Increased post-exercise (PEX) insulin sensitivity, first demonstrated in 1982, is among the best documented exercise benefits linked to improved health, but identification of the mechanism has been elusive. Exercise by lean, normal individuals has little effect on proximal insulin signaling, suggesting exercise alters a distal site. Progress stalled until the discovery of a sustained PEX increase in the most distal signaling step known to be crucial for glucose transport (GT): phosphorylation of Akt Substrate of 160 kDa (AS160). The sustained PEX increase in phosphorylated AS160 (pAS160) tracks closely with elevated insulin-induced GT in lean rats, and sustained pAS160 is also found in muscle of lean humans PEX. Increased pAS160 has emerged as an attractive candidate to explain improved insulin sensitivity PEX. The broad, long-term goal is to fully elucidate the mechanisms that underlie enhanced insulin sensitivity PEX. The 3 Specific Aims are: 1) Identify the mechanism for the sustained increase in AS160 phosphorylation in skeletal muscle of lean rats after exercise. 2) By expressing in rat skeletal muscle AS160 that is genetically modified to prevent phosphorylation on key sites, determine AS160's role in exercise-induced changes in GT in lean rats. 3) Identify the similarities and differences between lean and obese rats in the specific mechanisms for their respective exercise-induced improvements in insulin-stimulated GT. Evidence indicates the sustained PEX increase in pAS160 is not attributable to persistent activation of kinases. A novel idea to be tested is that the sustained elevation in pAS160 is because of attenuated AS160 dephosphorylation by Ser/Thr protein phosphatases. Because preliminary data implicate protein phosphatase 2A (PP2A) in AS160 dephosphorylation, multiple approaches will be used for Aim 1 to probe PP2A's regulation of pAS160.
Aim 2 will use an innovative method to measure GT by single muscle fibers that are matched for fiber type, but differ by expression of wildtype AS160 or AS160 genetically modified to prevent phosphorylation on key sites to learn if the improved PEX insulin-mediated GT in lean rats is attributable to greater pAS160.
Aim 3 will determine if the well-known exercise benefits on insulin sensitivity for lean and obese rats are accrued by distinct mechanisms. Exercise by obese rats is predicted to reduce high muscle levels of mediators of insulin resistance (inducible nitric oxide synthase;protein S- nitrosylation;lipid metabolites;JNK, IKK &PKC? activation) leading to enhanced insulin signaling and GT. However, in muscles from lean rats, exercise is predicted to not greatly alter their already low levels of mediators or normal levels of proximal insulin signaling. The sustained increase in pAS160 PEX observed in lean humans was reported to be less in obese people. Accordingly, experiments will be performed to test if the greater PEX insulin-mediated GT previously found for lean vs. obese rats is attributable to greater pAS160 PEX in lean rats. Completion of the proposed research will provide novel insights into the specific mechanisms that account for improved insulin sensitivity, a major health benefit for both lean and obese individuals.

Public Health Relevance

The proposed research is relevant to public health because insulin resistance for glucose disposal by skeletal muscle is an essential and perhaps primary defect for Type 2 diabetes, and exercise can greatly improve insulin-mediated glucose uptake. Because of the related epidemics of obesity, insulin resistance and diabetes, it is crucial to elucidate mechanisms for improved insulin sensitivity in insulin resistant individuals. It is also important to understand mechanisms for improved insulin sensitivity in normal individuals because the level of insulin sensitivity found in sedentary lean individuals may not confer optimal health and because identifying mechanisms in healthy individuals has the potential to inspire the development of new therapies that benefit insulin-resistant people.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK071771-06
Application #
8234373
Study Section
Skeletal Muscle and Exercise Physiology Study Section (SMEP)
Program Officer
Laughlin, Maren R
Project Start
2005-07-01
Project End
2015-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
6
Fiscal Year
2012
Total Cost
$338,213
Indirect Cost
$120,713
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
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
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
Cartee, Gregory D; Hepple, Russell T; Bamman, Marcas M et al. (2016) Exercise Promotes Healthy Aging of Skeletal Muscle. Cell Metab 23:1034-47
Sharma, Pragya; Arias, Edward B; Cartee, Gregory D (2016) Protein Phosphatase 1-α Regulates AS160 Ser588 and Thr642 Dephosphorylation in Skeletal Muscle. Diabetes 65:2606-17
Cartee, Gregory D (2015) AMPK-TBC1D4-dependent mechanism for increasing insulin sensitivity of skeletal muscle. Diabetes 64:1901-3
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-κB 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
Castorena, Carlos M; Arias, Edward B; Sharma, Naveen et al. (2015) Fiber type effects on contraction-stimulated glucose uptake and GLUT4 abundance in single fibers from rat skeletal muscle. Am J Physiol Endocrinol Metab 308:E223-30
Cartee, Gregory D (2015) Mechanisms for greater insulin-stimulated glucose uptake in normal and insulin-resistant skeletal muscle after acute exercise. Am J Physiol Endocrinol Metab 309:E949-59

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