1547-P: The Differential Effect of Glucagon-Like Peptide-1 Receptor Blockade on Glucose Metabolism in People With and Without Type 2 Diabetes

Abstract

Glucagon-Like Peptide-1 (GLP-1) is present within the islet but the effects of GLP-1 Receptor (GLP1R) blockade on islet function in humans remains unknown. To address this, we studied 12 nondiabetic individuals (54 ± 2 years, 33 ± 1 kg/m2) and 11 people with type 2 diabetes (DM2 - 58 ± 2 years, 34 ± 2 kg/m2) on 2 occasions in random order. On each occasion, after an overnight fast, [3-3H] glucose was used to measure glucose turnover during fasting and a hyperglycemic clamp (~9 mmol/l) using the tracer dilution technique. On one occasion exendin-9,39 (300pmol/kg/min) was infused to block GLP1R, while on the other saline was infused. Exendin-9,39 increased fasting glucose concentrations in those without (4.6 ± 0.4 vs. 5.5 ± 0.1 mmol/l, saline vs. exendin-9,39 respectively, p = 0.04) and in those with DM2 (7.3 ± 0.5 vs. 8.3 ± 0.6 mmol/l, p = 0.03). Fasting islet hormone concentrations were unchanged, but inappropriate for the higher fasting glucose observed during exendin-9,39 infusion. The same pattern was seen in people with DM2 except that fasting glucagon concentrations increased (8.3 ± 0.5 vs. 10.2 ± 0.6 pmol/l, p < 0.01) and remained elevated throughout hyperglycemia (4.7 ± 0.4 vs. 7.7 ± 0.6 pmol/l, p < 0.02). Insulin secretion rate calculated by deconvolution of C-peptide concentrations was also decreased in DM2 (0.54 ± 0.08 vs. 0.51 ± 0.08 nmol/min, p = 0.02). Consequently, suppression of endogenous glucose production by hyperglycemia was impaired in people with DM2 (2.9 ± 0.4 vs. 5.7 ± 0.3 μmol/kg/min, p < 0.01). Intriguingly, 1st phase response to hyperglycemia was decreased in those without DM2 (3.5 ± 0.6 vs. 2.5 ± 0.5 nmol per 10 min, p = 0.04). These data show that in humans, GLP1R blockade impairs fasting α- and β-cell function resulting in fasting hyperglycemia. Subtle effects are also present in response to hyperglycemia. This implies that intra-islet GLP1R activation sustains islet responses to glucose and it does so to a greater degree in people with DM2. Disclosure A.A. Welch: None. R.A. Farahani: None. M. Zeini: None. A.M. Egan: None. M.C. Laurenti: None. C. Cobelli: None. C. Dalla Man: Research Support; Sanofi-Aventis Deutschland GmbH, Becton, Dickinson and Company. A. Vella: Other Relationship; Novo Nordisk. Advisory Panel; Rezolute, Inc. Consultant; Crinetics Pharmaceuticals, Inc., Hanmi Pharm. Co., Ltd., Zealand Pharma A/S. Funding National Institute of Diabetes and Digestive and Kidney Diseases (R01DK126206)