Colorado State University Study Links Brain Shrinkage and Dementia to Brain Chemical Imbalance; Discovery Could Lead to New Treatments

Colorado State University researchers have linked brain shrinkage and memory loss and dementia in diabetes and Alzheimer’s patients with reduced levels of two chemicals in the brain, according to the results of a study presented in Washington D.C. Nov. 13. The results may lead to new treatments for Alzheimer’s and diabetes-induced dementia, and also questions current theories that complications from diabetes are regulated by glucose levels alone.

Low levels of both insulin and a hormone called insulin-like growth factors, or IGFs, may accelerate brain shrinkage and the abnormal death of brain cells in Alzheimer’s and diabetic patients, says Douglas Ishii, principal investigator of the study and a biochemistry, molecular biology and biomedical sciences professor at Colorado State. IGFs are produced by genes, and Ishii has found a link between levels of insulin and the expression of genes within the brain – including those leading to IGF production.

Ishii and his team of scientists tested the impact of releasing supplemental levels of IGFs into the brain and found that increasing the chemical prevented learning and memory impairment. In addition, the group found that tiny doses of insulin delivered into the brain regulated brain weight and prevented brain shrinkage. This information could help to prevent the progression of dementia and keep patients independent and out of nursing homes, saving billions of health-care dollars.

"Because of the cooperative effect of insulin and IGFs on cells, I believe the brain receives a double whammy when the neurological protective effects of both insulin and IGFs decline in aging and disease," said Ishii. "I am optimistic that these novel findings may lead directly to new treatments for Alzheimer’s and diabetic dementia, independent of the current focus on the role of glucose levels in the brain. These findings suggest that insulin has many other important roles in the brain, such as controlling the loss of protein and impacting the expression of hundreds of genes within the brain. But we must be cautious because these results are in laboratory tests. Clinical trials based on these findings are needed."

The human brain begins to slowly shrink after approximately the age of 25, but this process is accelerated in people with Alzheimer’s disease and diabetes, who experience abnormal brain cell death. The average life expectancy is about eight years after the onset of dementia. Dementia results from severe impairments in learning and memory such that patients lose the capacity for self-care.

In Colorado State laboratory tests, IGF treatment prevented impaired learning but had only a small effect on brain shrinkage and cell loss. Ishii’s team wanted to test a hypothesis that reduced insulin in the brain — not elevated levels of glucose in diabetic patients — was the main culprit leading to brain shrinkage.

Ishii’s study also showed in laboratory tests that insulin directly regulates brain weight. He believes this fact may be the "smoking gun" that implicates reduced insulin in the brain as the prime suspect for accelerated brain shrinkage in Alzheimer’s and diabetic patients; the development of brain insulin resistance may be the main cause of brain shrinkage. Ishii believes that the slow loss of IGFs over decades may predominantly contribute to dementia.

Scientists know that plaque deposits and tangles accumulate in the brains of Alzheimer’s patients, but IGFs may preserve memory in a variety of ways. IGFs support the function of synapses in the brain, help generate new neurons, prevent the death of certain brain cells and help clear plaque deposits.

Virtually all clinicians believe that when diabetic dementia is treated with insulin, oral drugs, or diet and exercise, patients improve because their sugar levels are reduced, said Ishii. It is also widely believed that elevated glucose levels are the culprit of many complications in people with diabetes, including brain damage. But Ishii’s experiments found that insulin receptors in the brain have many functions in addition to regulating glucose levels.

"There are two primary pathways in the brain that are regulated by insulin. One pathway regulates glucose levels, but the second pathway, which has previously been neglected in diabetes and dementia research, is a pathway that regulates hundreds of genes — including the genes that produce IGFs," said Ishii. "IGFs regulate many brain functions. Based on these findings, we can see that insulin has many important roles in preventing complications of diabetes and dementia, beyond regulating glucose."

"We wanted to find out if diabetic neurological complications are the result of excess glucose or reduced IGF levels," said Ishii. "Research shows that despite the best methods of glucose control, neurological complications continue to progress in 40 percent of diabetic patients."

"What is particularly exciting about this discovery," said Ishii, "is that supplementing the levels of IGF in the brain prevents loss of brain protein, and therefore the loss of brain function. This might help to arrest or retard the progression of dementia in Alzheimer’s and diabetic patients. Current treatments for dementia are only transiently effective. If we could prevent the progression of dementia, it would help keep patients independent and out of nursing homes, and save billions of health-care dollars."  

Research has hinted at a close association between diabetes and Alzheimer’s disease. For example, people with diabetes are at nearly double the risk of developing dementia, and Alzheimer’s disease is associated with a type 2 diabetes-like environment of insulin resistance in the brain. These two diseases both share reduced insulin brain signaling and reduced levels of IGFs.

In 1984, Ishii’s research discovered the role of IGFs in supporting the nervous system. IGF levels, which also are impacted by age and disease, help nerve cell survival, nerve regeneration, sprouting of nerve terminals and synapse formation. His belief that the two chemicals – IGFs and insulin — are key protective factors in the nervous system led him to further study their roles in dementia.

Ishii’s most recent finding of the connection between insulin and IGFs to brain function and brain protein mass, may also mean that the peripheral nerves in diabetes patients may be regulated by these two chemicals. That means that the nerve damage or neuropathy experienced by many people with diabetes may be a result of an imbalance in insulin and IGFs rather than due to high blood sugar levels, although it remains important to keep sugar levels under control.

There are about 28 million people with Alzheimer’s disease in the world, including 4.5 million Americans, according to the National Institute of Aging, the Alzheimer’s Disease Education and Referral Center and the Alzheimer’s Association. Nearly 16 million people in the United States have diabetes. The rising elderly population is expected to triple the number with dementia by 2050. The direct and indirect health care costs to treat dementia are estimated to be $100 billion in the United States today.