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ENDOCRINE PHYSIOLOGY AND METABOLISM

Rapamycin does not improve insulin sensitivity despite elevated mammalian target of rapamycin complex 1 activity in muscles of ob/ob mice

Department of Exercise Science, Skidmore College, Saratoga Springs, New York

Submitted 16 May 2008 ; accepted in final form 25 August 2008

Studies of cultured cells have indicated that the mammalian target of rapamycin complex 1 (mTORC1) mediates the development of insulin resistance. Because a role for mTORC1 in the development of skeletal muscle insulin resistance has not been established, we studied mTORC1 activity in skeletal muscles of ob/ob (OB) mice and wild-type (WT) mice. In vivo insulin action was assessed in muscles of mice 15 min following an intraperitoneal injection of insulin or an equivalent volume of saline. In the basal state, the phosphorylation of S6K on Thr³⁸⁹, mTOR on Ser²⁴⁴⁸, and PRAS40 on Thr²⁴⁶ were increased significantly in muscles from OB mice compared with WT mice. The increase in basal mTORC1 signaling was associated with an increase in basal PKB phosphorylation on Thr³⁰⁸ and Ser⁴⁷³. In the insulin-stimulated state, no differences existed in the phosphorylation of S6K on Thr³⁸⁹, but PKB phosphorylation on Thr³⁰⁸ and Ser⁴⁷³ was significantly reduced in muscles of OB compared with WT mice. Despite elevated mTORC1 activity in OB mice, rapamycin treatment did not improve either glucose tolerance or insulin tolerance. These results indicate that the insulin resistance of OB mice is mediated, in part, by factors other than mTORC1.

insulin resistance; signal transduction; skeletal muscle

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