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 p85alpha-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 p85alpha-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 p85alpha-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 p85alpha-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 PI-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.
Andreelli
F
F
INSERM U.449 and Centre de Recherche en Nutrition Humaine de Lyon, Faculté de Médecine R.T.H. Laënnec, and Service d'Endocrinologie Diabétologie et Nutrition, Hopital E. Herriot, France.
Laville
M
M
Ducluzeau
P H
PH
Vega
N
N
Vallier
P
P
Khalfallah
Y
Y
Riou
J P
JP
Vidal
H
H
D000273:Adipose Tissue / Q000201:enzymology*; D000328:Adult; D001786:Blood Glucose / Q000378:metabolism; D003920:Diabetes Mellitus / Q000201:enzymology / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015309:Glucose Clamp Technique; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D007262:Infusions, Intravenous; D007328:Insulin / Q000494:pharmacology / Q000502:physiology / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000201:enzymology*; D009765:Obesity / Q000201:enzymology / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D012016:Reference Values; D014158:Transcription, Genetic
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D012333:RNA, Messenger; D019869:Phosphatidylinositol 3-Kinases