A group of drugs under development for treatment of Type II diabetes --- the glucagon-like peptide receptor agonists --- has been linked to increased heart rate and elevated blood pressure in animal studies, according to an article in the July issue of the Journal of Clinical Investigation. These new findings suggest that the brain's response to the agonists may involve changes in autonomic function, leading to the observed changes in heart rate and blood pressure.

A naturally occurring hormone that is produced by cells lining the intestine, the peptide was first targeted as a diabetes treatment about 15 years ago, according to the study's senior author Joel Elmquist, D.V.M., Ph.D.

"Glucagon-like peptide-1 stimulates insulin secretion and controls feeding and drinking behavior, and also regulates neuroendocrine responses to agents that elicit illness-like behaviors," he explained. "The effect on insulin secretion made the hormone an obvious target for treating diabetes."

Type II diabetes accounts for the majority of cases of the disease, and it is a huge public health problem: As many as 16 million individuals in the United States have Type II diabetes, which puts them at risk for a number of serious complications, including cardiovascular disease.

Although Type II diabetes can often be controlled through diet, exercise, and existing medications, the magnitude of the problem has given rise to the development of a number of new drugs to better manage the disease, including the peptide receptor agonists. These agents, which are currently being tested in clinical trials, work by targeting the rate of gastric emptying and by stimulating insulin secretion from islet cells in the pancreas.

Circulating levels of the naturally occurring hormone in healthy individuals are low when the body is in a fasting state, according to Elmquist. After a person has eaten, hormone levels rise, only to fall within minutes as a result of enzymatic activity. He noted that continuous infusion of the hormone does not increase either blood pressure or heart rate in humans with Type II diabetes.

However, in drug form, analogs such as EXENDIN-4 have a far more potent and long-lasting influence. In the studies on rodents conducted in Elmquist's lab, the researchers demonstrated that EXENDIN-4 -- which is being tested as a therapeutic agent -- activated several key autonomic regulatory sites in the brain, leading to increased heart rate and blood pressure in the animals.

"Despite accumulating data linking glucagon-like peptide-1 to autonomic and neuroendocrine responses, the pathways [responsible] for the actions were previously not well understood," explains Elmquist. "Although these new findings in animals will need to be studied further, especially in diabetic models, this research suggests that the central glucagon-like peptide-1 system can regulate sympathetic outflow including raising heart rate and blood pressure."