259-OR: The Effect of Impaired Glucagon Suppression on Endogenous Glucose Production Is Independent of Insulin Action

Type 2 diabetes is a disease characterized by impaired insulin secretion and defective glucagon suppression in the postprandial period. We examined the effect of impaired glucagon suppression on glucose concentrations and Endogenous Glucose Production (EGP) at different degrees of insulin secretory impairment. The contribution of anthropometric characteristics, peripheral, and hepatic, insulin action to this variability was also examined. To do so, we studied 54 nondiabetic subjects on two occasions in which endogenous hormone secretion was inhibited by somatostatin, with glucagon infused at a rate of 0.65 ng/kg/min, at 0 min to prevent a fall in glucagon (non-suppressed day) or at 120 min to create a transient fall in glucagon (suppressed day). Subjects received glucose (labeled with [3-3H]-glucose) infused to mimic the systemic appearance of 50g oral glucose. Insulin was infused to mimic a prandial insulin response in 18 subjects, another 18 received 80% of the dose and the remaining 18 received 60%. EGP was measured using the tracer-dilution technique. Decreased prandial insulin resulted in greater % increase in peak glucose (56±5 vs. 44±6 vs. 31±6 %, p=0.01 - 0.6, 0.8 and 1.0 dose respectively) but not in integrated (area above basal - AAB) glucose (39±4 vs. 43±9 vs. 36±9 %, p=0.82) caused by non-suppressed glucagon. The % change in integrated EGP was unaffected by insulin dose (51±20 vs. 27±19 vs. 22±18 %, p=0.53). Multivariate regression analysis, adjusted for age, sex, weight and insulin dose, did not show a relationship (R2=0.04, p=0.21) between the EGP response to impaired suppression of glucagon and insulin action as measured at the time of screening by oral glucose tolerance. A similar analysis for hepatic insulin action did not show a relationship (R2=0.06, p=0.06) with the EGP response to non-suppressed glucagon. These data indicate that the change in EGP produced by impaired glucagon suppression is independent of anthropometric characteristics and insulin action. Disclosure M. C. Laurenti: None. A. M. Egan: None. D. Schembri wismayer: None. C. Cobelli: None. C. Dalla man: Research Support; Self; Becton, Dickinson and Company, Sanofi-Aventis Deutschland GmbH. A. Vella: Research Support; Self; Novo Nordisk. Funding National Institutes of Health (DK116231, DK78646)