Identifying Genes in Pancreatic Beta-Cell Function using a Novel High-Thoughput Cell-Based Screening Assay

Type 2 diabetes mellitus is a complex disorder caused by elevated blood glucose levels that arise from peripheral insulin resistance and/or impaired insulin secretion from the pancreatic beta-cells. It is a global epidemic affecting millions of people around the world, bringing serious economic burden to health care systems. Thus, the underlying components of this disorder are under extensive investigation. The interest of my thesis project has been on the insulin secretion phenotype of type 2 diabetes. Therefore, a highthroughput surrogate cell-based assay for pancreatic beta-cell insulin secretion has been developed through which the screen of novel genes and the genes having genetic evidences of susceptibility to type 2 diabetes were screened, in order to assign them pertinent roles in beta-cell secretory function. In this respect, we have screened the Insulin Resistance Atherosclerosis Family Study (IRASFS) positional candidate genes and the Wnt signaling pathway components, where the genes with significant impacts on glucose-stimulated secretion were subject to further delineation. The IRASFS gene list was established through linkage analysis of quantitative trait loci for measures of glucose homeostasis by our collaborator. Our aim was to add a functional layer to the genetic evidence through the screens performed on IRASFS genes. On the other hand, previous reports have shown the involvement of several Wnt signaling pathway components in beta-cell secretory function. In this respect, the strongest evidence comes from x independent genomic studies that have highly associated the development of type 2 diabetes and impaired insulin secretion to the polymorphisms within the TCF7L2 gene. In addition, an active Wnt signaling pathway was suggested in the mouse and human pancreas by the confirmed expressions of several Wnt and Frizzled isoforms, along with the evidence highlighting the requirement of the co-receptor LRP5 for glucose-stimulated insulin secretion (GSIS) in the mouse islets. We have performed a general screen on the Wnt signaling pathway components in order to complete the picture between the genes TCF7L2 and LRP5 and to delineate this pathway with respect to beta-cell secretory function. Our findings have validated the importance of this pathway, where a β-catenin dependent path of glucose-induced insulin secretion is suggested.

Grantor dc:publisher

Wake Forest University

Year dc:date.issued

2009

Author dc:creator

• Tuncer, Feyza

• Genes

Language dc:language.iso

en_US

Handle dc:identifier.uri

http://hdl.handle.net/10339/14772

OAI identifier oai:identifier

oai:wakespace.lib.wfu.edu:10339/14772