Muscle-Specific Pten Deletion Protects against Insulin Resistance and Diabetes

Abstract

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.

ACKNOWLEDGMENTS

This work was supported by grants to M.W. from the Canadian Institutes of Health Research (OP 57893) and the Banting and Best Diabetes Centre and to A.K. from the Earl DuHane Grant from the Canadian Diabetes Association. M.W. is supported by a Canadian Institutes of Health Research New Investigator Award. D.K. was supported by a fellowship from the Swiss National Science Foundation (grant 81ZH-57433), the Research Institute of The Hospital for Sick Children (Clinician Scientist Award), and the Züricher Diabetes-Gesellschaft.

We thank Paul Dogherty, Armen Manoukian, Stephanie Backman, and Kinh Tung Nguyen for critical editing of the manuscript and helpful discussions. We also thank Xudong Xhu, Kelvin So, and Michelle Sleiman for their technical assistance. We thank Lifescan Johnson and Johnson for providing glucometer strips.