Date of Award

January 2019

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Jonathan S. Bogan

Abstract

The body tightly regulates glucose production and disposal despite changing metabolic demands, including large post-prandial and fasting fluctuations. Specifically, under the action of insulin, muscle contraction, ischemia, and poor nutrient availability, cells increase the amount of the glucose transporter type 4 (GLUT4) at the plasma membrane by mobilizing a sequestered pool of transporters. In this work, we demonstrate that the TUG (tether containing a UBX domain for GLUT4) protein mediates both insulin-dependent and insulin-independent pathways to increase GLUT4 at the plasma membrane. In mice fed a high fat diet to induce insulin resistance, the regulation of the endoproteolytic cleavage of the TUG protein was disrupted. We also present evidence that helps to identify the key protease, Usp25m, that cleaves the tethering protein TUG in both an insulin-dependent and insulin-independent manner, releasing GLUT4 from its storage location in the basal state to the plasma membrane in an activated state. Finally, our results also suggest that in the adipocytes and myocytes, activated AMPK leads to cleavage of the TUG protein.

Comments

This is an Open Access Thesis.

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