Elucidating the Trafficking and Function of the Class III Glucose Transporters GLUT8 and GLUT12

Date of Award

Summer 8-15-2010

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Molecular Cell Biology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

In mammals requiring glucose as a primary energy source for the brain, blood glucose levels are tightly regulated to ensure the adequate delivery of glucose to tissues. Skeletal muscle is the primary tissue aiding the disposal of blood glucose in the postprandial state. The transport of glucose into muscle cells regulates whole body glucose homeostasis and is considered the rate-limiting step in glucose metabolism. The most prominently expressed facilitative glucose transporter protein in skeletal muscle is GLUT4. This transporter isoform resides in an intracellular compartment and translocates to the plasma membrane in response to insulin stimulation where it facilitates the transport of glucose into the cell. Reduced insulin stimulated glucose transport has been implicated in the development of type II diabetes. Surprisingly, female GLUT4 null mouse skeletal muscle exhibits augmented glucose transport upon insulin stimulation, suggesting the presence of an alternate insulin responsive glucose transporter system. Since the time of the initial GLUT4 null studies, several new members of the facilitative glucose transporter family have been identified in skeletal muscle including the Class III transporters GLUT8 and GLUT12. GLUT8 translocates to the cell surface in murine blastocysts in response to insulin. GLUT12 is expressed in heart, fat, and skeletal muscle, which suggests it may play a role in regulating glucose uptake in insulin sensitive tissue. The role of these transporters in regulating hexose sugar transport and glucose homeostasis during physiological and pathophysiological conditions remains largely undefined. To gain insight into the physiological role of GLUT8 and GLUT12 in mammalian cells, we examined the intracellular and cell surface trafficking of the transporters in CHO, HEK293, and HeLa cells. We find that GLUT8 and GLUT12 localize to distinct cellular compartments and that the trafficking of each GLUT is influenced by the amino acid sequence immediately upstream of the amino-terminal dileucine motif. To examine the function of GLUT12 in vivo, we created transgenic mice that overexpress the transporter. Here we show that mice overexpressing GLUT12 have enhanced whole body insulin sensitivity and that GLUT12 facilitates glucose uptake into skeletal muscle in response to insulin stimulation. Our data shows that GLUT12 acts as a second insulin responsive glucose transport in insulin sensitive tissue.

Language

English (en)

Chair and Committee

Jean Schaffer

Committee Members

Simon Fisher, Paul Hruz, Stuar Kornfeld, Kelle Moley, Michael Mueckler

Comments

Permanent URL: https://doi.org/10.7936/K7P848V7

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