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

doi:10.2337/db20-0439

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 journal › Article › peer-review

13 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 language	English
Pages (from-to)	2294-2309
Number of pages	16
Journal	Diabetes
Volume	69
Issue number	11
DOIs	https://doi.org/10.2337/db20-0439
State	Published - Nov 2020

Bibliographical note

Publisher Copyright:
© 2020 by the American Diabetes Association.

Funding

The authors thank the Harvard Biopolymers Facility for performing RNA sequencing, Joslin Bioinformatics Core for analyzing RNA sequencing results, Joslin Physiology Core for CLAMS analysis, Dr. Olga Ilkayeva and Dr. Christopher Newgard from Duke University for plasma amino acid analysis, Harvard Medical School Histology Core for H-E staining of muscles, and all the Kahn laboratory members for useful discussion. This project was funded by an American Diabetes Association postdoctoral fellowship to G.W. (1-18-PDF-171); National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), grants R01DK031036 to C.R.K. and R01DK101043 to L.G.; and the Joslin Diabetes Research Center grant P30DK036836 and the Mary K. Iacocca Professorship (to C.R.K.). W.C. was supported by NIDDK, NIH, grants K01 DK120740 and P30 DK057521-20. Part of this study was performed at the National Mouse Metabolic Phenotyping Center at University of Massachusetts supported by NIDDK, NIH, grant 5U2C-DK093000 to J.K.K. Acknowledgments. The authors thank the Harvard Biopolymers Facility for performing RNA sequencing, Joslin Bioinformatics Core for analyzing RNA sequencing results, Joslin Physiology Core for CLAMS analysis, Dr. Olga Ilkayeva and Dr. Christopher Newgard from Duke University for plasma amino acid analysis, Harvard Medical School Histology Core for H-E staining of muscles, and all the Kahn laboratory members for useful discussion. Funding. This project was funded by an American Diabetes Association postdoctoral fellowship to G.W. (1-18-PDF-171); National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), grants R01DK031036 to C.R.K. and R01DK101043 to L.G.; and the Joslin Diabetes Research Center grant P30DK036836 and the Mary K. Iacocca Professorship (to C.R.K.). W.C. was supported by NIDDK, NIH, grants K01 DK120740 and P30 DK057521-20. Part of this study was performed at the National Mouse Metabolic Phenotyping Center at University of Massachusetts supported by NIDDK, NIH, grant 5U2C-DK093000 to J.K.K. Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. G.W. and C.R.K. conceived the project, designed the research, and wrote the manuscript. G.W. performed most physiological, biochemical, and molecular studies. S.Su., H.L.N., and J.K.K. performed and supervised euglycemic-hyperinsulinemic clamps. M.H., P.N., and L.G. performed and supervised the ex vivo glucose uptake. W.C., T.M.B., Y.Y., M.E.L., and S.So. helped in sacrificing mice, harvesting tissues, and editing the manuscript. Y.Y. helped significantly during revision of the manuscript by doing Western blotting and helping with GSIS. C.R.K. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Prior Presentation. Parts of this study were presented in abstract form at the 79th Scientific Sessions of the American Diabetes Association, San Francisco, CA, 7–11 June 2019.

Funders	Funder number
National Institutes of Health (NIH)
American Diabetes Association Inc	1-18-PDF-171
National Institute of Diabetes and Digestive and Kidney Diseases	K01DK120740, R01DK101043, P30DK036836, R01DK031036
Duke-Kunshan University
Michigan Diabetes Research Center	P30 DK057521-20, 5U2C-DK093000, K01 DK120740

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

ASJC Scopus subject areas

Internal Medicine
Endocrinology, Diabetes and Metabolism

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10.2337/db20-0439

Cite this

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

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.",

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

note = "Publisher Copyright: {\textcopyright} 2020 by the American Diabetes Association.",

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doi = "10.2337/db20-0439",

language = "English",

volume = "69",

pages = "2294--2309",

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AU - Suk, Sujin

AU - Noh, Hye Lim

AU - Hirshman, Michael

AU - Nigro, Pasquale

AU - Li, Mengyao Ella

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AU - Goodyear, Laurie

AU - Kim, Jason K.

AU - Kahn, C. Ronald

PY - 2020/11

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AB - 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.

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

Abstract

Bibliographical note

Funding

UN SDGs

ASJC Scopus subject areas

Access to Document

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