1564-P: Impaired Insulin Secretion Increases Glucagon Action on the Liver

Abstract

The transition from prediabetes to diabetes is characterized by defects in insulin secretion and glucagon suppression in response to glucose. However, simultaneous estimation of both hormones actions on endogenous glucose production (EGP) remains a challenge. To address this, we studied 36 nondiabetic subjects on 2 occasions when endogenous hormone secretion was inhibited by somatostatin. Glucagon was infused at 0.65 ng/kg/min, at 0 min to prevent a fall in its concentration (non-suppressed - NS) or at 120 min to create a transient fall (suppressed - S). [3-3H]-glucose was infused to mimic an oral glucose challenge together with a prandial insulin infusion - one group received the full dose (100%), another 80% and another 60%. We tested models describing EGP as a function of glucose, insulin and glucagon concentrations. The optimal model assumes that EGP is suppressed by the actions of glucose, its rate of change and insulin in a remote compartment, while plasma glucagon stimulated EGP (through parameter SGn), with an effect that is evanescent. With 60% replacement (corresponding to severely impaired insulin secretion), SGn was significantly higher than with 80% (moderately impaired) and 100% replacement (p=0.02, Fig.1). This demonstrates that glucagon action on EGP is modulated by insulin concentrations, emphasizing the need to quantify secretion and action of both hormones when measuring postprandial islet function. Disclosure A. Tonello: None. M.C. Laurenti: None. C. Cobelli: None. A. Vella: Other Relationship; Novo Nordisk. Advisory Panel; Rezolute, Inc. Consultant; Crinetics Pharmaceuticals, Inc., Hanmi Pharm. Co., Ltd., Zealand Pharma A/S. C. Dalla Man: Research Support; Sanofi-Aventis Deutschland GmbH, Becton, Dickinson and Company. Funding Italian Minister for Education; National Institutes of Health (DK116723)