Grant: Operating Grant - Priority Announcement: INMD Start Up Funds (bridge funding)

Type 2 diabetes mellitus results from malfunction of, damage, or loss of insulin producing pancreatic beta cells. Typically, our immune system surveys the body for foreign and non-foreign signals, a process critical for pathogen defense, but also for normal cellular turnover and tissue remodeling after damage. It has been known for a long time that Type 1 diabetes (classically juvenile onset) occurs when the patient's own immune system kills the insulin producing beta cells. Interestingly, I have been involved in recent research showing that the body's own immune system also contributes to beta cell malfunction in type 2 diabetes (classically adult onset). My research group investigates what goes wrong with our immune system and how this harms the insulin producing beta cell in type 2 diabetes. This proposal focuses on the interaction between a classic immune cell, the macrophage, and the pancreatic beta cell using animal models of pre-diabetes and type 2 diabetes. Macrophages can have negative effects on how a tissue normally works, or can actually promote the healing and regeneration of a tissue after it has been damaged. I have shown that there are more macrophages in damaged pancreatic islets (where beta cells are located) in patients with type 2 diabetes, but we don't know what effect they have on the normal function of beta cells. Here I propose to answer two main questions regarding the interaction of macrophages with beta cells in pre-diabetes and type 2 diabetes: 1) Do macrophages contribute to the malfunction of, damage, and loss of insulin producing beta cells in type 2 diabetes? 2) Can we turn "bad" macrophages into "good" healing and regenerative macrophages, to treat type 2 diabetes? Since current therapies for type 2 diabetes do not fix the underlying cause of beta cell failure in this disease, this knowledge should assist in devising new strategies to halt and reverse beta cell failure in type 2 diabetes.