261-OR: Dorzagliatin, a Dual-Acting Glucokinase Activator. Improves Insulin Secretion and Glucose Sensitivity in Glucokinase-Maturity-Onset Diabetes of the Young (GCK-MODY)

Abstract

Glucokinase maturity onset diabetes of the young (GCK-MODY) is caused by heterozygous inactivating mutations in GCK that is not responsive to conventional glucose lowering drugs. We investigated the effects of dorzagliatin, a novel allosteric activator of hepatic and beta-cell GCK on insulin secretion rates (ISR) and glucose sensitivity (GS) in GCK-MODY and recent onset type 2 diabetes (T2D) . In a double-blind, randomized cross-over study, 8 GCK-MODY (mean±SD age 36.1­±6.4years) and T2D subjects (mean age 50.2±6.9 years, median T2D duration 0.90 [0.60-1.42] years) underwent 2-hour 12 mmol/L hyperglycemic clamps following a single oral dose of dorzagliatin 75mg or matched placebo. Insulin and C-peptide were measured. GCK-MODY group showed significantly higher absolute (mean±SD 432±85 versus 272±91 pmol/min/m2, p=0.002) and incremental (342­±91 vs. 241±74 pmol/min/m2, p=0.004) second-phase ISR following dorzagliatin versus placebo. Dorzagliatin significantly improved GS in GCK-MODY (51±21 vs. 33­±13 pmol/min/m2 per mmol/L p=0.028) with an upward and leftward shift in ISR-glucose response. In T2D, basal ISR was significantly improved following dorzagliatin (102±57 vs. 60±42, p=0.018) with smaller increases in second phase ISR and GS. Dorzagliatin improves second phase ISR and GS, with larger effects in GCK-MODY than T2D. Disclosure E.Chow: Research Support; Hua Medicine, Medtronic, Powder Pharmaceuticals Inc., Speaker's Bureau; Novartis AG, Sanofi. L.Chen: Employee; Hua Medicine. J.C.Chan: Board Member; Asia Diabetes Foundation, Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Celltrion, Merck Sharp & Dohme Corp., Roche Diabetes Care, Viatris Inc., Research Support; Applied Therapeutics, AstraZeneca, Eli Lilly and Company, Hua Medicine, Servier Laboratories, Stock/Shareholder; GemVCare Ltd. K.Wang: None. C.K.P.Lim: None. S.Tsoi: None. B.Fan: None. A.Luk: None. R.C.Ma: Other Relationship; Bayer AG, Boehringer Ingelheim International GmbH, Research Support; AstraZeneca, Bayer AG, Novo Nordisk A/S, Pfizer Inc., Tricida, Inc. E.Ferrannini: Advisory Panel; Boehringer Ingelheim International GmbH, Novo Nordisk, Oramed Pharmaceuticals, Consultant; Elgia Therapeutics, Research Support; Janssen Research & Development, LLC, Oramed Pharmaceuticals, Sanofi-Aventis U.S., Speaker's Bureau; Boehringer Ingelheim International GmbH. A.Mari: Consultant; Lilly, Research Support; Lilly. Funding Hua Medicine Investigator Initiated Clinical Research