The regulation of glucose homeostasis is a complex process, which is disrupted in disease states such as type 2 diabetes. Insulin is the primary hormone regulating glucose homeostasis. Insulin stimulates glucose uptake in muscle and fat by causing the movement of GLUT4 glucose transporters out of intracellular membranes and to the cell surface. This effect of insulin is impaired in the setting of overnutrition, inactivity, ad genetic predisposition, resulting in insulin resistance and contributing to the development of diabetes. Therefore, to understand the pathogenesis of metabolic disease, it is necessary to understand the molecular mechanisms that control the targeting of GLUT4 among intracellular membranes, and by which this targeting is modulated by insulin. Previous work by this project identified the TUG protein as a regulator of GLUT4 targeting and glucose uptake in muscle, as in fat, and showed that this mechanism controls energy expenditure in mice. The data support a model in which GLUT4 is specifically retained within cells not stimulated by insulin by a protein complex containing TUG. Insulin then mobilizes GLUT4, in part by triggering TUG endoproteolytic cleavage. Cleavage may coordinate the regulation of glucose uptake with other effects on physiology and metabolism, which can result from the action of proteins that are produced by cleavage or co-regulated with GLUT4. This project focuses on the cleavage mechanism itself, and on how the ability of insulin to stimulate cleavage may be modulated to control insulin sensitivity.
Aim 1 will define the relationship between TUG-bound vesicles and the insulin-responsive GLUT4 storage vesicles, and will study how TUG interacts with vesicle proteins, particularly IRAP, and undergoes proteolytic cleavage. To understand the physiologic role of TUG in the regulation in muscle, we will create muscle-specific TUG knockout mice and study glucose homeostasis in these animals.
Aim 2 will study how acetylation of the TUG protein affects insulin sensitivity. We will test the hypothesis that acetylation modulates the interaction of the TUG carboxyl terminus with ACBD3, a protein present at the Golgi matrix, to control the size of an insulin-responsive pool of GLUT4. We will further study if a sirtuin protein regulates this acetylation to control insulin sensitivity in muscle, using knockout mice. We anticipate that, together, these studies will result in an improved understanding of molecular mechanisms regulating glucose metabolism and energy expenditure, with implications for the prediction, prevention, and treatment of diabetes and the metabolic syndrome.

Public Health Relevance

This project will study the molecular mechanisms by which insulin stimulates glucose uptake in muscle and fat cells. Impairment of these mechanisms contributes to the development of type 2 diabetes, and understanding these mechanism may lead to new approaches to prevent or treat diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK092661-04
Application #
9116816
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Haft, Carol R
Project Start
2011-07-01
Project End
2019-07-31
Budget Start
2016-08-01
Budget End
2017-07-31
Support Year
4
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
Habtemichael, Estifanos N; Li, Don T; Alcázar-Román, Abel et al. (2018) Usp25m protease regulates ubiquitin-like processing of TUG proteins to control GLUT4 glucose transporter translocation in adipocytes. J Biol Chem 293:10466-10486
Xu, Yingke; Toomre, Derek K; Bogan, Jonathan S et al. (2017) Excess cholesterol inhibits glucose-stimulated fusion pore dynamics in insulin exocytosis. J Cell Mol Med 21:2950-2962
Quan, Nanhu; Sun, Wanqing; Wang, Lin et al. (2017) Sestrin2 prevents age-related intolerance to ischemia and reperfusion injury by modulating substrate metabolism. FASEB J 31:4153-4167
Tol, Marc J; Ottenhoff, Roelof; van Eijk, Marco et al. (2016) A PPAR?-Bnip3 Axis Couples Adipose Mitochondrial Fusion-Fission Balance to Systemic Insulin Sensitivity. Diabetes 65:2591-605
Xu, Yingke; Nan, Di; Fan, Jiannan et al. (2016) Optogenetic activation reveals distinct roles of PIP3 and Akt in adipocyte insulin action. J Cell Sci 129:2085-95
Habtemichael, Estifanos N; Alcázar-Román, Abel; Rubin, Bradley R et al. (2015) Coordinated Regulation of Vasopressin Inactivation and Glucose Uptake by Action of TUG Protein in Muscle. J Biol Chem 290:14454-61
Castorena, Carlos M; Arias, Edward B; Sharma, Naveen et al. (2015) Fiber type effects on contraction-stimulated glucose uptake and GLUT4 abundance in single fibers from rat skeletal muscle. Am J Physiol Endocrinol Metab 308:E223-30
Belman, Jonathan P; Bian, Rachel R; Habtemichael, Estifanos N et al. (2015) Acetylation of TUG protein promotes the accumulation of GLUT4 glucose transporters in an insulin-responsive intracellular compartment. J Biol Chem 290:4447-63
Bogan, Jonathan S (2014) Endocytic cycling of glucose transporters and insulin resistance due to immunosuppressive agents. J Clin Endocrinol Metab 99:3622-4
Cantley, Jennifer L; Vatner, Daniel F; Galbo, Thomas et al. (2014) Targeting steroid receptor coactivator 1 with antisense oligonucleotides increases insulin-stimulated skeletal muscle glucose uptake in chow-fed and high-fat-fed male rats. Am J Physiol Endocrinol Metab 307:E773-83

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