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 receptor, 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-insulin-dependent) diabetes mellitus and 7 non-diabetic obese subjects. The in vivo regulation by insulin was studied using a 3-h euglycaemic, hyperinsulinaemic clamp. There were no differences in the basal concentrations of the three mRNAs in skeletal muscle between groups. Insulin infusion produced a twofold reduction in insulin receptor substrate-1 mRNA expression in the three groups (p < 0.02). In contrast, insulin increased p85 alpha-phosphatidylinositol-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 similar defect in insulin action on p85 alpha-phosphatidylinositol-3-kinase mRNA expression was observed in abdominal subcutaneous adipose tissue ( + 138 +/- 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 on p85 alpha-phosphatidylinositol-3-kinase mRNA in diabetic subjects was probably not due to a deleterious effect of hyperglycaemia since improvement of 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 regulation by insulin of PT-3K gene expression in Type II diabetic patients, thus reinforcing the concept that alterations at the gene expression might be involved in the pathogeny of Type II diabetes.