Defective regulation of phosphatidylinositol-3-kinase gene expression in skeletal muscle and adipose tissue of non-insulin-dependent diabetes mellitus patients

We investigated the regulation of the mRNA expression of the insulin recept or, insulin receptor substrate-1 (IRS-1) and p85 alpha-phosphatidylinositol -3-kinase (PI-3K). three major actors of insulin action. in skeletal muscle from 10 healthy lean volunteers. 13 obese patients with Type II (non-insul in-dependent) diabetes mellitus and 7 non-diabetic obese subjects. The in v ivo regulation by insulin was studied using a 3-h euglycaemic, hyperinsulin aemic clamp. There were no differences in the basal concentrations of the t hree mRNAs in skeletal muscle between groups. Insulin infusion produced a t wofold reduction in insulin receptor substrate-1 mRNA expression in the thr ee groups (p < 0.02). In contrast, insulin increased p85 alpha-phosphatidyl inositol-3-kinase mRNA expression in muscle from non-diabetic subjects ( 98 +/- 22 % in lean and + 127 +/- 16 % in obese, p < 0.02) but this effect was totally impaired in Type II diabetic patients ( + 5 +/- 12 %, NS). A si milar defect in insulin action on p85 alpha-phosphatidylinositol-3-kinase m RNA expression was observed in abdominal subcutaneous adipose tissue ( + 13 8 +/- 25 %, p < 0.01 in lean and + 46 +/- 14 %, p < 0.02 in obese and + 29 +/- 11 %, NS in Type II diabetic patients). The lack of action of insulin o n p85 alpha-phosphatidylinositol-3-kinase mRNA in diabetic subjects was pro bably not due to a deleterious effect of hyperglycaemia since improvement o f the glycaemic control for 10 days did not restore the response in muscle or in adipose tissue. This study provides evidence for a defect in the regu lation by insulin of PT-3K gene expression in Type II diabetic patients, th us reinforcing the concept that alterations at the gene expression might be involved in the pathogeny of Type II diabetes.