Shuqin Luo

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

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.

Bromocriptine Reduces Obesity, Glucose Intolerance and Extracellular Monoamine Metabolite Levels in the Ventromedial Hypothalamus of Syrian Hamsters

We examined whether reductions in body fat stores and insulin resistance in Syrian hamsters induced by bromocriptine are associated with reductions in daily norepinephrine (NE) and serotonin activities as indicated by their extracellular metabolite levels in the ventromedial hypothalamus (VMH). High levels of these monoamines within the VMH have been suspected to induce obesity and insulin resistance. Microdialysate samples from the VMH of freely moving obese male hamsters (BW: 208 ± 5 g) were collected hourly over a 25-hour period before bromocriptine treatment, during the first day of and after 2 weeks of bromocriptine treatment (800 µg/animal daily, i.p.), and body composition and glucose tolerance analyses were conducted before and after 2 weeks of treatments. The microdialysate samples were analyzed by HPLC for metabolites of serotonin: 5-hydroxy-indoleacetic acid (5-HIAA), NE: 3-methoxy-4-hydroxy-phenylglycol (MHPG), and dopamine: homovanillic acid (HVA). Bromocriptine treatment for 14 days significantly reduced body fat by 60% and areas under the glucose and insulin curves during a glucose tolerance test by 50 and 46%, respectively. Concurrently, extracellular VMH contents of 5-HIAA, MHPG, and HVA were reduced by 50, 29 and 66%, respectively (p < 0.05). Similarly, VMH 5-HIAA and MHPG contents were 48 and 44% less, respectively (p < 0.05), in naturally glucose-tolerant hamsters compared with naturally glucose-intolerant hamsters. Bromocriptine induced reductions of body fat, and improvements in glucose intolerance may result in part from its ability to decrease serotonin and NE activities in the VMH.

Chronic Ventromedial Hypothalamic Infusion of Norepinephrine and Serotonin Promotes Insulin Resistance and Glucose Intolerance

The ventromedial hypothalamus (VMH) is involved in the regulation of peripheral metabolism. We and others have shown that activities, or extracellular metabolites of norepinephrine (NE) and serotonin (5-HT) are elevated in the VMH of both genetically and seasonally insulin-resistant and glucose-intolerant animals. This study examined whether chronic increases in VMH NE and 5-HT concentration of normal animals might lead to insulin-resistant and glucose-intolerant conditions in hamsters. Euinsulinemic, glucose-tolerant hamsters were infused continuously for 5 weeks into the right VMH with either vehicle, NE (5 or 25 nmol/h), 5-HT (2.5 nmol/h), or NE (5 or 25 nmol/h) plus 5-HT (2.5 nmol/h) through osmotic minipumps. Compared to vehicle, NE (25 nmol/h) significantly increased the glucose total area under the curve (TAUC) by 32% during glucose tolerance tests (GTT) conducted after 5 weeks’ infusion. 5-HT alone significantly increased the GTT insulin TAUC (131%) and basal plasma insulin level (116%) but not glucose TAUC. NE (5 nmol/h) plus 5-HT infusion significantly increased insulin TAUC (129%) and basal plasma insulin (120%), whereas NE (25 nmol/h) plus 5-HT infusion significantly increased both the GTT glucose and insulin TAUC (43 and 113%, respectively), as well as basal plasma insulin level (158%), relative to vehicle infusion. Our findings demonstrate for the first time the differential and, more importantly, interactive effects of increased VMH NE and 5-HT in producing hyperinsulinemia, insulin resistance and glucose intolerance.

Long-term infusion of norepinephrine plus serotonin into the ventromedial hypothalamus impairs pancreatic islet function

To examine the possibility of a cause-effect relationship between enhanced monoamine content in the ventromedial hypothalamus ([VMH] a characteristic of hyperinsulinemic and insulin-resistant animals) and islet dysfunction, we infused norepinephrine ([NE] 25 nmol/h) and/or serotonin ([5-HT] 2.5 nmol/h) into the VMH of normal hamsters for 5 weeks and then examined insulin release from the isolated pancreatic islets. VMH infusion of NE + 5-HT, but not of either neurotransmitter alone, produced a marked leftward shift in the dose-response curve of glucose-induced insulin release (twofold to sixfold increase at 5 to 7.5 mmol/L glucose v vehicle-treated animals). In addition, the islet responsiveness to 1 micromol/L NE and 10 micromol/L acetylcholine was abolished in these NE + 5-HT VMH-infused hamsters. These findings indicate that an increase of NE and 5-HT content in the VMH can induce dysregulation of islet insulin release in response to glucose and neurotransmitters. Inasmuch as VMH NE and 5-HT levels are elevated in hyperinsulinemic and insulin-resistant animals, the present findings suggest that an endogenous increase in these hypothalamic monoamines may contribute to islet dysfunction, which is one of the characteristics of type 2 diabetes.

Dopaminergic neurotoxin administration to the area of the suprachiasmatic nuclei induces insulin resistance.

DOPAMINERGIC neuron neurotoxin (6-hydroxydopamine; 6-OHDA) administration directed to the hypothalamic area of the mammalian pacemaker, the suprachiasmatic nuclei (SCN), was carried out on lean, glucose tolerant hamsters to investigate the possibility that dopaminergic input to the vicinity of the SCN is necessary to maintain this metabolic condition. Glucose tolerance tests (GTT, 3 g glucose/kg) were performed 4 days prior to and 16 days after neurotoxin lesioning. 6OHDA administration to the area of the SCN resulted in both a significant 58% increase in daily food consumption by the 16th day post-lesioning, and a 85% increase in weight gain 4 and 8 weeks after lesioning relative to controls. Such treatment also significantly increased the total areas under the GTT glucose and insulin curves by 48% and 400% respectively, compared with controls. These findings indicate that body weight gain, glucose intolerance and insulin resistance result from decreased dopaminergic input to the area of the SCN.

Suprachiasmatic nuclei monoamine metabolism of glucose tolerant versus intolerant hamsters.

A critical role for temporal organization of dopaminergic and serotonergic activities within the suprachiasmatic nuclei (SCN) in the regulation of peripheral glucose metabolism has been postulated. This study employed in vivo microdialysis to investigate the temporal extracellular profiles of dopamine and serotonin metabolites in the SCN of freely behaving naturally glucose tolerant and intolerant Syrian hamsters. Microdialysis samples from the right SCN of awake, glucose tolerant or intolerant hamsters held on 14 h daily photoperiods were collected every 2 h over a 24 h period and assayed via HPLC for the metabolites of dopamine: homovanillic acid (HVA) and serotonin (5-hydroxyindolacetic acid, 5-HIAA). Among glucose tolerant hamsters, daily rhythms of SCN HVA and 5-HIAA were observed with coincident plateaus throughout the nocturnal phase of the day (both p<0.01). Relative to glucose tolerant hamsters, glucose intolerant animals exhibited a loss in the daily rhythm of SCN HVA (p<0.0001) and 5-HIAA (p<0.02) due to marked reductions (70%) throughout the 24 h period in HVA levels and comparative decreases (35%) in nocturnal peak levels of 5-HIAA. These findings demonstrate that daily profiles of extracellular dopamine and serotonin activities in the SCN, known to influence glucose metabolism, differ between glucose tolerant and intolerant hamsters.

Association of the antidiabetic effects of bromocriptine with a shift in the daily rhythm of monoamine metabolism within the suprachiasmatic nuclei of the Syrian hamster.

Bromocriptine, a dopamine D2 agonist, inhibits seasonal fattening and improves seasonal insulin resistance in Syrian hamsters. Alterations in daily rhythms of neuroendocrine activities are involved in the regulation of seasonal metabolic changes. Changes in circadian neuroendocrine activities that regulate metabolism are believed to be modulated by central circadian oscillators within the hypothalamic suprachiasmatic nuclei (SCN) of seasonal animals. We examined the association of metabolic responses to bromocriptine with its effects on the daily rhythms of metabolic hormones and daily monoamine profiles within the SCN, a primary circadian pacemaker known to regulate metabolism, in Syrian hamsters. Obese glucose-intolerant male Syrian hamsters (body weight [BW] 185 ± 10 g) held on 14h daily photoperiods were treated at light onset with bromocriptine (800 μg/animal/day, ip) or vehicle for 2 weeks. Animals were then subjected to a glucose tolerance test (GTT) (3 g/kg BW, ip). Different subsets of animals (n = 6) from each treatment group were sacrificed at 0h/24h, 5h, 10h, 15h, or 20h after light onset for analyses of SCN monoamines, plasma insulin, prolactin, cortisol, thyroxin (T4), triiodothyronine (T3), glucose, and free fatty acids (FFAs). Compared with control values, bromocriptine treatment significantly reduced weight gain (14.9 vs. −2.9 g, p <. 01) and the areas under the GTT glucose and insulin curves by 29% and 48%, respectively (p <. 05). Basal plasma insulin concentration was markedly reduced throughout the day in bromocriptine-treated animals without influencing plasma glucose levels. Bromocriptine reduced the daily peak in FFA by 26% during the late light span(p <. 05). Bromocriptine significantly shifted the daily plasma cortisol peak from the early dark to the light period of the day, reduced the plasma prolactin (mean 1.8 vs. 39.4 ng/dL) and T4 throughout the day (mean 1.6 vs. 3.8 μg/dL), and selectively reduced T3 during the dark period of the day (p <. 01). Concurrently, bromocriptine treatment significantly reduced SCN dopamine turnover during the light period and shifted daily peaks of SCN serotonin and 5-hydroxy-indoleacetic acid (5-HIAA) content by 12h from the light to the dark period of the day (p <. 05). This was confirmed by a further in vivo microdialysis study in which bromocriptine increased SCN extracellular 5-HIAA of glucose-intolerant hamsters during the dark phase (47% increase, p <. 05) toward levels observed in normal glucose-tolerant hamsters. Thus, bromocriptine-induced resetting of daily patterns of SCN neurotransmitter metabolism is associated with the effects of bromocriptine on attenuation of the obese insulin-resistant and glucose-intolerant condition. A large body of corroborating evidence suggests that such bromocriptine-induced changes in SCN monoamine metabolism may be functional in its effects on metabolism. (Chronobiology International, 17(2), 155–172, 2000)