Douglas Ishii
Colorado State University, USA
Title: Insulin-like Growth Factors (IGFs) Prevent Diabetic Peripheral Neuropathy Despite Unabated Hyperglycemia: Why Hyperglycemia Interventions Fail in Clinical Trials
Biography
Biography: Douglas Ishii
Abstract
Sensory, motor and autonomic neuropathy caused by dying-back axonopathy are common complications in diabetes that may result in limb amputations, impotence, loss of bladder control, increased risk of cardiovascular mortality, and other disturbances. Present therapy is palliative; the development of meaningful treatments requires improved understanding of the pathogenesis of axonopathy. The dominant hypothesis for decades has been that hyperglycemia results in polyol accumulation, protein glycation, accumulation of AGE and subsequent injury to peripheral nerves. rn The alternative hypotheses were tested that a) neuropathy arises mainly as a consequence of a decline in combined neurotrophic insulin and IGF activities, and b) neuropathy can be prevented by restoration of IGF levels irrespective of hyperglycemia (Ishii, 1995; Ishii and Lupien, 2003). IGF levels decline progressively with aging, and more rapidly in obese, T1D and T2D patients. Diabetic rats have reduced IGF gene expression in nerves, spinal cord, brain and livers. Subcutaneous administration of IGF prevented multiple manifestations of sensory, motor and autonomic neuropathy despite unabated hyperglycemia in diabetic rats. IGF blockade in non-diabetic rodents mimics diabetic neuropathy. New results show that insulin provides additive neurotrophic support for the nervous system via pathways separate from glucoregulation. Clinical trial end-points to prevent diabetic neuropathy in T2D should be directed at increasing IGF levels and reducing insulin resistance, whereas hyperglycemia is an unreliable end-point. Indeed, intensive anti-hyperglycemic therapy in T2D, which comprises 90% of diabetic cases, does not prevent microvascular disease (neuropathy, nephropathy and retinopathy). rn