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Dorzagliatin, a Dual-Acting Glucokinase Activator, Increases Insulin Secretion and Glucose Sensitivity in Glucokinase-Maturity-Onset Diabetes of the Young (GCK-MODY) and Recent-Onset Type 2 Diabetes.

Authors :
Chow, Elaine
Wang, Ke
Lim, Cadmon K.P.
Tsoi, Sandra T.F.
Fan, Baoqi
Poon, Emily
Luk, Andrea O.Y.
Ma, Ronald C.W.
Ferrannini, Ele
Mari, Andrea
Chen, Li
Chan, Juliana C.N.
Source :
Diabetes. Feb2023, Vol. 72 Issue 2, p299-308. 10p.
Publication Year :
2023

Abstract

Glucokinase-maturity-onset diabetes of the young (GCK-MODY) is caused by heterozygous inactivating mutations in glucokinase (GK, gene symbolGCK) and impaired glucose sensing. We investigated effects of dorzagliatin, a novel allosteric GK activator, on insulin secretion rates (ISR) and beta-cell glucose-sensitivity (βCGS) in GCK-MODY and recent-onset type 2 diabetes. In a double-blind, randomized cross-over study, eight participants with GCK-MODY and 10 with type 2 diabetes underwent 2-hour 12-mmol/L hyperglycemic clamps following a single oral dose of dorzagliatin 75mg or matched placebo. Effects of dorzagliatin on wild-type and mutant GK enzyme activity were investigated using a nicotinamide adenine dinucleotide phosphate (NADP+) coupled assay with glucose-6-phosphate dehydrogenase (G6PD) in vitro. In GCK-MODY, dorzagliatin significantly increased absolute and incremental second-phase ISR versus placebo but not the acute insulin response. Dorzagliatin improved βCGS in GCK-MODY with a upward and leftward shift in ISR-glucose response. Dorzagliatin increased basal ISR in type 2 diabetes with smaller changes in second-phase ISR compared with GCK-MODY. In vitro, dorzagliatin directly reduced the glucose half saturation concentration (S0.5) of wild-type GK and selected GK mutants to varying degrees. Dorzagliatin directly restored enzyme activity of select GK mutants and enhanced wild-type GK activity, thereby correcting the primary defect of glucose sensing in GCK-MODY. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
00121797
Volume :
72
Issue :
2
Database :
Academic Search Index
Journal :
Diabetes
Publication Type :
Academic Journal
Accession number :
161416187
Full Text :
https://doi.org/10.2337/db22-0708