981-P: GIP and GLP-1 Potentiate Sulfonylurea-Induced Insulin Secretion in HNF1A Diabetes

Sulfonylurea (SU) is considered first-line treatment of hepatocyte nuclear factor 1-alpha (HNF1A)-diabetes but rarely provides lasting glycemic control. In a randomized, double-blinded, cross-over study, we evaluated the insulinotropic effect of exogenous glucose-dependent insulinotropic peptide (GIP) and glucagon-like-peptide 1 (GLP-1), respectively, with and without SU in patients with HNF1A-diabetes. Ten patients with HNF1A-diabetes ([mean±SD] BMI 22.4±1.5 kg/m2; HbA1c 6.0±0.6% [42.3±6.6 mmol/mol]) and 10 matched healthy controls (BMI 22.2±2.4 kg/m2; HbA1c 5.1±0.3% [31.9±2.8 mmol/mol]) were subjected to six 2 h glucose clamps (time 0-60 minutes at fasting plasma glucose (FPG) and 60-120 minutes at 1.5 × FPG) preceded by administration of 1 mg of glimepiride or placebo (PLA) at time -90 min. Two-hour infusion of either GIP (1.5 pmol/kg/min), GLP-1 (0.5 pmol/kg/min) or saline (NaCl) was initiated at time 0 min. Insulin secretion was quantified as baseline-subtracted area under the curve (bsAUC) from 0 to 120 minutes (Figure). In patients with HNF1A-diabetes both SU+GIP and SU+GLP-1, respectively, showed significantly greater insulin secretion vs. PLA+GIP, PLA+GLP-1, SU+NaCl and PLA+NaCl, while this was only the case for SU+GLP-1 in controls. In conclusion, GIP and GLP-1 potentiate SU-induced insulin secretion in patients with HNF1A-diabetes and in nondiabetic controls. Disclosure A.S. Christensen: None. S. Haedersdal: None. H. Storgaard: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc. K. Rose: None. N.L. Hansen: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. T. Hansen: None. F.K. Knop: Advisory Panel; Self; AstraZeneca, MedImmune, Merck Sharp & Dohme Corp., Mundipharma, Novo Nordisk A/S, Sanofi. Consultant; Self; Amgen Inc., Carmot Therapeutics, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Novo Nordisk A/S. Speaker's Bureau; Self; AstraZeneca, MedImmune, Merck Sharp & Dohme Corp., Mundipharma, Norgine, Novo Nordisk A/S. T. Vilsbøll: None.