Additive Effects of Dorzagliatin and Glucagon-Like Peptide 1 Receptor Agonism in a Novel Mouse Model of <i>GCK</i> -MODY and in Obese <i>db/db</i> Mice
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.
Authors
- Guy A. Rutter (ORCID: https://orcid.org/0000-0001-6360-0343)
- Rana Melhem
- Mark O. Huising (ORCID: https://orcid.org/0000-0002-6594-2205)
- Luis Fernando Delgadillo-Silva (ORCID: https://orcid.org/0000-0002-2721-5920)
- Francis Migneault (ORCID: https://orcid.org/0000-0001-7331-4498)
- Priscila Carapeto (ORCID: https://orcid.org/0000-0002-8987-9116)
- Audrey Provencher-Girard
- Giada Ostinelli
- Sergio Miguel Salazar (ORCID: https://orcid.org/0000-0001-5218-3361)
- Malik Chaker-Margot (ORCID: https://orcid.org/0000-0002-8439-6027)
- Imane Kaci
- Julie Turgeon
- Marie-Josèe Hébert
- Karen Dakessian
- Mohamed Mourad Kenfaoui
Institutions
- Nanyang Technological University (SG)
- Hammersmith Hospital (GB)
- McGill University Health Centre (CA)
- Université du Québec (CA)
- Université de Montréal (CA)
- University of California, Davis (US)
Publication Details
- Journal
- Diabetes
- Published
- 2025-11-06
- DOI
- https://doi.org/10.2337/db25-0520
- Citations
- 1
- Primary Topic
- Pancreatic function and diabetes
- Type
- article
- Field-Weighted Citation Impact
- 2.01