Insulin stimulates the rate of glucose transport into adipocytes approximately 20-fold within ten minutes. This remarkable effect is largely due to the translocation of a specific isotype of the glucose transporter (Glut4) from within the cell to the plasma membrane. The long-term objective is to elucidate at the molecular level how this translocation of Glut4 occurs and is regulated by insulin. The intracellular Glut4 appears to be located in a specialized exocytotic vesicle, which is largely uncharacterized.
The specific aims for the coming grant period are focused on characterizing components of this vesicle, as follows: (1) Other proteins specific to the Glut4 vesicles will be identified and their cDNAs will be cloned. Initially, this effort will be directed toward three groups of proteins for which we have preliminary data. These are: the synaptobrevins, a family of proteins previously considered to be located only in the synaptic and synaptic-like secretory vesicles; a 175 kD protein, which is a major component of the Glut4 vesicles and appears to translocate to the plasma membrane like Glut4; a group of three proteins in the 21-29 kD range that may be small guanine nucleotide binding proteins. (2) The properties and functions of these Glut4 vesicle proteins will be established. It will be determined whether each protein is colocalized with Glut4 in the rat adipocyte, whether it translocates to the plasma membrane in response to insulin, and whether its distribution among various tissues and cultured cells coincides with that of Glut4. The possible occurrence of specific associations between the different vesicle proteins will be examined. Potential functions for each of the newly defined proteins will be investigated by a variety of approaches, which will be guided by information about the structure of the protein and possibly its role in another context. For example, a potential role for a protein in the genesis of the Glut4 vesicle and/or the translocation process will be examined by attempting to block its expression in 3T3-L1 adipocytes with antisense oligonucleotides and RNA and by expressing the protein in cells that normally lack it. The proposed research is of direct relevance to the disease diabetes. A detailed knowledge of how insulin signals the translocation of Glut4 and how the process occurs may serve as the basis for the design of better therapeutic agents and/or regimes for both types I and II diabetes. Moreover, in the case of type II diabetes, where the basic cause(s) are not yet known, this knowledge may provide the framework for identifying a cause.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Metabolism Study Section (MET)
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Haft, Carol R
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Dartmouth College
Schools of Medicine
United States
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Sano, Hiroyuki; Peck, Grantley R; Blachon, Stephanie et al. (2015) A potential link between insulin signaling and GLUT4 translocation: Association of Rab10-GTP with the exocyst subunit Exoc6/6b. Biochem Biophys Res Commun 465:601-5
Sano, Hiroyuki; Peck, Grantley R; Kettenbach, Arminja N et al. (2011) Insulin-stimulated GLUT4 protein translocation in adipocytes requires the Rab10 guanine nucleotide exchange factor Dennd4C. J Biol Chem 286:16541-5
Dash, S; Langenberg, C; Fawcett, K A et al. (2010) Analysis of TBC1D4 in patients with severe insulin resistance. Diabetologia 53:1239-42
Lyons, Patrick D; Peck, Grantley R; Kettenbach, Arminja N et al. (2009) Insulin stimulates the phosphorylation of the exocyst protein Sec8 in adipocytes. Biosci Rep 29:229-35
Dash, Satya; Sano, Hiroyuki; Rochford, Justin J et al. (2009) A truncation mutation in TBC1D4 in a family with acanthosis nigricans and postprandial hyperinsulinemia. Proc Natl Acad Sci U S A 106:9350-5
Peck, Grantley R; Chavez, Jose A; Roach, William G et al. (2009) Insulin-stimulated phosphorylation of the Rab GTPase-activating protein TBC1D1 regulates GLUT4 translocation. J Biol Chem 284:30016-23