Role of IRS-2 in Diabetes and Beta Cell Function

Joslin Diabetes Center, Boston MA

Investigators

Abstract

DESCRIPTION (provided by applicant): Pancreatic Beta-cell function and insulin secretion is essential in the pathogenesis of type II diabetes Previous studies reveal that IRS-2 disruption causes overt type II diabetes in mice due to insulin resistance and failure of Beta-cell compensation Mice with specific IRS-2 deletion in pancreatic t3-cells exhibit progressively elevated blood glucose levels at fasting and fed states, and impairment of glucose tolerance (preliminary data) However, IRS-2 deletion was also detected in certain hypothalamic neurons in the latter mice Although these data suggest an autonomous role of IRS-2 in Beta-cells, the effect of IRS-2 deletion in hypothalamus can not be rifled out This proposal aims to determine whether IRS-2 disruption in Beta-cell alone is sufficient to induce diabetes, how IRS-2 disruption causes failed B-cell expansion, and whether there is any complementary effect between IRS-I and IRS-2 on B-cell function IRS-2 deletion in Beta-cells will be achieved by Cre-loxP mediated gene disruption system Three lines of transgenic Cre mice, which all express Cre under the control of I_-cell specific promoters, will be used to rule out potential complication of IRS-2 deletion in other tissues Glucose homeostasis and Beta-cell mass will be examined and compared in knockout mice Defects at Beta-cell expansion will be assessed by examining B-cell differentiation, proliferation and apoptosis. Expression and activities of critical molecules potentially involved in these processes will be studied, including transcription factors, cell cycle regulators, and apoptotic proteins To assess the presence of complementary role between IRS proteins, mice lacking both IRS-2 and IRS-I in Beta-cells will be created and assessed Insights gained from these studies may advance our understanding on the pathogenesis of type II diabetes and provide novel therapeutic strategy for the treatment of diabetes.