Type 2 diabetes mellitus is a polygenic, heterogeneous disorder characterized by the presence of both beta cell dysfunction and insulin resistance. Although a clear genetic component exists for the common forms of human type 2 diabetes, few susceptibility genes have been identified. The purpose of the parent K23 grant is to elucidate the genetic underpinnings of insulin secretion through well-controlled prospective clinical studies of several candidate gene variants. The purpose of this R03 is to extend these studies by investigating a new gene variant in the betacellulin gene that my group has recently identified. This variant associates with type 2 diabetes and may affect insulin secretion. The proposed studies will help to clarify this new betacellulin variant's role in insulin secretion. Furthermore, despite the concurrences that type 2 diabetes is a polygenic disorder, few studies have been performed which address gene-gene interactions. To test our hypotheses, we propose to prospectively recruit non-diabetic subjects with the betacellulin variant, individually and in combination with other variants (BETA2/NeuroD Ala45Thr, IRS2 GIy1057Asp, b3AR Trp64Arg) and characterize insulin secretion using the insulin-modified frequently sampled intravenous glucose tolerance test, insulin oscillation studies, and proinsulin levels. By elucidating the effects of the betacellulin gene variant, individually and in combination with these other variants on insulin secretion, we will provide critical insight into the underlying molecular mechanisms of a-cell dysfunction and the polygenic nature of type 2 diabetes. In turn, this will lead to new preventative strategies and new molecular targets for the design and effective therapeutic agents.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Small Research Grants (R03)
Project #
5R03DK062923-02
Application #
6734249
Study Section
Special Emphasis Panel (ZDK1-GRB-8 (O3))
Program Officer
Hyde, James F
Project Start
2003-04-15
Project End
2005-03-31
Budget Start
2004-04-01
Budget End
2005-03-31
Support Year
2
Fiscal Year
2004
Total Cost
$74,250
Indirect Cost
Name
University of Maryland Baltimore
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201