Type II diabetes, which is characterized by peripheral insulin resistance and defective insulin secretion, is a disease which affects >5% of the population in developed countries, causing great human suffering and financial losses. Therefore, the identification of naturally existing pathways which can modulate the effectiveness of insulin is a reasonable goal. In this proposal, I seek to clarify the effects the tyrosine phosphatase SHP-2, a potential negative regulator of insulin action, on growth and metabolic signaling by IRS-1, a major substrate of the insulin and insulin-like growth factor-1 (IGF-1) receptor kinases. This study will take place in a mouse model system to allow physiological assessment of the role of SHP-2. Because SHP-2 functions in many pathways besides those initiated by insulin/IGF-1, SHP-2 will be specifically uncoupled from insulin/IGF signals by mutation of the SHP-2 binding sites in IRS-1 using a homologous gene replacement strategy. Based on data from cultured cells, and on the previous characterization of mice completely lacking IRS-1, mice expressing only the SHP-2-uncoupled IRS-1 protein (IRS-1[-SHP2]) are expected to exhibit enhanced peripheral insulin sensitivity, as well as possible in utero or post-natal overgrowth due to hyperactivation of mitogenic pathways downstream of IGFs. A full characterization of the IRS- 1[-SHP2] mice is proposed that will determine the role of SHP-2 in growth, whole-body glucose metabolism, and activation of various intracellular signaling pathways. To determine if the predicted enhanced insulin sensitivity of IRS-1[-SHP2] mice can overcome a genetic disposition toward insulin resistance, IRS- 1[-SHP2] mice will be placed on a high fat diet to induce peripheral insulin resistance, and also mated to mice lacking IRS-2, a model for type II diabetes. An ability of IRS-1[-SHP2] to overcome insulin resistance/diabetes in these models will indicate that SHP-2 may be a reasonable drug target for the treatment of type II diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32DK010182-02
Application #
6516955
Study Section
Endocrinology Study Section (END)
Program Officer
Hyde, James F
Project Start
2002-03-01
Project End
Budget Start
2002-03-01
Budget End
2003-02-28
Support Year
2
Fiscal Year
2002
Total Cost
$46,192
Indirect Cost
Name
Joslin Diabetes Center
Department
Type
DUNS #
071723084
City
Boston
State
MA
Country
United States
Zip Code
02215