Insulin resistance and IGF-I sensitivity in vascular cells - impact of hybrid receptors : With special regard to diabetes

Sammanfattning: Diabetic complications largely affect the circulation and are associated with resistance to insulin and altered levels of insulin-like growth factor-I (IGF-I). Insulin resistance and altered IGF-I levels are also associated with vascular disease. Insulin and IGF-I are highly homologous peptides and can cross react with each others respective receptors, insulin receptors (IR) and IGF-I receptors (IGFIR), which also share homology to a large extent and can form hybrid IR/IGF-IR. Cultured endothelial and vascular smooth muscle cells from different vascular beds express considerably more IGF-IR than IR. Since the direct action of insulin and IGFs on the vasculature remains poorly understood, our aim was to study mechanisms behind insulin resistance and IGF-I sensitivity and the possible impact of hybrid IR/IGF-IR in vascular cells.This thesis is based on four papers investigating the presence of IR and IGF-IR in cultured endothelial and vascular smooth muscle cells, and in tissue specimens from human left internal mammary artery (LIMA). We examined, in cultured vascular smooth muscle cells and endothelial cells, the phosphorylation of IR and IGF-IR, and IR and IGF-IR mediated actions, i e subsequent downstream signalling and biological effects, in response to physiologic and supraphysiologic concentrations of insulin, IGF-I and IGF-II. We also examined the presence of insulin/IGF-I hybrid receptors in these cell types. To compare our results in vitro with the in vivo situation we investigated the relative gene expression of IGF-IR to IR in LIMA.We conclude that: 1) the relative abundance of IGF-IR is considerably higher than IR in vascular cells in vitro and in vivo; 2) in addition to IR and IGF-IR, hybrid IR/IGF-IR are present in vascular cells; 3) IR activation at physiological concentrations (≤10-9M) does not propagate downstream signalling and biological effects in endothelial and vascular smooth muscle cells; 4) low concentrations of IGF-I activate IGF-IR, as well as IR due to the presence of hybrid IR/IGF-IR, and propagate downstream signalling and biological effects in endothelial and vascular smooth muscle cells; and 5) the biological effects mediated by IGF-II suggests a role for IGF-II in vascular smooth muscle cells.The papers included in this thesis provide new insight on how IGFs and insulin act in the vasculature. The preponderance of IGF-IR relative to IR in addition to sequestration of IR into hybrid IR/IGF-IR contributes to an insulin resistance located at the receptor level in endothelial and vascular smooth muscle cells.Hence, our results suggest that IGFs rather than insulin have an impact on vascular function.