(Verbatim from application) By age 60-74 years, approximately 1/3 of Americans suffer from abnormal glucose tolerance. Skeletal muscle insulin resistance is an essential defect in age-related progression to type 2 diabetes. Calorie restriction (CR; consuming approximately 60 percent of ad libitum, AL, intake) improves insulin sensitivity. The broad, long-term objective is to elucidate mechanisms underlying CR-induced improvement in insulin action. This project focuses on cellular processes regulating glucose transport (rate-limiting step for glucose metabolism) in skeletal muscle.
Specific Aim 1 is to identify the mechanism for CR-enhancement in amount of tyrosine phosphorylated IRS-1 and insulin receptor in insulin-stimulated muscle. Protein tyrosine phosphatases which dephosphorylate IRS-1 and the insulin receptor will be studied because CR does not increase insulin receptor tyrosine kinase which phosphorylates IRS-1 and the receptor.
Specific Aim 2 is to determine if CR enhances insulin-mediated phosphatidylinositol (PI) 3-kinase function. This enzyme is essential for CR-effect on glucose transport although CR does not alter PI 3-kinase activity determined by conventional assay with IRS-l-immunoprecipitated samples. Insulin-stimulated muscle from CR and AL rats will be compared for: a) abundance and IRS-binding of p50alpha regulatory subunit of PI 3-kinase (this isoform has been reported to elicit greater PI 3,4,5-trisphosphate production than p85alpha in intact cells, but not in IRS-l-immunoprecipitated samples); b) PI 3-kinase lipid product (PI 3,4,5-trisphosphate) levels formed by intact insulin-stimulated muscles (because CR effect may require internal milieu of intact cells); and c) activation of protein kinase B (insulin signaling step distal to and dependent on PI 3-kinase).
Specific Aim 3 is to ascertain the effect of CR on 0-linked N-acetylglucosamine (G1cNAc)-modification of proteins. CR lowers muscle levels of UDP-N-acetylhexosamine (substrate for 0-GlcNAc transferase). Insulin resistance has been associated with elevated 0-GIcNAc-modified proteins (e.g., IRS-1), so lowering 0-GlcNAc-protein levels by CR could be significant for increased insulin action. Elucidating mechanisms for enhanced insulin sensitivity with CR has important implications for improving health and quality of life of older people. This research will also provide fundamental insights into CR's pleiotropic effects: tyrosine phosphatases and PI 3-kinase play key roles in several signaling pathways, and altered 0-G1cNAc-modification of proteins may mediate multiple CR-induced outcomes.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Geriatrics and Rehabilitation Medicine (GRM)
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Finkelstein, David B
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University of Michigan Ann Arbor
Other Domestic Higher Education
Ann Arbor
United States
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Oki, Kentaro; Arias, Edward B; Kanzaki, Makoto et al. (2018) Prior treatment with the AMPK activator AICAR induces subsequently enhanced glucose uptake in isolated skeletal muscles from 24-month-old rats. Appl Physiol Nutr Metab 43:795-805
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Wang, Haiyan; Arias, Edward B; Cartee, Gregory D (2016) Calorie restriction leads to greater Akt2 activity and glucose uptake by insulin-stimulated skeletal muscle from old rats. Am J Physiol Regul Integr Comp Physiol 310:R449-58
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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
Cartee, Gregory D; Hepple, Russell T; Bamman, Marcas M et al. (2016) Exercise Promotes Healthy Aging of Skeletal Muscle. Cell Metab 23:1034-1047
Sharma, Naveen; Wang, Haiyan; Arias, Edward B et al. (2015) Mechanisms for independent and combined effects of calorie restriction and acute exercise on insulin-stimulated glucose uptake by skeletal muscle of old rats. Am J Physiol Endocrinol Metab 308:E603-12
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 (2014) Let's get real about the regulation of TBC1D1 and TBC1D4 phosphorylation in skeletal muscle. J Physiol 592:253-4
Sharma, Naveen; Sequea, Donel A; Castorena, Carlos M et al. (2014) Heterogeneous effects of calorie restriction on in vivo glucose uptake and insulin signaling of individual rat skeletal muscles. PLoS One 8:e65118

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