Homozygous receptors for insulin and not IGF-1 accelerate intimal hyperplasia in insulin resistance and diabetes

Qian Li; Jialin Fu; Yu Xia; Weier Qi; Atsushi Ishikado; Kyoungmin Park; Hisashi Yokomizo; Qian Huang; Weikang Cai; Christian Rask-Madsen; C. Ronald Kahn; George L. King

doi:10.1038/s41467-019-12368-2

Homozygous receptors for insulin and not IGF-1 accelerate intimal hyperplasia in insulin resistance and diabetes

Qian Li, Jialin Fu, Yu Xia, Weier Qi, Atsushi Ishikado, Kyoungmin Park, Hisashi Yokomizo, Qian Huang, Weikang Cai, Christian Rask-Madsen, C. Ronald Kahn, George L. King

Molecular and Cellular Biochemistry

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28 Scopus citations

Abstract

Insulin and IGF-1 actions in vascular smooth muscle cells (VSMC) are associated with accelerated arterial intima hyperplasia and restenosis after angioplasty, especially in diabetes. To distinguish their relative roles, we delete insulin receptor (SMIRKO) or IGF-1 receptor (SMIGF1RKO) in VSMC and in mice. Here we report that intima hyperplasia is attenuated in SMIRKO mice, but not in SMIGF1RKO mice. In VSMC, deleting IGF1R increases homodimers of IR, enhances insulin binding, stimulates p-Akt and proliferation, but deleting IR decreases responses to insulin and IGF-1. Studies using chimeras of IR(extracellular domain)/IGF1R(intracellular-domain) or IGF1R(extracellular domain)/IR(intracellular-domain) demonstrate homodimer IRα enhances insulin binding and signaling which is inhibited by IGF1Rα. RNA-seq identifies hyaluronan synthase2 as a target of homo-IR, with its expression increases by IR activation in SMIGF1RKO mice and decreases in SMIRKO mice. Enhanced intima hyperplasia in diabetes is mainly due to insulin signaling via homo-IR, associated with increased Has2 expression.

Original language	English
Article number	4427
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-12368-2
State	Published - Dec 1 2019

Bibliographical note

Publisher Copyright:
© 2019, The Author(s).

Funding

This study was supported by NIH grant R01-DK-053105. We are grateful for the expert technical assistance provided by Biostatistic and Bioinformatic Core, Advanced Microscopy Core, Flow Cytometry Core, Mouse Physiology Core, Genomic Core, which are supported by NIH grants 5P30DK036836 and S10OD021740. We thank Dr. Kevin Croce for the technique support in femoral artery wire injury. The content of this paper is solely the responsibility of the authors, and does not necessarily represent the official views of the funding agencies.

Funders	Funder number
National Institutes of Health (NIH)	S10OD021740, 5P30DK036836
National Institutes of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases	R01DK053105
National Institute of Diabetes and Digestive and Kidney Diseases

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

UN SDGs

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

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abstract = "Insulin and IGF-1 actions in vascular smooth muscle cells (VSMC) are associated with accelerated arterial intima hyperplasia and restenosis after angioplasty, especially in diabetes. To distinguish their relative roles, we delete insulin receptor (SMIRKO) or IGF-1 receptor (SMIGF1RKO) in VSMC and in mice. Here we report that intima hyperplasia is attenuated in SMIRKO mice, but not in SMIGF1RKO mice. In VSMC, deleting IGF1R increases homodimers of IR, enhances insulin binding, stimulates p-Akt and proliferation, but deleting IR decreases responses to insulin and IGF-1. Studies using chimeras of IR(extracellular domain)/IGF1R(intracellular-domain) or IGF1R(extracellular domain)/IR(intracellular-domain) demonstrate homodimer IRα enhances insulin binding and signaling which is inhibited by IGF1Rα. RNA-seq identifies hyaluronan synthase2 as a target of homo-IR, with its expression increases by IR activation in SMIGF1RKO mice and decreases in SMIRKO mice. Enhanced intima hyperplasia in diabetes is mainly due to insulin signaling via homo-IR, associated with increased Has2 expression.",

author = "Qian Li and Jialin Fu and Yu Xia and Weier Qi and Atsushi Ishikado and Kyoungmin Park and Hisashi Yokomizo and Qian Huang and Weikang Cai and Christian Rask-Madsen and Kahn, {C. Ronald} and King, {George L.}",

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AU - Park, Kyoungmin

AU - Yokomizo, Hisashi

AU - Huang, Qian

AU - Cai, Weikang

AU - Rask-Madsen, Christian

AU - Kahn, C. Ronald

AU - King, George L.

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Homozygous receptors for insulin and not IGF-1 accelerate intimal hyperplasia in insulin resistance and diabetes

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

UN SDGs

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