Does chronic leptin treatment decrease glucagon responsiveness in STZ-induced type 1 diabetic rats?

Abstract

Central administration of leptin normalizes blood glucose (BG) concentrations in streptozotocin (STZ)-induced diabetic rats. We hypothesize that this is due to a leptin-mediated decrease in glucagon responsiveness. Male Wistar rats (n=12) were implanted with an intracerebroventricular (ICV) cannula. Eight rats were induced with diabetes by an intraperitoneal (IP) injection of STZ (50 mg/kg), while four rats were given control injections. Half of the diabetic rats received daily injections of leptin (DL) (5 µg), while the other diabetic group (DV) and non-diabetic (NDV) group received daily injections of vehicle. BG concentrations were determined daily. After BG concentrations of DL rats were normalized to NDV values, rats were fasted (DL rats for 6 hours and others for 21 hours). Additional fasting time was given so that the rats would be timed controlled to when they would be infused with glucagon. An IP injection of pyruvate (2 g/kg) was given and BG concentrations were determined periodically over the next 2 hours. Days later, rats were fasted (as described above) and the jugular vein and carotid artery were cannulated. Rats were intravenously (IV) infused with somatostatin followed by a one hour IV infusion of somatostatin-glucagon. An IP injection of pyruvate was administered and BG concentrations were determined following prior pyruvate challenge measures, as described above. Both DV and NDV rats had an increased blood glucose response to the pyruvate challenge in the presence of high levels of glucagon. In contrast, the response to pyruvate was not increased by glucagon in DL rats. This suggests that central leptin treatment decreases the hepatic responsiveness to pyruvate in the presence of high levels of glucagon, and therefore supports the contention that BG normalization in leptin-treated diabetic rats is due to a leptin-mediated decrease in glucagon responsiveness.