Progressive HNF1A-MODY pathophysiology revealed by a translational mouse model.
HNF1A-MODY, the most common monogenic diabetes, exhibits progressive β cell dysfunction, but existing mouse models fail to recapitulate human disease progression, limiting understanding of pathogenic mechanisms. We developed mice with heterozygous deletion of the Hnf1a transactivation domain (Hnf1a+/Δe4-10) to model human HNF1A haploinsufficiency, conducted cross-sectional metabolic characterization, and validated our findings in HNF1A-deficient human islets. Unlike previous models, Hnf1a+/Δe4-10 mice successfully recapitulated temporal HNF1A-MODY progression. Male mice developed sequential pathophysiology: early insulin resistance in young adults (7 weeks), followed by testosterone deficiency and fasting hyperglycemia in adult mice (10 weeks). Glucose intolerance emerged in middle-aged mice (30 weeks), progressing to multi-organ dysfunction in aged mice (44-70 weeks), characterized by elevated hepatic gluconeogenesis, impaired renal glucose handling, and hepatic steatosis/fibrosis. This dual pathophysiology involving β cell dysfunction and peripheral insulin resistance was associated with dysregulated hormone secretion from both α and β cells in aged mice (40-70 weeks). Human islet studies with HNF1A knockdown confirmed translational relevance, demonstrating reduced SGLT2 protein expression and inappropriate glucagon and insulin secretion. This work established a physiologically relevant HNF1A-MODY model, identified early insulin resistance as a key mechanism triggering hormonal dysfunction, and revealed HNF1A's role in multi-organ pathophysiology beyond traditional β cell dysfunction.