February 28, 2013

Discovery Lecture explores brain’s sensitivity to insulin

Diabetes has a big impact on the brain.

C. Ronald Kahn, M.D., talks about insulin’s impact on the brain during his recent Flexner Discovery Lecture. (photo by Anne Rayner)

Diabetes has a big impact on the brain.

Patients with diabetes have more cognitive dysfunction, are at increased risk for developing Alzheimer’s disease, and have higher rates of depression and eating disorders.

What’s going on is the brain is actually a metabolic organ, exquisitely sensitive to insulin, internationally known diabetes researcher C. Ronald Kahn, M.D., said during last week’s Flexner Discovery Lecture/Irwin Eskind Lecture in Biomedical Science at Vanderbilt University Medical Center.

“Changing insulin signaling in the brain changes brain function in terms of things the brain normally does, which is mood and behavior activity,” said Kahn, the Mary K. Iaccoca Professor of Medicine at Harvard Medical School.

Through studies of genetically manipulated “knock-out” mice lacking brain receptors for insulin, Kahn and his colleagues have shown that insulin signaling affects the function of neurotransmitters including dopamine and serotonin, which in turn regulate mood and behavior.

These mice “show increased anxiety and signs of depression, which improve through treatment by antidepressant drugs,” he said.

How does insulin affect mood and behavior? One way is through regulation of cholesterol synthesis, Kahn said.

“The brain is the most cholesterol-rich organ in the body,” he said. “Twenty-five percent of all the cholesterol in our bodies is in the brain. Seventy percent of it goes to help make myelin sheaths and 30 percent of it actually goes to make membranes — neurons, glial cells.

“Cholesterol … in the blood doesn’t cross the blood-brain barrier (so) the brain … has to make its own,” Kahn continued.

Mice that lack brain receptors for insulin have decreased cholesterol synthesis and a decline in the number of synapses being formed. “Ultimately this leads to decreased synapse function, decreased neurotransmission (and) behavioral changes,” he said.

Cholesterol synthesis is probably not the only metabolic pathway influenced by insulin signaling. Kahn is collaborating with Richard Caprioli, Ph.D., and Michelle Reyzer, Ph.D., in Vanderbilt’s Mass Spectrometry Research Center to determine how disrupted insulin signaling in the knock-out mice may affect levels of other metabolites.

“I think (mass spectrometry) is going to be a powerful technology to look more broadly at metabolic changes in the brain,” Kahn said.

The Irwin Eskind Lecture in Biomedical Science is named for the late Irwin Eskind, M.D., a Vanderbilt alumnus and well-known Nashville physician and philanthropist.

Eskind’s sons, Steven Eskind, M.D., and Jeffrey Eskind, M.D., attended Kahn’s lecture, which was sponsored by the Vanderbilt Diabetes Center and by the Department of Molecular Physiology and Biophysics.

For a complete schedule of the Flexner Discovery Lectures and archived video of previous lectures, go to www.mc.vanderbilt.edu/discoveryseries.