Isotope dilution studies of ketone body (KB) turnover have usually been performed using a single 14C tracer and the so called 'combined KB specific activity'. By definition, this approach does not allow to evaluate the individual kinetics of acetoacetate (AcAc) and 3-hydroxybutyrate (R-BHB) which is feasible only using the separate administration of 14C tracer AcAc and R-BHB. In the present study we followed a different approach using the simultaneous administration in vivo of [1,2,13C2] AcAc and m [1,2,3,4(13)C4] R-BHB which allows to evaluate the individual kinetics of the two KB in the some study, thus minimizing the magnitude of blood sampling and the potential changes in the metabolic conditions of each subject. The four isotopic 13C/12C KB ratios of AcAc and R-BHB tracer and tracee blood concentrations along with the fluorimetric measurement of 12C concentrations were determined in each blood sample. Using compartmental analysis following single dose bolus injection the production rate of KB was 206 +/- 57 mumol/min/1.73 m2 (mean +/- SD). The turnover rate of KB using noncompartmental analysis, during continuous infusion in a separate study was 294 +/- 41. The plasma clearance rates of AcAc and R-BHB were 1966 +/- 502 and 1443 +/- ml/min/1.73 m2, respectively. The mean residence time was 17 +/- 3 min and the total distribution volume 20 +/- 9.7 l/m2. We conclude that: (1) stable isotope tracer infusion allows the contemporary in vivo administration of the two KB and the simultaneous assessment of individual AcAc and R-BHB kinetics; (2) the estimated compartmental and noncompartmental parameters of KB turnover were similar to those observed in normal overnight fasting subjects following separate radioactive tracer injections.

3-Hydroxybutyric Acid↗

PubMedDate not supplied

Impulse response model in reconstruction of insulin secretion by deconvolution: role of input design in the identification experiment.

Insulin secretion rate (ISR) in vivo can be reconstructed by deconvolution of plasma concentration of C-peptide (CP), a peptide co-secreted with insulin but not extracted by the liver and exhibiting linear kinetics. Deconvolution requires the knowledge of the CP impulse response. A two exponential model is usually chosen to describe the CP impulse response but three exponential and one exponential models have also been used. The purpose of this paper is to investigate the role of the CP impulse response model order in reconstructing ISR by deconvolution in three standard physiological/clinical situations: ultradian oscillations, rapid pulses, and biphasic response to a glucose stimulus. By resorting to simulation, we first show that, in each situation, the validity of impulse response models with different orders depends on the input chosen in the impulse response identification experiment. Real data are then used which support the simulation results.

Activity Cycles↗

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Parameter estimation in distributed models of blood-tissue exchange: a Monte Carlo strategy to assess precision.

Distributed parameter models of blood-tissue exchange are increasingly used to interpret multiple tracer dilution data in regional kinetic studies. To derive a measure of the precision with which the model parameters are estimated is therefore of paramount importance. The standard approach to deriving precision of estimates does not take into account the fact that some of the model parameters are fixed. Thus, the precision of parameter estimates is not realistic and, in all likelihood, it is overestimated. The aim of this study is to describe a Monte Carlo method devised to obtain a theoretically sound measure of the precision of estimates, which takes into account both measurement error and the uncertainty associated with the fixed parameters. The fixed parameter values are taken from a probability distribution. By letting the fixed parameters vary according to their distribution, a large number of synthetic datasets is generated. Noise is then added. Estimating the parameters in each of these synthetic datasets allows the derivation of a Monte Carlo mean and standard deviation, which provides a realistic measure of precision. The methodology is illustrated for a simulated data case study dealing with the estimation of the capillary permeability-surface area product in a two tracer experiment.

Animals↗

PubMedDate not supplied

Estimation of blood flow heterogeneity distribution in human skeletal muscle from positron emission tomography data.

Regional blood flow distribution in animal skeletal muscle is markedly uneven at rest and during various physiological states (exercise and hyperemia). It has been hypothesized that the vasodilatory properties of insulin may concur with insulin action on the myocite in determining stimulation of muscle glucose metabolism in vivo. In this study, we developed a method to determine noninvasively both bulk flow and regional flow heterogeneity in human skeletal muscle. Positron emission tomography studies with [15O] water were performed in seven normal subjects, both in the basal state and after 1 hr of euglycemic hyperinsulinemia. Hyperinsulinemia almost doubled skeletal muscle blood flow, but apparently did not affect the relative dispersion, the skewness, or the kurtosis of the flow distribution. However, the regression line between basal and insulin-stimulated flow values showed a nonzero intercept, and the relationship between basal flow and its insulin-stimulated fractional change was hyperbolic. These findings suggest that insulin vasodilated proportionally more the areas with the lowest basal perfusion values. These are the first data to demonstrate that in human skeletal muscle: (i) blood flow is heterogeneous; and (ii) insulin, although doubling muscle bulk flow, does not affect the relative dispersion of its distribution. This result implies that regional redistribution of perfusion is not involved in determining the metabolic response of skeletal muscle to insulin. Yet, since insulin vasodilates proportionally more the less perfused areas, it still exerts an optimizing effect on flow distribution in human muscle.

Adult↗

PubMedDate not supplied

Estimation of beta-cell secretion and insulin hepatic extraction by the minimal modelling technique.

Mathematical models are a necessary tool to quantify physiological processes the direct measurement of which is not possible. Pancreatic beta-cell and liver are respectively the secreting and the major degrading site of insulin. To provide a quantitative description of these processes, we have conceived a method which exploits two minimal mathematical models. By using one model the post-hepatic delivery of insulin into the systemic circulation, IDRT(t), is estimated; the other model yields CPST(t), i.e. the secretion rate of C-peptide, which is equimolarly released by the beta-cell with insulin, but is not degraded by the liver. The estimated C-peptide flow rate into plasma is thus representative of that of pre-hepatic insulin. The difference between CPST(t) and IDRT(t) gives the insulin extraction by the hepatocytes. The parameters of the models are estimated in every single subject from the analysis of glucose, insulin, and C-peptide concentration data measured after an intravenous glucose injection. As an example of its usefulness, the method has been applied in patients with liver cirrhosis and in obese non-diabetic subjects, with the purpose of elucidating which mechanism is responsible for the peripheral dynamic hyperinsulinaemia characteristic of such metabolic states. Because mechanism is responsible for the peripheral dynamic hyperinsulinaemia characteristic of such metabolic states. Because of its relative non-invasiveness compared to other techniques this model-based method should prove useful in several other clinical investigations.

Blood Glucose↗

PubMedDate not supplied

The effect of cyclosporine vs FK 506 on glucose metabolism.

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Adult↗

PubMedDate not supplied

The subcutaneous route to insulin-dependent diabetes therapy.

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Administration, Cutaneous↗

PubMedDate not supplied

A priori identifiability of distributed models of blood-tissue exchange.

A priori identifiability deals with the uniqueness of the solution for the unknown parameters of a dynamic model from a given input-output experiment, and is a prerequisite for well posedness of parameter estimation from the data. Identifiability has been extensively investigated for lumped parameter, linear, and nonlinear dynamic models, in particular, compartmental models of biological systems. Much less attention has been devoted to distributed parameter model, in particular, those describing blood-tissue exchange, which are normally used to interpret regional multiple tracer dilution experiments. In this paper, we study a priori identifiability of distributed parameter models of transcapillary exchange, focusing first on a single capillary (one-region) model, then moving on to a single capillary-interstitial fluid (two-region) model, and finally to an organ model also describing flow heterogeneity.

Capillaries↗

PubMedDate not supplied

Generalized sensitivity functions in physiological system identification.

Parameters of physiological models are commonly associated in an input-output experiment with a specific pattern of the system response. This association is often made on an intuitive basis by traditional sensitivity analysis, i.e., by inspecting the variations of model output trajectories with respect to parameter variations. However, this approach provides limited information since, for instance, it ignores correlation among parameters. The aim of this study is to propose a new set of sensitivity functions, called the generalized sensitivity functions (GSF), for the analysis of input-output identification experiments. GSF are based on information theoretical criteria and provide, as compared to traditional sensitivity analysis, a more accurate picture on the information content of measured outputs on individual model parameters at different times. Case studies are presented on an input-output model and on two structural circulatory and respiratory models. GSF allow the definition of relevant time intervals for the identification of specific parameters and improve the understanding of the role played by specific model parameters in describing experimental data.

Animals↗

PubMedDate not supplied

Estimation of blood flow heterogeneity in human skeletal muscle using intravascular tracer data: importance for modeling transcapillary exchange.

Distributed models of blood-tissue exchange are widely used to measure kinetic events of various solutes from multiple tracer dilution experiments. Their use requires, however, a careful description of blood flow heterogeneity along the capillary bed. Since they have mostly been applied in animal studies, direct measurement of the heterogeneity distribution was possible, e.g., with the invasive microsphere method. Here we apply distributed modeling to a dual tracer experiment in humans, performed using an intravascular (indocyanine green dye, subject to distribution along the vascular tree and confined to the capillary bed) and an extracellular ([3H]-D-mannitol, tracing passive transcapillary transfer across the capillary membrane in the interstitial fluid) tracer. The goal is to measure relevant parameters of transcapillary exchange in human skeletal muscle. We show that assuming an accurate description of blood flow heterogeneity is crucial for modeling, and in particular that assuming for skeletal muscle the well-studied cardiac muscle blood flow heterogeneity is inappropriate. The same reason prevents the use of the common method of estimating the input function of the distributed model via deconvolution, which assumes a known blood flow heterogeneity, either defined from literature or measured, when possible. We present a novel approach for the estimation of blood flow heterogeneity in each individual from the intravascular tracer data. When this newly estimated blood flow heterogeneity is used, a more satisfactory model fit is obtained and it is possible to reliably measure parameters of capillary membrane permeability-surface product and interstitial fluid volume describing transcapillary transfer in vivo.

Blood Flow Velocity↗

PubMedDate not supplied

Estimation of organ transport function for recirculating indicator dilution curves.

The transport function of an indicator through an organ allows the calculation of important physiological parameters, but its estimation, especially in the presence of recirculation, can be difficult. In this paper, we estimate the transport function of 3H-mannitol (an extracellular tracer of glucose) in the human leg skeletal muscle. To do so, an indicator bolus is administered into the femoral artery and its recirculating dilution curves are nonuniformly sampled in both the femoral artery and the femoral vein. A new deconvolution-based method is used to simultaneously estimate the indicator transport function and the organ plasma flow. Subsequently, the indicator mean transit time and distribution volume are calculated. The reliability of the method is assessed by Monte Carlo simulation. The ability to estimate parameters, like mean transit time and extracellular distribution volume, is critical to the study of pathophysiologic states such as diabetes, insulin resistance, and hypertension.

Bias↗

PubMedDate not supplied

Accessible pool and system parameters: assumptions and models.

Quantitative assessment of substrate metabolism from in vivo tracer kinetic data requires a model of the system, i.e., a hypothesis on the structure and functioning of the system. Some fundamentals of modeling important for studying intermediary metabolism in the steady state will be discussed. Accessible pool and system parameters are defined. Although the calculation of accessible pool parameters is structure-free, that of system parameters requires the use of non-compartmental or compartmental structures. Assumptions, bases for choice, and relative merits of these two modeling strategies are discussed. Glucose and leucine metabolism serve as prototypes to illustrate the theoretical points.

Glucose↗

PubMedDate not supplied

Leucine metabolism in man: lessons from modeling.

The metabolism of amino acids is far more complicated than a 1- to 2-pool model, yet, such simple models have been extensively used with many different isotopically labeled tracers to study protein metabolism. A tracer of leucine and measurement of leucine kinetics has been a favorite choice for following protein metabolism. However, administering a leucine tracer and following it in blood will not adequately reflect the complex, multi-pool nature of the leucine system. Using the tracer enrichment of the ketoacid metabolite of leucine, alpha-ketoisocaproate (KIC), to reflect intracellular events of leucine was an important improvement. Whether this approach is adequate to follow accurately leucine metabolism in vivo or not has not been tested. From data obtained using simultaneous administration of leucine and KIC tracers, we developed a 10-pool model of the in vivo leucine-KIC and bicarbonate kinetic system. Data from this model were compared with conventional measurements of leucine kinetics. The results from the 10-pool model agreed best with the simplified approach using a leucine tracer and measurement of KIC enrichment.

Bicarbonates↗