The Apparent Increase in Insulin Sensitivity of Leptin-Treated Rats Appears to be Due to a Decrease in Blood Glucose Concentrations in Response to Fasting

Abstract

To distinguish between the effects of insulin stimulation and fasting on blood glucose homeostasis in leptin-treated animals, streptozotocin(STZ)-induced diabetic (STZ-D) and non-diabetic rats given chronic intracerebroventricular (icv) injections of leptin (5 µg/5 µl) or vehicle (5 µl) underwent insulin tolerance tests (ITT) with either intraperitoneal (ip) injection of insulin (1 U/kg) or saline (0.9% NaCl) in a cross-over design study. Regardless of whether the rats were diabetic or non-diabetic, the insulin-mediated decrease in blood glucose tended to be greater in leptin-treated rats than in vehicle-treated animals, indicating enhanced insulin sensitivity. However, leptin treatment also resulted in a significant decline in blood glucose after saline injection (P < 0.005), which served as a control for the change in blood glucose due to fasting sustained during the ITT testing period (90 min). This decrease due to the fast during the ITT accounted for 92 % of the difference in response between the leptin-treated and vehicle-treated rats given insulin. This suggests that most of the difference between leptin-treated and vehicle-treated rats given insulin was due to a leptin-induced decrease in blood glucose due to fasting and not to enhanced insulin sensitivity. In addition, leptin-treated rats maintain normoglycemia in the fed state, while blood glucose is markedly diminished during an acute (3.5 h) fast relative to vehicle-treated animals (P < 0.0001). Thus, without access to food, leptin-treated animals appear unable to maintain proper blood glucose levels. Liver glycogen levels were markedly decreased in leptin-treated animals compared to vehicle-treated controls during fasting (P < 0.0005). Short-term (3 h) fasting also caused a significant increase in mRNA expression levels of both phosphoenolpyruvate-carboxykinase (PEPCK) and glucose-6-phosphate (G6Pase), two key gluconeogenic enzymes, while the mRNA expression of glucokinase (GCK), a glycolytic enzyme, was decreased. Together, these results suggest that the stimulation of either glycogenolysis or gluconeogenesis was not effected during fasting in leptin treated rats. Nevertheless, a corresponding increase in glucose-6-phosphatase (G6Pase) activity and elevation in hepatic glucose output were not observed, which indicates leptin may reduce blood glucose levels via alternative regulatory mechanisms. Overall, these results demonstrate a potent blood glucose-lowering effect of leptin independently of insulin action that inhibits leptin-treated rats from adequately raising blood glucose concentration during a fast and normalizes blood glucose concentrations in diabetic rats in the fed state.