Regulation of gene expression during severe caloric restriction: lack of induction of p85 alpha phosphatidylinositol 3-kinase mRNA in skeletal muscle of patients with type II (non-insulin-dependent) diabetes mellitus.
OBJECTIVE
Alterations in the regulation of gene expression could be involved in the development of Type II (non-insulin-dependent) diabetes mellitus.


METHODS
We compared the mRNA concentrations of eight genes encoding proteins involved in insulin action and intermediary metabolism in skeletal muscle of healthy volunteers and Type II diabetic patients. The in vivo regulation of the expression of these genes was investigated after 5 days of hypocaloric diet (1045 kJ/day).


RESULTS
In the basal state, diabetic muscle showed reduced insulin receptor (-38%), hexokinase II (-73%), glycogen synthase (-45%) and lipoprotein lipase (-70%) mRNA expression. There was no difference in the mRNA abundances of IRS-1, GLUT 4, p85 alpha phosphatidylinositol-3-kinase (p85 alpha PI3K) or Rad. In both groups, caloric restriction induced weight loss, reduced glycaemia and increased plasma ketone body concentrations. The diet also increased plasma concentrations of fatty acids and decreased whole-body insulin sensitivity in control subjects. In control subjects, the diet increased p85 alpha PI3K (+146%), insulin receptor (+100%) and Rad (+40%) mRNA concentrations in muscle. In Type II diabetic patients, the diet increased insulin receptor (+41%) and Rad (+31%) mRNAs but the expression of p85 alpha PI3K was not modified.


CONCLUSIONS
The regulation of the expression of p85 alpha PI3K is altered during caloric restriction in skeletal muscle of Type II diabetic patients. Because we have shown in an earlier study that there is also a defective regulation of p85 alpha PI3K gene expression in response to insulin, these data support the hypothesis that alterations in the regulation of gene expression could be involved in the pathogenesis of Type II diabetes.
Andreelli
F
F
INSERM U.449, René Laënnec Faculty of Medicine, Lyons, France.
Laville
M
M
Vega
N
N
Riou
J P
JP
Vidal
H
H
D000328:Adult; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000378:metabolism*; D004032:Diet; D002149:Energy Intake; D005260:Female; D005786:Gene Expression Regulation; D006006:Glycogen Synthase / Q000235:genetics; D006593:Hexokinase / Q000235:genetics; D006728:Hormones / Q000097:blood; D006801:Humans; D008071:Lipoprotein Lipase / Q000235:genetics; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism*; D011972:Receptor, Insulin / Q000235:genetics
D006728:Hormones; D012333:RNA, Messenger; D006006:Glycogen Synthase; D019869:Phosphatidylinositol 3-Kinases; D006593:Hexokinase; D011972:Receptor, Insulin; D008071:Lipoprotein Lipase