Type 2 diabetes is one of the most common diseases in America and carries an enormous impact on public health, having reached epidemic proportions worldwide. Type 2 diabetes is characterized by a defective response to insulin, which prevents normal uptake of post-prandial glucose into muscle and adipose tissue and contributes to hyperglycemia and long-term complications. Glucose transporter 4 (GLUT4) is the major insulin responsive glucose transporter. Translocation of GLUT4 from intracellular membranes to the cell surface is required for insulin to enhance glucose uptake, and defects in this process in this process contribute to type 2 diabetes pathogenesis. Much research has indicated the importance of insulin signaling pathways in this defect but increasing evidence points to a role in GLUT4 trafficking itself. However, the precise mechanisms controlling GLUT4 trafficking are largely unclear. Tether containing a UBX domain for GLUT4 (TUG) was discovered by my mentor and shown to be an important regulator of GLUT4 trafficking, essential for intracellular retention of GLUT4 within cells not stimulated by insulin. Although the TUG C-terminus is necessary for this retention, it is not known how TUG performs this function. The goal of my PhD thesis and this proposal is to study how the TUG C-terminus mediates intracellular retention of GLUT4 and how acetylation of the TUG C-terminus modulates its function. As part of this, we look to test our favored model that, based on both preliminary and published data, hypothesizes TUG to function in an intracellular anchoring mechanism for GLUT4 involving the trans-Golgi network (TGN) protein GCC185, a known mediator of vesicle trafficking. Further, we propose that acetylation of TUG is important for this anchoring function. We will test these hypotheses with two Specific Aims. In the first Aim, I will employ genetic knockdown of GCC185 to test if this disrupts intracellular sequestration of GLUT4 in unstimulated 3T3-L1 adipocytes. In the second Aim, I will study how TUG acetylation modulates its function, and will test the hypotheses that acetylation controls the size of the insulin- responsive GLUT4 pool and is required for TUG to bind to GCC185. We will investigate other candidate anchors already identified by our lab and other functions of TUG acetylation as needed. The results of this research will elucidate how GLUT4 traffics within cells, and will enhance the understanding of how insulin sensitivity may be controlled by acetylation. These are important questions for type 2 diabetes, and may also have more fundamental significance for cell biology and physiology.

Public Health Relevance

Type 2 diabetes is a disease characterized by the body's defective response to insulin, leading to elevated blood glucose levels and significant morbidity and mortality. Glucose transporter 4 (GLUT4) is the major insulin responsive glucose transporter and its translocation to the cell surface during insulin stimulation is a primary defect in type 2 diabetes. This project will provide insight into the basic mechanisms that control GLUT4 trafficking in the cell.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Special Emphasis Panel (ZDK1-GRB-9 (O1))
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Castle, Arthur
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Yale University
Anatomy/Cell Biology
Schools of Medicine
New Haven
United States
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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
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
Belman, Jonathan P; Habtemichael, Estifanos N; Bogan, Jonathan S (2014) A proteolytic pathway that controls glucose uptake in fat and muscle. Rev Endocr Metab Disord 15:55-66
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Löffler, Michael G; Birkenfeld, Andreas L; Philbrick, Katerina M et al. (2013) Enhanced fasting glucose turnover in mice with disrupted action of TUG protein in skeletal muscle. J Biol Chem 288:20135-50
Bogan, Jonathan S; Rubin, Bradley R; Yu, Chenfei et al. (2012) Endoproteolytic cleavage of TUG protein regulates GLUT4 glucose transporter translocation. J Biol Chem 287:23932-47