High levels of glutamate in brain linked to depression, low cognitive function

Researchers at the Joslin Diabetes Center and several other institutions have for the first time linked high levels of glutamate – a neurotransmitter in the brain produced from glucose – in people with type 1 diabetes to symptoms of depression and lower levels of cognitive performance. The findings may lead to a better understanding of the underlying mechanisms of these conditions in people with diabetes. 

“These findings could lead to new ways to both understand and treat these conditions,” said Alan Jacobson, M.D., Chief of Psychiatry at Joslin Diabetes Center, Professor of Psychiatry at Harvard Medical School and senior author of the paper published in the August issue of Archives of General Psychiatry, who noted that higher levels of both mild depression and lower scores on tests of cognitive function have been noticed for some time in patients with diabetes.

The study, which involved researchers at institutions in both the United States and Korea, documents increased levels of glutamate in the prefrontal area of the brains of people with type 1 diabetes, an area associated with both higher-level thinking and regulation of emotions. At the same time, the study shows a link between those high levels of glutamate to poorer glucose control, more symptoms of depression and lower scores on tests of cognitive function in those with diabetes.

“The importance of this paper lies in the linkage of a neurotransmitter that, in high levels, can cause damage to neurons, the degree of diabetic hyperglycemia (high blood glucose) and alterations in cognitive function and depression levels previously found in diabetes,” said Jacobson.

The findings suggest that therapies to alter the transmission of glutamate may be of benefit in treating these conditions. While the study focused on people with type 1 diabetes, Dr. Jacobson suggests the findings could also be beneficial to individuals with type 2 diabetes as well.

Using proton magnetic resonance spectroscopy imaging, the researchers looked at brain glutamate levels in 123 people with type 1 diabetes with varying degrees of lifetime glycemic control and 38 subjects without diabetes.

According to the data, concentrations of glutamate were nine percent higher in the subjects with diabetes. At the same time, performances on tests of memory, executive function and psychomotor speed were lower in the diabetes group. An association with mild depression was also found. According to the paper, depression affects up to 25 percent of people with type 1 diabetes.

If confirmed, the findings could help further science’s understanding of high blood sugar levels, said Jacobson, noting that the emphasis has until now been on the association between low blood sugar and brain damage.

Further, the findings on glutamate and its effects on the brain may lead to a new line of investigation into both types 1 and 2 diabetes in terms of interventions to improve the health of the brain, including possibly new medications for both diabetes and depression, he said.

The study was funded by the National Institute of Health, the National Alliance for Schizophrenia and Depression, the Korean Research Foundation and the Korean Ministry of Science and Technology.

Others participating in the research included: In Kyoon Lyoo, M.D., Ph.D., of McLean Hospital, Harvard Medical School and Seoul National University, first author; Sujung J. Yoon, M.D., Ph.D., of Catholic University Medical College; Gail Musen, Ph.D., and Katie Weinger, Ed.D., of Joslin Diabetes Center and Harvard Medical School; Donald C. Simonson, M.D., M.P.H., of Brigham and Women’s Hospital; Nicolas Bolo, Ph.D., and Perry F. Renshaw, M.D., Ph.D., of McLean Hospital and Harvard Medical School; Christopher M. Ryan, Ph.D., of the University of Pittsburgh School of Medicine; and Jieun E. Kim, M.D., M.S., of Seoul National University.