Insulin resistance for glucose disposal by skeletal muscle is an essential and perhaps primary defect for Type 2 diabetes. The broad, long-term objective is to fully understand the mechanisms whereby insulin- and exercise intersect to co-regulate skeletal muscle glucose transport, a rate-limiting step for glucose disposal. In this project, we focus on a key health benefit of acute exercise: a substantial and long-lasting increase in insulin-stimulated glucose transport. We will test a novel model that proposes that the mechanism for this exercise effect begins with, Triggering Events (essential and transient prerequisites) that induce one or more Memory Element (persistent, post-exercise outcomes linking triggers to downstream mediators). After exercise, Mediators are the key insulin signaling steps that, as a consequence of Memory Elements, and upon engagement by a physiologic insulin concentration, lead to improved insulin action. The Mediators lead to increased cell-surface localized GLUT4, which is the End-effector ultimately responsible for increased insulin-stimulated glucose transport. We have 4 Specific Aims: 1) Determine if elements of the humoral kallikrein-kinin system (KKS) are essential triggers for elevated post-exercise glucose transport in insulin- stimulated skeletal muscle. 2) Determine if AMP-activated protein kinase (AMPK) is an essential trigger for post-exercise elevation in insulin-stimulated glucose transport in skeletal muscle. 3) Elucidate the effects of insulin and exercise on the amount of GLUT4 associated with TUG (TUG-GLUT4) and determine the relationship of putative triggers (humoral-KKS and AMPK) with TUG-GLUT4. 4) Identify sequential links from triggers to memory elements to insulin signaling;steps that mediate GLUT4 recruitment to the cell surface thereby leading to elevated insulin-stimulated glucose transport. We will probe relationships among the model's components because only a comprehensive approach can reveal the integrated mechanisms for this complex process. Because physical activity is all too common, millions of Americans can potentially improve their insulin sensitivity via exercise. Illuminating the mechanisms for post-exercise improvement in insulin action should facilitate the design of optimal exercise programs for each person's abilities and development of other interventions to improve insulin action in those who cannot perform sufficient exercise.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK071771-05
Application #
7849510
Study Section
Skeletal Muscle and Exercise Physiology Study Section (SMEP)
Program Officer
Laughlin, Maren R
Project Start
2006-07-01
Project End
2011-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
5
Fiscal Year
2010
Total Cost
$288,648
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Miscellaneous
Type
Other Domestic Higher Education
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Arias, E B; Wang, H; Cartee, G D (2017) Akt substrate of 160 kDa dephosphorylation rate is reduced in insulin-stimulated rat skeletal muscle after acute exercise. Physiol Res :
Pataky, Mark W; Wang, Haiyan; Yu, Carmen S et al. (2017) High-Fat Diet-Induced Insulin Resistance in Single Skeletal Muscle Fibers is Fiber Type Selective. Sci Rep 7:13642
Sharma, Pragya; Arias, Edward B; Cartee, Gregory D (2016) Protein Phosphatase 1-? Regulates AS160 Ser588 and Thr642 Dephosphorylation in Skeletal Muscle. Diabetes 65:2606-17
Cartee, Gregory D; Hepple, Russell T; Bamman, Marcas M et al. (2016) Exercise Promotes Healthy Aging of Skeletal Muscle. Cell Metab 23:1034-1047
Cartee, Gregory D; Arias, Edward B; Yu, Carmen S et al. (2016) Novel single skeletal muscle fiber analysis reveals a fiber type-selective effect of acute exercise on glucose uptake. Am J Physiol Endocrinol Metab 311:E818-E824
Sharma, Naveen; Arias, Edward B; Cartee, Gregory D (2016) Inhibition of Akt2 phosphorylation abolishes the calorie restriction-induced improvement in insulin-stimulated glucose uptake by rat soleus muscle. Appl Physiol Nutr Metab 41:1208-1211
Zheng, Xiaohua; Cartee, Gregory D (2016) Insulin-induced Effects on the Subcellular Localization of AKT1, AKT2 and AS160 in Rat Skeletal Muscle. Sci Rep 6:39230
Castorena, Carlos M; Arias, Edward B; Sharma, Naveen et al. (2015) Effects of a brief high-fat diet and acute exercise on the mTORC1 and IKK/NF-?B pathways in rat skeletal muscle. Appl Physiol Nutr Metab 40:251-62
Cartee, Gregory D (2015) Roles of TBC1D1 and TBC1D4 in insulin- and exercise-stimulated glucose transport of skeletal muscle. Diabetologia 58:19-30
Cartee, Gregory D (2015) AMPK-TBC1D4-dependent mechanism for increasing insulin sensitivity of skeletal muscle. Diabetes 64:1901-3

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