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

  • Diabetes. 2022 Oct 28;db220708. doi: 10.2337/db22-0708.
Elaine Chow  1  2  3 ,  Ke Wang  1  2  3 ,  Cadmon Kp Lim  1  2 ,  Sandra Tf Tsoi  1  2 ,  Baoqi Fan  1  2 ,  Emily Poon  1 ,  Andrea Oy Luk  1  2  3 ,  Ronald Cw Ma  1  2 ,  Ele Ferrannini  4 ,  Andrea Mari  5 ,  Li Chen  6 ,  Juliana Cn Chan  1  2
Affiliations
  • 1. Department of Medicine and Therapeutics.
  • 2. Phase 1 Clinical Trial Centre.
  • 3. Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong.
  • 4. CNR Institute of Clinical Physiology, Pisa, Italy.
  • 5. CNR Institute of Neuroscience, Padua, Italy, and.
  • 6. Hua Medicine, China.
PMID: 36342518 DOI: 10.2337/db22-0708
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.

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