Intracerebroventricular Administration of Bromocriptine Ameliorates the Insulin-Resistant/Glucose-Intolerant State in Hamsters

Abstract

Bromocriptine, a potent dopamine D₂ receptor agonist, suppresses lipogenesis and improves glucose intolerance and insulin resistance. Recent evidence suggests that bromocriptine may produce these effects by altering central nervous system (CNS) regulation of metabolism. To determine whether or not the CNS plays a critical role in these bromocriptine-mediated effects on peripheral metabolism, we compared the metabolic responses to bromocriptine when administered peripherally versus centrally in naturally obese and glucose intolerant Syrian hamsters. Male hamsters (BW 194 ± 5 g) were treated with bromocriptine or vehicle either intraperitoneally (i.p., 800 µg/animal) or intracerebroventricularly (i.c.v., 1 µg/animal) daily at 1 h after light onset for 14 days while held on 14-hour daily photoperiods. Glucose tolerance tests (GTTs, 3 g glucose/kg BW) were conducted after treatment. Compared to control animals, bromocriptine i.p. significantly reduced weight gain (11.7 vs. –2.4 g) and the areas under the glucose and insulin GTT curves by 29 and 48%, respectively. Similarly, compared with vehicle-treated controls, bromocriptine i.c.v. at 1 µg/animal substantially reduced weight gain (8.7 vs. –6.3 g), the areas under the glucose and insulin GTT curves by 31 and 44% respectively, and the basal plasma insulin concentration by 41% (p < 0.05). Furthermore, both treatments significantly improved insulin-mediated suppression of hepatic glucose production during a hyperinsulinemic-euglycemic clamp. Thus, daily administration of bromocriptine at a very low dose i.c.v. replicates the metabolic effects of bromocriptine administered i.p. at a much higher dose. This finding demonstrates for the first time that the CNS is a critical target of bromocriptine’s metabolic effects.

Effects of Ovariectomy and 17&lt;i&gt;β&lt;/i&gt;-Estradiol Replacement on Dopamine D2 Receptors in Female Rats: Consequences on Sucrose, Alcohol, Water Intakes and Body Weight

“…However, D2 receptors involvement in sucrose intake was not elucidated. On the one hand, previous studies reported that systemic [60] [61] [62] and intracerebral [63] bromocriptine administration in insulin-resistant animals, declined hepatic glucose production and gluconeogenesis, reduced adipose tissue lipolysis, and improved insulin sensitivity [43]. On the other hand, Hajnal et al [15] reported that D2 receptors were involved in heightened sucrose intake observed in the OLETF obese rat.…”

Weighted Effects of Bromocriptine Treatment on Glucose Homeostasis during Hyperglycemic versus Euglycemic Clamp Conditions in Insulin Resistant Hamsters: Bromocriptine as a Unique Postprandial Insulin Sensitizer

“…Body weight and food consumption were recorded during the treatment stage. Such animals of this age, sex and photoperiod exposure have been established to be severely insulin resistant and glucose intolerant [1,2,15]. Animal maintenance and all experimental procedures were conducted in accordance with the National Institute of Health Guide for the Care and Use of Laboratory Animals.…”

“…Euglycemic-hyperinsulinemic and hyperglycemic-hyperinsulinemic clamp study procedures were carried out as described previously [2,16]. Following two weeks of treatment the carotid artery and jugular vein were cannulated under pentobarbital anesthesia.…”

“…Timed daily systemic or intracerebroventricular administration of bromocriptine, a dopamine D2 receptor agonist, to hyperinsulinemic, insulin resistant animals or once daily (morning) systemic administration of bromocriptine-QR, a quick release formulation of bromocriptine to such humans improves fasting hyperinsulinemia and impaired glucose tolerance by simultaneously reducing post glucose challenge plasma glucose and insulin levels [1][2][3][4]. However in these studies, fasting plasma glucose reductions in response to such treatment varied from not at all to moderate depending upon the prevailing glucose level.…”

Association of dopamine D2 receptor polymorphisms Ser311Cys and TaqIA with obesity or type 2 diabetes mellitus in Pima Indians

“…Dopaminergic agonists such as dextroamphetamine and bromocriptine are powerful suppressors of appetite and weight gain, whereas antagonists, such as haloperidol, enhance appetite. 5,6 The anti-obesity drugs fen¯uramineadexfen¯uramine and phentermine may also act, at least indirectly, through the DRD2 receptor. 7,8 Consistent with such a role, dopamine transporter mRNA was found to be increased in the CNS of Zucker faafa rats.…”