Muscle-specific insulin receptor overexpression protects mice from diet-induced glucose intolerance but leads to postreceptor insulin resistance

Guoxiao Wang, Yingying Yu, Weikang Cai, Thiago M. Batista, Sujin Suk, Hye Lim Noh, Michael Hirshman, Pasquale Nigro, Mengyao Ella Li, Samir Softic, Laurie Goodyear, Jason K. Kim, C. Ronald Kahn

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Skeletal muscle insulin resistance is a prominent early feature in the pathogenesis of type 2 diabetes. In attempt to overcome this defect, we generated mice overexpressing insulin receptors (IR) specifically in skeletal muscle (IRMOE). On normal chow, IRMOE mice have body weight similar to that of controls but an increase in lean mass and glycolytic muscle fibers and reduced fat mass. IRMOE mice also show higher basal phosphorylation of IR, IRS-1, and Akt in muscle and improved glucose tolerance compared with controls. When challenged with high-fat diet (HFD), IRMOE mice are protected from diet-induced obesity. This is associated with reduced inflammation in fat and liver, improved glucose tolerance, and improved systemic insulin sensitivity. Surprisingly, however, in both chow and HFD-fed mice, insulin-stimulated Akt phosphorylation is significantly reduced in muscle of IRMOE mice, indicating postreceptor insulin resistance. RNA sequencing reveals downregulation of several postreceptor signaling proteins that contribute to this resistance. Thus, enhancing early insulin signaling in muscle by overexpression of the IR protects mice from diet-induced obesity and its effects on glucose metabolism. However, chronic overstimulation of this pathway leads to postreceptor desensitization, indicating the critical balance between normal signaling and hyperstimulation of the insulin signaling pathway.

Original languageEnglish
Pages (from-to)2294-2309
Number of pages16
JournalDiabetes
Volume69
Issue number11
DOIs
StatePublished - Nov 2020

Bibliographical note

Publisher Copyright:
© 2020 by the American Diabetes Association.

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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