Grant: Project Grant

Peptide (small protein) hormones are made by endocrine cells throughout the body and play important roles in many bodily functions, including metabolism, digestion, growth, reproduction, stress, and appetite. These peptide hormones are first made in endocrine cells as larger inactive proteins called prohormones, that are cut inside the cells by enzymes into their smaller, active forms before their release into the blood, where they can circulate to other tissues to perform their important functions. Dysfunction of these prohormone processing enzymes, including those caused by genetic mutations, can cause profound disturbances to health, including obesity, diabetes, and infertility. As an example, children born with mutations in the prohormone processing enzyme PC1/3 may die as babies because of poor function of their intestines after birth, yet later in life can become obese and diabetic. In the pancreas, endocrine cells called beta cells produce insulin as well as another peptide hormone called islet amyloid polypeptide (IAPP) or amylin. There is strong evidence that the prohormone precursor forms of IAPP and insulin (called proIAPP and proinsulin), as well as other modified forms of these proteins, are altered or increased in the blood in diabetes. In the intestines, endocrine cells produce a number of hormones, including peptide hormones such as GLP-1 and GLP-2 derived from the prohormone proglucagon, that play important roles in glucose metabolism and digestion. In this proposal, using genetically engineered mouse models, clinical samples from patients with diabetes, and pancreatic islets from human organ donors, we aim to identify how alterations in the function of prohormone processing enzymes in different endocrine cells, particularly in the pancreatic islets, contribute to diabetes, obesity, and failure to thrive after birth.