Our brains are packed with cholesterol, almost all of which has to be produced within the brain itself, where it is critical for normal brain functions. Now, a new study in the December Cell Metabolism, a Cell Press publication, reveals how that critical cholesterol synthesis in the brain is derailed in mice with diabetes.

The findings offer a new explanation for the neurologic and cerebral complications that come with diabetes, including cognitive dysfunction, depression, and an increased risk of Alzheimer's disease, according to the researchers.

"People with diabetes can have a lot of problems with brain function, especially if it is uncontrolled," said C. Ronald Kahn of Harvard's Joslin Diabetes Center. "The assumption had been that this was related to the effects of poor glucose control. Our findings suggest a completely new concept."

The discovery came out of a general exploration of changes in global gene activity in the brain's hypothalamus in insulin-deficient diabetic mice. Those screens turned up changes in genes involved in appetite and feeding, as expected. But they also turned up many genes involved in cholesterol synthesis.

"The changes were not large, but they were in many genes in the pathway and they were all in the same direction," Kahn said.

Further study showed that the insulin-deficient mice showed a reduction in a gene, called SREBP-2, which is a master controller of cholesterol metabolism. That change reduced the production of cholesterol in the brain and lowered the amount of cholesterol in cell membranes that are important for the communications from one neuron to the next.

The cholesterol in those cell membranes turns over rapidly, Kahn explained, and effects could be seen in animals with uncontrolled diabetes after just a week or two. That brief period of insulin deficiency did not lead to changes in the cholesterol-rich myelin that insulates neurons. It's possible that uncontrolled diabetes over a longer period of time—months or even years—might lead to changes in the myelin, too, he said.

The changes they observed were traced to the direct effects of insulin on brain cells. Cholesterol synthesis was completely restored when the animals were injected with insulin.

Kahn said it is clear that the changes in cholesterol metabolism could have broad effects on brain function, with the potential to influence memory, physical functioning, and hormone levels, depending on which parts of the brain are most affected. They hope to get a handle on those secondary effects through further study in animals and to ultimately begin to explore the relevance of the new findings to human patients.

As for what those who have diabetes might take from the findings, Kahn said, "This is another reason to think that keeping good control over blood sugar might make a difference."

The findings also point to a general need in science to learn much more about cholesterol metabolism in the brain and what might affect it, for better or worse. For instance, he added, the results raise the prospect that cholesterol-lowering statins—some of which can cross the blood-brain barrier—might have unintended consequences for the brain and its function. Earlier studies designed to look for a potential effect of statins on cognitive function in patients have so far yielded conflicting results, the researchers noted.