Insulin sensitivity and liver glucose production in the rat are influenced by lifetime food restriction.

In both humans and rats, food restriction leads to increased insulin sensitivity and predisposition to hypoglycemia. We hypothesized that metabolic responses to hypoglycemic episodes could be altered in food-restricted rats. To test our hypothesis, plasma glucose levels and liver glucose production during insulin-induced hypoglycemia were assessed. Rats either had free access to food (FF group) or were food restricted from birth (FR group). As adults, they were subjected to insulin-induced hypoglycemia after an overnight fast. Plasma glucose was measured before (time 0) the intraperitoneal injection of insulin (1 U/kg) and at regular intervals for 300 minutes. Some FF and FR rats received oral glucose (100 mg/kg) 15 minutes after insulin injection, and the same time intervals were investigated. The FR rats showed a larger decrease and slower recovery of plasma glucose than the FF group, and this was not influenced by oral glucose. Liver glucose production from glycogenolysis and gluconeogenesis (ie, before and during the infusion of L-alanine) was higher and lower, respectively, in the FR rats than in the FF rats, either with or without oral glucose before liver perfusion. Preference for glycogenolysis could be a metabolic adaptation for the maintenance of plasma glucose levels during fasting despite lower food availability in the FR rats. However, long-term FR increased the severity of hypoglycemia and impaired plasma glucose recovery. In addition, hypoglycemia could not be prevented by glucose administration. Therefore, food restriction in individuals with intensive insulin therapy should be more rigorously examined.