Bromocriptine: A Sympatholytic, D2-dopamine Agonist for the Treatment of Type 2 Diabetes

Ralph A. DeFronzo, MD

Disclosures

Diabetes Care. 2011;34(4):789-794. 

In This Article

Mechanism of Action

Bromocriptine is unique in that it does not have a specific receptor that mediates its action on glucose and lipid metabolism. Rather, its effects are mediated via resetting of dopaminergic and sympathetic tone within the CNS.[7] Because the human brain is not accessible to sampling, much of what we have learned about the mechanism of action of bromocriptine has been derived from animal studies.

Mammalian species living in the wild have an incredible ability to alter their metabolism from the insulin-sensitive/glucose-tolerant state to the insulin-resistant/glucose-intolerant state at exactly the right time of the year to survive long periods when food is sparse (rev. in[7]). During transition to the insulin-resistant state, basal lipolytic activity increases to spare glucose utilization by peripheral (muscle) tissues, fat oxidation becomes predominant, and hepatic glucose production and gluconeogenesis rise to supply glucose to the CNS during prolonged periods (seasons) of food deprivation. At the end of the season, animals revert back to their insulin-sensitive/glucose-tolerant state. Such seasonal metabolic changes are characteristic of all migrating birds and hibernating animals and are governed by changes in monoaminergic concentrations/activity in the suprachiasmatic nuclei (SCN) of the hypothalamus—the mammalian circadian pacemaker—and in the ventromedial hypothalamus (VMH).[7] These neurogenic and metabolic changes are consistent with the thrifty gene hypothesis,[8] which proposes that conversion to the obese, insulin-resistant state during periods of inadequate food supply provides a survival advantage. It is noteworthy that development of the insulin-resistant state during these periods of seasonal change precisely mimics the type 2 diabetic state: insulin resistance in muscle and liver, accelerated hepatic glucose production/gluconeogenesis, hyperglycemia, adipocyte insulin resistance and increased lipolysis, enhanced fat oxidation, increased plasma FFA and triglyceride levels, and obesity. These changes also mimic those observed in people with the insulin resistance syndrome.[5,9]

A large body of evidence implicates endogenous dopaminergic and serotonergic rhythms in SCN and VMH in the transition from the insulin-sensitive to insulin-resistant state. The VMH has multiple connections with other hypothalamic nuclei and plays a pivotal role in modulating autonomic nervous system function, hormonal secretion, peripheral glucose/lipid metabolism, and feeding behavior.[10–13]

Within the VMH, multiple studies have documented that both serotonin and noradrenergic levels and activity are increased during the insulin-resistant state and decrease to normal with return to the insulin-sensitive state in animals that undergo seasonal changes in metabolism.[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, selective destruction of dopaminergic neurons in the SCN causes severe insulin resistance,[22] and animal models of nonseasonal 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 adipose 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 bromocriptine administration improves glycemic control and dyslipidemia without change in body weight in type 2 diabetic and obese nondiabetic humans.[29–31] The proposed mechanism of action of bromocriptine to improve glucose tolerance is summarized in Fig. 1.

Figure 1.

Proposed mechanism of action of bromocriptine to improve glucose homeostasis and insulin sensitivity. HGP, hepatic glucose production; TG, triglyceride.

In summary, in vertebrates circadian rhythms of target tissue response to insulin, i.e., lipolysis, hepatic glucose production, and muscle insulin sensitivity, are mediated via circadian rhythms within the CNS, i.e., the SCN and VMH, and act temporarily to regulate seasonal changes in metabolism and body fat stores/muscle mass.

How do these circadian rhythms apply to humans and what are the implications for bromocriptine as a therapy for type 2 diabetes since humans do not manifest these pronounced circadian oscillations/seasonal changes in metabolism? As reviewed by Cincotta and colleagues,[7,29,32] hypothalamic centers (SCN and VMH) that regulate these circadian rhythms not only receive photic inputs via the optic chiasm but also receive input from other centers throughout the CNS, neurogenic stimuli from peripheral tissues and gastrointestinal tract, hormonal signals, and signals from circulating metabolites. The net result after all of these inputs are integrated within the hypothalamus needs not to be circadian in nature. Nonetheless, interventions, such as bromocriptine, which alter monoamine neurotransmitter levels within these hypothalamic circadian centers, can exert significant effects on glucose and lipid metabolism.

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