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

Grant Number: 5F31GM150237-02
NIH Institute/Center: NIH
Principal Investigator: KaLia Burnette