Long-Term Intracerebroventricular Infusion of Insulin, but Not Glucose, Modulates Body Weight and Hepatic Insulin Sensitivity by Modifying the Hypothalamic Insulin Signaling Pathway in Type 2 Diabetic Rats

BACKGROUND/AIMS: It has been reported that the short-term injection of insulin and glucose into the hypothalamus modulates body weight and hepatic glucose production in non-diabetic rats. However, the effect of hypothalamic insulin and glucose on peripheral glucose metabolism in diabetic animals remains uncertain. We investigated how intracerebroventricular (ICV) infusion of insulin and glucose modified body weight and peripheral glucose homeostasis in 90% pancreatectomized rats that exhibited symptoms of mild and non-obese type 2 diabetes. METHODS: The diabetic rats that were fed a high fat diet were ICV administered with either insulin (0.3 U/day), glucose (10 mg/day), insulin plus glucose (insulin+glucose), or artificial cerebrospinal fluid (control) by means of osmotic pumps for 4 weeks. RESULTS: Central insulin and insulin+glucose reduced body weight with a slight decrease of food intake compared to the control and glucose groups in diabetic rats. In addition, during euglycemic hyperinsulinemic clamp, ICV infusion of insulin and insulin+glucose increased glucose infusion rates and decreased hepatic glucose production compared to the control and glucose groups. The improvement of insulin sensitivity was associated with the activation of both hypothalamic and hepatic insulin signaling cascades. Central glucose did not affect hypothalamic insulin action in diabetic rats. CONCLUSION: Long-term central infusion of insulin enhanced energy metabolism and hepatic glucose homeostasis in type 2 diabetic rats partly via potentiating hypothalamic insulin signaling. However, central glucose infusion did not modulate the central and peripheral metabolism.