Grant: Project Grant

Patients with type 2 diabetes are unable to produce sufficient insulin to meet demand and blood sugars rise as a result. The disease worsens as insulin-producing beta cells in the pancreas lose their function and die. Loss of beta cells is thought to be due to several causes, one being the formation of toxic protein aggregates called islet amyloid, formed by accumulation of a small protein made in the pancreas along with insulin, called islet amyloid polypeptide (IAPP). In type 2 diabetes, the islets in the pancreas, where the insulin-producing beta cells reside, also show signs of inflammation, including increased numbers of immune cells called macrophages. We found that aggregates of IAPP - the toxic amyloid deposits - play an important role in inducing this inflammation within the islet, activating these macrophages to produce other toxic proteins called cytokines. We have also found that when insulin-producing beta cells die, these macrophages produce proteins that induce new beta cell growth and improve beta cell function. In this proposal, we aim to understand the mechanisms by which islet macrophages are activated to produce proteins that may be deleterious or helpful to beta cells, and therefore may contribute to or protect from diabetes. These studies have the potential to identify therapeutic approaches that improve beta cell survival and function in diabetes by targeting islet macrophages.