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Author Notes:

Correspondence to: Kathy K. Griendling, Ph.D., Emory University, Division of Cardiology, 1639 Pierce Dr, WMB 319, Atlanta, GA 30322, Email: kgriend@emory.edu

We thank Dr. Jie Du for the IGF1R adenovirus.

Disclosures: None

Subjects:

Research Funding:

Sources of Funding: This work was supported by the National Institutes of Health (HL075209).

Keywords:

  • IGF1R
  • insulin resistance
  • diabetes
  • inflammation
  • vascular smooth muscle

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

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Journal Title:

Arteriosclerosis, Thrombosis, and Vascular Biology

Volume:

Volume 29, Number 3

Publisher:

, Pages 408-415

Type of Work:

Article | Post-print: After Peer Review

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.

Copyright information:

© 2009 American Heart Association, Inc. All rights reserved.

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