What diabetes may be doing to your brain

People with type 2 diabetes, the kind you are more likely to get as an adult, are at risk for a host of additional medical problems.

Stroke and heart attack. Kidney disease. Blindness. Skin infections. Numbness in the feet.

Add one more you and even your doctor may not have heard is connected: dementia. Diabetes at least doubles your risk of developing it. Even diabetics without dementia can have subtle cognitive problems.

"Your average diabetologist, internal medicine doctor, they're still not aware of that information," said Luke Stoeckel, a neuropsychologist at the National Institute of Diabetes and Digestive and Kidney Diseases. "That's eye-opening to people."

As director of the almost two-year-old cognitive and clinical neuroscience of obesity and diabetes program, he has to make sense of fast-growing, conflicting research on the interplay between our brains and metabolic dysfunction.

While it's still far from clear how diabetes or obesity causes cognitive problems, Stoeckel thinks doctors should be thinking about more than kidneys and eyes when they examine diabetic patients.

Figuring out how to prevent or delay dementia has taken on more urgency as the oldest members of the baby boom generation turn 70 this year. Risk rises dramatically with age. Meanwhile, close to 10 percent of Americans - 29 million people - have diabetes. Another third of adults have prediabetes, or elevated blood sugar levels. Obesity, a diabetes risk factor, remains a huge and stubborn public health problem.

Hence the growth in studies focusing on the role of diabetes, blood sugar, and insulin on the brain and, to a smaller degree, how changes in the brain may affect metabolism. Inflammation, a byproduct of diabetes, is another possible culprit. Scientists are also exploring whether medicines used to treat diabetics can help people with dementia. Insulin is being investigated as both a cause of brain problems and a possible treatment.

Stoeckel recently asked a group of experts to produce a "white paper" on the subject that catalogued the myriad avenues of early research producing intriguing, but also often contradictory, results. The group concluded that there is an urgent need for identifying the research paths most likely to be fruitful. They bemoaned what they called the dearth of research at the intersection of obesity, diabetes, and dementia even though each is common and much studied.

Even less is known about whether there is a link between Type 1 diabetes and dementia, authors wrote.

William Milberg, a Harvard Medical School psychologist, was among the first to study the role that problems in tiny blood vessels in the brain played in cognitive disorders of aging. Others were more focused on the brain proteins called plaques and tangles that build up in Alzheimer's.

He has a lot more company now as others have questioned why diabetes, which causes vascular problems, increases dementia risk.

"I feel much less like I'm a lone wolf in this right now," he said.

While it is clear that diabetes and dementia are connected somehow, experts were quick to point out how little they know for sure about how diabetes affects the brain. Obesity, especially in midlife, also increases the risk of dementia and other thinking problems. Again, the mechanism is under study.

Dementia itself is a mixed bag. Alzheimer's disease gets most of the attention. But vascular dementia, which is often associated with small strokes, is also common. It has similar symptoms but progresses differently. Patients can often have both forms of dementia.

Because it is well-known that diabetes increases risk for cardiovascular disease and stroke, the connection with vascular dementia is clearest. Doctors also feel sure that Alzheimer's symptoms progress more quickly in people with diabetes.

The disease "basically amplifies your risks in terms of disability and going down quickly," said Ausim Azizi, chair of neurology at Temple University's Lewis Katz School of Medicine.

Diabetes damages blood vessels through elevated insulin and blood sugar and other inflammatory substances, said Serge Jabbour, director of the division of endocrinology, diabetes, and metabolic diseases at Sidney Kimmel Medical College, Thomas Jefferson University.

The brain, a big energy consumer, needs a rich blood supply, Milberg said. He said that axons, the long appendages that connect neurons, are particularly susceptible to microvascular damage.

Some researchers also suspect that diabetes plays a role in the development of plaques and tangles, but the evidence for that is not as strong. David Wolk, codirector of the Penn Memory Center, said there is also evidence that vascular damage reduces the brain's ability to rid itself of such "trash" as the errant Alzheimer's proteins.

Then there's insulin. Type 2 diabetes occurs when the pancreas has to produce too much insulin because cells have become "resistant" to its effect. The hormone allows glucose to move from blood into cells and regulates blood sugar levels. Over time, the body becomes less able to produce so much insulin and blood-sugar levels rise. This process is hard on tissues and organs.

Researchers, including Steven Arnold, a neurologist at Massachusetts General Hospital, have also found insulin resistance in the brain tissue of people who died of Alzheimer's, whether they had diabetes or not. Some have called Alzheimer's type 3 diabetes, an idea that Arnold, who formerly worked at Penn, opposes because insulin's primary role in the brain is not sugar regulation. There are other mechanisms for that. Insulin is a growth regulator that keeps brain cells healthy.

Arnold will soon begin studying brain insulin resistance in living people.

Inhaled insulin is among the treatments being tested for dementia. Early results showed promise, but Arnold is concerned about that because researchers still don't know whether people with Alzheimer's have too little or too much insulin in their brains. Giving more of the hormone might make things worse in the long run.

He is more optimistic about diabetes such drugs as metformin, which makes cells more sensitive to insulin and can cross the blood-brain barrier. It is in the early stages of testing as a dementia treatment.

Although there's no proof yet that controlling diabetes well or following the usual admonitions - lose weight and exercise more - will reduce the risk of dementia for diabetics, doctors strongly suspect that there will be.

Of course, preventing diabetes in the first place should be a high priority. Jabbour said overweight people likely have insulin resistance long before they develop diabetes. He said patients who lose weight often tell him, "My memory is better. I can think better."

Doctors were loathe to suggest a specific diet or to target particular "bad" foods. They said that there's good evidence for the Mediterranean diet, but that patients should pick a diet they can stick to.

Martha Clare Morris, a nutritional epidemiologist, at Rush University in Chicago, has been studying the MIND diet, a hybrid of the Mediterranean and DASH diets, which often are recommended for people with diabetes, high blood pressure, or prediabetes. Her diet includes foods such as leafy greens, whole grains, and berries that already have been shown to support brain health. MIND calls for very little cheese (a big source of saturated fat) or sweets. (She said sugar itself hasn't been proven bad for the brain, but it is a source of empty calories.) Her team analyzed what people who were in the Rush Memory and Aging Project were already eating. Strong adherence to the diet was associated with lower likelihood of getting Alzheimer's and slower cognitive decline.

Her results, which were not specifically aimed at people with diabetes, were so intriguing that the government has given $14.5 million to test whether people who switch to the MIND diet lower their risk of dementia. That trial will start in Chicago and Boston late this year.

Wolk said worried patients have started asking about diet. He and Milberg think those at high genetic risk for Alzheimer's should try extra hard to exercise and eat well.

Whether people with diabetes will be more likely to change their ways to protect their brains than they have been to protect their hearts and eyes remains to be seen.

Arnold is hopeful. "Studies indicate that people would rather have cancer or a heart attack than they would Alzheimer's disease," he said.

The good news is that doctors know how to prevent diabetes and have better treatments for it than for Alzheimer's. Lifestyle changes, hard as they are, can make a big difference.

"Our ability to cure or treat [Alzheimer's] disease has run up against a big wall," Morris said. "We don't have drugs out there, therapies to prevent or cure the disease, and that shifts the limelight to prevention."

sburling@phillynews.com

215-854-4944

@StaceyABurling