Grant: Project Grant

The pancreatic beta cell produces not only insulin, but also another peptide hormone called islet amyloid polypeptide (IAPP) or amylin. Both insulin and IAPP are released from beta cells in response to high blood sugar or following a meal, and can be measured circulating in the blood. Insulin and IAPP, like other hormones, are first made as larger precursor proteins that are cut by enzymes in the beta cell, and sometimes undergo other modifications before they are packaged into small compartments in the cell awaiting the signal for their release into the bloodstream. There is strong evidence that the precursor forms of IAPP and insulin (called proIAPP and proinsulin), as well as other modified forms of these proteins, are altered or increased in diabetes, perhaps even prior to disease onset. In this proposal, using genetically engineered mouse models, clinical samples from patients with diabetes, and human islets from organ donors, we aim to identify forms of proIAPP and proinsulin that are altered in disease, how these forms might contribute to loss of beta cells in diabetes, and whether measuring these proteins in blood could help predict disease.