Public Release:  Alcohol abuse can damage the brain by decreasing insulin and insulin-like growth factor receptors

Alcoholism: Clinical & Experimental Research

Too much alcohol can cause permanent brain damage, such as Wernicke-Korsakoff syndrome, which is largely related to thiamine deficiency. Previous animal studies have shown that alcohol can also cause brain injury and degeneration by inhibiting insulin and insulin-like growth factor (IGF). A new study using postmortem human brain tissue has found that chronic alcohol abuse can decrease levels of genes needed for brain cells to respond to insulin/IGF, leading to neurodegeneration similar to that caused by Type 2 diabetes mellitus.

Results will be published in the September issue of Alcoholism: Clinical & Experimental Research and are currently available at OnlineEarly.

"Insulin is one of the most important hormones in the body," said Suzanne de la Monte, professor of pathology/ neuropathology and clinical neuroscience at Rhode Island Hospital and the Warren Alpert School of Medicine at Brown University. "It has many functions, including regulation of metabolism. Cells throughout the body depend upon insulin just to stay alive and carry out 'ordinary daily functions.' The best known diseases associated with abnormalities in insulin's availability or actions are Type 1 and Type 2 diabetes." De la Monte is also the study's corresponding author.

During the past several years, she added, there has been growing interest in insulin's effects on brain function. Scientists now believe that deficiencies in insulin, and the loss of brain cells' ability to respond to insulin, are critical factors leading to neurodegeneration, including Alzheimer's dementia. Alcohol may exacerbate the problem.

"Alcohol is a toxin that clearly can injure or kill brain cells," de la Monte said. "Fortunately, alcohol has to pass through the gastrointestinal tract and liver where enzymes detoxify alcohol, and consequently reduce the levels that reach the brain. However, in either high concentrations, or at lower levels over a longer period of time, alcohol will dissolve some of the lipid in the cell's membrane."

This is where insulin and IGF receptors normally sit, in the cell's membrane, waiting to initiate a signal that tells the cells to make more energy. Earlier animal and tissue research showed that alcohol-related damage causes insulin and IGF receptors to become less accommodating, and the signals needed for cells to increase energy production and stay alive instead become weak and ineffective.

For this study, researchers examined brain tissue from six male chronic alcoholics with a mean age of 57.7 years, and six male "controls" without alcoholism with a mean age of 57.5 years, provided through the New South Wales Tissue Resource Centre at The University of Sydney. Two brain regions were selected for study - the cerebellar cortex in the anterior superior cerebellar vermis region, and the anterior cingulate gyrus in the frontal lobe - as they represent major targets of alcohol's neurotoxicity.

"Our study of human alcoholic brains is really the first of its kind, where we were able to study the effects of chronic alcohol abuse on brain degeneration," said de la Monte. "The subjects had all signed up to donate their brains, and they were included only if alcohol was the only drug used in life."

The results showed that in chronic alcoholics' brains, there was significant insulin and IGF resistance in those regions known to be highly sensitive to alcohol's toxic effects.

"Insulin and IGF resistance in the cerebellum and frontal lobe was associated with loss of neurons and their connections, and decreased levels of neurotransmitters needed for learning, memory, and motor function," said de la Monte. "The damage that we saw in the cerebellum would account for the poor balance, and increased rates of falling and trauma we see in alcoholics. The insulin and IGF resistance in alcoholics' frontal lobes would account for their associated problems in memory."

De la Monte added that the insulin resistance their study found was quite similar to what happens in Type 2 diabetes, which means that alcoholic brain disease may be treatable in part by use of drugs that make brain cells more responsive to insulin and IGF.

"Public-health warnings about problems associated with alcohol abuse are fairly prevalent today, but the major emphasis seems to be on the short-term effects related to impairments that cause accidents and promote violence," said de la Monte. "Most people also seem to know that alcohol abuse damages the liver. What I believe is not well known to the public is that, over the long haul, heavy drinking will permanently damage the brain and cause dementia. Some of the dementia is certainly related to a lack of thiamine, also known as Vitamin B1, however, in the majority of cases, thiamine deficiency is not the principal problem. Our study indicates that chronic alcohol abuse causes a Type 2 diabetes effect in certain brain regions."

De la Monte recommended that readers who are concerned about family or friends having problems with memory or behavior, and are concerned about dementia, to consider prior drinking habits and report this to a professional if warranted. "All dementias are not caused by Alzheimer's disease," she said.

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Alcoholism: Clinical & Experimental Research (ACER) is the official journal of the Research Society on Alcoholism and the International Society for Biomedical Research on Alcoholism. Co-authors of the ACER paper, "Insulin and Insulin-like Growth Factor Resistance in Alcoholic Neurodegeneration," were: Ming Tong, Ariel C. Cohen and Jack R. Wands of the Departments of Medicine and Pathology at Rhode Island Hospital, and Warren Alpert School of Medicine at Brown University; and Donna Sheedy and Clive Harper of The University of Sydney, Australia. The study was funded by the National Institute on Alcohol Abuse and Alcoholism, the New South Wales (Australia) Department of Health, and the National Health and Medical Research Council.

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