Heterozygous Hnf1a Mutation in Mice Reveals Multiple Pathogenic Mechanisms of HNF1A-MODY

Heterozygous mutations in HNF1A cause HNF1A-MODY, the most common form of monogenic diabetes, characterized by age-dependent onset and progression. Despite HNF1A 's established role in beta cell function, the mechanisms underlying disease progression remain poorly understood, with conventional mouse models failing to recapitulate the gradual metabolic deterioration observed in patients. We developed mice with a heterozygous deletion of the Hnf1a transactivation domain ( Hnf1a ^+/Δe4–10 ) that successfully models the temporal progression of HNF1A-MODY. Like their human counterparts, these mutant mice were normoglycemic at birth, with metabolic abnormalities emerging progressively with age. Male mutant mice, but not females, exhibited a sequential cascade of metabolic dysfunction: testosterone deficiency emerged during puberty (8–12 weeks), preceding fasting hyperglycemia in young adulthood (12–16 weeks), followed by glycosuria and glucose intolerance in mature adults (25–35 weeks) that worsened with advanced age (> 45 weeks). Aging mutant mice displayed elevated fasting glucagon levels, increased endogenous glucose production, and hepatic fat accumulation, while maintaining normal plasma insulin levels compared to wild-type siblings. Isolated islets revealed reduced Androgen Receptor expression not observed in liver tissue, complex hormonal dysregulation, dysregulated glucose-stimulated insulin secretion (GSIS) and defective glucagon suppression, with preserved sulfonylurea sensitivity. Parallel knockdown studies in human islets demonstrated HNF1A' s critical role in alpha cell function, where haploinsufficiency reduced SGLT2 protein expression while increasing glucagon content and secretion. These findings establish HNF1A as a master regulator of multiple hormonal pathways and identify testosterone deficiency as a potential trigger for disease onset in males, suggesting therapeutic strategies for HNF1A-MODY that extend beyond insulin-centric approaches.