MODY PDX1^P33T: a mouse model reveals phenotypic divergence from human disease

Area of Science:

• Endocrinology
• Genetics
• Molecular Biology

Background:

• Maturity-onset Diabetes of the Young (MODY) is a rare genetic diabetes form.
• PDX1-MODY, caused by PDX1 gene mutations, impairs pancreatic beta cell function.
• Existing mouse models do not accurately represent human PDX1-MODY.

Purpose of the Study:

• To generate and characterize the first mouse model of PDX1-MODY with a common human mutation (P33T).
• To investigate the in vivo phenotype and molecular changes in PDX1-MODY mice.

Main Methods:

• CRISPR-Cas9 technology used to create the PDX1-P33T mouse model.
• 18-week in vivo phenotyping on chow and high-fat diets.
• Transcriptomic, proteomic, and islet architecture analyses.

Main Results:

• Homozygous PDX1-P33T mice showed no significant metabolic differences from wild-type controls.
• Male PDX1-P33T mice had increased islet size/number on chow diet, suggesting stress resilience.
• These mice failed to adapt to a high-fat diet, unlike human patients.

Conclusions:

• Significant differences exist between mouse and human PDX1 function.
• Current mouse models require refinement for accurate PDX1-MODY pathophysiology studies.