Inhibitory Effect of Central Leptin on Hepatic Glucose Production in Streptozotocin (STZ) -Induced Diabetic Rats

Abstract

Uncontrolled hepatic glucose production contributes significantly to hyperglycemia in type 2 diabetic patients. Leptin plays important roles in the regulation of blood glucose homeostasis. Recent studies have suggested that chronic central leptin administration can normalize blood glucose concentrations without increasing serum leptin and insulin concentrations. We hypothesize that leptin inhibits hepatic glucose output by inhibiting gluconeogenesis. This work sought to directly examine hepatic glucose output in leptin-treated diabetic rats via an isolated perfused liver system and to determine the glucose production rate in response to lactate and fructose. Leptin-treated rats had nearly a 4-fold lower glucose response to lactate gavage than did vehicle-treated rats, suggesting that hepatic gluconeogenesis from lactate is severely blunted in leptin-treated rats. However, the results of hepatic glucose production from fructose were different from the results from lactate. When fructose was used as the gluconeogenic precursor, there was no difference in the hepatic glucose production between leptin- and vehicle-treated rats. Additionally, gastric gavage of fructose resulted in a greater increase in blood glucose concentrations in leptin-treated rats than the gastric gavage of lactate in leptin-treated rats. To further understand the effect of intracerebroventricular (ICV) leptin on the role of leptin in hepatic glucose metabolism, we isolated liver cells from leptin- and vehicle treated diabetic rats, and compared the ability of these cells to produce glucose in the presence of a gluconeogenic precursor in the freshly prepared or cultured state. We found that compared with the control group, in the presence of different concentration of lactate (1mM, 2mM, 5mM and 10Mm) the production of glucose by the primary cultured hepatocytes in leptin-treated group was significantly reduced 41 %, 44 %, 53 % and 58 %, respectively. However, glucose production in the freshly prepared liver cells was not different between cells derived from leptin-treated rats as compared with vehicle-treated rats. Therefore, leptin is capable of reducing glucose production from lactate in isolated hepatocytes. In conclusion, chronic central leptin inhibits hepatic gluconeogenesis to help control whole body glucose levels preventing the overproduction of glucose in diabetic rats. These results indicate that uncontrolled diabetes can be rescued without insulin by leptin to eliminate hepatic overproduction of glucose. Determining the mechanism by which this occurs may lead to new therapeutic agents that help control diabetes, independent of or in conjunction with insulin.