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
Type of DegreeThesis
DepartmentNutrition and Food Science
MetadataShow full item record
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.