Albert H. Meier

Bromocriptine improves glycaemic control and serum lipid profile in obese Type 2 diabetic subjects: a new approach in the treatment of diabetes

Bromocriptine, a potent dopamine D(2) receptor agonist, has been shown to reduce insulin resistance, glucose intolerance and hyperlipidaemia in both numerous animal studies and in Phase II studies. Bromocriptine has been used worldwide for over 20 years to treat Parkinsons disease, macroprolactinoma and other disorders; it has been found to be generally safe. We therefore investigated the possible beneficial effects of Ergoset(R) (Ergo Science Corp.), a new quick release formulation of bromocriptine, on glycaemic control and serum lipid profile in obese Type 2 diabetic subjects in two large Phase III studies. A large, randomised, double-blind placebo-controlled study was conducted in which Ergoset was given once daily at 8 am. (4.8 mg maximum dose) for 24 weeks as adjunctive therapy to sulphonylurea (485 subjects) to obese Type 2 diabetics held on a weight- maintaining diet. Treatment efficacy parameters included change from baseline in glycated haemoglobin A(1c) (HbA(1c)), fasting and post-prandial serum glucose, insulin, triglyceride and free fatty acid levels. Baseline glycated haemoglobin, fasting glucose, insulin, triglyceride and free fatty acid levels did not differ between treatment groups. and on average were 9.4 +/- 0.05%, 222 +/- 2 mg/dl, 24 +/- 1 µU/ml, 248 +/- 11 mg/dl, and 850 +/- 32 µEq/l, respectively. A similarly designed study of Ergoset as monotherapy in Type 2 diabetics (154 subjects) with similar baseline clinical characteristics was conducted. Addition of Ergoset treatment to sulphonylurea reduced percent glycated HbA(1c) by 0.55 (P < 0.0001) (approximately 1.0 for responders, 65% of population), fasting and post-prandial glucose by 23 and 26 mg/dl (P < 0.0002), fasting and post-prandial triglycerides by 72 and 63 mg/dl (P < 0.005) and fasting and post-prandial free fatty acids by 150 and 165 µEq/l (P < 0.05), relative to placebo. Twelve percent of all Ergoset subjects, compared to 3% of placebo subjects, withdrew from the study due to adverse events. The most common events causing withdrawal were nausea, dizziness, asthenia, and rhinitis (representing 4.5, 3.3, 2.0, and 0.8% of the total Ergoset populations, respectively). The incidence of serious adverse events did not differ between Ergoset- (3.4%) and placebo- (4.3%) treated subjects. Ergoset as monotherapy also improved glycaemic control (0.56 HbA(1c) decrease relative to placebo after 24 weeks of treatment; P < 0.02). Once daily Ergoset treatment improves glycaemic control and serum lipid profile and is well-tolerated in obese Type 2 diabetics.

Bromocriptine (Ergoset) Reduces Body Weight and Improves Glucose Tolerance in Obese Subjects

OBJECTIVE A double-blind placebo controlled study investigated long-term effects of Ergoset, a new quick release formulation of bromocriptine, on body weight, body fat, and glucose tolerance in a group (n = 17) of obese subjects who were instructed to follow a moderate hypocaloric diet. RESEARCH DESIGN AND METHODS Obese individuals (> 25% body fat for men and > 30% body fat for women) were instructed to follow a calorie-restricted diet (70% of weight maintaining based on study entry weight) and were randomized to daily treatment with Ergoset (1.6–2.4 mg/day) or placebo at 0800 over an 18-week treatment period. Oral glucose tolerance tests were performed on subjects before initiation and again at termination of treatment. Body weight and body fat (determined by skinfold measurements) were quantified every 2 weeks during the course of treatment. RESULTS Ergoset treatment for 18 weeks significantly reduced body weight and body fat versus placebo (6.3 ± 1.5 and 5.4 ± 1.1 kg vs. 0.9 ± 1.0 and 1.5 ± 0.6 kg. respectively, P < 0.01). Ergoset, but not placebo, also improved glucose tolerance (P < 0.02); the stimulated area under the oral glucose tolerance curve was reduced by 46% (from 121 ± 23 to 64 ± 32 mg · h−1 · dl−1), while the stimulated area under the insulin curve was reduced by 30%. CONCLUSIONS When combined with instruction to follow a moderate hypocaloric diet, Ergoset, but not placebo, improves glucose tolerance and promotes significant weight and body fat loss in obese subjects over an 18- week treatment period.

Diurnal variations of metabolic responses to prolactin in lower vertebrates

Abstract Several responses to prolactin are shown to vary diurnally. On 16-hour photoperiods, midday injections induce fattening in the golden topminnow, Fundulus chrysotus, the leopard frog, Rana pipiens, the green anole, Anolis carolinensis, and the white-throated sparrow, Zonotrichia albicollis. Such injections, carried out over a period of 1 week, increase the total body lipid to levels found during the annual cycle when lipid deposits are greatest. Midday injections also promote a catabolic effect in the fish and the bird, and induce nocturnal restlessness in the white-throated sparrow, a nocturnal migrant. On the other hand, early injections (2 hours after the beginning of the photoperiod) cause a loss in fat stores in the fish and the bird and fail to produce nocturnal restlessness in the bird. Early injections, however, promote growth responses (increase in dry nonlipid materials) in all four vertebrates. The fattening and catabolic responses to prolactin injections at midday are still present in unfed fish. The diurnal variation in responses to prolactin offer an explanation for the conflicting and diverse reports regarding the function of prolactin and emphasize the importance of time in understanding the physiology of prolactin.

Diurnal and seasonal variations of plasma adrenal steroid hormone in the white-throated sparrow, Zonotrichia albicollis ☆

Abstract Plasma adrenal steroid hormone in male and female white-throated sparrows, Zonotrichia albicollis , was measured fluorometrically during winter, prenuptial molt, spring migration, and postnuptial molt periods. A diurnal rhythm was found at each period. However, the phase of the rhythm and shape of the curve changed during the course of the annual cycle. Seasonal variation in mean daily levels of plasma adrenal steroid was found also. Adrenal steroid levels were highest in winter and decreased linearly through prenuptial molt, spring migration, and postnuptial molt. These data support the concept that seasonal changes in the phase of diurnal rhythms of hormones are instrumental in regulating seasonal physiological and behavioral conditions.

Diurnal variations of the fattening response to prolactin in the White-throated Sparrow, Zonotrichia albicollis

Abstract Increases in body weight and fat deposits were induced in the photorefactory White-throated Sparrow, Zonotrichia albicollis , by injections of prolactin. The increases in lipid reserves were comparable to photoperiodically induced fattening and to that observed during the migratory seasons. However, the time of injection was of fundamental importance. Daily injections of prolactin at 5 and 10 hours after the beginning of a 16-hour photoperiod were stimulatory to fattening; injections made at 0 and 5 hours after the beginning of the photoperiod suppressed body weight and lipid reserves. These results suggest that the phasing of diurnal rhythms of prolactin release from the pituitary by the photoperiod may be important in regulating the annual cycle of fat stores.

Temporal synergism of corticosterone and prolactin controlling fat storage in the white-throated sparrow, Zonotrichia albicollis☆

Abstract Increases in body fat were induced by daily injections of corticosterone. However, the time of injection is of critical importance. Injections given 6 hr after the onset of a daily photoperiod of 6 hr caused fat increases, whereas injections at 12 or 18 hr after “dawn” were ineffective. In addition to fat increases, injections at 6 hr after “dawn” also induced nocturnal locomotor activity in the white-throated sparrow, a nocturnal migrant. Nocturnal activity was absent in the untreated birds as well as in those receiving corticosterone at 12 or 18 hr after “dawn.” Apparently, the daily variations in responses to corticosterone depend on the circadian release of endogenous pituitary prolactin. In birds kept on continuous light, it was discovered that a temporal synergism of injected corticosterone and injected prolactin can regulate the level of fat stores. Daily injections of prolactin at 4 or 12 hr after corticosterone produced high levels of obesity in lean photorefractory birds after 5 days. Injections at 8 or 20 hr after corticosterone depressed fat stores, and injections at 0 or 16 hr after the adrenal steroid produced intermediate levels of fat. It is concluded that seasonal levels of fat stores are the cumulative results of daily changes that are regulated by a temporal synergism of corticosterone and prolactin.

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.

Temporal Synergism of Corticosterone and Prolactin Controlling Gonadal Growth in Sparrows

Gonadal growth was controlled in two avian species by corticosterone and prolactin injected daily at various times. Testicular growth was induced in photorefractory house sparrows (Passer domesticus) kept in continuous light by prolactin injected 4 or 8 hours after administration of corticosterone. Other temporal patterns were ineffective. Gonadal growth was also stimulated in photosensitive white-throated sparrows (Zonotrichia albicollis) kept in continuous light by prolactin injected 12 hours after administration of corticosterone. Daily injections of prolactin 8 hours after injection of corticosterone inhibited gonadal growth. The seasonal cycle of reproductive photorefractoriness and photosensitivity is controlled by a changing relation between the daily rhythms of plasma concentrations of corticosterone and prolactin.

Seasonal variations in the diurnal rhythm of pituitary prolactin content in the White-throated Sparrow, Zonotrichia albicollis

Abstract Marked diurnal rhythms of pituitary prolactin content occur both in May and in August. However, the phase of the rhythm with respect to the photoperiod differs at the two seasons. In May, the peak occurs at noon, but in August it occurs at midnight. It is concluded that the time of the diurnal release of pituitary prolactin is an important regulator of seasonal physiological and behavioral conditions in the White-throated Sparrow.

Temporal Synergism of Prolactin and Adrenal Steroids in the Regulation of Fat Stores

Summary Daily variations in fattening responses to prolactin may be phased or driven by injections of adrenal steroids in a fish, Fundulus grandis, a lizard, Anolis carolinensis, and a pigeon, Columba livia. Daily injections of prolactin about 24 hr after injections of adrenocortical hormones favor the accumulation of fat stores; whereas daily injections of prolactin 6 hr after the adrenal steroids cause losses in fat. An experiment on the fish indicated that the rhythm of fat responsiveness to prolactin is capable of self-sustaining circadian oscillations on continuous light following initial synchronization by exogenous hydrocortisone. An experiment on the pigeon indicated that a daily rhythm of cropsac sensitivity to prolactin may also be driven by daily injections of corticosterone, but the temporal pattern of the adrenal steroid and prolactin that favors cropsac proliferation is not in the same phase relations with those that favor accumulation of body fat, liver fat, and increases in intestinal weight. It is concluded that a temporal synergism of prolactin and the adrenal steroids is an important organizational unit in the vertebrate system.