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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 &amp;gt;85%, and GSIS eliminated. Homozygous GckKI\/KI mice displayed frank diabetes (fasting blood glucose &amp;gt;18 mmol\/L; HbA1c \u223c108 mmol\/mol), ketosis, and nephropathy. Heterozygous GckKI\/+ mice were glucose intolerant (HbA1c \u223c37 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\u00a0vitro. 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Article Highlights<\/jats:title>\n                    <jats:p>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 \u223c85%. Whereas heterozygous mutant mice are mildly hyperglycemic, homozygotes have frank diabetes but survive to adulthood. Dorzagliatin potentiates the effects of glucagon\u2013like 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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.2337\/db25-0520","type":"journal-article","created":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T17:08:58Z","timestamp":1762448938000},"page":"99-114","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":4,"title":["Additive Effects of Dorzagliatin and Glucagon-Like Peptide 1 Receptor Agonism in a Novel Mouse Model of\n                    <i>GCK<\/i>\n                    -MODY and in Obese\n                    <i>db\/db<\/i>\n                    Mice"],"prefix":"10.2337","volume":"75","author":[{"given":"Shadai","family":"Salazar","sequence":"first","affiliation":[{"name":"Research Center of the Hospital Center of the University of Montreal and University of Montreal 1 , Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis Fernando","family":"Delgadillo-Silva","sequence":"additional","affiliation":[{"name":"Research Center of the Hospital Center of the University of Montreal and University of Montreal 1 , Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priscila","family":"Carapeto","sequence":"additional","affiliation":[{"name":"Research Center of the Hospital Center of the University of Montreal and University of Montreal 1 , Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed Mourad","family":"Kenfaoui","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Medicine, Universit\u00e9 de Montr\u00e9al 2 , Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Dakessian","sequence":"additional","affiliation":[{"name":"Research Center of the Hospital Center of the University of Montreal and University of Montreal 1 , Quebec, 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University of Montreal 1 , Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Imane","family":"Kaci","sequence":"additional","affiliation":[{"name":"Research Center of the Hospital Center of the University of Montreal and University of Montreal 1 , Quebec, Canada"},{"name":"D\u00e9partement de M\u00e9decine, Universit\u00e9 de Montr\u00e9al 3 , Montr\u00e9al, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francis","family":"Migneault","sequence":"additional","affiliation":[{"name":"Research Center of the Hospital Center of the University of Montreal and University of Montreal 1 , Quebec, Canada"},{"name":"D\u00e9partement de Microbiologie, Infectiologie et Immunologie, Facult\u00e9 de M\u00e9decine, Universit\u00e9 de Montr\u00e9al 4 , Montr\u00e9al, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark O.","family":"Huising","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, Physiology and Behavior, College of Biological Sciences, University of California 5 , Davis, Davis, CA"},{"name":"Department of Physiology and Membrane Biology, School of Medicine, University of California 6 , Davis, Davis, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-Jos\u00e9e","family":"H\u00e9bert","sequence":"additional","affiliation":[{"name":"Research Center of the Hospital Center of the University of Montreal and University of Montreal 1 , Quebec, Canada"},{"name":"D\u00e9partement de M\u00e9decine, Universit\u00e9 de Montr\u00e9al 3 , Montr\u00e9al, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malik","family":"Chaker-Margot","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Medicine, Universit\u00e9 de Montr\u00e9al 2 , Quebec, 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