ICA512 AND RECEPTOR TYROSINE PHOSPHATASES IN GENE EXPRESSION AND ADHESION OF PANCREATIC BETA CELLS

Diabetes is the most common metabolic disorder. It affects over hundred million people worldwide and its prevalence is rapidly increasing. It is the major cause of severe complications, including legal blindness, kidney failure, and cardiovascular accidents. The most common form of diabetes is type 2 diabetes (T2D), accounting for more than 90% of the cases. T2D is a genetic disorder resulting from the unfavorable interaction of multiple genes with the environmental factors. Most of these genes are unknown. The hallmark of the disease is the presence of too high circulating glucose levels, partly because of the insufficient release of insulin in the blood by specific cells in the pancreas, known as beta cells. Insulin is the hormone that lowers the glucose levels by promoting its uptake by other cells in the body. Understanding the mechanisms that control insulin production and release by beta cells is a key step towards developing better strategies for the prevention and treatment of T2D. With this proposal, I intend to study the role of the gene ICA512. The protein encoded by this gene is associated with the insulin-secretory machinery of beta cells. Recent studies indicate that ICA512 regulates insulin secretion, but how it is still not clear. My working hypothesis is that upon exposure at the cell surface, ICA512 promotes the clustering of beta cells. Aggregation is known to boosts individual beta cell ability to secrete insulin, a feature that seems to be altered in T2D. Using novel molecular and cell biological approaches, I will investigate the role of ICA512 in beta cell adhesion and in generating hypothesized signals to constantly adjust the synthesis of secretory proteins, including insulin. Such a feedback mechanism would be relevant for the homeostasis and, ultimately, the viability of beta cells.