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PubMed2005

The effect of stimulus duty cycle and "off" duration on BOLD response linearity.

An ongoing question in functional MRI is precisely how measured signal changes relate to neuronal activity. While this question has been probed using animal models and electrophysiologic measures of neuronal activity, it has also been probed by examining, in humans, the spatial location, magnitude, and temporal dynamics of signal changes to well understood stimuli. With regard to dynamics, several earlier studies have revealed a larger than expected response to brief stimuli, hypothesized to result from nonlinearities in either the hemodynamics or the neuronal activity. In this study, we investigate the linearity of the increase in blood oxygenation level dependent (BOLD) contrast as a function of stimulus duty cycle, as well as the linearity of the decrease in BOLD as a function stimulus "off" duration. These findings not only shed further light on the mechanisms behind BOLD contrast but also give practical information as to what to keep in mind when performing and interpreting event related fMRI experiments. These experiments demonstrated: a) the BOLD signal decrease, on stimulus cessation, was smaller than predicted by a linear system--opposite to what has been reported in the literature associated with a signal increase, and b) the deconvolved event-related BOLD signal is highly dependent on duty cycle (the fraction of time activated vs. non-activated), Several potential mechanisms explaining these dynamics are discussed and modeled. We find that the experimental results are most consistent with a nonlinear neuronal response, but do not rule out significant effects of nonlinear hemodynamic factors, in particular the nonlinear relationship between oxygen extraction fraction and blood flow.

Adaptation, Physiological↗
PubMed2002

Mechanisms of active hair bundle motion in auditory hair cells.

Sound stimuli vibrate the hair bundles on auditory hair cells, but the resulting motion attributable to the mechanical stimulus may be modified by forces intrinsic to the bundle, which drive it actively. One category of active hair bundle motion has properties similar to fast adaptation of the mechanotransducer channels and is explicable if gating of the channels contributes significantly to the mechanics of the hair bundle. To explore this mechanism, we measured hair bundle compliance in turtle auditory hair cells under different conditions that alter the activation range of the channel. Force-displacement relationships were nonlinear, possessing a maximum slope compliance when approximately one-half of the transducer channels were open. When the external calcium concentration was reduced from 2.8 to 0.25 mm, the position of maximum compliance was shifted negative, reflecting a comparable shift in the transducer channel activation curve. Assuming that the nonlinearity represents the compliance attributable to channel gating, a single-channel gating force of 0.25 pN was calculated. By comparing bundle displacements with depolarization with and without an attached flexible fiber, the force contributed by each channel was independently estimated as 0.47 pN. These results are consistent with fast active bundle movements resulting from changes in mechanotransducer channel gating. However, several observations revealed additional components of hair bundle motion, with slower kinetics and opposite polarity to the fast movement but also linked to transducer adaptation. This finding argues for multiple mechanisms for controlling hair bundle position in auditory hair cells.

Animals↗
PubMed1986

[Methods of automatic feedback regulation for anesthesia. Concepts and clinical use].

Dosing of drugs used in general anaesthetic practice is largely based on experience and trial-and-error. From the very beginning, anaesthesiological research has always attempted to supply a rational description of the rules governing the dose-response relationship. During the last few decades it became possible to identify pharmacokinetics as a main constituent of the relationship, since the rate of efficacy is primarily governed by the kinetics of the drug and the dose. On the other hand, the complete nonlinearity of the dose-response relationship can be demonstrated by means of a pharmacodynamic model. Control of anaesthesia by pharmacokinetic-dynamic models may be considered satisfactory as long as there is no pronounced scatter of the model parameters within a given population. Closed-loop feedback control is contrasted to feedforward control that attempts to monitor a given variable within a preset range by feeding back a measured signal to the drug delivery system. The present article reviews the experience and application of automatic feedback control systems used in anaesthesia. It was shown in all cases that adaptive, model-based feedback control is superior to non-adaptive methods. Pharmacokinetic and/or pharmacodynamic models were successfully applied to the servocontrol of volatile anaesthetics, intravenous hypnotics and neuromuscular blocking agents. Over and above these three applications, directly related to anaesthesia, the impact of feedback control on the regulation of blood pressure and blood glucose is reviewed.

Anesthesia, General↗
PubMed2002

A study of the effect of non-linearities in the equation of bone remodeling.

In this paper, we introduced a high-order non-linear equation of bone remodeling to combine with FEM by introducing two non-linearities, i.e. the remodeling coefficient B(t) and the order of non-linear remodeling equation. The influence of each non-linearity was tested based on its mechanical and physiological implications discussed. We use two finite element models to investigate the influences of non-linearities in this equation: a plate subjected to a ramp load, and a 2D model of the cross-section of a vertebra. By importing the idea of topology optimization in engineering, their external shapes and internal density distributions were simulated from unfixed configurations. To a certain extent, the high-order non-linear equation of bone remodeling we suggested here can control the remodeling processes of bones in different stages of growth or at different anatomic sites more effectively, and make it more consistent with physiological reality, i.e. express the remodeling characteristic that bone's best morphology is adapted to its mechanical environment. Furthermore, it is likely to describe the process of bone growth and evolution.

Biomechanical Phenomena↗
PubMed2004

Identifying parameter by identical synchronization between different systems.

In this paper, parameters of a given (chaotic) dynamical system are estimated from time series by using identical synchronization between two different systems. This technique is based on the invariance principle of differential equations, i.e., a dynamical Lyapunov function involving synchronization error and the estimation error of parameters. The control used in this synchronization consists of feedback and adaptive control loop associated with the update law of estimation parameters. Our estimation process indicates that one may identify dynamically all unknown parameters of a given (chaotic) system as long as time series of the system are available. Lorenz and Rossler systems are used to illustrate the validity of this technique. The corresponding numerical results and analysis on the effect of noise are also given.

Algorithms↗
PubMed2006

How may anticancer chemotherapy with fluorouracil be individualised?

Fluorouracil is used clinically against various solid tumours. Both fluorouracil toxicity and pharmacokinetics vary highly within and between individuals. The reasons why doses are not individualised routinely are difficulties in defining, predicting and achieving an optimal fluorouracil exposure or dose because of a narrow therapeutic index, nonlinear pharmacokinetics, variabilities in administration rates and metabolism, and in targets like thymidylate synthase. To individualise fluorouracil administration before the first dose, assessment of the individual dihydropyrimidine dehydrogenase (DPD) activity may be useful, because this genetically highly polymorphic enzyme controls approximately 80% of fluorouracil elimination. A complete or partial loss of DPD activity in 0.1 and 3-5% of Caucasians, respectively, leads to increased fluorouracil exposure and toxicity. Several methods to assess DPD activity in patients have been proposed (genotyping, various phenotyping methods), but each of them has limitations, as has the fluorouracil test dose approach. To adapt exposure towards fluorouracil a priori, a combination of genotyping and phenotyping may yield better prediction of toxicity than one method alone. A prerequisite for dose adaptation is the definition of fluorouracil exposure ranges with sufficient therapeutic activity, but without serious toxicity. While an increased risk of leukopenia, diarrhoea, stomatitis, and hand-foot syndrome during continuous 5-day infusions was related to fluorouracil exposures above an area under the plasma concentration-time curve (AUC) threshold of 25-30 mg.h/L, tumour response was higher when an AUC of approximately 30 mg.h/L was achieved, illustrating the extremely narrow therapeutic window of fluorouracil. Pharmacokinetic target values are less clear for other regimens, including chronomodulated regimens, which yielded a superior clinically efficacy and tolerability in several trials. However, the monitoring of fluorouracil plasma concentrations seems principally useful for individual a posteriori dose adjustment. Whether an adaptation of the fluorouracil starting dose to the results of two DPD activity tests before fluorouracil administration a priori, and the adaptation of doses to fluorouracil exposure a posteriori is a reasonable approach to better prevent toxicity and increase efficacy, remains to be evaluated in randomised clinical studies comparing these strategies to routine clinical safety monitoring.

Antimetabolites, Antineoplastic↗
PubMed2003

Corrected small-sample estimation of the Bayes error.

MOTIVATION: A major problem of pattern classification is estimation of the Bayes error when only small samples are available. One way to estimate the Bayes error is to design a classifier based on some classification rule applied to sample data, estimate the error of the designed classifier, and then use this estimate as an estimate of the Bayes error. Relative to the Bayes error, the expected error of the designed classifier is biased high, and this bias can be severe with small samples. RESULTS: This paper provides a correction for the bias by subtracting a term derived from the representation of the estimation error. It does so for Boolean classifiers, these being defined on binary features. Although the general theory applies to any Boolean classifier, a model is introduced to reduce the number of parameters. A key point is that the expected correction is conservative. Properties of the corrected estimate are studied via simulation. The correction applies to binary predictors because they are mathematically identical to Boolean classifiers. In this context the correction is adapted to the coefficient of determination, which has been used to measure nonlinear multivariate relations between genes and design genetic regulatory networks. An application using gene-expression data from a microarray experiment is provided on the website http://gspsnap.tamu.edu/smallsample/ (user:'smallsample', password:'smallsample)').

Algorithms↗
PubMed1994

Neurohumoral mediation of exercise-induced growth.

To assess exercise effects on growth, other variables modulating growth need to be taken into account. Endogenous control of growth proceeds from local actions of growth factors and dependence on nutrition abundance through guidance by growth hormone (GH) and other anabolic hormones to neuroendocrine suppression of growth. Nutrient abundance controls the reparative growth of lean body mass in adulthood by coupling it to anabolic endocrine reflexes. Growth is blocked when catabolic endocrine reflexes govern energy expenditure. The relationship between exercise intensity and growth is nonlinear. Growth is an intermittent process. Its expression and stimulation are dependent on ultradian and circadian rhythms of energy metabolism and neurohumoral release. High-resistance exercise selectively stimulates growth of the musculoskeletal system through expression of growth factor genes in the challenged tissues and without the GH guidance or abundant nutritional support. Habitual endurance exercise stimulates reparative growth of lean body mass through the neuroendocrine adaptations including increased pulsatile GH secretion. These also facilitate oxidative utilization of storage lipids thereby contributing to the regulation of body composition in adulthood. In the absence of sufficient high-resistance and endurance exercise regulation of adult body mass is impaired: excess LBM is lost during energy deficit, and excess fat accumulates during energy surplus.

Adaptation, Physiological↗
PubMedDate not supplied

Muscle-tendon model with length history-dependent activation-velocity coupling.

We developed muscle-tendon models incorporating Hill-type structure and length-dependent coupling between activation and velocity. The models were evaluated in electrically stimulated cat soleus muscles. Dynamic model parameters were estimated by a nonlinear parameter estimation algorithm from input-output data obtained during simultaneous random stimulation and length changes. Static parameters were estimated from the length-tension curve. A model with length history-dependent activation-velocity coupling predicted the behavior of the muscle under a wide variety of conditions, including during random perturbations and during isovelocity movements, where it captured short range stiffness and length history-dependent postyielding behavior. Furthermore, the model predicted twitch responses. The generality of this fixed parameter model makes it especially suitable for simulation and feedforward control, where muscle responses are not available for on-line parameter adaptation.

Animals↗
PubMed2001

Information theoretical evaluation of parametric models of gain control in blowfly photoreceptor cells.

Models are developed and evaluated that are able to describe the response of blowfly photoreceptor cells to natural time series of intensities. Evaluation of the models is performed using an information theoretical technique that evaluates the performance of the models in terms of a coherence function and a derived coherence rate (in bit/s). Performance is gauged against a maximum expected coherence rate determined from the repeatability of the response to the same stimulus. The best model performs close to this maximum performance, and consists of a cascade of two divisive feedback loops followed by a static nonlinearity. The first feedback loop is fast, effectively compressing fast and large transients in the stimulus. The second feedback loop also contains slow components, and is responsible for slow adaptation in the photoreceptor in response to large steps in intensity. Any remaining peaks that would drive the photoreceptor out of its dynamic range are handled by the final compressive nonlinearity.

Adaptation, Ocular↗
PubMed2006

Hemodynamics and autonomic control of heart rate turbulence.

INTRODUCTION: Late heart rate deceleration parallels the increase of systolic blood pressure during heart rate turbulence (HRT) after ventricular premature complexes (VPC). This is consistent with the involvement of baroreflex mechanism. Physiological background of systolic blood pressure dynamics is not known. Enhanced sympathetic activation and nonautonomic post-VPC changes of stroke volume have been speculated on. METHODS AND RESULTS: We studied 28 subjects (aged 56 +/- 11 years; 20 males; 18 normal and 10 abnormal left ventricular (LV) function) with spontaneous occurrence of VPCs. HRT indices and baroreflex sensitivity were analyzed from the ECGs and finger arterial pressure recordings during 30 minutes of spontaneous respiration in supine position. Beat-by-beat stroke volume and peripheral vascular resistance were computed by a nonlinear, self-adaptive model of aortic input impedance (Modelflow, Finapres Medical Systems, Arnhem, The Netherlands). Indices of HRT and baroreflex sensitivity were highly correlated. In patients with preserved LV function, there was no substantial dynamics of stroke volume in the late phase after VPC, while peripheral vascular resistance increased significantly. In patients with impaired LV function, potentiated first sinus beat after VPC triggered transient hemodynamic alternans. Dynamics of peripheral vascular resistance was attenuated and stroke volume was depressed in the late phase after VPC. CONCLUSIONS: Delayed sympathetically mediated vasomotor response to VPC produces systolic blood pressure overshoot. This subsequently induces vagally mediated late heart rate deceleration. Under physiologic conditions, there is no evidence of other hemodynamic and/or mechanical effect outside the autonomic reflex arch. In patients with LV dysfunction, both depressed vagal and sympathetic modulation and, indirectly, enhanced postextrasystolic potentiation account for attenuated HRT.

Analysis of Variance↗
PubMed1976

Response of unmyelinated (C) polymodal nociceptors to thermal stimuli applied to monkey's face.

1. The response of C polymodal nociceptors to thermal and mechanical stimuli applied to the monkey's face was recorded extracellulary in the trigeminal ganglion in rhesus monkeys anesthetized with sodium pentobarbital. Conduction velocities, determined from electrical stimulation of receptive fields (RFs), were in the range for unmyelinated C fibers (mean=0.82 m/s, n=20; SD=+/-0.17). With two exceptions cutaneous RFs were single spots (median=2 mm2; n=37) and usually were identical for thermal and mechanical stimuli. The median force threshold for the sample of units was 1.2 g (von Frey technique; n = 39; range = 0.07-8.5 g). 2. Discharges to thermal stimuli were investigated with a feedback-controlled contact thermode which permitted temperature changes less than or equal 12.0 degrees C/s. Thermal thresholds ranged from 38 degree to 49 degree C (median=46 degrees C; n=37), and maximum discharge frequencies were obtained in the noxious heat range (45-55 degrees C). For a graded series of 5 s duration stimuli from an adapting temperature of 35 degrees C, the number of impulses increased as a monotonic function of stimulus intensity over the range from threshold temperature to 50-53 degrees C. Many stimulus-response functions were positively accelerated, and linear regression analyses showed that most units examined were best fit by nonlinear functions. 3. The typical pattern of activity to 5 s duration temperature shifts into the noxious heat range was a short accelerating burst of impulses followed by deceleration to a lower rate of discharge prior to termination of the stimulus. The temporal profile of the discharge of impulses was virtually identical at different adapting temperatures. In units tested with 30 s duration stimuli at 2-6 degrees C above threshold, the mean frequency of discharge during the final 25 s was 1.46 impulses/s (n=6; SD=+/-0.89). 4. Application of noxious heat stimuli a few degrees above threshold temperature typically sensitized or enhanced the response of the unit to subsequent application of heat stimuli. The signs of sensitization consisted of a decrease in threshold temperature, increased frequency of discharge, decreased latency to the first impulse, and afterdischarges. Units failed to respond throughout the duration of 30 s stimuli if the final temperature exceeded 50 degrees C. Depressed responses were sometimes produced by application of intense (greater than or equal 55 degrees C) stimuli, presumably as a result of partial inactivation of the receptor. 5. In a correlative analysis, the latency and pattern of discharge in a sample of units were compared with escape responses in two monkeys to temperature shifts into the noxious heat range (49 and 51 degrees C). The analysis revealed that the discharge of C polymodal nociceptors alone cannot account for fast escape responses, but the discharge may contribute to escape responses which occur more than 3.5 s after the onset of stimulation.

Adaptation, Physiological↗
PubMed2006

Loss of lag-response curvilinearity of indices of heart rate variability in congestive heart failure.

BACKGROUND: Heart rate variability (HRV) is known to be impaired in patients with congestive heart failure (CHF). Time-domain analysis of ECG signals traditionally relies heavily on linear indices of an essentially non-linear phenomenon. Poincaré plots are commonly used to study non-linear behavior of physiologic signals. Lagged Poincaré plots incorporate autocovariance information and analysis of Poincaré plots for various lags can provide interesting insights into the autonomic control of the heart. METHODS: Using Poincaré plot analysis, we assessed whether the relation of the lag between heart beats and HRV is altered in CHF. We studied the influence of lag on estimates of Poincaré plot indices for various lengths of beat sequence in a public domain data set (PhysioNet) of 29 subjects with CHF and 54 subjects with normal sinus rhythm. RESULTS: A curvilinear association was observed between lag and Poincaré plot indices (SD1, SD2, SDLD and SD1/SD2 ratio) in normal subjects even for a small sequence of 50 beats (p value for quadratic term 3 x 10-5, 0.002, 3.5 x 10-5 and 0.0003, respectively). This curvilinearity was lost in patients with CHF even after exploring sequences up to 50,000 beats (p values for quadratic term > 0.5). CONCLUSION: Since lagged Poincaré plots incorporate autocovariance information, these analyses provide insights into the autonomic control of heart rate that is influenced by the non-linearity of the signal. The differences in lag-response in CHF patients and normal subjects exist even in the face of the treatment received by the CHF patients.

Adaptation, Physiological↗
PubMed2006

Adaptive Q-S (lag, anticipated, and complete) time-varying synchronization and parameters identification of uncertain delayed neural networks.

In this paper, a new type of generalized Q-S (lag, anticipated, and complete) time-varying synchronization is defined. Adaptive Q-S (lag, anticipated, and complete) time-varying synchronization and parameters identification of uncertain delayed neural networks have been considered, where the delays are multiple time-varying delays. A novel control method is given by using the Lyapunov functional method. With this new and effective method, parameters identification and Q-S (lag, anticipated, and complete) time-varying synchronization can be achieved simultaneously. Simulation results are given to justify the theoretical analysis in this paper.

Action Potentials↗
PubMed2000

Temporal frequency deficits in the electroretinogram of the cone system in X-linked retinoschisis.

We investigated the extent of, and basis for, abnormalities in the flicker electroretinogram (ERG) of the cone system of patients with X-linked retinoschisis (XLRS), a form of hereditary vitreoretinal degeneration. ERGs were recorded from six patients with XLRS and from six visually normal subjects using high-contrast sinusoidal flicker that ranged in temporal frequency from 8 to 96 Hz, and that was presented against a rod-desensitizing adapting field. Compared to the control subjects, the patients with XLRS showed a significant reduction in the amplitude of the ERG response fundamental at temporal frequencies of 32 Hz and higher. In addition, their response phases were at or below the lower limits of normal (representing a phase lag) for temporal frequencies greater than 8 Hz. The higher harmonics of the patients' ERG responses to a low frequency stimulus were attenuated over the same temporal frequency range as was the response fundamental. This finding indicates that a major component of the abnormal temporal filtering responsible for the ERG abnormalities in XLRS occurs beyond the level of the early retinal nonlinearity that generates the harmonic components of the ERG response, and therefore is most likely postreceptoral in origin. Consistent with this interpretation, the ERG waveforms of the XLRS patients showed a significant attenuation of the ON-response component, with a normal OFF response. The overall pattern of results suggests that the marked reduction of ERG response amplitudes and the phase lag at the higher temporal frequencies in XLRS stem, at least in part, from a predominant attenuation of the ON-bipolar cell contribution to the flicker ERG.

Adolescent↗
PubMed2001

Contribution of nitric oxide to arterial pressure and heart rate variability in rats submitted to high-sodium intake.

The aim of this study was to determine the contribution of NO to arterial pressure and heart rate variability in normotensive rats subjected to high sodium intake. Arterial pressure, heart rate, and arterial pressure and heart rate variability, baroreflex sensitivity, and pressure responsiveness were measured in male Wistar rats treated for 6 weeks (control and high sodium [1%] intake groups), before and after acute NO synthesis blockade. After treatment, no changes were observed in arterial pressure or heart rate. Arterial pressure variability was increased after sodium intake; however, heart rate variability and baroreflex sensitivity were not modified in high-sodium rats. NO synthase blockade increased arterial pressure in both groups but was higher in the high-sodium group (from 110+/-5 to 162+/-1.5 mm Hg) compared with the control group (from 109+/-6.7 to 144+/-10 mm Hg). The increase in arterial pressure was accompanied by a decrease in heart rate (from 354+/-28 to 303+/-25 bpm in control rats and from 380+/-34 to 298+/-30 bpm in high-sodium rats). NO synthase blockade increased the tachycardic response to sodium nitroprusside in high-sodium rats. Arterial pressure variability, evaluated by a nonlinear method (3D return maps), showed a larger reduction in response to NO synthase inhibition in the high-sodium group (from 162+/-26 to 34.8+/-8.6 for general index of beat-to-beat blood pressure variability) than in the control group (from 58+/-9.6 to 36+/-4.7 for general index of beat-to-beat blood pressure variability). Heart rate variability, evaluated by the SD of the R-R intervals, was not changed in control rats but was increased by NO synthase inhibition in the high-sodium rats (from 9.5+/-0.2 to 21.9+/-1.7 milliseconds). These findings suggest an important role for increased NO production in adaptation to high-sodium intake. The increase in NO system sensitivity in high-sodium intake may contribute to changes in the autonomic nervous system regulating heart rate and, especially, arterial pressure variability.

Animals↗
PubMed1997

Stability and Intermittency in Large-Scale Coupled Oscillator Models for Perceptual Segmentation

The coupled map lattice, a system of locally coupled nonlinear maps, is proposed as a model for perceptual segmentation. Patterns of synchronized activity are obtained in the model from high-dimensional, deterministic chaos. These patterns correspond to segmented topographical mappings of the visual field. The chaotic dynamic has a dual role of contributing to pattern creation in unsynchronized states and of noise revolting against stabilization in synchronized states. The dynamic allows rapid transitions between unsynchronized and synchronized states. Their stability characteristics are explored using analytical tools and numerical simulations. Stability or instability are shown to be determined by network coupling strength, in proportion to the rate of chaotic divergence. The introduction of adaptive connections, in combination with stimulus-controlled oscillation, enables stable or meta-stable patterns of synchronized activity to occur, depending on the perceptual structure in the visual field. For a perceptually ambiguous pattern, the system switches between alternative meta-stable segmentations. The switching-time distribution obtained from the model was found in agreement with those observed in the experimental literature. Copyright 1997 Academic Press. Copyright 1997 Academic Press

Journal Article↗
PubMed2002

Adaptation of ovine fetal pancreatic insulin secretion to chronic hypoglycaemia and euglycaemic correction.

Fetal pancreatic adaptations to relative hypoglycaemia, a characteristic of intra-uterine growth restriction, may limit pancreatic beta-cell capacity to produce and/or secrete insulin. The objective of this study was to measure beta-cell responsiveness in hypoglycaemic (H) fetal sheep and ascertain whether a 5 day euglycaemic recovery period would restore insulin secretion capacity. Glucose-stimulated insulin secretion (GSIS) was measured in euglycaemic (E) control fetuses, fetuses made hypoglycaemic for 14 days, and in a subset of 14-day hypoglycaemic fetuses returned to euglycaemia for 5 days (R fetuses). Hypoglycaemia significantly decreased plasma insulin concentrations in H (0.13 +/- 0.01 ng ml(-1)) and R fetuses (0.11 +/- 0.01 ng ml(-1)); insulin concentrations returned to euglycaemic control values (0.30 +/- 0.01 ng ml(-1)) in R fetuses (0.29 +/- 0.04 ng ml(-1)) during their euglycaemic recovery period. Mean steady-state plasma insulin concentration during the GSIS study was reduced in H fetuses (0.40 +/- 0.07 vs. 0.92 +/- 0.10 ng ml(-1) in E), but increased (P < 0.05) in R fetuses (0.73 +/- 0.10 ng ml(-1)) to concentrations not different from those in the E group. Nonlinear modelling of GSIS showed that response time was greater (P < 0.01) in both H (15.6 +/- 2.8 min) and R (15.4 +/- 1.5 min) than in E fetuses (6.3 +/- 1.1 min). In addition, insulin secretion responsiveness to arginine was reduced by hypoglycaemia (0.98 +/- 0.11 ng ml(-1) in H vs. 1.82 +/- 0.17 ng ml(-1) in E, P < 0.05) and did not recover (1.21 +/- 0.15 ng ml(-1) in R, P < 0.05 vs. E). Thus, a 5 day euglycaemic recovery period from chronic hypoglycaemia reestablished GSIS to normal levels, but there was a persistent reduction of beta-cell responsiveness to glucose and arginine. We conclude that programming of pancreatic insulin secretion responsiveness can occur in response to fetal glucose deprivation, indicating a possible mechanism for establishing, in fetal life, a predisposition to type 2 diabetes.

Adaptation, Physiological↗