1275-OR: Central Regulation of Glucose Production Is Affected by Insulin Levels

Introduction and Objective: Central KATP channel activation with diazoxide (DZX) suppresses endogenous glucose production (EGP) in rodents and humans (JCI 121:4916, 2011), suggesting that brain signals help regulate glucose metabolism. This regulation may require adequate insulin levels (Diabetes 60:3132, 2011). Since previous studies were performed at insulin levels ~20 µU/ml, we evaluated this regulation under reduced insulin conditions by studying subjects with low basal insulin requirements. Methods: Non-diabetic, insulin sensitive subjects (n=8 male, age 45±13, BMI 27±2, HOMA-IR 1.3±0.8) were studied during 7 hour normoglycemic ‘pancreatic clamp’ studies with constant glucoregulatory hormone levels and individualized insulin infusion rates (IIR) to maintain euglycemia (Fig1A). Subjects received DZX 6 mg/kg or placebo (PLC) in randomized, double-blind fashion. Results: Since these subjects required ~65% lower IIR to maintain euglycemia, studies were performed at ~60% lower insulin levels than in prior studies. In contrast to 30% suppression of EGP with DZX in prior studies, EGP did not differ between DZX (1.5±0.1) and PLC (1.5±0.1) in the current studies (p=0.9; Fig1B,C). Conclusion: DZX-mediated suppression of EGP was not observed at the low insulin levels used to maintain euglycemia in these subjects. This suggests that insulin is an important determinant of central glucose regulation in humans, and insulin resistant patients would be more likely to benefit from activating central pathways. Disclosure R. Lopez Fanas: None. L. Payano: None. O. Sandu: None. K. Zhang: None. M. Hawkins: None. M. Nogueira: None. Funding National Institutes of Health (R01DK069861)