Regulation by insulin of gene expression in human skeletal muscle and adipose tissue - Evidence for specific defects in type 2 diabetes

Defective regulation of gene expression may be involved in the pathogenesis of type 2 diabetes. me have characterized the concerted regulation by insu lin (3-h hyperinsulinemic clamp) of the expression of 10 genes related to i nsulin action in skeletal muscle and in subcutaneous adipose tissue, and we have verified whether a defective regulation of some of them could be spec ifically encountered in tissues of type 2 diabetic patients. Basal mRNA lev els (determined by reverse transcriptase-competitive polymerase chain react ion) of insulin receptor, insulin receptor substrate-1, p85 alpha phosphati dylinositol 3-kinase (PI3K), p110 alpha PI3K, p110 beta PI3K, GLUT4, glycog en synthase, and sterol regulatory-element-binding protein-1c (SREBP-1c) we re similar in muscle of control (n = 17), type 2 diabetic (n = 9), type 1 d iabetic (n = 9), and nondiabetic obese (n = 9) subjects. In muscle, the exp ression of hexokinase II was decreased in type 2 diabetic patients (P < 0.0 1). In adipose tissue, SREBP-1c (P < 0.01) mRNA expression was reduced in o bese (nondiabetic and type 2 diabetic) subjects and was negatively correlat ed with the BMI: of the subjects (r = -0.63, P = 0.02). Insulin (<plus/minu s>1,000 pmol/L) induced a two- to threefold increase (P < 0.05) in hexokina se II, p85 alpha PI3K, and SREBP-1c mRNA levels in muscle and in adipose ti ssue in control subjects, in insulin-resistant nondiabetic obese patients, and in hyperglycemic type 1 diabetic subjects. Upregulation of these genes was completely blunted in type 2 diabetic patients. This study thus provide s evidence for a specific defect in the regulation of a group of important genes in response to insulin in peripheral tissues of type 2 diabetic patie nts.