BenchtoClinicSymposia EDITORIAL REVIEW Bromocriptine: A Sympatholytic, D2-Dopamine Agonist for the Treatment of Type 2 Diabetes romocriptine is a sympatholytic disease and stroke, it is a relatively weak (muscle) tissues, fat oxidation becomes B D2-dopamine agonist that has been risk factor compared with other more es- predominant, and hepatic glucose pro- approved for the treatment of type 2 tablished risk factors such as dyslipide- duction and gluconeogenesis rise to sup- diabetes. Based on animal and human mia,hypertension,obesity,andthe ply glucose to the CNS during prolonged studies, timed bromocriptine administra- insulin resistance (metabolic) syndrome periods (seasons) of food deprivation. At tion within 2 h of awakening is believed (4,5). However, even after correction of the end of the season, animals revert back to augment low hypothalamic dopamine dyslipidemia, hypertension, and dysgly- to their insulin-sensitive/glucose-tolerant levels and inhibit excessive sympathetic cemia, type 2 diabetic patients still remain state. Such seasonal metabolic changes tone within the central nervous system at high risk for atherosclerotic cardiovas- are characteristic of all migrating birds (CNS), resulting in a reduction in post- cular complications (6). Therefore, anti- and hibernating animals and are governed meal plasma glucose levels due to en- diabetic agents that not only improve by changes in monoaminergic concentra- hanced suppression of hepatic glucose glycemia but also reduce cardiovascular tions/activity in the suprachiasmatic nu- production. Bromocriptine has not been risk are desirable. clei (SCN) of the hypothalamus—the shown to augment insulin secretion or Recently, timed-release bromocrip- mammalian circadian pacemaker—and enhance insulin sensitivity in peripheral tine (Cycloset), a sympatholytic dopa- in the ventromedial hypothalamus (VMH) tissues (muscle). Addition of bromocrip- mine D2 receptor agonist, has been (7). These neurogenic and metabolic tine to poorly controlled type 2 diabetic approved by the U.S. Food and Drug Ad- changes are consistent with the thrifty patients treated with diet alone, metfor- ministration (FDA) for the treatment of gene hypothesis (8), which proposes that min, sulfonylureas, or thiazolidinediones type 2 diabetes. This centrally acting an- conversion to the obese, insulin-resistant – produces a 0.5 0.7 decrement in HbA1c. tidiabetic agent has a novel mechanism of state during periods of inadequate food Bromocriptine also reduces fasting and action; reduces plasma glucose, triglycer- supply provides a survival advantage. It postmeal plasma free fatty acid (FFA) ide, and FFA levels; and in a prospective is noteworthy that development of the and triglyceride levels. In a 52 double- 1-year study reduced cardiovascular insulin-resistant state during these periods blind, placebo-controlled study in type events. In this review, we will examine of seasonal change precisely mimics the 2 diabetic patients, bromocriptine re- the mechanism of action, pharmacoki- type 2 diabetic state: insulin resistance duced the composite cardiovascular end netic properties, glucose-lowering effi- in muscle and liver, accelerated hepatic point by 40%. The mechanism of the cacy, potential antiatherogenic benefits, glucose production/gluconeogenesis, hy- drug’sbeneficial effect on cardiovascular and safety of Cycloset. perglycemia, adipocyte insulin resistance disease remains to be determined. and increased lipolysis, enhanced fat oxi- Mechanism of action dation, increased plasma FFA and triglyc- Introduction Bromocriptine is unique in that it does eride levels, and obesity. These changes Type 2 diabetes is a chronic metabolic not have a specific receptor that mediates also mimic those observed in people with disorder characterized by insulin resistance, its action on glucose and lipid metabo- the insulin resistance syndrome (5,9). impaired b-cell function, and multiple lism. Rather, its effects are mediated via A large body of evidence implicates other metabolic/endocrine abnormalities resetting of dopaminergic and sympa- endogenous dopaminergic and seroto- (1). Because of its multifactorial pathogen- thetic tone within the CNS (7). Because nergic rhythms in SCN and VMH in the esis, restoration of normoglycemia is diffi- the human brain is not accessible to sam- transition from the insulin-sensitive to cult to achieve and requires multiple pling, much of what we have learned insulin-resistant state. The VMH has antidiabetic medications that have differ- about the mechanism of action of bromo- multiple connections with other hypo- ent mechanisms of action and can be used criptine has been derived from animal thalamic nuclei and plays a pivotal role in in combination to produce an additive studies. modulating autonomic nervous system effect (1,2). Therefore, the development Mammalian species living in the wild function, hormonal secretion, peripheral of antidiabetic agents that have novel have an incredible ability to alter their glucose/lipid metabolism, and feeding mechanisms of action and can be used in metabolism from the insulin-sensitive/ behavior (10–13). combination with currently approved glucose-tolerant state to the insulin- Within the VMH, multiple studies medications for the treatment of type 2 resistant/glucose-intolerant state at exactly have documented that both serotonin diabetes is highly desirable. the right time of the year to survive long and noradrenergic levels and activity are Type 2 diabetic patients are at high periods when food is sparse (rev. in 7). increased during the insulin-resistant risk for atherosclerotic cardiovascular During transition to the insulin-resistant state and decrease to normal with return complications (3). Although hyperglyce- state, basal lipolytic activity increases to to the insulin-sensitive state in animals that mia is a risk factor for coronary artery spare glucose utilization by peripheral undergo seasonal changes in metabolism care.diabetesjournals.org DIABETES CARE, VOLUME 34, APRIL 2011 789 Bromocriptine and type 2 diabetes (14–19). Conversely, dopamine levels are low during the insulin-resistant state and increase to normal following return of the insulin-sensitive state (20,21). Further, se- lective destruction of dopaminergic neu- rons in the SCN causes severe insulin resistance (22), and animal models of non- seasonal obesity (i.e., ob/ob mouse [16], Zucker fatty rat [23], high energy–fed male Sprague-Dawley rats [24]) have re- duced dopamine levels in VMH and lateral hypothalamic nuclei. Chronic infusion of norepinephrine and/or serotonin into the VMH of insulin-sensitive animals causes severe insulin resistance, glucose intoler- ance, and accelerated lipolysis in hamsters and rats (19,25). Conversely, systemic (20,26,27) and intracerebral (28) bromo- criptine administration in insulin-resistant animals leads to a decrease in elevated VMH noradrenergic and serotonergic levels (measured in vivo by microdialysis) with a resultant decline in hepatic glucose production/gluconeogenesis, reduced ad- ipose tissue lipolysis, and improved insu- lin sensitivity. Systemic bromocriptine also inhibits VMH responsiveness to norepinephrine (17), and, conversely, norepinephrine infusion into the VMH antagonizes the beneficial effect of bromo- criptine on glucose tolerance and insulin sensitivity (29). Consistent with these observations in animals, systemic bromo- Figure 1—Proposed mechanism of action of bromocriptine to improve glucose homeostasis and criptine administration improves glyce- insulin sensitivity. HGP, hepatic glucose production; TG, triglyceride. mic control and dyslipidemia without change in body weight in type 2 diabetic and obese nondiabetic humans (29–31). tissues and gastrointestinal tract, hor- biliary route with an elimination half-life The proposed mechanism of action of monal signals, and signals from circulat- of ;6 h. Within the liver, bromocriptine bromocriptine to improve glucose toler- ing metabolites. The net result after all of is extensively metabolized by the cyto- ance is summarized in Fig. 1. these inputs are integrated within the hy- chrome P450 system, specifically CYP3A4. In summary, in vertebrates circadian pothalamus needs not to be circadian in There are some 20–30 metabolites, but rhythms of target tissue response to in- nature. Nonetheless, interventions, such their biologic activity is largely unknown. sulin, i.e., lipolysis, hepatic glucose pro- as bromocriptine, which alter mono- Cycloset differs from traditional bro- duction, and muscle insulin sensitivity, amine neurotransmitter levels within mocriptine formulations, such as Parlodel, are mediated via circadian rhythms within these hypothalamic circadian centers, in its quick release that provides peak the CNS, i.e., the SCN and VMH, and act can exert significant effects on glucose concentrations within 60 min. There is no temporarily to regulate seasonal changes and lipid metabolism. AB-rated equivalent for Cycloset. Cyclo- in metabolism and body fat stores/muscle set comes as 0.8 mg tablets. The starting mass. Pharmacokinetics and dose dose is 0.8 mg/day and can be titrated to How do these circadian rhythms ap- Following ingestion, Cycloset (bromo- a maximum of 4.8 mg/day. Cycloset is ply to humans and what are the impli- criptine mesylate) tablets are rapidly dis- administered as a once daily dose within cations for bromocriptine as a therapy solved and absorbed within 30 min (29). 2 h of awaking. Type 2 diabetic individ- for type 2 diabetes since humans do not