Insulin-Like Growth Factor-1 Receptor Expression Masks the Antiinflammatory and Glucose Uptake Capacity of Insulin in Vascular Smooth Muscle Cells

• Type of Material: Article
• Authors: Niels Engberding, Emory University; Alejandra San Martin Almeyda, Emory University; Abel Martin-Garrido, Emory University; Mitsuhisa Koga, Emory University; Lily Pounkova, Emory University; Erin Lyons, Emory University; Bernard P Lassegue, Emory University; Kathy Griendling, Emory University
• Language: English
• Date: 2009-03
• Publisher: American Heart Association
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2009 American Heart Association, Inc. All rights reserved.
• Final Published Version (URL): http://atvb.ahajournals.org/content/29/3/408.long
• Title of Journal or Parent Work: Arteriosclerosis, Thrombosis, and Vascular Biology
• ISSN: 1079-5642
• Volume: 29
• Issue: 3
• Start Page: 408
• End Page: 415
• Grant/Funding Information: Sources of Funding: This work was supported by the National Institutes of Health (HL075209).
• Keywords: vascular smooth muscle; IGF1R; diabetes; insulin resistance; inflammation
• Research Categories: Health Sciences, General; Biology, Physiology

Abstract

Objective Insulin resistance of vascular smooth muscle cells (VSMCs) has been linked to accelerated atherosclerosis in diabetes; however, the effects of insulin on VSMCs remain controversial. Most VSMC insulin receptors are sequestered into insulin-insensitive hybrids with insulin-like growth factor-1 receptors (IGF1R). Thus we hypothesized that regulation of IGF1R expression may impact cellular insulin sensitivity. Methods and Results IGF1R expression was increased in aortas from diabetic mice. IGF1R overexpression in VSMCs impaired insulin-induced Akt phosphorylation. Conversely, IGF1R downregulation by siRNA allowed assembly of insulin holoreceptors, enhanced insulin-induced phosphorylation of its receptor, Akt, Erk1/2 and further augmented insulin-induced glucose uptake. IGF1R downregulation uncovered an insulin-induced reduction in activation of NF-κB and inhibition of MCP-1 upregulation in response to TNF-α. Conclusions Downregulation of IGF1R increases the fraction of insulin receptors organized in holoreceptors, which leads to enhanced insulin signaling and unmasks potential anti-inflammatory properties of insulin in VSMCs. Therefore, IGF1R, which is susceptible to feedback regulation by its own ligand, may represent a novel target for interventions designed to treat insulin resistance in the vasculature.