Effects of hypoglycemia and prolonged fasting on insulin and glucagon gene expression. Studies with in situ hybridization

In situ hybridization of proinsulin and proglucagon mRNA was performed in rat pancreas to assess prohormone gene expression during various glucopenic conditions. During a 4-d fast mean blood glucose declined by 48 mg/dl; proinsulin mRNA signal density remained normal while proglucagon mRNA signal density more than doubled. At the end of a continuous 12-d insulin infusion blood glucose averaged 53 ± 12 mg/dl; proinsulin mRNA signal density declined to 30% of controls while proglucagon mRNA signal density more than doubled. In insulinoma-bearing NEDH rats blood glucose averaged 34 ± 3.5 mg/dl; the proinsulin mRNA signal was virtually undetectable and proglucagon mRNA signal density was more than twice the controls. There was no detectable change in either β-cell area or islet number in rats subjected to fasting or insulin infusion, but in insulinoma-bearing rats β cell area was markedly reduced. Thus compensation during 4 d of starvation involves an increase in glucagon gene expression without change in insulin gene expression or β cell mass. In moderate insulin-induced hypoglycemia glucagon gene expression is increased and insulin gene expression decreased. In more profound insulinoma-induced hypoglycemia, in addition to the foregoing changes in hormone gene expression, there is a profound reduction in the number of insulin-expressing cells.