One of the most interesting aspects of covering developments in the type 2 diabetes community is when researchers or companies announce a new medication for controlling and managing diabetes.
That’s certainly the case with Rhode Island-based VeroScience (http://www.veroscience.com), which is introducing its Cycloset® therapy to the diabetes marketplace. Cycloset is VeroScience’s brand name for bromocriptine mesylate, a dopamine agonist that until recently has been used primarily to treat Parkinson’s disease, pituitary tumors, and other ailments. Its arrival as a treatment for type 2 treatment introduces a drug that works on brain chemistry rather than the pancreas, liver, or kidneys.
Dopamine is “the happy hormone,” says Anthony H. Cincotta, PhD, president and chief scientific officer at VeroScience. He calls it that because of its association with beneficial mood control, energy level, pleasurable outcomes, and more—in short, “a happy hormone.”
Diabetes Health recently interviewed Cincotta and asked him to give me some background on Cycloset’s development. How did VeroScience think of bringing dopamine to the marketplace as a legitimate diabetes management tool?
“Since antiquity humans have observed cycles in the body fat and metabolism of animals,” says Cincotta. “They can vary over the course of a year from thin to obese. So that our starting point for our study of the brain chemistry that affects obesity in mammals, a phenomenon we call ‘seasonal insulin resistance.’ Our question was, how does this happen? It seems to arrive out of the blue and then vanish into the blue.
“It turns out that what we were looking at was a powerful survival mechanism when there was very little food,” particularly in winter.
He explains how seasonal insulin resistance works no matter what animals’ specific approach to surviving winter.”Every species has developed a different strategy for coping with winter: hibernation, migration, or over wintering. Regardless of any specie’s winter coping mechanism, all have in common an initiation of brain chemistry that allows for the induction of insulin resistance. The tissues of the body become resistant to insulin, so glucose doesn’t move into them as well as usual. However, the body produces more glucose, which, with no insulin to control it, gets shunted to the brain. The brain cannot last very long—a few minutes at best—without glucose as its energy source.
“So we asked ourselves, can we copy this? We were able to map out the brain chemistry involved when animals transition from obese insulin-resistant winter into the lean. insulin-sensitive springtime.” VeroScience inserted probes into animals’ brains and then adjusted the light they were sensing to mimic certain parts of the year—short winter hours versus longer spring and summer hours. “We observed during these tests that dopamine levels upon waking would vary according to the season. Dopamine appears and works very briefly upon awakening; it’s at its highest when you wake up.
“Depending on the season we found that dopamine activates hypothalamic brain neural centers to send signals to the body’s periphery either to become insulin-sensitive and improve glucose disposal or insulin resistant. Seasonal insulin resistance correlates with low dopamine at its natural circadian peak—namely upon wakening.
Cincotta rejects the concept that slothfulness is a main driver in developing diabetes or obesity. “That doesn’t really hold up. We’re looking at a coping mechanism developed over hundreds of thousands years.” Migrating birds are at their fattest when they start out on their journeys, he says, so weight gain is far more a matter of survival than it is a behavioral problem.
Cincotta explains that Cycloset, which comes in tablet form, works by quickly releasing bromocriptine into the bloodstream, which is then quickly absorbed via the gut. “It mimics the natural circadian rhythm of peak dopamine upon waking that we see in healthy, insulin-sensitive individuals. We’re trying to replenish that dopamine peak in the morning.” Because it mimics the natural appearance of dopamine in the morning, it has to be administered within two hours after awakening; otherwise users must skip a day.
Because Cycloset is designed to improve insulin sensitivity, it works best with secretory agents like DPP4 inhibitors, GLP1s, and prandial insulin. “When teamed with these drugs we see good responses from type 2 patients. These drugs work to stimulate insulin production while Cycloset stimulates insulin responsiveness and sensitivity. They provide the insulin, we provide the increased sensitivity to it.”
Cincotta adds that one of the hallmarks of insulin induction resistance is an elevation of sympathetic nervous system activity. Such activity associates with increased blood pressure, increased heart rate, increased plasma triglycerides, a history of hypertension, and average blood sugar levels of 150 mg/dL or more. “These are biomarkers that we can use to identify patients who would respond well to Cycloset. This is because it lowers sympathetic nervous ‘tone’ by providing an increased dopamine level. This is its major mechanism for improving glycemic control.
“So, you find patients with elevated sympathetic nervous system activities, which can be determined by pulse rate, heart beats, blood pressure measurements, history of hypertension, average blood sugar levels of 150 mg/dL plus, etc. Those symptoms can be mitigated by Cycloset. We also see good responses on patients who use prandial insulin. Most of the work Cycloset does occurs after the post-prandial period because it works as an insulin sensitizer.”