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. 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, p85alpha phosphatidylinositol 3-kinase (PI3K), p110alphaPI3K, p110betaPI3K, 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, p85alphaPI3K, 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.
Ducluzeau
P H
PH
Institut National de la Santé et de la Recherche Médicale INSERM U.449, Faculty of Medicine R. Laennec, Lyon, France.
Perretti
N
N
Laville
M
M
Andreelli
F
F
Vega
N
N
Riou
J P
JP
Vidal
H
H
D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism*; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D051275:Glucose Transporter Type 4; D006006:Glycogen Synthase / Q000235:genetics; D006801:Humans; D006946:Hyperinsulinism; D007328:Insulin / Q000097:blood / Q000494:pharmacology* / Q000502:physiology; D008297:Male; D008875:Middle Aged; D009004:Monosaccharide Transport Proteins / Q000235:genetics; D009124:Muscle Proteins; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009765:Obesity / Q000235:genetics* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D051275:Glucose Transporter Type 4; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D012333:RNA, Messenger; C495692:SLC2A4 protein, human; C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D006006:Glycogen Synthase; D019869:Phosphatidylinositol 3-Kinases