Progressive HNF1A-MODY pathophysiology revealed by a translational mouse model

Area of Science:

• Endocrinology
• Genetics
• Metabolic Diseases

Background:

• Hepatocyte Nuclear Factor 1-Alpha (HNF1A)-Maturity-Onset Diabetes of the Young) (MODY) is the most common monogenic diabetes, characterized by progressive β cell dysfunction.
• Existing mouse models do not accurately reflect the temporal progression of human HNF1A-MODY, hindering the study of its pathogenesis.

Purpose of the Study:

• To develop and characterize a novel mouse model that recapitulates human HNF1A haploinsufficiency and the progressive nature of HNF1A-MODY.
• To investigate the underlying mechanisms of HNF1A-MODY, including β cell function, insulin resistance, and multi-organ involvement.

Main Methods:

• Generation of mice with heterozygous deletion of the Hnf1a transactivation domain (Hnf1a+/Δe4-10) to mimic human HNF1A haploinsufficiency.
• Cross-sectional metabolic characterization of Hnf1a+/Δe4-10 mice at various ages.
• Validation of findings in HNF1A-deficient human islets with HNF1A knockdown.

Main Results:

• Hnf1a+/Δe4-10 mice exhibited temporal HNF1A-MODY progression, including early insulin resistance, testosterone deficiency, hyperglycemia, and glucose intolerance.
• Aged mice showed multi-organ dysfunction (liver, kidney) with elevated hepatic gluconeogenesis, impaired renal glucose handling, and hepatic steatosis/fibrosis.
• Human islet studies confirmed reduced SGLT2, inappropriate glucagon/insulin secretion, and translational relevance.

Conclusions:

• The Hnf1a+/Δe4-10 mouse model accurately recapitulates human HNF1A-MODY pathophysiology.
• Early insulin resistance is identified as a key driver of hormonal dysfunction and multi-organ pathophysiology in HNF1A-MODY.
• HNF1A plays a critical role in maintaining multi-organ homeostasis beyond its traditional role in β cell function.