insulin on adipose tissue glycogen synthase and phosphorylase activity in normal (n=11), hyperinsulinaemic (n=8), and impaired glucose tolerant and Type 2 diabetic (n=8) rhesus monkeys. Adipose tissue samples were obtained before and during a euglycaemic hyperinsulinaemic clamp. Glycogen synthase fractional velocity, independent and total activities were significantly higher in the insulin-stimulated samples compared to the basal samples in the normal group (p<0.05, respectively). In the hyperinsulinaemic group, however, insulin had no effect on glycogen synthase fractional velocity or independent activity, but did increase the total activity of glycogen synthase and phosphorylase (p<0.05, respectively). Furthermore, both the basal and the insulin-stimulated total activities of these two enzymes were significantly greater in the hyperinsulinaemic group as compared to both the normal and the diabetic groups (p<0.05, respectively). In the diabetic group, insulin was without effect on glycogen synthase fractional velocity, independent activity or total activity. We conclude that the covalent activation of adipose tissue glycogen synthase by insulin is absent in both obese hyperinsulinaemic and in spontaneously diabetic monkeys.     

Carbohydrate feeding and glycogen synthesis during exercise in man

In 7 male cyclists glycogen synthesis during exercise and rest was studied. Each subject did two exercise trials (A and B), in random order. In both trials, after determining the maximal workload (W _max), intermittent exercise was given to exhaustion. After the exhaustive exercise and taking a muscle biopsy the subjects either exercised at 40%W _max for 3 h (trial A) or rested for 3 h (trial B), during which they consumed approximately 21 of a 25% malto-dextrine drink in both trials. After 3 h rest (trial A) or 3 h of mild exercise (trial B) a second muscle biopsy was taken for total glycogen and histochemistry (ATPase and PAS). Blood glucose and insulin levels were elevated during the first 2 h of exercise (p<0.05). Glycogen depletion was most pronounced in type I and to a less extent in type IIA fibers. In trial A muscle glycogen increased from 136±66 to 199±71 mmol/kg DW, and in trial B from 145±56 to 257±79 mmol/kg DW. During exercise glycogen repletion was restricted to type IIA and IIB fibers, whereas during rest glycogen synthesis occurred both in type I and type II fibers. The present study demonstrates that oral carbohydrate administered during exercise may not only provide substrate for energy metabolism, but can also be utilized for glycogen synthesis in the non-active muscle fibers.     

Muscle glycogen repletion and pre-exercise glycogen content: effect of carbohydrate loading in rats previously fed a high fat diet

We have recently reported that rates of muscle glycogen repletion during the early period of recovery were increased by carbohydrate (CHO) loading in rats previously fed a high fat diet. However, the reason for this remained unanswered. The purpose of this study was to examine whether an increase of glycogen utilization due to an elevated pre-exercise glycogen store would enhance rates of glycogen repletion in muscle. Despite an equal degree of glycogen depletion, the rates of glycogen repletion of soleus, red and white gastrocnemius muscles by postexercise administration of glucose (3.0 g · kg^–1 body mass) and citrate (0.5 g · kg^–1 body mass) were faster in the CHO loaded (3 days) rats than in the nonloaded rats, as a result of elevated pre-exercise glycogen content and consequently the greater glycogen utilization. The higher rate of muscle glycogen repletion may in part be explained by increased postexercise glycogen synthase activity.     

丙硫咪唑对囊尾蚴糖原作用的观察

猪囊尾蚴于体外经驱虫药丙硫味唑在0,20,50,100μg/ml和96小时作用后,进行了组织化学观察。对照组囊尾蚴的糖原分布在头颈部和外囊壁上,颈部区糖原分布较均匀,外囊壁糖原较多。实验各组头颈部糖原均有减少,而外囊壁糖原无显著变化。     

Hepatitis C virus NS5A promotes insulin resistance through IRS-1 serine phosphorylation and increased gluconeogenesis

AIM: To investigate the mechanisms of insulin resistance in human hepatoma cells expressing hepatitis C virus(HCV) nonstructural protein 5A(NS5A).METHODS: The human hepatoma cell lines,Huh7 and Huh7.5,were infected with HCV or transientlytransfected with a vector expressing HCV NS5 A. The effect of HCV NS5 A on the status of the critical players involved in insulin signaling was analyzed using realtime quantitative polymerase chain reaction and Western blot assays. Data were analyzed using Graph Pad Prism version 5.0.RESULTS: To investigate the effect of insulin treatment on the players involved in insulin signaling pathway,we analyzed the status of insulin receptor substrate-1(IRS-1) phosphorylation in HCV infected cells or Huh7.5 cells transfected with an HCV NS5 A expression vector. Our results indicated that there was an increased phosphorylation of IRS-1(Ser307) in HCV infected or NS5 A transfected Huh7.5 cells compared to their respective controls. Furthermore,an increased phosphorylation of Akt(Ser473) was observed in HCV infected and NS5 A transfected cells compared to their mock infected cells. In contrast,we observed decreased phosphorylation of Akt Thr308 phosphorylation in HCV NS5 A transfected cells. These results suggest that Huh7.5 cells either infected with HCV or ectopically expressing HCV NS5 A alone have the potential to induce insulin resistance by the phosphorylation of IRS-1 at serine residue(Ser307) followed by decreased phosphorylation of Akt Thr308,Fox01 Ser256 and GSK3β Ser9,the downstream players of the insulin signalingpathway. Furthermore,increased expression of PECK and glucose-6-phosphatase,the molecules involved in gluconeogenesis,in HCV NS5 A transfected cells was observed.CONCLUSION: Taken together,our results suggest the role of HCV NS5 A in the induction of insulin resistance by modulating various cellular targets involved in the insulin signaling pathway.     

Correlation between serum Dickkopf-1 (DKK1) levels and coronary artery stenosis

Background and aimsTo study the correlation between the level of serum Dickkopf-1 (DKK1) and the degree of coronary artery stenosis in patients with coronary atherosclerotic heart disease.Methods and resultsIn 2018, general data and biochemical indexes of 311 patients who underwent coronary angiography were recorded. Before procedure, arterial blood was drawn and the concentrations of DKK1, retinol binding protein 4 (RBP4), plasminogen activator inhibitor (PAI-1) were measured. Based on coronary angiography results, subjects were divided into a coronary heart disease (CHD) group; and a non-coronary heart disease (non-CHD)group. The CHD group was divided into three subgroups: the low Gensini score; the middle Gensini score; and the high Gensini score subgroups. Compared with those of the non-CHD group, DKK1, RBP4 and PAI-1 of the CHD group were significantly higher, while the OC was lower.DKK1,RBP4 and PAI-1 levels of the middle and high Gensini subgroups were significantly higher, compared with that of the low Gensini subgroup. Differences between osteocalcin (OC), beta-isomerized C-terminal telopeptidase (β-CTX), and 25(OH)₂D₃ of the three subgroups were not significant.Correlation between DKK1 and the inflammatory factors, RBP4 and PAI-1, was positive. Correlation between DKK1 and β - CTX, 25(OH)₂D₃ and OC was not significant. DKK1 was a risk factor for CHD. The degree of coronary artery stenosis was related to DKK1 concentration.ConclusionsSerum DKK1 levels in coronary heart disease patients were significantly higher, and positively correlated with the degree of coronary artery stenosis. DKK1 level is an independent risk factor for coronary heart disease.