<b>Additive effects of dorzagliatin and glucagon-like peptide-1 receptor agonism in a novel mouse model of </b><b><i>GCK</i></b><b>-MODY and in obese </b><b><i>db/db</i></b><b> mice</b>

<p dir="ltr">Glucokinase (GK) catalyses the key regulatory step in glucose-stimulated insulin secretion. Correspondingly, hetero- and homozygous mutations in human <i>GCK </i>cause maturity-onset diabetes of the young (GCK-MODY) and permanent neonatal diabetes mellitus (PNDM), respectively. To explore the possible utility of glucokinase activators (GKA) and of glucagon–like receptor-1 (GLP-1) agonists in these diseases, we have developed a novel hypomorphic <i>Gck </i>allele in mice encoding an aberrantly-spliced mRNA. In islets from homozygous knock-in (Gck^KI/KI) mice, GK immunoreactivity was reduced by >85%, and glucose-stimulated insulin secretion eliminated. Homozygous Gck^KI/KI mice displayed frank diabetes (fasting blood glucose >18 mmol/L; HbA1c ~108 mmol/mol), ketosis and nephropathy. Heterozygous Gck^KI/+ mice were glucose intolerant (HbA1c ~37 mmol/mol). Abnormal glucose-stimulated Ca²⁺ dynamics in Gck^KI/+ islets were completely reversed by the GKA, dorzagliatin, which was largely inactive in homozygous Gck^KI/KI mouse islets. The GLP-1 receptor agonist exendin-4 improved glucose tolerance in male Gck^KI/+mice, an action potentiated by dorzagliatin. Sex-dependent additive effects of these agents were also observed on insulin secretion <i>in vitro</i>. Similar additive effects of the drugs were observed in obese hyperglycemic <i>db/db</i> mice. <a href="" target="_blank">Combined treatment with GKA and incretin mimetics may thus be useful in <i>GCK</i>-MODY and in more common forms of type 2 diabetes.</a></p>