Similar to other neuroendocrine peptide hormones, insulin is initially synthesized as a larger precursor molecule called proinsulin. Proinsulin is processed into mature, secreted insulin through a series of enzyme-mediated proteolytic cleavages. 

We are interested in understanding how beta cells adjust their insulin translation and processing capacities in response to various stimuli present in acute nutrient overload and chronic diabetogenic milieu.

Reference: 

1. Islet prohormone processing in health and disease.

2. Deletion of carboxypeptidase E in β-cells disrupts proinsulin processing but does not lead to spontaneous development of diabetes in mice.

Despite experiencing targeted attacks by immune cells, some pancreatic beta cells survive in individuals living with type 1 diabetes (T1D). These residual beta cells continue to produce proinsulin and other peptide hormones, such as pro-islet amyloid polypeptide (IAPP). 

We are interested in understanding the impact of elevated peptide hormone production and impaired processing on beta cell integrity and susceptibility to autoimmunity. Specifically, we aim to investigate whether an increased insulin biosynthesis burden compromises beta-cell function, whether unprocessed or partially processed peptide hormones become neoepitopes or form hybrid peptides, and whether these events further promote beta cell death and antigen spreading.

Reference: 

1. Altered β-Cell Prohormone Processing and Secretion in Type 1 Diabetes.

2. Quantitative analysis of islet prohormone convertase 1/3 expression in human pancreas donors with diabetes.

IAPP is the second most abundant peptide hormone secreted by pancreatic beta cells. Human IAPP aggregates to form islet amyloid plaques in the pancreas, contributing to islet inflammation and beta cell death.

We are interested in understanding how human IAPP aggregates are removed both intracellularly and extracellularly, and whether defects in islet amyloid clearance lead to increased islet inflammation in obesity and diabetes or to islet graft failure in islet transplantation.

Reference: 

1. PAM haploinsufficiency does not accelerate the development of diet- and human IAPP-induced diabetes in mice.

2. Elevated islet prohormone ratios as indicators of insulin dependency in auto-islet transplant recipients .