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Molecular and Cellular Biology, February 2005, p. 1135-1145, Vol. 25, No. 3
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.3.1135-1145.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Muscle-Specific Pten Deletion Protects against Insulin Resistance and Diabetes

Nadeeja Wijesekara,1,{dagger} Daniel Konrad,1,{dagger},{ddagger} Mohamed Eweida,2,{dagger} Craig Jefferies,1 Nicole Liadis,2 Adria Giacca,3 Mike Crackower,4 Akira Suzuki,5 Tak W. Mak,6 C. Ronald Kahn,7 Amira Klip,1 and Minna Woo2,8*

Programme in Cell Biology, The Hospital for Sick Children,1 Division of Cellular and Molecular Biology, Ontario Cancer Institute,2 Department of Physiology, University of Toronto,3 Advanced Medical Discoveries Institute,6 St. Michael's Hospital, Toronto, Ontario, Canada,8 Amgen Inc., Thousand Oaks, California,4 Department of Biochemistry, Akita University School of Medicine, Akita, Japan,5 Research Division, Joslin Diabetes Center, and Department of Medicine, Harvard Medical School, Boston, Massachusetts7

Received 27 July 2004/ Returned for modification 25 August 2004/ Accepted 27 October 2004

Pten (phosphatase with tensin homology), a dual-specificity phosphatase, is a negative regulator of the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway. Pten regulates a vast array of biological functions including growth, metabolism, and longevity. Although the PI3K/Akt pathway is a key determinant of the insulin-dependent increase in glucose uptake into muscle and adipose cells, the contribution of this pathway in muscle to whole-body glucose homeostasis is unclear. Here we show that muscle-specific deletion of Pten protected mice from insulin resistance and diabetes caused by high-fat feeding. Deletion of muscle Pten resulted in enhanced insulin-stimulated 2-deoxyglucose uptake and Akt phosphorylation in soleus but, surprisingly, not in extensor digitorum longus muscle compared to littermate controls upon high-fat feeding, and these mice were spared from developing hyperinsulinemia and islet hyperplasia. Muscle Pten may be a potential target for treatment or prevention of insulin resistance and diabetes.


* Corresponding author. Mailing address: Ontario Cancer Institute, 8-205, 610 University Ave., Toronto, Ontario, Canada M5G 2N9. Phone: (416) 946-4501, ext. 3971. Fax: (416) 946-2086. E-mail: mwoo{at}uhnres.utoronto.ca.

{dagger} N.W., D.K., and M.E. contributed equally towards this work.

{ddagger} Present address: Division of Endocrinology and Diabetology, University Children's Hospital, Zurich, Switzerland.


Molecular and Cellular Biology, February 2005, p. 1135-1145, Vol. 25, No. 3
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.3.1135-1145.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.




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