Researchers from Joslin Diabetes Center at Harvard Medical School may have uncovered an explanation for why patients with diabetes are more likely to develop anxiety and depression than patients with other chronic conditions requiring similar levels of management.
Researchers from Joslin Diabetes Center at Harvard Medical School may have uncovered an explanation for why patients with diabetes are more likely to develop anxiety and depression than patients with other chronic conditions requiring similar levels of management. The potential explanation they provide lies in the results of a mouse study.
For a study published online ahead of print on March 2, 2015 in the Proceedings of the National Academy of Sciences of the United States of America, or PNAS, the researchers genetically modified mice to have a brain-specific knockout of the insulin receptor, which they dubbed NIRKO mice.They found these mice exhibited “brain mitochondrial dysfunction with reduced mitochondrial oxidative activity, increased levels of reactive oxygen species, and increased levels of lipid and protein oxidation in the striatum and nucleus accumbens.” In other words, those mice that were made to be resistant to insulin exhibited behaviors suggestive of anxiety and depression.
“This is one of the first studies that directly shows that insulin resistance in the brain actually can produce a behavioral change,” said senior author C. Ronald Kahn, MD, Chief Academic Officer at Joslin Diabetes Center and the Mary K. Iacocca Professor of Medicine at Harvard Medical School.
When multiple tests commonly used to analyze anti-anxiety and anti-depressant drugs were conducted to assess the genetically modified mice, Kahn and colleagues found that young mice behaved quite similarly to normal mice. However, when mice were tested at age 17 months (the beginning of late middle-age for mice), significant behavioral disorders were observed.
Chief among these changes was altered metabolism in cell mitochondria, particularly the increased production of monoamine oxidase A and B (MAO A and B), whichincrease dopamine turnover. The study authors noted that “studies in cultured neurons and glia cells indicate that these changes in MAO A and B are direct consequences of loss of insulin signaling.” Kahn added that “these mice release a normal amount of dopamine, but because of these changes in the mitochondria they metabolize that dopamine faster, and it’s not around as long. We think that contributes to these behaviors, and in fact when we give the mice antidepressants that work by slowing dopamine degradation [specifically MAO inhibitors and the tricyclic antidepressant imipramine], we can correct some of the behavioral changes.”
Despite the younger NIRKO mice not displaying the behavioral effects observed in the older NIRKO mice, Kahn and colleagues did discover similar changes in their brain cells. Although the reasoning behind why these behavioral changes appear to increase with age remains unclear, this effect is commonly observed in mouse models of neurological disorders, as well as the same human neurological diseases, according to Kahn.
Indeed, previous human studies have suggested a connection between insulin resistance and other neurodegenerative conditions, particularly Alzheimer’s disease. “Preliminary studies have shown that treating people with Alzheimer's disease with insulin inhaled through the nose, which is supposed to allow more insulin to get delivered directly to the brain, might slow their changes in cognitive function,” Kahn said. “It’s obviously too early to tell, because we’re looking at very early-stage research, but one could imagine that intranasal insulin might actually have some effects in anti-depression or anti-anxiety in people with diabetes.”