Evidence for Specific Defects in Type 2 Diabetes
Defective regulation of gene expression may be involved in the pathogenesis of type 2 diabetes. We have characterized the concerted regulation by insulin (3-h hyperinsulinemic clamp) of the expression of 10 genes related to insulin action in skeletal muscle and in subcutaneous adipose tissue, and we have verified whether a defective regulation of some of them could be specifically encountered in tissues of type 2 diabetic patients. Basal mRNA levels (determined by reverse transcriptase–competitive polymerase chain reaction) of insulin receptor, insulin receptor substrate-1, p85α phosphatidylinositol 3-kinase (PI3K), p110αPI3K, p110βPI3K, GLUT4, glycogen synthase, and sterol regulatory-element-binding protein-1c (SREBP-1c) were similar in muscle of control (n = 17), type 2 diabetic (n = 9), type 1 diabetic (n = 9), and nondiabetic obese (n = 9) subjects. In muscle, the expression of hexokinase II was decreased in type 2 diabetic patients (P < 0.01). In adipose tissue, SREBP-1c (P < 0.01) mRNA expression was reduced in obese (nondiabetic and type 2 diabetic) subjects and was negatively correlated with the BMI of the subjects (r = −0.63, P = 0.02). Insulin (±1,000 pmol/l) induced a two- to threefold increase (P < 0.05) in hexokinase II, p85αPI3K, and SREBP-1c mRNA levels in muscle and in adipose tissue 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 provides 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 patients.
Address correspondence and reprint requests to Hubert Vidal, PhD, INSERM U.449, Faculté de Médecine R. Laennec, Rue G. Paradin, F-69372 Lyon Cédex 08, France. E-mail:.
Received for publication 31 July 2000 and accepted in revised form 5 February 2001.
P.-H.D. and N.P. contributed equally to this work.
IRS, insulin receptor substrate; PCR, polymerase chain reaction; PI3K, phosphatidylinositol 3-kinase; p85αPI3K, p85α regulatory subunit of phosphatidylinositol 3-kinase; p110αPI3K, p110α catalytic subunit of phosphatidylinositol 3-kinase; p110βPI3K, p110β catalytic subunit of phosphatidylinositol 3-kinase; Rad, Ras protein associated with diabetes; RT-cPCR, reverse transcriptase–competitive polymerase chain reaction; SREBP-1c, sterol regulatory-element-binding protein-lc.