The incidence of diabetes is rising throughout the world due to increased industrialization, and nationally with the "greying" of America. Neuropathy is a highly debilitating consequence of diabetes in about 10% of patients. Particularly distressing problems include third nerve palsy, muscular weakness, bowel dysfunction, bladder dysfunction, impotence, heart rate abnormalities, severe unremitting pain, diabetic foot, and limb amputation. The economic costs to the individual and society are considerable, and there is a pressing need for new modalities of treatment, as well as a better understanding of the underlying cause of neuropathy. These are among recommendations of the National Diabetes Advisory Board. The long-term goal of this project is to study the medically relevant neurobiology of insulin-like growth factors (IGFs). This renewal application proposes continued study of two highly promising, independent but interrelated hypotheses: (i) Exogenously administered IGFs can prevent or ameliorate the syndrome of diabetic neuropathy, and (ii) IGFs play a role in the pathogenesis of diabetic neuropathy. A new theory for pathogenesis is proposed, and preliminary tests of key predictions of the theory have been validated. In a striking observation, it was found that locally infused IGF-II can prevent impairment of conduction velocity in diabetic rats, despite continued hyperglycemia. The specific aims are to determine whether infused IGFs can prevent and/or reverse impairment of a range of neural functions known to be afflicted in diabetic rats, including conduction velocity, nerve regeneration, size spectra of neuronal cell bodies, and functional regeneration. Moreover, experiments will determine whether endogenous IGF mRNA content is reduced in afflicted nerve and nerve targets in diabetic rats. The results may directly lead to new therapies for treatment of diabetic neuropathy. The main studies will be done with rats, mice will provide NGF, and fertile eggs will be used to bioassay IGFs and NGF.