Regulation of gene expression during severe caloric restriction: lack of induction of p85alpha phosphatidylinositol 3-kinase mRNA in skeletal muscle of patients with Type II (non-insulin-dependent) diabetes mellitus

Aims/hypothesis. Alterations in the regulation of gene expression could be involved in the development of Type II (non-insulin-dependent) diabetes mel litus. Methods. We compared the mRNA concentrations of eight genes encoding protei ns involved in insulin action and intermediary metabolism in skeletal muscl e of healthy volunteers and Type II diabetic patients. The in vivo regulati on of the expression of these genes was investigated after 5 days of hypoca loric diet (1045 kJ/day). Results. In the basal state, diabetic muscle showed reduced insulin recepto r (-38%), hexokinase II (-73%), glycogen synthase (-45%) and lipoprotein li pase (-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 g lycaemia and increased plasma ketone body concentrations. The diet also inc reased plasma concentrations of fatty acids and decreased whole-body insuli n sensitivity in control subjects. In control subjects, the diet increased p85 alpha PI3K (+ 146%), insulin receptor (+ 100%) and Rad ( + 40%) mRNA co ncentrations in muscle. In Type II diabetic patients, the diet increased in sulin receptor ( + 41%) and Rad ( + 31%) mRNAs but the expression of p85aPI 3K was not modified. Conclusion/interpretation. The regulation of the expression of p85 alpha PI 3K is altered during caloric restriction in skeletal muscle of Type II diab etic 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 in sulin, these data support the hypothesis that alterations in the regulation of gene expression could be involved in the pathogenesis of Type II diabet es.