Diabetes and the brain
Dr. Cory Toth’s research could help protect the brains of people with diabetes.
Story by Laura Ly/Illustration by Huan Tran
Most of us know that diabetes is associated with insulin deficiency—either the body does not produce enough insulin (type 1 diabetes), or the body does not respond to the insulin that is produced (type 2 diabetes). However, diabetes also affects the brain; studies have shown that long-term diabetes can result in brain shrinkage and abnormalities, as well as a decline in cognition. Dr. Cory Toth is looking for causes of these brain changes in hopes of developing therapies to prevent them.
Dr. Toth, who also has a special interest in neuropathic pain, focused on diabetic neuropathy in his initial work on diabetes. Diabetic neuropathy occurs when the nerves in the body become damaged as a result of sustained high blood sugar levels. It occurs in roughly 50% of diabetic patients and can result in symptoms such as tingling and numbness. The condition starts in the feet where the longest nerves are and, eventually, affects the arms. “Some patients will have diabetes for a number of years, decades even, before they develop any features of neuropathy. The condition is extremely variable, and we don’t know why some patients develop neuropathy and others don’t. However, we know that patients with high glucose levels or poor control of their diabetes are more likely to get the disease over time,” says Dr. Toth.
While treating diabetic and neuropathic patients in his clinic, Dr. Toth observed that his patients often related difficulties with memory recall, thinking, and attention. This led him to hypothesize that long-term diabetes might be affecting cognition and related brain processes. Using the diabetic model he developed in his lab to study neuropathy, he looked at the brains of mice that had an animal form of diabetes to see if he could find a cause of these cognitive problems. “Sure enough, we saw that the brains of the mice with diabetes had shrunk, developing widespread brain atrophy. Their brains showed a loss of white matter and associated synaptic connections within the brain,” he explains. “The research also showed that cognition starts to wane after many, many weeks of diabetes in a mouse, which is akin to several years of diabetes in a human. This is similar to the chronic onset of dementia.”
Dr. Toth’s research is focused on two possible causes of changes in the brain: insulin deficiency and the role of advanced glycation end-products (AGEs) in the body. Glycation occurs when a protein bonds with a sugar molecule without a controlling enzyme, and these reactions produce AGEs. A buildup of AGEs in the body can become toxic. “AGEs are known to accumulate in conditions like Alzheimer’s disease, other degenerative conditions, and in diabetic tissue,” says Dr. Toth.
He is particularly interested in RAGE, the receptor for AGEs. His research looks at mouse models that are RAGE deficient. When compared to mice with the same degree of diabetes, the RAGE-deficient mice had better cognition, less brain atrophy, and fewer changes in white matter. This suggests that RAGE plays an important role in the mechanisms that cause brain abnormalities in diabetic patients. Dr. Toth aims to find potential therapies to block this pathway in patients and is further studying the role of RAGE in the body to determine how it may contribute to these changes in the brain.
Dr. Toth is also interested in how different insulin-delivery methods can affect or reduce the development of brain abnormalities during diabetes. “When you receive insulin injections, very little insulin gets into the brain and the nervous system. These areas remain quite insulin deficient, almost as if they are ‘starving’ for insulin. As a result, we started wondering if insulin itself could play a role in the brain changes and the development of diabetic neuropathy.”
In collaboration with the University of Calgary’s Dr. Doug Zochodne, Dr. Toth is looking at the effects of delivering insulin through the nasal passages. It is estimated that 98% of insulin reaches the brain when delivered through the nasal passages; in contrast, only 2% of insulin from an injection into the skin reaches the brain. “We did a lengthy experiment where we delivered insulin either through the nose or through injection. Only the diabetic mice that received the intranasal insulin were protected from the long-term effects of both the brain disease and neuropathy,” explains Dr. Toth. A clinical trial was recently launched to test the effect and safety of intranasal insulin delivery in humans.
In 2006, Dr. Toth started Canada’s first clinic for treating and assessing neuropathic pain. The clinic allows him to bring the results of his research directly to patients and is a major step in helping him achieve his research goals: “I want to be able to help diabetic patients in two areas: first, I want to develop new therapies to reduce the amount of neuropathy and associated features of pain they experience; and secondly, I want to see if I can find particular causes of brain atrophy or cognitive decline and, hopefully, intervene and prevent those over time.”