Humans and animals with deficient ataxia telangiectasia mutated (ATM) are insulin-resistant or hyperglycemic. ATM reportedly indirectly influences insulin signaling, including phosphorylation of Akt, in various cell types. There is also evidence that ATM is an activating kinase for the AMP-activated protein kinase (AMPK), a mediator of insulin-independent stimulation of glucose transport. However, the potential roles of ATM in AMPK- and insulin-stimulated glucose transport have not previously been addressed in skeletal muscle, the predominant tissue in insulin-stimulated glucose disposal. Preliminary data from cultured myotubes demonstrate that a specific ATM inhibitor prevents stimulation of glucose transport by insulin and the AMPK activator AICAR.
The specific aims are: 1) to test the hypothesis that ATM plays a role in insulin-independent stimulation of glucose transport by AMPK-activating treatments (e.g. exercise and/or the AMPK activator AICAR) in skeletal muscle, 2) to test the hypothesis that ATM plays a role in insulin-stimulated glucose transport and insulin signaling in skeletal muscle, and 3) to test the hypothesis that ATM directly phosphorylates and/or alters activity of components of the insulin signaling pathway in skeletal muscle. Experimental tools will include ATM deficient transgenic mice, a specific inhibitor of ATM, and an antibody specific for proteins that have been phosphorylated by ATM. Elucidating the possible role of a factor like ATM that might play a role in regulation of glucose transport stimulated by either AMPK or insulin--or both--is potentially valuable to describing new approaches to prevention or treatment of diabetes.
STATEMENT: The project will examine the potential role of a protein called ATM in regulation of sugar transport into muscle in response to exercise and insulin, a hormone that enters the bloodstream when blood sugar levels increase. Understanding the factors that cause muscles to clear sugar from the bloodstream is vital to developing strategies to treat or prevent the high blood sugar concentrations that are the hallmark of diabetes.
|Spears, Larry D; Tran, Andrew V; Qin, Charles Y et al. (2016) Chloroquine increases phosphorylation of AMPK and Akt in myotubes. Heliyon 2:e00083|
|Andrisse, Stanley; Patel, Gaytri D; Chen, Joseph E et al. (2013) ATM and GLUT1-S490 phosphorylation regulate GLUT1 mediated transport in skeletal muscle. PLoS One 8:e66027|
|Ching, James Kain; Spears, Larry D; Armon, Jennifer L et al. (2013) Impaired insulin-stimulated glucose transport in ATM-deficient mouse skeletal muscle. Appl Physiol Nutr Metab 38:589-96|
|Ching, James Kain; Luebbert, Stephen H; Collins 4th, Roy L et al. (2013) Ataxia telangiectasia mutated impacts insulin-like growth factor 1 signalling in skeletal muscle. Exp Physiol 98:526-35|
|Patel, Akshar Y; McDonald, Todd M; Spears, Larry D et al. (2011) Ataxia telangiectasia mutated influences cytochrome c oxidase activity. Biochem Biophys Res Commun 405:599-603|
|Jeong, I; Patel, A Y; Zhang, Z et al. (2010) Role of ataxia telangiectasia mutated in insulin signalling of muscle-derived cell lines and mouse soleus. Acta Physiol (Oxf) 198:465-75|
|Ching, James Kain; Rajguru, Pooja; Marupudi, Nandhini et al. (2010) A role for AMPK in increased insulin action after serum starvation. Am J Physiol Cell Physiol 299:C1171-9|
|Turcotte, Lorraine P; Fisher, Jonathan S (2008) Skeletal muscle insulin resistance: roles of fatty acid metabolism and exercise. Phys Ther 88:1279-96|