Current Projects

Sex differences are recognized in metabolism but poorly understood. Families in which carriers of the S64F MAFA variant manifest extreme sex dimorphism in which men are prone to diabetes while women succumb to β cell tumors (insulinomas) and refractory hypoglycemia. Our mouse model remarkably phenocopies this extreme condition, which is largely independent of adult sex hormones. This model is a rare tool to molecularly interrogate underlying sex differences in a critical metabolic cell type and provide insights into how sex differences manifest in physiology and disease states.

Using a model of a rare form of monogenic diabetes (S64F MAFA), we have shown that diabetes in males is associated with widespread accelerated pancreatic islet β cell senescence and aging - features noted in type 1 and type 2 diabetes. This project will exploit this model to understand mechanisms underlying accelerated β cell senescence and evaluate the utility of senolytics in the treatment or prevention of β cell dysfunction.

Beta cell heterogeneity is a feature of all islets and efforts to characterize discrete cell populations are underway using single cell technologies. Strategies to understand contributions of unique cell populations, and efforts to preserve baseline heterogeneity could launch new treatment strategies in preserving or modulating islet function.