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

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

doi:10.1038/s41467-019-12368-2

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.

Highlights

Insulin and insulin-like growth factor-1 (IGF-1) actions in vascular smooth muscle cells (VSMC) are associated with accelerated arterial intima hyperplasia and restenosis after angioplasty, especially in diabetes
The expressions of insulin receptors (IR) in the brain, liver, kidney, and adipocyte were similar between SMIRKO and WT mice, IR were partially reduced in the heart of SMIRKO mice, Deletion of IGF-1 receptors (IGF1R) in VSMC of SMIGF1RKO mice
IGF1R protein expression was decreased by 70% in the aorta of SMIGF1RKO mice compared with WT mice, which was unchanged in the heart and brain (Supplementary Fig. 6)

Summary

Introduction

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. There is a long-standing controversy on whether the accelerated intimal hyperplasia in insulin-resistant and diabetic states are due to the actions of insulin or IGF1, as well as their respective receptors[15] This lack of clarity on whether insulin or IGF-1 is the main driver of restenosis in diabetes and insulin-resistance states is due to the fact that both insulin and IGF-1 and their receptors have very similar and overlapping cellular and biological responses in VSMC and in many other cell types[16]. IGF-1 with minor contribution from insulin enhances the growth activities in VSMC, most likely by binding to IGF-1 receptors

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Conclusion