Additive Effects of Dorzagliatin and Glucagon-Like Peptide 1 Receptor Agonism in a Novel Mouse Model of GCK -MODY and in Obese db/db Mice

Glucokinase (GK) catalyzes the key regulatory step in glucose-stimulated insulin secretion (GSIS). Correspondingly, hetero- and homozygous mutations in human GCK cause maturity-onset diabetes of the young (GCK-MODY) and permanent neonatal diabetes mellitus, respectively. To explore the possible utility of GK activators (GKAs) and of glucagon-like peptide 1 (GLP-1) receptor agonists in these diseases, we have developed a novel hypomorphic Gck allele in mice encoding an aberrantly spliced mRNA. In islets from homozygous knock-in (GckKI/KI) mice, GK immunoreactivity was reduced by >85%, and GSIS eliminated. Homozygous GckKI/KI mice displayed frank diabetes (fasting blood glucose >18 mmol/L; HbA1c ∼108 mmol/mol), ketosis, and nephropathy. Heterozygous GckKI/+ mice were glucose intolerant (HbA1c ∼37 mmol/mol). Abnormal glucose-stimulated Ca2+ dynamics in GckKI/+ islets were completely reversed by the GKA dorzagliatin, which was largely inactive in homozygous GckKI/KI mouse islets. The GLP-1 receptor agonist exendin-4 improved glucose tolerance in male GckKI/+ mice, an action potentiated by dorzagliatin. Sex-dependent additive effects of these agents were also observed on insulin secretion in vitro. Similar additive effects of the drugs were observed in obese hyperglycemic db/db mice. Combined treatment with GKA and incretin mimetics may thus be useful in GCK-MODY and in more common forms of type 2 diabetes. ARTICLE HIGHLIGHTS: Glucokinase (GK) deficiency can drive maturity-onset diabetes of the young (GCK-MODY) in heterozygotes and permanent neonatal diabetes in homozygotes. We describe a hypomorphic Gck allele that results in aberrant splicing in islets and liver lowering GK activity by ∼85%. Whereas heterozygous mutant mice are mildly hyperglycemic, homozygotes have frank diabetes but survive to adulthood. Dorzagliatin potentiates the effects of glucagon-like receptor-1 receptor activation sex dependently in heterozygous Gck mice and in obese hyperglycemic db/db mice. Combined use of these drugs may be useful in some forms of GCK-MODY and in obesity-related type 2 diabetes.