Igf-I signaling in response to hyperglycemia and the development of diabetic
Authors Clemmons D, Maile L, Xi G, Shen X, Radhakrishnan Y
Submitted By Richard McIndoe on 2/22/2012
Status Published
Journal Current diabetes reviews
Year 2011
Date Published 7/1/2011
Volume : Pages 7 : 235 - 245
PubMed Reference 21707534
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 IGF-I
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 kinase and the MAP 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.