Grant: Project Grant

The hormone insulin, which is critical for control of blood glucose levels, is produced by islets - clusters of hundreds of insulin-producing beta cells in the pancreas. When beta cells are lost or are impaired in function, diabetes occurs. A type of white blood cell called macrophages - the garbage eaters of the body- are now recognized as important regulators of the function of many organs, including insulin-producing beta cells. Although macrophages comprise only a few cells out of hundreds of cells in each islet, they can produce powerful chemical modulators including proteins called cytokines which strongly affect how beta cells work. It is now becoming appreciated that macrophages in islets in the pancreas can play important supportive roles, producing growth factors for beta cells, or during disease states can produce proteins that contribute to inflammation in the pancreas, leading to loss insulin production and contributing to the development of diabetes. We have found that one important trigger of the activation of macrophages in the pancreas, leading to inflammation, is a protein accumulation called amyloid. Here we propose to study islet macrophages in the pancreas in health and in disease, using mouse models and pancreas tissue obtained from human organ donors. We aim to understand how certain protein aggregates can activate islet macrophages and trigger inflammation, and to learn what signals stimulate them to produce factors that help islets function better. We will test drugs that target pathways in islet macrophages to turn down inflammation, to try to slow diabetes. We will try to identify factors made by islet macrophages that might be used as drugs in the treatment of diabetes. The overall goal is to understand how these garbage eating cells in the pancreas regulate the life and death of insulin-producing cells, and to exploit this knowledge towards the creation and testing of drugs for the treatment of diabetes.