Exploring mechanisms of insulin secretion regulators using C. elegans

Abstract

Diabetes mellitus is a group of disorders characterized by disrupted glucose homeostasis. Diabetes is one of the most dangerous diseases worldwide since it affects currently more than 500 million people. The pathogenesis of the disease is associated with the insufficient production of insulin and is characterized by increased blood glucose levels. Insulin secretion takes place in pancreatic β-cells in the response to elevated glucose levels and is regulated by various factors. This thesis is aimed to understand the functions of three proteins and characterize their novel roles in the regulation of insulin signaling and secretion. The first study showed the role of ENPL-1 in the positive regulation of insulin secretion. Loss of enpl-1 resulted in reduced insulin signaling and inhibited insulin secretion. Furthermore, we identified proinsulin as a novel client protein of ENPL-1 and showed that ENPL-1 was required for its maturation. The next study was based on the previous findings showing that ASNA-1 is a positive regulator of insulin secretion. Our study showed that ASNA-1 is present in two redox states, oxidized and reduced and that the multiple functions of ASNA-1 are dependent on its redox states. Our analysis showed, that forcing ASNA-1 into the oxidized state, reduced its function of inserting tail-anchored proteins into the endoplasmic reticulum, without affecting the insulin secretion function. In the next study, we focused on the mutual role of both previously mentioned proteins. We identified the interaction of ASNA-1 and ENPL-1 and showed that proinsulin is required for this interaction to take place. Our study indicated that oxidized ASNA-1 rather than the reduced form was likely interacting with ENPL-1. In the last study, we focused on the role of a third protein, SMN-1, and its impact on the regulation of insulin secretion. Our analysis showed that loss of SMN-1 resulted in neuropeptide secretion defect and caused redistribution of insulin from its original place. In summary, we characterized the functions of three proteins and indicated their importance in the regulation of insulin secretion processes.