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Birds, Migration and Diabetes

A couple of weeks ago we had a new product blurb about Cycloset(tm), an old drug with a new indication for diabetes. Many of you wrote to ask me for information on how the medication works and where the idea came from. I had our current PharmD candidate, Robert Fredenrich, do some additional research for you.


Birds, Migration and Diabetes
Robert Fredenrich, PharmD Candidate
University of Florida, College of Pharmacy

altA flock of birds flies overhead, and you wonder to yourself what allows them to make that flight. How do they have the energy to fly such great distances? What happens to them metabolically to allow them to make those trips seasonally? The answer is surprisingly universal. In preparation for long winters other vertebrates exhibit similar metabolic events in preparation for hibernation. Metabolically, they experience excess insulin production, decreased resistance to insulin, and elevated cholesterol levels which helps them to store the excess energy they are consuming that is necessary for their expected hibernation or migrations. Surprisingly these changes occur seasonally in all vertebrates except for humans, and continue even when in an environment isolated from typical changes in temperature or length of day that occur when seasons change. Despite the lack of seasonal changes in humans, this metabolic phenomenon resembles the changes that occur in humans when they suffer from Type 2 diabetes, especially insulin resistance syndrome. Unfortunately, in humans, these changes do not naturally reverse themselves when it is no longer necessary to store energy for intense physical activity or periods of famine, such as winter. Modern humans no longer worry about the availability of food during winter. However, when these changes occur, humans now lack the ability to naturally “turn off” these metabolic changes once they have started. Cycloset (bromocriptine) acts to reset the system, allowing it to return to normal activity and shut off the metabolic changes that occur and lead up to insulin resistance syndrome.

Bromocriptine administration is shown in animal studies to reduce the amount of food consumption. This effect occurred separate from the metabolic effects to reduce blood glucose levels, and may aid obese patients in reducing body fat. This is more pronounced in patients who have obesity due to diet than patients who have genetic causes for obesity. In addition to decreasing food intake, there was also an increase in movement in animals treated with bromocriptine, further leading to decreases in body fat due to the increased usage of energy from locomotion. These effects show that bromocriptine not only affects the physiological changes seen in diabetes, but may also help with some of the behavioral activities that lead up to the development of insulin resistance.

Additionally, bromocriptine administration is shown to reduce body fat even without reducing intake of food. These effects are realized through an adjustment of energy usage away from the generation of lipids and fat cells towards the production of proteins. Reductions of free fatty acid oxidation are also seen, which contribute to a decrease in hepatic glucose production. This occurs due to limiting glucose production that occurs from the more rapid free fatty acid oxidation seen in obese individuals.

Bromocriptine significantly reduces the secretion of prolactin. Effects on prolactin are likely responsible for the decreased lipolysis and lipogenesis experienced. Shifting the peak concentrations of prolactin to a different time of day prevents it from assisting in the metabolic activities of lipolysis and lipogenesis. Central effects on the hypothalamus are responsible for alterations resulting in insulin resistance. Acting on the suprachiasmatic nuclei allows the human body to “turn off” the changes and revert to normal metabolic activity and insulin response.

Cycloset (0.8 mg) given once daily every morning can affect these changes in humans. It can reset the system and reduce insulin resistance, excess insulin production, and elevated cholesterol levels acting centrally on the hypothalamus and hormonal release. These changes also lead to decreased body fat and increased muscle mass through alterations of energy usage. In addition, it can also help curb behaviors, reducing intake of food and lead to increased activity which will further contribute to reductions of body fat. The heart-healthy reductions of lipids due to inhibition of prolactin also aid in glycemic control, limiting gluconeogenesis in the liver. Though current evidence on this new drug is limited, it has a promising future in the treatment of Type 2 diabetes and it all started with observation of birds.

References:
Cincotta, A. H., MacEachern, T. A., and Meier, A. H. Bromocriptine Redirects Metabolism and Prevents Seasonal Onset of Obese Hyperinsulinemic State in Syrian Hamsters. Am J Physiol. 1993 Feb;264(2 Pt 1):E285-93.
Cincotta AH, Meier AH. Bromocriptine Inhibits In Vivo Free Fatty Acid Oxidation and Hepatic Glucose Output in Seasonally Obese Hamsters (Mesocricetus auratus). Metabolism. 1995 Oct;44(10):1349-55.
Davis LM, Michaelides M, Cheskin LJ, et al. Bromocriptine Administration Reduces Hyperphagia and Adiposity and Differentially Affects Dopamine D2 Receptor and Transporter Binding in Leptin-Receptor-Deficient Zucker Rats and Rats with Diet-Induced Obesity. Neuroendocrinology. 2009;89(2):152-62. Epub 2008 Nov 4.
Pijl H, Ohashi S, Matsuda M, Et Al. Bromocriptine: a novel approach to the treatment of type 2 diabetes. Diabetes Care. 2000 Aug;23(8):1154-61.
Scranton, R. E., Gaziano, J. M., Rutty, D., et. al. A Randomized, Double-Blind, Placebo-Controlled Trial to Assess Safety and Tolerability During Treatment of Type 2 Diabetes with Usual Diabetes Therapy and Either Cycloset or Placebo.

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