Insulin and Insulin‐Like Growth Factor Resistance in Alcoholic Neurodegeneration

Abstract

Chronic alcohol feeding of adult Long Evans rats causes major central nervous system abnormalities that link neuronal loss and impaired acetylcholine homeostasis to ethanol inhibition of insulin and insulin-like growth factor (IGF) signaling and increased oxidative stress. We now characterize the integrity of insulin and IGF signaling mechanisms and assess molecular indices of neurodegeneration in the cerebellar vermis and anterior cingulate gyrus of human alcoholics. Alcoholic cerebella had increased neuronal loss, gliosis, lipid peroxidation, and DNA damage relative to control. Quantitative RT-PCR studies demonstrated reduced expression of insulin, insulin receptor and IGF-II receptor in the anterior cingulate, and reduced expression of insulin, IGF-I, and their corresponding receptors in the vermis. Competitive equilibrium binding assays revealed significantly reduced specific binding to the insulin, IGF-I, and IGF-II receptors in both the anterior cingulate and vermis of alcoholic brains. These effects of chronic alcohol abuse were associated with significantly reduced expression of choline acetyltransferase, which is needed for acetylcholine biosynthesis. The results suggest that alcoholic neurodegeneration in humans is associated with insulin and IGF resistance with attendant impairment of neuronal survival mechanisms and acetylcholine homeostasis.