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Diabetes 51:2703-2708, 2002
© 2002 by the American Diabetes Association, Inc.

Isoform-Specific Regulation of 5' AMP-Activated Protein Kinase in Skeletal Muscle From Obese Zucker (fa/fa) Rats in Response to Contraction

Brian R. Barnes1, Jeffrey W. Ryder1, Tatiana L. Steiler1, Lee G.D. Fryer2, David Carling2, and Juleen R. Zierath1

1 Department of Clinical Physiology and Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden
2 MRC Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital, London, U.K.

Glucose transport can be activated in skeletal muscle in response to insulin via activation of phosphoinositide (PI) 3-kinase and in response to contractions or hypoxia, presumably via activation of 5' AMP-activated protein kinase (AMPK). We determined the effects of insulin and muscle contraction/hypoxia on PI 3-kinase, AMPK, and glucose transport activity in epitrochlearis skeletal muscle from insulin-resistant Zucker (fa/ fa) rats. Insulin-stimulated glucose transport in isolated skeletal muscle was reduced 47% in obese versus lean rats, with a parallel 42% reduction in tyrosine-associated PI 3-kinase activity. Contraction and hypoxia elicited normal responses for glucose transport in skeletal muscle from insulin-resistant obese rats. Isoform-specific AMPK activity was measured in skeletal muscle in response to insulin, contraction, or hypoxia. Contraction increased AMPK{alpha}1 activity 2.3-fold in lean rats, whereas no effect was noted in obese rats. Hypoxia increased AMPK{alpha}1 activity to a similar extent (more than sixfold) in lean and obese rats. Regardless of genotype, contraction, and hypoxia, each increased AMPK{alpha}2 activity more than fivefold, whereas insulin did not alter either AMPK{alpha}1 or -{alpha}2 activity in skeletal muscle. In conclusion, obesity-related insulin resistance is associated with an isoform-specific impairment in AMPK{alpha}1 in response to contraction. However, this impairment does not appear to affect contraction-stimulated glucose transport. Activation of AMPK{alpha}2 in response to muscle contraction/ exercise is associated with a parallel and normal increase in glucose transport in insulin-resistant skeletal muscle.



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