Oscillations In Plasma Levels Research Articles

Selection of in-phase or out-of-phase synchronization in a model based on global coupling of cells undergoing metabolic oscillations

On the basis of experimental observations, it has been suggested that glycolytic oscillations underlie the pulsatile secretion of insulin by pancreatic beta cells, with a periodicity of about 13 min. If beta cells within an islet are synchronized through gap junctions, the question arises as to how beta cells located in different islets of Langerhans synchronize to produce oscillations in plasma levels of insulin. We address this question by means of a minimal model that incorporates the secretion of insulin by cells undergoing glycolytic oscillations. Global coupling and synchronization result from the inhibition exerted by insulin on the production of glucose, which serves as the substrate for metabolic oscillations. Glycolytic oscillations are described by a simple two-variable model centered on the product-activated reaction catalyzed by the allosteric enzyme phosphofructokinase. We obtain bifurcation diagrams for the cases in which insulin secretion is controlled solely by the product or by the substrate of the metabolic oscillator. Remarkably, we find that the oscillating cells in these conditions synchronize, respectively, in phase or out of phase. Numerical simulations show that in-phase and out-of-phase synchronization can sometimes coexist when insulin release is controlled by both the substrate and the product of the metabolic oscillator. The results provide an example of a system in which the selection of in-phase or out-of-phase synchronization is governed by the nature of the coupling between the intracellular oscillations and the secretion of the biochemical signal through which the oscillating cells are globally coupled.

Rapid oscillations in plasma insulin, glucagon, and glucose in obese and normal weight humans.

We have previously identified in fasting monkeys large amplitude, rapid oscillations in plasma levels of insulin, glucagon, and glucose. To determine whether such spontaneous oscillations also occur in man, we studied 9 healthy normal weight subjects and 11 obese volunteers (145-316% ideal body weight). During the morning hours after a 16-h fast, peripheral venous blood was withdrawn at precise 1- or 2-min intervals over 40-120 min. Spectral analysis of the assay results showed significant oscillations in plasma levels of insulin and glucose, with periods ranging from 8-16 min (P less than 0.05). In this range, the means of the oscillatory periods in normal weight subjects were 12.1 +/- 1.0 min for insulin and 11.2 +/- 0.8 min for glucose. The oscillatory periods on obese subjects were not different from those in normal weight subjects (12.4 +/- 0.7 min for insulin and 12.1 +/- 0.9 min for glucose). Periodicity in plasma levels of glucagon was observed in the range of 12-23 min. Based on cross-correlation analysis, the periodic fluctuations in insulin, glucose, and glucagon showed no consistent relationships; the patterns observed did not support the presence of feedback loops among these parameters as the mechanism of these spontaneous fluctuations. Our data indicate that basal plasma levels of insulin, glucagon, and glucose fluctuate rapidly in man. The physiological function of these oscillations is yet to be identified; they may play a role in the regulation of responsiveness of the respective target tissues or of their own release into the circulation.

Influence of nutritional state on periodicity in plasma insulin levels in monkeys.

Rapid sustained oscillations in basal plasma levels of insulin, glucose, and glucagon (9-12 min/cycle) have been identified in rhesus monkeys and in humans. To assess the possible regulatory role of nutritional state in the control of these plasma fluctuations, 12 chronically cannulated conscious rhesus monkeys were studied at varying intervals following ingestion of a mixed meal. Blood samples were withdrawn at 2-min intervals for periods of 10-30 min. In the postprandial period both absolute and relative amplitudes (half amplitude percent) of oscillations increased up to 16 h postfeeding to maximal amplitudes of +/- 32% for insulin, +/- 4% for glucose, and +/- 22% for glucagon. Periods were consistently in the 9- to 12-min range for insulin and glucose. Progressive deprivation to 88 h produced decreases in amplitudes and more irregularity in fluctuations but did not affect the underlying periodicity of these oscillations in plasma levels of insulin, glucose, and glucagon. Results are consistent with the existence of one or more inherent oscillators in the pancreas that act to synchronize the release of hormones from particular types of islet cells. The amplitude of these oscillations but not the frequencies is associated with changes in liver metabolism and nutritional state.

Rapid fluctuations in plasma catecholamines in monkeys under undisturbed conditions.

We have demonstrated in monkeys and in man sustained synchronous oscillations in plasma levels of insulin, C-peptide, glucagon, and glucose that have periods ranging from 8 to 11 min. To identify the mechanisms of these oscillations, we studied plasma levels of catecholamines in search for periodic fluctuations. Blood was obtained at 2-min intervals from fasting, undisturbed, chair-adapted male rhesus monkeys via chronically implanted central venous catheters. Plasma levels of epinephrine, norepinephrine, and dopamine were measured by a radioenzymatic assay. Large fluctuations in plasma epinephrine were observed with an average peak-to-trough amplitude of 34 pg/ml at a mean level of 122 pg/ml. Similar fluctuations in norepinephrine and dopamine occurred and were correlated to those of epinephrine: r = 0.51 and 0.35, respectively. The most common periodicity in all three catecholamines was 6-13 min/cycle as determined by spectral analyses. Cross-correlation analyses indicated that fluctuations in the catecholamines were significantly negatively correlated with oscillations in insulin and were unrelated to fluctuations in glucagon. These fluctuations in plasma catecholamines may be related to mechanisms controlling the periodicity observed in plasma insulin and glucose.

Neural influences on oscillations in basal plasma levels of insulin in monkeys.

The effects of cholinergic and adrenergic blocking agents on the period and amplitude of sustained oscillations in plasma levels of insulin and glucose were studied in 16 overnight-fasted conscious rhesus monkeys. Blood samples were withdrawn at 2-min intervals before and during or following administration of drugs that affect neurotransmission. Cholinergic blockade with atropine had no effect on the oscillations. alpha-Adrenergic blockade with phentolamine caused a rise in plasma insulin that lasted less than 10 min and was followed by a slight, although not consistent, decrease in mean insulin and a consistent small decrease in glucose. There was a sustained increase in heart rate, but no effect on the oscillations of insulin or glucose. beta-Adrenergic blockade induced by propranolol led to persistent decreases in mean plasma insulin 60% below the base line, small but variable decreases in glucose, and a sustained decrease in heart rate, but no change in period or relative amplitude of the oscillations in plasma levels of either insulin or glucose. General anesthesia with pentobarbital did not eliminate these oscillations. Our observations on the failure of the blockade of certain putative efferent pathways or depression of higher cortical centers to alter the period of the oscillations of insulin reduce the likelihood that the oscillations are transmitted from a pacemaker in the central nervous system.

Polyethylene glycol 400: Solvent and anticonvulsant?

In drug research, administration of agents with limited water solubility frequently requires the use of solvent systems. Such systems are intended to serve as vehicles and ideally, should not possess intrinsic pharmacological activity at useful doses. For over 30 years, the polymeric glycols have enjoyed widespread use because of their unusual solubility characteristics, low order of toxicity and wide range of compatibilities (1). More often than not, their “inertness” has been assumed rather than tested. In the assessment of anticonvulsant efficacy in our monkey model, drugs are administered by continuous intravenous infusion to circumvent the problems of incomplete bioavailability and oscillations in plasma levels. Polyethylene glycol (PEG) has been used at concentrations of 35 to 65% to solubilize carbamazepine, clonazepam and 3-bromo-n-ethylcinnamamide. In all three studies, PEG was also tested alone to control for its potential efficacy. These controls reveal that this solvent possess a defined spectrum of anticonvulsant activity and toxicity.

Rapid Oscillations in Plasma Levels of Testosterone, Luteinizing Hormone, and Follicle-Stimulating Hormone in Men

A study designed to define the oscillatory pattern of plasma levels of testosterone luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in 4 young adult men was carried out. Blood samples were obtained every 2 minutes for 8 hours from the 3 normal and 1 oligospermic subjects. In each subject a different pattern of changes in hormone levels was found. In Subject 1 the predominant pattern was a slow sinusoidal fluctuation in testosterone levels. In Subject 2 changes in LH levels were the predominant finding. Subject 3 showed irregularly occurring FSH peaks that exceeded the coefficients of variation and which could have been undetected if less frequent sampling had been employed. Subject 4 the oligospermic volunteer demonstrated marked fluctuations in both FSH and LH. His LH levels were the highest and his FSH levels showed a regular sinusoidal pattern with a periodicity of approximately 30 minutes. In all subjects rapid variations in plasma testosterone levels were noted. No correlation was apparent between the levels of the 3 hormones in any of the subjects. It is concluded that although the observations made in the study cast doubt on the present concepts of negative feedback control of the pituitary-testicular axis additional studies are necessary to establish the physiological significance of the rapid oscillations in levels of plasma testosterone LH and FSH.