Physical exercise increases glucose transport and improves insulin sensitivity in skeletal muscle, the major site responsible for total body glucose disposal. Consequently, physical exercise has major effects on glucose homeostasis in both healthy individuals and in people with diabetes. Despite the physiological importance of exercise in regulating glucose transport in skeletal muscle, the molecular mechanisms that mediate this important phenomenon are still not fully understood. Thus, the overall goal of this project is to elucidate the mechanisms through which physical exercise increases glucose transport and insulin sensitivity in skeletal muscle. There is considerable evidence that the AMP-activated protein kinase (AMPK) is part of the signaling mechanism by which exercise increases glucose transport in skeletal muscle. In addition to AMPK, it is now clear that there must be other mechanisms involved in exercise regulation of glucose transport. Several critical approaches will be integrated to address 5 specific aims: 1) Elucidate AMPK substrates that mediate glucose transport in skeletal muscle, and determine the specific functions of the (1 and (2 catalytic subunit isoforms in regulating glucose transport in skeletal muscle; 2) Determine the function of the AMPK ( subunits in the regulation of glucose transport and AMPK catalytic activity in skeletal muscle; 3) Define the role of CAPsm and TC10 signaling in exercise- and insulin-stimulated glucose transport; 4) Determine the mechanism of H202-induced glucose transport in skeletal muscle; and 5) Test the hypothesis that there are redundant signaling mechanisms leading to contraction-stimulated glucose transport. These experiments should give us better understanding of the underlying molecular mechanisms for exercise-stimulated glucose transport in skeletal muscle. Ultimately, these studies should provide us with a better understanding of glucose regulation during exercise in healthy people and in individuals with diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR045670-08
Application #
6944866
Study Section
Special Emphasis Panel (ZRG1-SMB (01))
Program Officer
Nuckolls, Glen H
Project Start
1998-09-30
Project End
2008-08-31
Budget Start
2005-09-01
Budget End
2006-08-31
Support Year
8
Fiscal Year
2005
Total Cost
$407,400
Indirect Cost
Name
Joslin Diabetes Center
Department
Type
DUNS #
071723084
City
Boston
State
MA
Country
United States
Zip Code
02215
Lauritzen, Hans P M M; Brandauer, Josef; Schjerling, Peter et al. (2013) Contraction and AICAR stimulate IL-6 vesicle depletion from skeletal muscle fibers in vivo. Diabetes 62:3081-92
Manabe, Yasuko; Gollisch, Katja S C; Holton, Laura et al. (2013) Exercise training-induced adaptations associated with increases in skeletal muscle glycogen content. FEBS J 280:916-26
Koh, Ho-Jin; Toyoda, Taro; Didesch, Michelle M et al. (2013) Tribbles 3 mediates endoplasmic reticulum stress-induced insulin resistance in skeletal muscle. Nat Commun 4:1871
Stanford, Kristin I; Middelbeek, Roeland J W; Townsend, Kristy L et al. (2013) Brown adipose tissue regulates glucose homeostasis and insulin sensitivity. J Clin Invest 123:215-23
Manabe, Yasuko; Miyatake, Shouta; Takagi, Mayumi et al. (2012) Characterization of an acute muscle contraction model using cultured C2C12 myotubes. PLoS One 7:e52592
Jessen, Niels; An, Ding; Lihn, Aina S et al. (2011) Exercise increases TBC1D1 phosphorylation in human skeletal muscle. Am J Physiol Endocrinol Metab 301:E164-71
Toyoda, Taro; An, Ding; Witczak, Carol A et al. (2011) Myo1c regulates glucose uptake in mouse skeletal muscle. J Biol Chem 286:4133-40
Witczak, Carol A; Jessen, Niels; Warro, Daniel M et al. (2010) CaMKII regulates contraction- but not insulin-induced glucose uptake in mouse skeletal muscle. Am J Physiol Endocrinol Metab 298:E1150-60
Treebak, Jonas T; Taylor, Eric B; Witczak, Carol A et al. (2010) Identification of a novel phosphorylation site on TBC1D4 regulated by AMP-activated protein kinase in skeletal muscle. Am J Physiol Cell Physiol 298:C377-85
Vichaiwong, Kanokwan; Purohit, Suneet; An, Ding et al. (2010) Contraction regulates site-specific phosphorylation of TBC1D1 in skeletal muscle. Biochem J 431:311-20

Showing the most recent 10 out of 73 publications