1887-LB: Effect of Dorzagliatin, a Dual-Acting Glucokinase Activator, on Insulin and Glucagon Secretion in Impaired and Normal Glucose Tolerance
Authors: BAI ZHENGLI , WANG KE , TSE LING YAU TIFFANY , POON EMILY W. , LUK ANDREA , MA RONALD C. , KONG ALICE P. , CHOW ELAINE , CHEN LI , CHAN JULIANA C. 
Published: June 2024

Dorzagliatin is a novel dual-acting allosteric activator of hepatic and beta-cell glucokinase (GCK). Dorzagliatin improved second-phase insulin secretion in type 2 diabetes and heterozygous carriers of GCK mutations. We investigated the effects of dorzagliatin on insulin secretion and glucagon suppression during hyperglycemic clamps in individuals with impaired glucose tolerance (IGT) and normal controls.

In a double-blind, single-dose, randomized cross-over study, 9 participants with IGT (mean age 55±7.5years, 5 female) and 10 controls (39.5±11.8 years, 5 female) underwent 2-hour 12 mmol/l hyperglycemic clamp following a single dose of dorzagliatin 50mg or matched placebo. Insulin, C-peptide and glucagon were measured at regular intervals.

In controls, dorzagliatin significantly increased basal insulin (48.2±26.5 vs 36.8±16.6 pmol/L, p=0.0006) and second-phase insulin area under the curve (AUC) (25164 ± 22525 vs 17533 ± 12043 pmol/L.min, p=0.049) compared with placebo. Glucagon was also significantly suppressed after dorzagliatin (AUC0-120min 161±58 vs 234±70 pmol/L.min, p=0.0009) in the control group. The IGT group showed significantly higher steady-state C-peptide response (2193±531 vs 1768±351 pmol/L, p=0.013) following dorzagliatin, but similar basal, acute insulin secretion and glucagon levels following both treatments. Dorzagliatin did not affect the insulin sensitivity in either subject group.

Dorzagliatin increased second-phase insulin secretion in IGT, while additionally suppressing glucagon and enhancing basal insulin secretion in normal controls.

Disclosure

Z. Bai: None. K. Wang: Employee; Hua Medicine (Shanghai) Ltd., Shanghai, China. T. Yau: None. E.W. Poon: None. A. Luk: Research Support; Novo Nordisk, Amgen Inc., Merck Sharp & Dohme Corp., Roche Pharmaceuticals, Biogen, Boehringer-Ingelheim, Shanghai Junshi Biosciences CO.Ltd. R.C. Ma: Advisory Panel; AstraZeneca. Other Relationship; Bayer Inc., Boehringer-Ingelheim. Advisory Panel; Merck & Co., Inc. Other Relationship; Roche Diagnostics, Novo Nordisk. Advisory Panel; Takeda Pharmaceutical Company Limited. Other Relationship; GemVCare Ltd. A.P. Kong: Speaker's Bureau; Abbott. Advisory Panel; Merck Sharp & Dohme Corp. Speaker's Bureau; Boehringer-Ingelheim, Bayer Inc., AstraZeneca. Other Relationship; Dexcom, Inc. Speaker's Bureau; Eli Lilly and Company, Novo Nordisk, Sanofi. Advisory Panel; Kyowa Kirin Co., Ltd., Abbott. E. Chow: Research Support; Merck KGaA. Speaker's Bureau; AstraZeneca. Advisory Panel; Boehringer-Ingelheim. Research Support; Medtronic. Speaker's Bureau; Zuellig Pharma Holdings Pte. Ltd., Abbott. L. Chen: None. J.C. Chan: Research Support; AstraZeneca, Hua Medicine. Consultant; Sanofi. Research Support; Servier Laboratories. Consultant; Viatris Inc. Research Support; Merck & Co., Inc. Stock/Shareholder; GemVCare Ltd. Board Member; Asia Diabetes Foundation. Speaker's Bureau; Zuellig Pharma Holdings Pte. Ltd. Advisory Panel; Bayer Inc. Speaker's Bureau; Boehringer-Ingelheim.

Funding

Hua Medicine investigator initiated study grant; Health and Medical Research Fund (CTC-CUHK)