Effect of Hyperglycemia on Synaptotgmin - 7, VAMP and CAPS in Insulin Secretion

Abstract

Diabetes Mellitus is a metabolic disorder which is characterized through persistent hyperglycemia ensuing from the defects in insulin secretion, insulin action or both. Chronic hyperglycemia is responsible form beta cell damage as well as shrinkage in cell size and number. The amount of insulin secreted by the surviving beta cells is not proportional to the calculated ideal amount. So there has to be another mechanism which affects the insulin secretion process. It is known that beta cells have originated from neuronal cell line thus the exocytosis process is conserved in beta cells. Secretion of insulin from vesicle in a glucose stimulated process. Glucose changes the ATP/ADP ratio, causing depolarization followed by influx of Ca2+ and eventually exocytosis of insulin vesicle. Exocytosis is a three step process involving docking, priming and fusion. The vesicle gets translocated towards the plasma membrane where VAMP forms the SNARE complex with syntaxin and SNAP-25, making the vesicle ready for fusion. Now when there is Ca2+ influx, it binds to the C2a domain of synaptotagmin-7 causing a confirmation change in the protein which leads to phospholipid binding. This causes the fusion of vesicles with the plasma membrane and insulin secretion. CAPS is a vesicular associated protein which helps in stabilizing the SNARE complex and increases the fusion rate of the vesicles. In vivo and In vitro studies were carried out to check the expression of Synaptotagmin-7, VAMP and CAPS were carried out in pancreatic tissue and Min6 cell line, respectively. The expression of VAMP and CAPS were downregulated in pancreatic tissue of diabetic rats, while the expression of Synaptotagmin-7 was upregulated. Insulin is secreted by beta cells, so it is important to check the expression of these protein in a beta cell line. The expression of Synaptotagmin-7 in Min6 cell line during hyperglycemic condition was upregulated. This could suggests that increase in the expression of Synaptotagmin-7 could be a compensatory mechanism by the cells to secrete the weakly primed insulin vesicles to counter -act hyperglycemia.