Protein Calorie Restriction Has opposite Effects on Glucose Metabolism and Insulin Gene Expression in the Fetal and Adult Rat Endocrine Pancreas

We previously demonstrated that fetuses from undernourished pregnant rats exhibited increased beta cell mass and hyperinsulinemia, whereas keeping food restriction until adult age caused reduced beta cell mass, hypoinsulinemia and decreased insulin secretion. As these alterations can be related to insulin availability, we have now investigated early and long-term effects of protein calorie food restriction on insulin mRNA levels as well as the possible mechanisms which could modulate the endogenous insulin mRNA content. We used fetuses at 21.5 days of gestation proceeding from food restricted rats during the last week of pregnancy and 70 day-old rats undernourished from day 14 of gestation until adult age, and with respective controls. Insulin mRNA levels, glucose transporters as well as total glycolysis and mitochondrial oxidative fluxes were evaluated. We additionally analyzed undernutrition effects on signals implicated in glucose-mediated insulin gene expression, especially PDX-1, p38/SAPK2 and PI 3-kinase. Undernourished fetuses showed increased insulin m-RNA, oxidative glucose metabolism and p38/SAPK2 levels, while undernutrition until adult age provoked a decrease in insulin gene expression, in oxidative glucose metabolism and in PDX-1 levels. The results indicate that food restriction caused changes in insulin gene expression and content leading to alterations in glucose-stimulated insulin secretion. The molecular events, increased p38/SAPK2 levels in fetuses and decreased PDX-1 levels in adults, seem to be the responsible for the altered insulin mRNA expression. Moreover, since PDX-1 activation appears to be regulated by glucose derived metabolite(s), the altered glucose oxidation caused by undernutrition could in some manner affect insulin mRNA expression.