Insulin and insulin-like growth factor resistance in alcoholic neurodegeneration.
BACKGROUND
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.


OBJECTIVE
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.


RESULTS
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.


CONCLUSIONS
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.
de la Monte
Suzanne M
SM
Department of Medicine and Pathology, Rhode Island Hospital and Warren Alpert School of Medicine at Brown University, Providence, Rhode Island 02903, USA. Suzanne_DeLaMonte_MD@Brown.ed
Tong
Ming
M
Cohen
Ariel C
AC
Sheedy
Donna
D
Harper
Clive
C
Wands
Jack R
JR
D000109:Acetylcholine / Q000378:metabolism; D000437:Alcoholism / Q000378:metabolism* / Q000503:physiopathology; D016022:Case-Control Studies; D002531:Cerebellum / Q000378:metabolism*; D004249:DNA Damage / Q000502:physiology; D006179:Gyrus Cinguli / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D019636:Neurodegenerative Diseases / Q000378:metabolism* / Q000503:physiopathology; D018384:Oxidative Stress / Q000502:physiology; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D017527:Receptor, IGF Type 2 / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D013002:Somatomedins / Q000378:metabolism*
C526292:IRS1 protein, human; C526297:IRS2 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D017527:Receptor, IGF Type 2; D013002:Somatomedins; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D000109:Acetylcholine