IGF-I Signaling in Response to Hyperglycemia and the Development of Diabetic Complications

David      Clemmons; Laura      Maile; Gang      Xi; Xinchun      Shen; Yashwanth      Radhakrishnan

Abstract

IGF-I is structurally related to proinsulin and when administered to human subjects it enhances insulin sensitivity. However because of its growth promoting properties and its relationship to growth hormone, it has been proposed as a etiologic factor in the development of diabetic complications. This review discusses recently published data regarding the ability of hyperglycemia to sensitize cells that are capable of dedifferentiating to the growth promoting effects of IGF-I. Under normoglycemic conditions vascular smooth muscle and endothelial cells are cystostatic and stimulation of the IGFI receptor activates the adaptor protein IRS-1 which leads to PI-3 kinase pathway activation. Following exposure to hyperglycemia these cell types undergo a signaling switch whereby an entirely different mechanism is utilized to activate both the PI-3 and the MAP kinase pathways. This leads to increased cell proliferation and migration. This molecular mechanism involves the coordinate regulation of signaling molecules and scaffolding proteins. Activation of this alternative signaling mechanism is directly linked to the stimulation of pathophysiologic processes that are involved in the pathogenesis of both diabetic retinopathy and atherosclerosis. Inhibition of activation of these intermediates has been shown to attenuate glucose induced pathophysiologic changes and results in the inhibition of both atherosclerotic lesion progression and diabetic retinopathy. In summary, hyperglycemia induces a signaling switch in vascular endothelial and smooth muscle cells that results in enhanced sensitivity to the growth promoting effects of IGF-I. This may be an important variable for determining the progression of atherosclerosis in poorly controlled diabetes and in the development of retinopathy.

Keywords: Mitogen, Vascular smooth muscle, Atherosclerosis, Retinopathy, Dedifferentiation, Hyperglycemia, Diabetic Complications, IGF-I Signaling, αVβ3 LIGANDS, Mitogen activated protein kinase