The Glut4 glucose transporter catalyzes the rate-limiting step in postprandial whole body glucose disposal. A disruption in the insulin-stimulated redistribution of Glut4 to the plasma membrane is the proximal cause of the peripheral insulin resistance associated with type 2 diabetes mellitus. Elucidation of the precise molecular pathways involved in the mechanism by which insulin stimulates the acute redistribution of Glut4 to the plasma membrane may thus be of considerable importance in understanding the pathogenesis of insulin resistant states. The regulated subcellular trafficking of Glut4 is partially dictated by the insulin- responsive AS160/Rab10 GTPase cycle, but additional unidentified factors are necessary to fully account for its basal intracellular sequestration and insulin-stimulated movement to the plasma membrane. Additionally, the specific structural features of Glut4 that direct its regulated subcellular trafficking remain poorly understood. We have identified a novel subcellular targeting motif (LXXLXP) within the carboxy-terminal 12 residues of the cytoplasmic tail of Glut4 that is shared with the insulin-responsive aminopeptidase. Unlike other Glut4 targeting motifs, alteration of the LXXLXP motif (herein referred to as IRM, insulin-responsive motif) has a profound effect on the steady-state distribution of the transporter and appears to completely abolish its basal recycling and insulin-stimulated translocation to the cell surface. The goal of this proposal is to gain fundamental insights into Glut4 regulation by delineating the role of the IRM and of a putative Akt-regulated GTPase activating protein, AS250, in this process. In order to accomplish this goal, the following specific aims will be undertaken: 1) to precisely define the IRM and how it interacts with other known Glut4 targeting motifs;2) to identify and characterize novel subcellular membrane compartments through which Glut4 moves;and 3) to elucidate the function of the AS250 complex, how insulin affects its function, and identify novel components of the AS250/KIAA1219 complex.

Public Health Relevance

This project proposes to investigate novel aspects of how glucose transport is regulated by insulin in fat cells. It is directly relevant to understanding the molecular mechanisms involved in the regulation of whole body glucose homeostasis and its derangement in insulin resistant states such as diabetes, obesity, and metabolic syndrome.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK085110-03
Application #
8223268
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Haft, Carol R
Project Start
2010-03-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
3
Fiscal Year
2012
Total Cost
$312,246
Indirect Cost
$106,821
Name
Washington University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130