Glut4-mediated glucose uptake represents the rate-limiting step of insulin-stimulated glucose disposal, and type 2 diabetes is associated with impaired translocation of Glut4 to the cell surface. The insulin- responsive pool of Glut4 is localized in intracellular membrane vesicles, or IRVs, that deliver Glut4 to the plasma membrane. Proteomics analyses performed in our and other laboratories have shown that, in addition to Glut4, these vesicles contain two major proteins, IRAP and sortilin. The challenge now is to understand how these seemingly unrelated proteins find each other in the cell and form a unique type of a vesicular carrier. Based on the results obtained in the previous funding period, we put forward a hypothesis that may explain the process of the IRV formation. According to our model, the cytoplasmic tails target the major IRV proteins to the perinuclear donor membranes, where Glut4 and IRAP interact with sortilin via lumenal domains. The heteromeric complex consisting of Glut4, IRAP and sortilin is distributed from the donor membranes to the IRV as a single entity with the help of GGA and ACAP-1 adaptors, small GTPases of the Arf family and phosphatidylinositol phosphates.
In Specific Aim 1, we will test this hypothesis and further characterize the role of lumenal interactions in protein targeting into the IRVs.
In Specific Aim 2, we will determine the biological functions of the individual IRV component proteins.
In Specific Aim 3, we will explore the actual mechanism of the IRV formation and, in particular, determine the role of cytoplasmic sortilin-binding proteins, Arf6 and PIP4 in this process.

Public Health Relevance

Impaired translocation of Glut4 to the cell surface may represent a primary factor for the development of type 2 diabetes mellitus. Recent studies point out to the cell biology of Glut4 recycling as a potential site of primary diabetes-related abnormalities. We propose to explore several unknown aspects of Glut4 traffic which may shed light on the molecular nature of insulin resistance and diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK052057-14
Application #
8300982
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Silva, Corinne M
Project Start
1997-02-28
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
14
Fiscal Year
2012
Total Cost
$346,405
Indirect Cost
$133,233
Name
Boston University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Chakrabarti, Partha; Kandror, Konstantin V (2015) The role of mTOR in lipid homeostasis and diabetes progression. Curr Opin Endocrinol Diabetes Obes 22:340-6
Singh, Maneet; Shin, Yu-Kyong; Yang, Xiaoqing et al. (2015) 4E-BPs Control Fat Storage by Regulating the Expression of Egr1 and ATGL. J Biol Chem 290:17331-8
Singh, Maneet; Kaur, Rajween; Lee, Mi-Jeong et al. (2014) Fat-specific protein 27 inhibits lipolysis by facilitating the inhibitory effect of transcription factor Egr1 on transcription of adipose triglyceride lipase. J Biol Chem 289:14481-7
Chakrabarti, Partha; Kim, Ju Youn; Singh, Maneet et al. (2013) Insulin inhibits lipolysis in adipocytes via the evolutionarily conserved mTORC1-Egr1-ATGL-mediated pathway. Mol Cell Biol 33:3659-66
Huang, Guanrong; Buckler-Pena, Dana; Nauta, Tessa et al. (2013) Insulin responsiveness of glucose transporter 4 in 3T3-L1 cells depends on the presence of sortilin. Mol Biol Cell 24:3115-22
Kim, Ju Youn; Kandror, Konstantin V (2012) The first luminal loop confers insulin responsiveness to glucose transporter 4. Mol Biol Cell 23:910-7
Karki, Shakun; Chakrabarti, Partha; Huang, Guanrong et al. (2011) The multi-level action of fatty acids on adiponectin production by fat cells. PLoS One 6:e28146
Chakrabarti, Partha; English, Taylor; Karki, Shakun et al. (2011) SIRT1 controls lipolysis in adipocytes via FOXO1-mediated expression of ATGL. J Lipid Res 52:1693-701
Chakrabarti, Partha; Kandror, Konstantin V (2011) Adipose triglyceride lipase: a new target in the regulation of lipolysis by insulin. Curr Diabetes Rev 7:270-7
Kandror, Konstantin V; Pilch, Paul F (2011) The sugar is sIRVed: sorting Glut4 and its fellow travelers. Traffic 12:665-71

Showing the most recent 10 out of 17 publications