Diabetes and the Brain
The Unseen Connection

by Elizabeth Norton Lasley

May, 2006

When citing the dangers of type II diabetes, doctors usually focus on associated, life-threatening conditions such as heart disease and risk of stroke. Research is beginning to show, how-ever, that diabetes can damage the brain directly—filling in the details of a picture in which insulin resistance, memory loss, and even Alzheimer’s disease are ominously intertwined.

“Insulin resistance is a core defect in many conditions including obesity, hypertension, cardiovascular disease, and impaired glucose tolerance,” says Suzanne Craft of the Veterans Affairs Puget Sound Medical Center and the University of Washington. Individually, each is a risk factor for Alzheimer’s disease. But in type II diabetes, more than one, and sometimes all, are present at the same time.

More than 20 million people in the United States alone have type II diabetes—half of them over 60—and people are living longer than ever before. “It’s not alarmist to say that insulin resistance in an aging population is a serious problem,” Craft says.

The role of insulin, a hormone produced in the pancreas, is to signal cells to open their membranes and let glucose in. In type II diabetes the cells disregard this signal, and the pancreas responds by producing more. Excess amounts of glucose and insulin build up but do not accomplish their jobs, while damaging many parts of the body including the heart and blood vessels, skin, eyes, and kidneys.

In the brain, imbalances in glucose can affect mental acuity even in people who are not diabetic. Carol Green-wood and Gordon Winocur at the Bay-crest Centre for Geriatric Care, Toronto, asked healthy adults to perform memory tasks, such as remembering paragraphs and lists of words, after a glucose drink. Those with greater-than-normal fluctuations in blood sugar did worse on the tests.

The brain uses large amounts of glucose, especially for memory. If insulin’s signal is unheeded, the brain may not get the fuel it needs. But insulin plays other roles as well, which come together to explain both memory loss and Alzheimer’s disease.

Insulin is involved in long-term potentiation, a process of memory formation at the cell level; it also regulates several of the chemical messengers involved in memory, such as acetylcholine. At low doses, insulin helps to contain inflammation and, at high doses, stimulates it.

“Understanding insulin’s role in Alzheimer’s disease may help treat and even prevent this tragic disease.”

Finally, Craft and colleagues have shown that excess insulin can increase levels of beta-amyloid protein. Because inflammation, reduced acetylcholine, and toxic accumulations of beta-amyloid protein are hallmarks of Alzheimer’s disease, insulin insensitivity is one route through which this disease may develop.

“Understanding insulin’s role in Alzheimer’s disease may help treat and even prevent this tragic disease,” Craft says.

New treatments are under investigation. In the March 2006 issue of the Neurobiology of Aging, Craft’s team showed that inhaled insulin improved verbal memory in some patients with early Alzheimer’s disease or impaired memory. In another study, a subgroup of Alzheimer’s patients showed memory improvement after being treated with rosiglitazone, an insulin-sensitizing drug. Results were published online January 2006 in Pharmacogenomics.

In both studies, the patients who responded to treatment were those who did not carry a specific variant of the APOE4 gene, a common mutation in Alzheimer’s disease, suggesting that factors related to insulin resistance and not the APOE4 gene contributed to the disease’s development in these patients.

Research is also pointing to the importance of lifestyle, showing how some of the simplest changes can reap great benefits. Regular, moderate exercise, for example, can cut the risk of type II diabetes in half, and can improve mood and memory in older people. Craft and colleagues are in the midst of examining the effects of moderate exercise in patients with early-stage Alzheimer’s disease.

Diet, too, is of paramount importance. Greenwood, working with Winocur, has found that rats with a diet high in saturated fats develop memory problems.

Their work dovetails with studies of humans showing that a diet high in the “good” fats, particularly those from fish, can ward off memory decline and even Alzheimer’s disease. In the July 2003 issue of the Archives of Neurology, a seven-year prospective study of 815 subjects age 65 to 94 showed that those who ate fish at least once a week had 60 percent less risk of developing Alzheimer’s than those who rarely or never ate fish.

Greenwood is now studying the “good” carbohydrates. A study published online March 6, 2006 in Diabetologia shows that carbohydrates with a low glycemic index (those that cause a less drastic rise in blood sugar, such as whole grains and pasta) resulted in better performance on memory tests after eating.

“For a long time we had to reserve comment, since our early studies were in rodents,” Greenwood says. “But now it’s clear that in humans, lifestyle habits have an enormous impact on brain health.”