https://zenodo.org/record/1259653/files/article.pdf

Hypothalamic-pituitary-adrenal axis, neuroendocrine factors and stress.

Celsus described four of the five cardinal signs of inflammation 2000 years ago, and Eustachio discovered the adrenal glands almost 500 years ago, but not until 1936 did Selye note that in rats exposed to stressors, the adrenal glands were enlarged, and the thymus and lymph nodes shrunken.1–3 Cortisone, the active principle of the adrenal glands, was isolated by Kendall and Reichstein in the late 1940s and shown to suppress immune organs. These scientists, along with Hench, received the Nobel Prize in Physiology and Medicine, after Hench and colleagues showed that cortisone could ameliorate rheumatoid arthritis.4,5 In recent . . .

The Hypothalamic–Pituitary–Adrenal Axis and Immune-Mediated Inflammation

1. In the first part of the paper, the model of non-parametric entrainment of circadian pacemakers is tested for the case of nocturnal rodents. The model makes use of the available data on freerunning period (τ) in constant darkness and on phase response curves (PRC) for short light pulses. It is tested in experiments using 1 or 2 light pulses per cycle. 2. Mesocricetus auratus and Peromyscus leucopus entrain to Zeitgebers involving 1 pulse (15' or 60') per cycle. The phase angle differences between rhythm and light cycle depends on the periods (τ and T) as predicted by the model. Entrainment of P. leucopus is unstable due to the after effects on τ created by the light pulse. 3. The limiting values of Zeitgeber period to which the animals entrain are much closer to 24 h than in Drosophila pseudoobscura, as the model predicts. However, frequent failures to entrain to T = 23 and T = 25 h are only explained if we take considerable interindividual variation in both τ and PRC into account. 4. With 2 pulses per cycle, the model predicts that entrainment will be more stable when activity is in the longer interval between the pulses than when it is in the shorter interval. This is true in the experimental data, where the phase relationships match predictions for skeleton photoperiods up to ca. 14 h. Increasing asymmetry forces animals into a "phase jump", so that activity shifts from the shorter to the longer interval. These ψ-jumps are accurately predicted in the hamster, but they occur at much longer photoperiods than predicted in P. leucopus. 5. Thus, the unqualified model, using a rigidly fixed species τ and PRC, is surely inadequate to explain entrainment. The extent to which variations in τ and PRC-shape, both "spontaneous" and induced by the entrainment process, can be known or inferred restricts the validity of the predictions. Yet we conclude, from a good deal of agreement between experiment and prediction (i), from the close correspondence between complete and skeleton photoperiods (ii), and on behavioural grounds (iii), that non-parametric entrainment by short light signals has a major share in the entrainment of nocturnal rodent rhythms in nature. 6. With these restrictions in mind, we analyse in the second part of the paper how the empirical regularities concerning τ and PRC contribute to the stabilization of the phase angle difference (ψ) between the pacemaker and the external world. Use is made of computer simulations of artificial pacemakers with variable τ and PRC. 7. ψ is most sensitive to instabilities in τ when ¯τ is close to 24 h. Thus the very circadian nature of these pacemakers helps to conserve ψ. Selection pressure for homeostasis of τ has been large in a species (M. auratus) where ¯τ = 24 h. The effect of ψ-instability is further reduced by entrainment with 2 pulses (dawn and dusk), made possible by the PRC's having both an advance and a delay section. 8. To analyze the contributions to ψ-conservation with seasonally changing photoperiod, we have assumed that it is of functional significance to conserve the phase of activity with respect to dusk (nocturnal animals) or to dawn (diurnal animals). We distinguish three contributions of nocturnal pacemaker behaviour to this type of ψ-conservation: increased amplitude of the PRC (i), asymmetry in the PRC, such that the slope of the delay-part is steeper than the slope of the advance-part (ii), and a short freerunning period in DD (iii). 9. A further contribution must derive from parametric effects of light, which are not traceable by the model, but certainly effective in preventing in complete photoperiods the ψ-jump which is seen in skeleton photoperiods. The existence of parametric effects is further demonstrated by the change of τ with light intensity in LL, described by Aschoffs Rule, which presumably reflects differences in PRC-shape between nocturnal and diurnal animals. 10. The paper concludes with an attempt to distinguish the features of circadian clocks that are analytically necessary for entrainment to occur (i), or have functional meaning, either in the measurement of the lapse of time (ii) or in the identification of local time (iii).

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A Functional Analysis of Circadian Pacemakers in Nocturnal Rodents. I. The Stability and Lability of Spontaneous Frequency

▪  The stress response is subserved by the stress system, which is located both in the central nervous system and the periphery. The principal effectors of the stress system include corticotropin-releasing hormone (CRH); arginine vasopressin; the proopiomelanocortin-derived peptides α-melanocyte-stimulating hormone and β-endorphin, the glucocorticoids; and the catecholamines norepinephrine and epinephrine. Appropriate responsiveness of the stress system to stressors is a crucial prerequisite for a sense of well-being, adequate performance of tasks, and positive social interactions. By contrast, inappropriate responsiveness of the stress system may impair growth and development and may account for a number of endocrine, metabolic, autoimmune, and psychiatric disorders. The development and severity of these conditions primarily depend on the genetic vulnerability of the individual, the exposure to adverse environmental factors, and the timing of the stressful events, given that prenatal life, infanc...

Endocrinology of the stress response.

1

Phase response curves for 15′ bright light pulses of four species of nocturnal rodents are described. All show delay phase shifts early in the subjective night, advance shifts in the late subjective night, and relative insensitivity during the subjective day.




2

The broad scatter in measured phase-shifts is largely due to error of measurement: the response of the pacemakers to light stimuli is more accurate than we observe.




3.

Indications are found that the response to a resetting stimulus at a given phase of the rhythm is correlated with the individual\(\bar \tau \) (freerunning period). Fast pacemakers (short\(\bar \tau \)) tend to be more delayed or less advanced by the light than slow pacemakers (long\(\bar \tau \)).




4.

Within individual mice (Mus musculus) the circadian pacemaker adjusts its resetting response to variations in its frequency: when τ is long (induced as after-effect of prior light treatment) light pulses at a defined phase of the oscillation (ct 15) produce smaller delay phase shifts than when τ is short.




5.

Among species there are conspicuous differences in the shape of the phase response curve: where\(\bar \tau \) is long, advance phase shifts are large and delay phase shifts small (Mesocricetus auratus); where\(\bar \tau \) is short, advance shifts are small, and delay shifts are large (Mus musculus;Peromyscus maniculatus).




6.

The functional meaning of the interrelationships of τ and PRC is briefly discussed.

A functional analysis of circadian pacemakers in nocturnal rodents

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

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 P −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.

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

The daily rhythm of plasma corticosteroid concentration was studied in nonhypophysectomized rats and in hypophysectomized rats implanted with beeswax pellets containing ACTH and T4. In the first experiment, male hypophysectomized rats were placed on a 12-h light, 12-h dark cycle (onset of light, 0600 h) with food and water available ad libitum. Beeswax pellets containing 1.5 mg ACTH and 150 micrograms T4 were implanted sc in these rats. Beginning 4 days after the implantation of ACTH and T4, daily rhythms of plasma corticosteroid concentration were detected in these rats on 3 successive days. The injection of sodium pentobarbital (40 mg/kg BW) or atropine sulfate (10 mg/kg BW) ip at 1200 h blocked the expected rise in plasma corticosteroid concentration at 1800 h in both these rats and a group of intact rats. In the second experiment, adrenal innervation was disrupted by spinal cord transection at the T-7 level. L-1-transected rats served as operated controls, and a third group was maintained as unoperated controls. One week after surgery, daily rhythms of plasma corticosteroid concentration were present in both unoperated and L-1 controls (P less than 0.01) but not in the T-7-transected rats. Inasmuch as an extrapituitary mechanism was capable of maintaining adrenocortical rhythmicity in hypophysectomized rats and disruption of adrenal innervation suppressed adrenocortical rhythmicity, it was hypothesized that adrenal innervation may be an extrapituitary mechanism which has a role in adrenocortical rhythmicity.

Adrenal Innervation May Be an Extrapituitary Mechanism Able to Regulate Adrenocortical Rhythmicity in Rats

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 activitie

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

A daily variation in the concentration of plasma corticosteroid hormone is present in hypophysectomized rats implanted with pellets of adrenocorticotropic hormone (ACTH) and thyroxine. Although ACTH is necessary to maintain a functional adrenal, and thyroxine is required to permit the expression of the plasma corticosteroid rhythm, a normal daily variation in plasma corticosteroid concentration does not appear to depend on the periodic release of pituitary hormones. (Endocrinology 98: 1475, 1976)

Albert H. Meier

Papers

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

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

Adrenal Innervation May Be an Extrapituitary Mechanism Able to Regulate Adrenocortical Rhythmicity in Rats

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

Daily Variation in Concentration of Plasma Corticosteroid in Hypophysectomized Rats