Leptin has been shown to improve insulin sensitivity and glucose metabolism in normoinsulinemic healthy or obese rodents. It has not been determined whether leptin may act independently of insulin in regulating energy metabolism in vivo. The present study was designed to examine the effects of leptin treatment alone on glucose metabolism in insulin-deficient streptozotocin (STZ)-induced diabetic rats. Four groups of STZ-induced diabetic rats were studied: 1) rats treated with recombinant methionine murine leptin subcutaneous infusion with osmotic pumps for 12-14 days (LEP; 4 mg x kg(-1) x day(-1), n = 10); 2) control rats infused with vehicle (phosphate-buffered saline) for 12-14 days (VEH; n = 10); 3) pair-fed control rats given a daily food ration matching that of LEP rats for 12-14 days (PF; n = 8); and 4) rats treated with subcutaneous phloridzin for 4 days (PLZ; 0.4 g/kg twice daily, n = 10). Phloridzin treatment normalizes blood glucose without insulin and was used as a control for the effect of leptin in correcting hyperglycemia. All animals were then studied with a hyperinsulinemic-euglycemic clamp (6 mU x kg(-1) x min(-1). Our study demonstrates that leptin treatment in the insulin-deficient diabetic rats restored euglycemia, minimized body weight loss due to food restriction, substantially improved glucose metabolic rates during the postabsorptive state, and restored insulin sensitivities at the levels of the liver and the peripheral tissues during the glucose clamp. The effects on glucose turnover are largely independent of food restriction and changes in blood glucose concentration, as evidenced by the minimal improvement of insulin action and glucose turnover parameters in the PF and PLZ groups. Our results suggest that the antidiabetic effects of leptin are achieved through both an insulin-independent and an insulin-sensitizing mechanism.

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