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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:408.)
© 2009 American Heart Association, Inc.

Cell Biology/Signaling

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

Niels Engberding; Alejandra San Martín; Abel Martin-Garrido; Mitsuhisa Koga; Lily Pounkova; Erin Lyons; Bernard Lassègue; Kathy K. Griendling

From the Department of Medicine, Division of Cardiology, Emory University, Atlanta, Ga.

Correspondence to Kathy K. Griendling, PhD, Emory University, Division of Cardiology, 1639 Pierce Dr, WMB 319, Atlanta, GA 30322. E-mail kgriend{at}emory.edu

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 (IGF1Rs). 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-B and inhibition of MCP-1 upregulation in response to TNF-.

Conclusions— Downregulation of IGF1R increases the fraction of insulin receptors organized in holoreceptors, which leads to enhanced insulin signaling and unmasks potential antiinflammatory 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.

Insulin-like growth factor-1 receptor (IGF1R) expression is inversely related to insulin sensitivity in VSMCs. While IGF1R downregulation allows the formation of insulin holoreceptors and leads to enhanced cellular insulin sensitivity, it also unveils antiinflammatory properties of insulin.

Key Words: IGF1R • insulin resistance • diabetes • inflammation • vascular smooth muscle

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