The Role of the Akt Substrate of 160 Kilodaltons (AS160) on Skeletal Muscle Glucose Uptake
Open Access
- Author:
- Kramer, Henning Fritz
- Graduate Program:
- Physiology
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- March 07, 2007
- Committee Members:
- Leonard Shelton Jefferson Jr., Committee Chair/Co-Chair
Laurie J Goodyear, Committee Chair/Co-Chair
Peter A Farrell, Committee Member
Thomas C Vary, Committee Member
Neil Sharkey, Committee Member
Ian Alexander Simpson, Committee Member - Keywords:
- glucose metabolism
insulin
exercise
diabetes
skeletal muscle - Abstract:
- Type 2 diabetes is characterized by a profound loss of insulin sensitivity. In humans and other mammals, skeletal muscle normally accounts for nearly 75% of whole body insulin-stimulated glucose transport. Impaired ability of the muscle to respond to insulin is therefore disruptive to systemic glucose homeostasis. Interestingly, skeletal muscle also possesses contractile properties that effectively restore glucose control in an insulin-independent manner, and this element is preserved in individuals with diabetes. While the precise mechanisms remain elusive, it is clear that both insulin and contraction signals converge on GLUT4 vesicles and promote their translocation to the cell membrane. Akt Substrate of 160 kDa (AS160) is a Rab-GTPase activating protein that was recently identified as the most distal regulatory molecule involved in insulin signaling to glucose uptake in adipocytes. However, the role of AS160 in skeletal muscle has not been explored. This dissertation examines AS160 phosphorylation and its putative regulation of glucose uptake in mouse skeletal muscle. It is demonstrated herein that: 1) insulin and contraction utilize distinct and additive upstream signaling mechanisms to stimulate AS160 phosphorylation in skeletal muscle in vivo and in vitro; 2) phosphorylation of AS160 by insulin and contraction is necessary for their full stimulation of skeletal muscle glucose uptake; and 3) the AS160 calmodulin-binding domain regulates contraction- but not insulin-stimulated glucose uptake in skeletal muscle. Collectively, our findings implicate AS160 as a point of convergence for both insulin and contraction signals leading to glucose uptake in skeletal muscle, although the mechanisms by which insulin and contraction mediate AS160 function are not identical. Future research should evaluate the efficacy of targeting AS160 for novel therapeutic diabetes interventions.