263-OR: Higher Glycemic Threshold for Glucagon Suppression in Impaired Fasting Glucose and Impaired Glucose Tolerance

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Impaired glucagon suppression is an overlooked contributor to the transition of prediabetes to type 2 diabetes. Graded Glucose Infusion (GGI) is a technique used to assess Insulin Secretion Rate (ISR) in response to rising glucose concentrations. We used GGI to examine the relationship of ISR and Glucagon Secretion Rate (GSR) with rising glucose. We studied 32 nondiabetic, weight-stable individuals (54 ± 2 yrs, 29 ± 1 Kg/M2) categorized on the basis of fasting and glucose tolerance status following a 75g OGTT at the time of screening. After an overnight fast, at 07:00 a variable insulin infusion was used to maintain glucose at ~4.4 mmol/L (until 08:30) enabling the subsequent measurement of the glycemic threshold for ISR and GSR. At 09:00 GGI commenced, starting at 1 mg/kg/min and doubling every 60 min until 13:00. GSR and ISR were calculated by nonparametric deconvolution from plasma concentrations of glucagon and c-peptide respectively. β-cell responsivity (Φ) was estimated from the relationship of ISR to glucose. The glycemic threshold for glucagon suppression was higher in subjects with impaired fasting glucose (IFG) than normal fasting glucose (NFG), 10.9 ± 0.8 vs. 8.3 ± 0.5 mmol/L, p<0.01, IFG vs. NFG respectively. This was also the case in subjects with impaired glucose tolerance (IGT) compared to normal glucose tolerance (NGT), 10.3 ± 0.7 vs. 8.5 ± 0.7 mmol/L, p=0.05. Φ did not differ in subjects with IGT vs. NGT (p=0.33) or in subjects with IFG vs. NFG (p=0.48). The glycemic threshold for stimulation of ISR was higher in subjects with IFG than NFG, 5.7 +/- 0.3 vs. 5.0 +/- 0.1 mmol/L, p<0.01, IFG vs. NFG respectively, but no different in subjects with IGT vs. NGT, 5.3 +/- 0.2 vs. 5.0 +/- 0.1 mmol/L, p=0.06, IGT vs. NGT respectively. These data show that in nondiabetic humans, IFG but not IGT is associated with a higher glycemic threshold for insulin secretion, and both IFG and IGT are associated with a higher glycemic threshold for glucagon suppression. Disclosure J. D. Kohlenberg: None. M. C. Laurenti: None. A. M. Egan: 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 Endocrine Fellows Foundation (DK078646DK116231)