Leptin Treatment in STZ-Induced Diabetic Rats Inhibits Glucagon Responsiveness and Hepatic Gluconeogenic Gene Expression

Abstract

Central administration of leptin normalizes blood glucose concentrations of streptozotocin (STZ)-induced diabetic rats and dramatically decreases blood glucose concentrations in leptin-treated rats during a fast as compared vehicle-treated controls. We hypothesize that central leptin administration decreases blood glucose concentrations by either decreasing serum glucagon concentrations or glucagon responsiveness, which ultimately decreases gluconeogenesis. Glucagon responsiveness was tested after fasting; a large dose of IP glucagon (750 ug/kg) did not increase the absolute blood glucose concentrations of leptin-treated diabetic rats back to levels observed in vehicle-treated diabetic rats. The expression of approximately thirty genes was determined in the liver by custom-made PCR arrays. Overall, the gene expression of several gluconeogenic enzymes, transcription factors, and coactivators, (G6pc3, Pck1, Ppargc1, Creb1, Mdh1 and IRS-2) appeared to increase in diabetic vehicle-treated rats compared to nondiabetic rats, and leptin treatment appeared to reverse this effect. This suggests that gluconeogenesis was suppressed in leptin-treated diabetic rats, despite the finding the serum glucagon concentrations were similar in vehicle-treated diabetic rats and leptin-treated diabetic rats. Therefore, it appears that leptin-treated diabetic rats were resistant to the effects of glucagon and that this contributed to lower daily blood glucose concentrations and decreased blood glucose concentrations during a fast.