Side Effects of Diabetes Drugs Involve Unsuspected Brain Region

A brain region involved in emotional and intellectual processes appears to also play an unsuspected role in the body’s visceral response to dangerously low blood sugar levels, according to research at Washington University School of Medicine in St Louis. Low blood sugar, called hypoglycemia, is a common and dangerous side effect of drugs that control insulin levels in people with diabetes.

The findings will be published online the week of March 15 in the Proceedings of the National Academy of Sciences. Philip E. Cryer, M.D., the Irene E. and Michael M. Karl Professor of Endocrinology and Metabolism, and William J. Powers, M.D., professor of neurology, neurological surgery and radiology, led the study.

According to Cryer, drugs that help keep blood sugar levels low often cause them to drop too far. The average person undergoing treatment for type 1 diabetes will experience symptoms of hypoglycemia about twice a week, with one episode of severe, temporarily disabling hypoglycemia per year. It also is a significant problem in people with advanced stages of type 2 diabetes.

“Hypoglycemia is the most difficult obstacle in the management of blood sugar in people with diabetes,” Cryer says. “To treat diabetes you have to lower glucose levels, but we haven’t figured out how to do so without the potential of triggering dangerously low levels.”

The symptoms of hypoglycemia, which include shakiness, anxiety, dizziness and confusion, are all part of the body’s innate response to danger. They’re warning bells, letting the individual know that something is wrong that must be addressed. Curiously, symptoms are much less intense if a person has recently been hypoglycemic. This phenomenon is known as hypoglycemia unawareness.

To understand why the warning bells become muted, Cryer, Powers and their colleagues began taking brain images of healthy individuals while systematically altering participants’ blood sugar levels.

Their initial study was intended to serve as a baseline, outlining the overall pattern of brain activation during an initial episode of hypoglycemia. The team then planned to compare these images with those taken following interval hypoglycemia, in which intervals of low blood sugar ultimately lead to hypoglycemia unawareness.

But the initial results proved much more exciting than expected: One of the main areas activated by low blood sugar levels was the medial prefrontal cortex, located toward the front of the brain. The responses in hypoglycemia are involuntary and highly visceral, so the researchers were surprised to find changes in activity in this brain region that is primarily associated with emotion and high-level thought processes.

“The unexpected discovery that this region is involved in hypoglycemia provides new insight into how the brain functions during such basic, primitive responses and demonstrates an anatomic link between cognitive processes and innate, physiological responses,” Powers says.

When Powers and Cryer discussed their surprising results with colleagues, they discovered that Joseph L. Price, Ph.D., professor of anatomy and neurobiology, is the author of several prominent studies outlining the connections between the medial prefrontal cortex and the brainstem and hypothalamus, the two primary brain areas known to be involved in low-level physiological responses like those seen in hypoglycemia. According to Price, the medial prefrontal cortex has been suspected of having a role in visceral responses but had never before been associated with such activity in the absence of an emotional component.

Price’s team is eager to use the data from this study to further explore connections between the brain’s low- and high-level response systems. Simultaneously, Powers and Cryer plan to use their data as they originally intended: as a baseline to study the brain’s response to interval hypoglycemia.


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