Identifying Gestational-induced Changes in Islet Macrophages as a Potential Target for Beta-cell Expansion

Abstract (30 line max) Diabetes mellitus is the leading cause of kidney failure, heart disease, and stroke, affecting 537 million people worldwide. Diabetes is diagnosed as an increase in blood glucose due to insufficient or ineffective insulin production by the pancreatic β-cell. The inability of the β-cell to adapt to changes in physiologic demand results in hyperglycemia. Under select conditions, such as injury and high-fat diet, the β-cell is capable of expansion, increasing in size and/or number to increase insulin production. Therefore, one potential strategy for mitigating hyperglycemic events is to stimulate β-cell replication. A crucial component for β-cell maturation and β-cell expansion in the adult pancreas is macrophages which support tissue growth through the production of cytokines and stimulatory factors. In models of injury, macrophages shift from their basal classically activated proinflammatory state to a more alternatively-activated anti-inflammatory state, supportive of tissue remodeling through the production of anti-inflammatory cytokines, such as TGF-β. Robust β-cell proliferation has also been measured during pregnancy as a result of reductions in insulin sensitivity and increased fetal demand, making pregnancy an ideal model for investigating expansion in mature β-cells under non-pathologic conditions. β-cell expansion during gestation and macrophage contribution to maternal β-cell growth has not been fully elucidated. I will assess changes in macrophage quantity and phenotype throughout pregnancy. I will determine the source of macrophage accumulation within the islet and whether it is a critical component for β-cell expansion in late gestation. I will also determine whether depletion of islet resident macrophages impairs β-cell expansion in late gestation. I hypothesize that pregnancy drives islet macrophages to an alternatively-activated phenotype, necessary for maternal β-cell expansion. To test this hypothesis, I will explore the following two aims: (1) Characterize the macrophage population within the islet throughout gestation. (2) Establish the requirement of macrophages for maternal β-cell expansion in late gestation. The completion of these aims will identify macrophage-specific responses during pregnancy and their effects on β-cell expansion. 1