Bromocriptine: a Sympatholytic, D2-Dopamine Agonist for the Treatment of Type 2 Diabetes

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 neurons 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 reduced 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 intolerance, and accelerated lipolysis in hamsters and rats (19,25). Conversely, systemic (20,26,27) and intracerebral (28) bromocriptine 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 insulin sensitivity. Systemic bromocriptine also inhibits VMH responsiveness to norepinephrine (17), and, conversely, norepinephrine infusion into the VMH antagonizes the beneficial effect of bromocriptine 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 When ingested on an empty stomach, uals are believed to have an early morning manifest these pronounced circadian the maximum plasma concentration is dip in dopaminergic tone, which leads to oscillations/seasonal changes in metab- reached within 60 min. Absorption is de- increased sympathetic activity (25). In olism? As reviewed by Cincotta and col- layed by food and peak plasma levels are vertebrate species circadian plasma pro- leagues (7,29,32), hypothalamic centers achieved at ;120 min in the fed state. lactin levels closely parallel changes in (SCN and VMH) that regulate these circa- There is extensive hepatic first-pass extrac- hypothalamic levels of dopamine and in- dian rhythms not only receive photic in- tion and metabolism, and only 5–10% of sulin sensitivity (rev. in 7 and 32). In lean, puts via the optic chiasm but also receive the ingested dose reaches the systemic cir- normal glucose-tolerant insulin-sensitive input from other centers throughout the culation (33–35). Ninety-eight percent of humans, plasma prolactin concentrations CNS, neurogenic stimuli from peripheral ingested bromocriptine is excreted via the peak at night during sleep. In contrast,

790 DIABETES CARE, VOLUME 34, APRIL 2011 care.diabetesjournals.org DeFronzo obese insulin-resistant individuals have el- during the first, physiologic insulin clamp Phase 3 efficacy trials evated (twofold) day time plasma prolac- step (80 mU/mL), although maximally Four phase 3 trials have evaluated the tin levels (29), consistent with reduced insulin-stimulated (377 mU/mL) glucose efficacy of Cycloset versus placebo in the dopaminergic tone (36). Administration disposal was increased. These results are treatment of type 2 diabetic patients of Cycloset within 2 h of awakening re- consistent with those observed with the (29,40,41). In all studies, Cycloset was duces the elevated prolactin levels insulin suppression test (31) and demon- administered in the morning within 2 h (29,37,38) and is thought to restore dopa- strate that, within the physiologic range of of awaking and individuals with atypical minergic activity, thereby reducing post- hyperinsulinemia, Cycloset does not im- day-night work shifts were excluded from prandial plasma glucose, triglyceride, and prove insulin action in muscle. During study. These four studies included 1) 24- FFA concentrations without increasing the first insulin clamp step, suppression week monotherapy trial (n =159)(29),2) plasma insulin levels (see subsequent dis- of hepatic glucose production was not two 24-week add-on to sulfonylurea trials cussion). enhanced by Cycloset. However, the (n = 494) (30), and 3) 52-week add-on to steady-state plasma insulin concentration, various oral antidiabetic agents trial (41) Mechanism of action—human trials although physiologic for muscle, was far (Table 1). Results of these four studies A number of phase 2 trials have been above that required for half-maximal sup- consistently demonstrated a placebo- performed to examine the mechanism pression of hepatic glucose production, subtracted decline in HbA1c of 0.5– of action of Cycloset. In a small study of making it difficult to ascertain whether 0.7%. Prior to randomization and after 12 nondiabetic obese hyperinsulinemic hepatic insulin sensitivity was enhanced 6 months, type 2 diabetic subjects in the ($20 mU/mL) subjects (38), bromocrip- by insulin. monotherapy and add-on to sulfonylurea tine (1.6 mg/day for 2 weeks) reduced the In a provocative study (39), insulin- studies (29) were admitted to the clinical fasting and postprandial (standardized treated type 2 diabetic subjects were ran- research center for 12 h (7 A.M. to 7 P.M.) meals) glucose levels without change in domized to placebo (n = 11) or Cycloset and received standardized meals for body weight and with a decrease in both (n = 21) (4.8 mg/day) for 12 weeks. Com- breakfast (0700 h), lunch (1200 h), and fasting and postprandial plasma insulin pared with placebo, Cycloset reduced dinner (1700 h). Serum glucose, insulin, ; concentrations by 50% (Supplementary HbA1c by 0.7% and mean plasma glucose FFA, and triglyceride concentrations were Fig. 1). concentration (7 A.M. to 7 P.M.)by8% measured prior to and at 1 and 2 h post- In a similar study, 8 weeks of timed without change in body weight. These re- meal ingestion. Relative to placebo, Cy- bromocriptine reduced day-long plasma sults are consistent with an improvement closet significantly reduced the fasting, glucose, triglyceride, and FFA levels within insulin sensitivity, although the site, i.e., postbreakfast, postlunch, and postdinner out change in body weight and a small liver versus muscle, remains to be defined. glucose concentrations (Supplementary decrease in plasma insulin concentration In a small (n = 17) double-blind, Fig. 4) without change in serum insulin in 13 nondiabetic obese women (Supple- placebo-controlled study (38) in nondia- level or body weight. Cycloset also signif- mentary Fig. 2) (31). Insulin-stimulated betic obese individuals with elevated di- icantly reduced fasting and postmeal se- glucose disposal, measured with the insu- urnal prolactin levels (changes in plasma rum FFA and triglyceride concentrations lin suppression test, was not altered. Since prolactin parallel seasonal changes in in- (Supplementary Fig. 5). the insulin suppression test primarily re- sulin sensitivity and glucose tolerance in In the monotherapy and add-on to flects insulin-mediated glucose disposal vertebrates [7]), Cycloset (1.6–2.4 mg/ sulfonylurea studies, a prespecified analysis in muscle, the improvement in postpran- day) plus a 25% calorie-restricted diet sig- was performed on Cycloset responders dial plasma glucose levels (31) most likely nificantly reduced body weight and body (minimum HbA1c decrease from baseline = reflects enhanced suppression of hepatic fat content compared with placebo plus 0.3% at week 8) versus the entire Cycloset- glucose production by insulin, similar to diet. However, in a larger (n = 387) placebo- treated group (Fig. 2). In monotherapy what has been described in animals (26). controlled 24-week study, Cycloset plus and add-on to sulfonylurea trials, the However, to date, no study has examined diet failed to produce a greater weight loss decrements in HbA1c from baseline hepatic glucose production following than placebo plus diet in obese nondiabetic were 20.65 and 20.63, respectively, and glucose ingestion or in response to a subjects (29). Of interest, a post hoc anal- responders represented 63 and 65% of physiologic increase in plasma insulin ysis revealed that obese subjects with the total Cycloset-treated group (29). concentration in man. The decline in elevated diurnal prolactin levels (who The placebo-subtracted difference in ; postprandial plasma FFA and triglyceride represented 1/4 of the group) lost more HbA1c inresponders was 1%inboth mono- concentrations (32) is similar to observa- weight (5.7 vs. 3.0 kg) than subjects with a therapy and add-on to sulfonylurea trials tions in animals (26,38). normal prolactin rhythm. (Fig. 2). In a 16-week double-blind, placebo- controlled study in 22 obese type 2 diabetic subjects treated with Cycloset for Table 1—Phase 3 Cycloset efficacy trials 16 weeks, HbA1c declined by 1.2%, fasting plasma glucose by 54 mg/dL, and Placebo-subtracted mean plasma glucose during oral glu- Duration Baseline change in cose tolerance test by 46 mg/dL without N (months) HbA (%) HbA (%) P change in plasma insulin concentration, 1c 1c body weight, or percent body fat (30) (Sup- Monotherapy 159 6 8.7 20.56 ,0.02 plementary Fig. 3). During a two-step Add-on to SU 494 6 9.4 20.55 ,0.0001 euglycemic-hyperinsulinemic clamp, there Add-on to various OHAs 3,095 12 8.3 20.6 to 20.9 ,0.01–0.001 was no improvement in insulin sensitivity SU, sulfonylurea. care.diabetesjournals.org DIABETES CARE, VOLUME 34, APRIL 2011 791 Bromocriptine and type 2 diabetes

Efﬁcacy data also are available from a large 52-week randomized, double- blind, placebo-controlled trial in which Cycloset was added to therapy in poorly . controlled (HbA1c 7.5%) type 2 diabetic patients who were taking one to two oral hypoglycemic agents (OHAs) – (41 43). Mean baseline HbA1c was 8.3%, mean age 58 years, mean BMI 33 kg/m2; 63% were male. In type 2 diabetic subjects who completed 24 weeks of treatment and who took $80% of their medication, the placebo-subtracted decrease in HbA1c ranged from 0.6 to 0.9% and was consistent in subjects failing any OHA, failing metformin 6 OHA, failing metformin + sulfonylurea, and failing thiazolidinedione 6 OHA (Supple- mentary Fig. 6) (41–43).

Safety and tolerability In the Cycloset monotherapy and add-on to sulfonylurea trials (29), side effects that occurred more commonly in Cycloset versus placebo were nausea (26 vs. 5%), asthenia (15 vs. 8%), constipation (11 vs. 4%), dizziness (11 vs. 6%), and rhinitis (8 vs. 5%). In general, these side effects were mild and transient. Thirteen percent

Figure 3—Top: Kaplan-Meier plot of time to ﬁrst cardiovascular (MACE) event (myocardial infarction, stroke, and death) in type 2 diabetic subjects treated with Cycloset or placebo for 52 weeks (ref. 41). Bottom: Kaplan-Meier plot of time to ﬁrst cardiovascular event (myocardial infarction, stroke, hospitalization for angina or CHF, coronary revascularization, and death) in 3,070 type 2 diabetic subjects treated with Cycloset or placebo for 52 weeks (ref. 42). CVEs, cardiovascular events.

of Cycloset-treated subjects withdrew be- (41). Mean age was 60 years, mean BMI – 2 cause of adverse events compared with 3 32.4 kg/m , and mean HbA1c 8.3%. Fifty- 5% of placebo-treated subjects (P , seven percent of subjects were male, and 0.01). There was no increase in serious ethnic background was 68% Caucasian adverse events in the Cycloset compared and 17% African American. Cycloset with placebo groups (2.4 vs. 4.3%, re- therapy was initiated at 0.8 mg/day and spectively). There was no difference in titrated to 4.8 mg/day, as tolerated. After the incidence of hypoglycemia between 3 months, alteration in other antidiabetic the Cycloset and placebo-treated groups medications was permitted. — Figure 2 Change in HbA1c in Cycloset (total in any trial. Overall, there were 8.6% serious group) and placebo-treated diabetic subjects. adverse events in the Cycloset group Cycloset responders (defined as a $0.3% de- fi All-cause safety trial and 9.6% serious adverse events in the crease in HbA1c at week 8) had a signi cantly A large (n = 3,070) 52-week, randomized, placebo group (hazard ratio [HR] 0.89, P = greater decline in HbA1c (placebo-subtracted D placebo-controlled (2:1), double-blind NS). Thirty-two diabetic patients (3.2%) HbA1c = 1.0%) than the total group (ref. 29). SU, sulfonylurea. *P , 0.01; **P , 0.001; trial evaluated overall and cardiovascular in the Cycloset group compared with †P , 0.04 for Cycloset responders vs. total Cy- safety of Cycloset in type 2 diabetic pa- 37 patients (1.8%) in the placebo group closet group; ††P , 0.0001 for Cycloset re- tients treated with diet alone, one to two experienced a prespecified cardiovascular sponders vs. placebo. OHAs, or insulin alone or with one OHA event (myocardial infarction, stroke,

792 DIABETES CARE, VOLUME 34, APRIL 2011 care.diabetesjournals.org DeFronzo hospitalization for angina, hospitalization involved in the development of athero- paradigm for the treatment of type 2 di- for congestive heart failure [CHF], coro- sclerosis, as well as multiple circulating abetes mellitus. Diabetes 2009;58:773–795 nary revascularization, and death) (HR cardiovascular risk factors (hyperglyce- 2. Rodbard HW, Jellinger PS, Davidson JA, 0.60, two-sided 95% CI 0.37–0.96, P = mia, hypertriglyceridemia, and elevated et al. Statement by an American Association 0.036) (Fig. 3). Using the major adverse FFA) and hypertension, improve with of Clinical Endocrinologists/American Col- lege of Endocrinology consensus panel on cardiac events (MACE) end point (myo- bromocriptine therapy. At present, it is type 2 diabetes mellitus: an algorithm for cardial infarction, stroke, and death), the unclear whether the salutatory effect of glycemic control. Endocr Pract 2009;15: HR was reduced in the Cycloset compared bromocriptine to reduce cardiovascular 540–559 with placebo-treated subjects (HR 0.45, events (41) is related to the drug’s bene- 3. Rydén L, Standl E, Bartnik M, et al.; Task two-sided 95% CI 0.205–0.996, P , 0.05) ficial effect on any of these pathologic Force on Diabetes and Cardiovascular (Fig. 3). Based on the composite cardiovas- processes/atherosclerotic risk factors. Diseases of the European Society of Car- cular outcome, 79 diabetic patients need to Further mechanistic studies and a large, diology (ESC); European Association for be treated for 1 year to avoid one cardiovas- long-term prospective study will be re- the Study of Diabetes (EASD). Guidelines cular event. quired to establish the mechanism of ac- on diabetes, pre-diabetes, and cardiovas- Adverse events that occurred at a tion and cardiovascular protective benefit cular diseases: executive summary. Eur Heart J 2007;28:88–136 frequency .5% and numerically were of bromocriptine therapy. 4. DeFronzo RA. Insulin resistance, lipo- greater in the Cycloset group included toxicity, type 2 diabetes and atheroscle- nausea (32.2 vs. 7.6%), dizziness (14.8 Summary Both as monotherapy and in combination rosis: the missing links. The Claude vs. 9.2%), fatigue (13.9 vs. 6.7%), head- Bernard Lecture 2009. Diabetologia 2010; with other OHAs, timed bromocriptine – ache (11.4 vs. 8.3%), vomiting (8.1 vs. – 53:1270 1287 3.1%), diarrhea (8.1 vs. 8.0%), and con- (Cycloset) causes a 0.6 0.7% reduction in 5. Reaven GM. Banting Lecture 1988: Role of stipation (5.8 vs. 5.1%). HbA1c and reduces plasma triglyceride insulin resistance in human disease. Di- The mechanism(s) via which timed and FFA concentrations in type 2 dia- abetes 1988;37:1595–1607 bromocriptine reduces cardiovascular betic patients. In a 52-week safety study, 6. Rosenzweig JL, Ferrannini E, Grundy SM, events in type 2 diabetic patients remains Cycloset decreased the cardiovascular et al.; Endocrine Society. Primary pre- to be defined. In the cardiovascular safety composite end point by 40%. Other ad- vention of cardiovascular disease and type vantages of Cycloset include absence of 2 diabetes in patients at metabolic risk: an trial (41), bromocriptine reduced HbA1c P , hypoglycemia since insulin secretion is endocrine society clinical practice guide- by 0.6% ( 0.0001), blood pressure line. J Clin Endocrinol Metab 2008;93: by 2/1 mmHg (P , 0.02), heart rate by not stimulated, weight neutrality, no – need for dose adjustment in patients with 3671 3689 1bpm(P = 0.02), and plasma triglyceride 7. Cincotta AH. Hypothalamic role in the P moderate renal insufficiency, lack of edema Insulin by 0.08 mmol/L ( =0.02).However, fi insulin resistance syndrome. In these changes were modest and seem un- and CHF, and good side effect pro le. Resistance Syndrome. Hansen B, Shaffrir E, likely to explain the 40% decrease in com- Eds. London, Taylor and Francis, 2002, – posite cardiovascular outcome. Although RALPH A. DEFRONZO, MD p. 271 312 “ ” notmeasuredinthesafetytrial,reduc- 8. Neel JV. Diabetes mellitus: a thrifty genotype rendered detrimental by “prog- tions in postprandial FFA levels have From the Diabetes Division, University of Texas ” – Health Science Center, San Antonio, Texas. ress ? Am J Hum Genet 1962;14:353 362 been observed in other trials with bromo- 9. DeFronzo RA, Ferrannini E. Insulin criptine (30,31). In animal studies, bro- Corresponding author: Ralph A. DeFronzo, albarado@ uthscsa.edu. resistance: a multifaceted syndrome re- mocriptine has been shown to attenuate DOI: 10.2337/dc11-0064 sponsible for NIDDM, obesity, hyperten- the effect of CNS sympathetic overactivity This article contains Supplementary Data online at sion, dyslipidemia, and atherosclerotic on the vasculature (44,45), and a direct http://care.diabetesjournals.org/lookup/suppl/ cardiovascular disease. Diabetes Care 1991; inhibitory effect of bromocriptine on doi:10.2337/dc11-0064/-/DC1. 14:173–194 © 2011 by the American Diabetes Association. 10. Morgane PJPJ. Hypothalamic Control mitogen-stimulated proliferation of rat Readers may use this article as long as the work is vascular muscle cells and human aortic ofMmetabolism. New York, Marcel Dekker, properly cited, the use is educational and not for – smooth muscle cells has been demon- profit, and the work is not altered. See http:// 1980, p. 519 555 strated in vitro (46). In the high fat–fed, creativecommons.org/licenses/by-nc-nd/3.0/ for 11. Luiten PG, ter Horst GJ, Steffens AB. The — details. hypothalamus, intrinsic connections and spontaneously hypertensive rat (SHR) outflow pathways to the endocrine sys- an animal model of the insulin resistance — — Acknowledgments R.A.D. has received tem in relation to the control of feeding syndrome and eNOS uncoupling grants from Takeda and Amylin Pharmaceu- and metabolism. Prog Neurobiol 1987;28: bromocriptine reduced pathologically el- ticals and has been a board member of and 1–54 evated endothelial nitric oxide synthase consulted for Takeda, Amylin Pharmaceuticals, 12. Borg MA, Sherwin RS, Borg WP, (eNOS) and inducible NOS (iNOS) levels Isis Pharmaceuticals, and Boehringer Ingelheim. Tamborlane WV, Shulman GI. Local (47). Uncoupled eNOS increases NAD No other potential conflicts of interest relevant ventromedial hypothalamus glucose per- [P]-H oxidase levels, resulting in genera- to this article were reported. fusion blocks counterregulation during Lorrie Albarado (University of Texas Health systemic hypoglycemia in awake rats. J tion of reactive oxygen species and de- – creased nitric oxide production, a potent Science Center, San Antonio, TX) provided ex- Clin Invest 1997;99:361 365 vasodilator and antiatherogenic agent. All pert secretarial assistance in preparation of the 13. Shimazu T. Neuronal regulation of he- manuscript. patic glucose metabolism in mammals. of these biochemical abnormalities were Diabetes Metab Rev 1987;3:185–206 reversed in the aorta of bromocriptine- cccccccccccccccccccccccc 14. Luo SHS, Cincotta AH. Increased daily treated SHR, and aortic stiffness was References turnover of noradrenaline and serotonin markedly reduced. Thus, a number of 1. Defronzo RA. Banting Lecture: From the in the ventral medial hypothalamus (VMH) biochemical/molecular abnormalities triumvirate to the ominous octet: a new of obese versus lean Zucker rats assessed by care.diabetesjournals.org DIABETES CARE, VOLUME 34, APRIL 2011 793 Bromocriptine and type 2 diabetes

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