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Insulin and IGF-I action on insulin receptors, IGF-I receptors, and hybrid insulin/IGF-I receptors in vascular smooth muscle cells

¹Department of Biomedicine and Surgery, Division of Cell Biology; and ²Diabetes Research Centre, Faculty of Health Sciences, Linköping University, Linköping, Sweden

Submitted 18 November 2005 ; accepted in final form 20 June 2006

Insulin and insulin-like growth factor I (IGF-I) are known to affect cardiovascular disease. We have investigated ligand binding and the dose-response relationship for insulin and IGF-I on vascular smooth muscle cells (VSMCs) at the receptor level. VSMCs from rat thoracic aorta were serum starved, stimulated with IGF-I or insulin, lysed, immunoprecipitated, and analyzed by Western blot. D-[U-¹⁴C]Glucose accumulation and [6-³H]thymidine incorporation into DNA were also measured. Specific binding of both insulin and IGF-I was demonstrated, being higher for IGF-I. Both IGF-I receptor (IGF-IR) and insulin receptor (IR) -subunits were detected and coprecipitated after immunoprecipitation (IP) against either of the two. No coprecipitation was found after reduction of disulphide bonds with dithiotreitol before IP. After stimulation with 10^–10–10^–9 M IGF-I, IP of the IGF-IR, or IR -subunit and immunoblot with anti-phosphotyrosine antibody, we found two distinct bands indicating phosphorylation of both the IGF-IR and the IR -subunit. Stimulation with 10^–10–10^–9 M insulin and IP against the IGF-IR did not show phosphorylation of either -subunit, whereas after IP of the IR we found phosphorylation of the IR -subunit. [¹⁴C]Glucose accumulation and [³H]thymidine incorporation were elevated in cells stimulated with IGF-I at 10^–10–10^–7 M, reaching maximum by 10^–9 M. Insulin stimulation showed measurable effects only at supraphysiological concentrations, 10^–8–10^–7 M. In conclusion, coprecipitation of both the IGF-IR and the IR -subunit indicates the presence of hybrid insulin/IGF-I receptors in VSMC. At a physiological concentration, insulin activates the IR but does not affect either glucose metabolism or DNA synthesis, whereas IGF-I both activates the receptor and elicits biological effect.

insulin-like growth factor I; ligand binding; receptor phosphorylation; immunopreciptation; dexoyribonucleic acid synthesis; glucose metabolism

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