Biomedical subjects

R Hovorka

Publications and source records attributed to R Hovorka.

At least 19 recordsLinked to original sources

PubMed1998

Reproducibility and comparability of insulin sensitivity indices measured by stable-label intravenous glucose tolerance test.

We have investigated the reproducibility of (1) insulin sensitivity (S*I) and glucose effectiveness (S*G) as measured by the stable-label (one compartment) minimal model, and (2) insulin sensitivity (S*Ib), plasma clearance rate (PCR), basal hepatic output (HGOb), and total hepatic glucose output (HGO0-240) as measured by the novel stable-label two compartment model of glucose disappearance during labelled intravenous glucose tolerance test (IVGTT) using 6,6-(2)H-glucose. Ten normal male subjects were studied on two occasions one week apart. Both models provided estimates of all indices with acceptable precision (CV of parameter estimates < or =50%). The within subject CVs of S*I and S*Ib were comparable (17% vs 19%) as were the within subject CVs of S*G and PCR (13% vs 16%). A highly significant linear relationship was observed between S*Ib and S*I (0.303 +/- 0.046 ml kg(-1) min(-1) per mU l(-1) vs 13.04 +/- 1.89 10(-4) min(-1) per mU l(-1), y = 0.0037 x + 0.0002, r = 0.90, p < 0.001; mean +/- SE), but not between PCR and S*G (1.98 +/- 0.15 ml kg(-1) min(-1) vs 0.0089 +/- 0.0005 min(-1), rs = 0.34, NS). The two compartment model provided a plausible time-profile of hepatic glucose output during IVGTT, reproducible estimates of HGOb (1.96 +/- 0.18 mg kg(-1) min(-1), 15%; mean +/- SE, within subject CV), and a highly reproducible HGO0-240 (7%; within subject CV). We conclude that the stable-label (one compartment) minimal model and the stable-label two compartment model provide reproducible estimates of parameters of glucose kinetics in normal subjects. Insulin sensitivity indices estimated by the two models are strongly linearly related.

Adult↗

PubMed1998

CODE: a deconvolution program implementing a regularization method of deconvolution constrained to non-negative values. Description and pilot evaluation.

A regularization method of deconvolution constrained to non-negative values is described. The method gives smooth estimates of the input function whilst providing a feasible fit (in terms of least squares) to measurements. A description of the program CODE (constrained deconvolution) which implements the method is given. A new methodology for a pilot evaluation of deconvolution programs is also proposed. The methodology is based on synthetic data. It employs a variety of shapes of the input function, low (1%) and high (15%) values of the measurement error, and incorporates primary (accuracy) and secondary (bias) performance measures. The performance of CODE is evaluated and it is suggested that CODE provides estimates of the input function with acceptable accuracy.

Data Interpretation, Statistical↗

PubMed1998

Measuring pre-hepatic insulin secretion using a population model of C-peptide kinetics: accuracy and required sampling schedule.

The accuracy of calculations of pre-hepatic insulin secretion were investigated, to provide independent validation of a population model of C-peptide kinetics. The effects of sampling frequency were also assessed. Five normal subjects (aged 28 to 43 years; BMI (kg/m2) 20.5 to 24.5) and five subjects with non-insulin-dependent diabetes mellitus (NIDDM) treated by diet alone (aged 34 to 57 years; BMI 22.6 to 25.6) were given a variable intravenous infusion of biosynthetic human C-peptide (BHCP) (t=-60 to 240 min) mimicking meal stimulated C-peptide secretion, with short-term oscillations (peak approximately every 12 min) superimposed on the infusion profile. Plasma C-peptide was measured every 5 min (t=0 to 240 min). The BHCP infusion was reconstructed from C-peptide measurements using a population model of C-peptide kinetics and a deconvolution method. Bias, defined as the percentage difference between the total amount of calculated BHCP and the total amount of infused BHCP (t=0 to 240 min), indicated that overall C-peptide secretion can be measured with 14% [95% confidence interval (CI) -11 to 39%] and 21% (95% CI -3 to 45%) accuracy in normal subjects and subjects with NIDDM respectively. Accuracy was not reduced by reducing the sampling frequency to every 30 min. The root mean square error, measuring the average deviation between the infused and normalised calculated BHCP profiles, was also independent of the sampling frequency [mean (95% CI) 0.9 (0.3 to 1.6) pmol/kg per min in normal subjects; 1.0 (0.9 to 1.1) pmol/kg per min in subjects with NIDDM]. Deconvolution employing a population model of C-peptide kinetics can be used to estimate postprandial total C-peptide secretion with biases of 14% and 22% respectively in normal subjects and subjects with NIDDM. Plasma C-peptide samples need only be drawn every 30 minutes.

Adult↗

PubMed1998

Preliminary experience of the DIAS computer model in providing insulin dose advice to patients with insulin dependent diabetes.

The Diabetes Advisory System (DIAS) is a model of human glucose metabolism which predicts hourly blood glucose concentrations and provides advice on insulin dose. Its ability to provide appropriate advice was assessed in 20 well-controlled IDDM patients (mean (SD) age 38 (11), duration 17 (9) years; HbA1 8.8 (0.9)%, reference range 5.4-7.6%). Patients recorded blood glucose measurements, insulin dose and food intake for 4 days. These data were used to generate insulin dose advice by both DIAS and a diabetes specialist nurse. Patients were then allocated to follow either DIAS or nurse advice for a further 4 days. There was no significant difference in mean recorded blood glucose values or frequency of reported hypoglycaemia between the DIAS and nurse groups either before or after insulin dose adjustment. The DIAS model, however, generated significantly lower insulin dose advice than the nurse (median (range)% change in insulin dose: DIAS group -13.3% (-25.0 to +11.6) versus nurse group 0% (-8.7 to +2.5), P < 0.05). We conclude that, in the patients studied, DIAS provided insulin dose advice which maintained good short term control of diabetes, despite significant reductions in dose in some cases.

Adult↗

PubMed1998

Using a double blind controlled clinical trial to evaluate the function of a Diabetes Advisory System: a feasible approach?

This paper assesses the feasibility of using a double blind controlled clinical trial to evaluate the function of a decision support system by applying such a design to the evaluation of a Diabetes Advisory System (DIAS). DIAS is based on a model of the human carbohydrate metabolism and is designed an interactive clinical tool, which can be used to predict the effects of changes in insulin dose or food intake on the blood glucose concentration in patients with insulin dependent diabetes. It can also be used to identify risk periods for hypoglycaemia. and to provide advice on insulin dose. The latter feature was evaluated in the present study. We believe double blind controlled clinical trials are prerequisites for clinical application of many decision support systems, and conclude that the present double blind controlled clinical trial is a suitable evaluation method for the function of DIAS.

Adolescent↗

PubMed1998

DIAS-NIDDM--a model-based decision support system for insulin dose adjustment in insulin-treated subjects with NIDDM.

A decision support system has been developed, Diabetes Insulin Advisory System for patients with non-insulin dependent diabetes mellitus (DIAS-NIDDM), assisting in the adjustment of insulin doses in insulin-treated subjects. DIAS-NIDDM uses a causal probabilistic network (CPN) model of carbohydrate metabolism to make stochastic predictions of blood glucose (BG) excursions. The CPN model is an extension of an existing model with an added component representing endogenous insulin secretion. A linear relationship between BG and insulin concentration due to BG stimulated insulin secretion is assumed. Model parameters (pancreatic sensitivity, insulin sensitivity, and time-to-peak of NPH insulin) are estimated by Bayesian probability updating from patient's specific data (food intake, insulin doses, BG measurements) recorded over a period of 4 days. The estimated parameters allow the system to be potentially used as a diagnostic tool to identify abnormalities of carbohydrate metabolism: impaired insulin secretion, insulin resistance and the severity of the impairments. DIAS-NIDDM was used to predict patient-specific BG profiles and advise on insulin doses during a pilot study in eight patients with NIDDM of whom five were treated with insulin. Compared to the administered insulin amount, daily insulin amount advised by DIAS-NIDDM was similar (within 4 U) in three patients, higher by 20% (19 U) in one patient and lower by 40% (18 U) and 50% (11 U) in two patients, respectively. The inter-day coefficient of variation of the daily insulin advice suggests that, at least according to DIAS-NIDDM criteria, day-to-day adjustment of insulin doses is necessary to maintain optimum control.

Computer Simulation↗

PubMed1998

Effect of growth hormone treatment on postprandial protein metabolism in growth hormone-deficient adults.

Growth hormone (GH) treatment of GH-deficient adults increases lean body mass. To investigate this anabolic effect of GH, body composition and postabsorptive and postprandial protein metabolism were measured in 12 GH-deficient adults randomized to placebo or GH treatment. Protein metabolism was measured after an infusion of [1-13C]leucine before and after a standard meal at 0 and 2 mo. After 2 mo, there was an increase in lean body mass in the GH group (P < 0. 05) but no change in the placebo group. In the postabsorptive state, there was increased nonoxidative leucine disappearance (NOLD; a measure of protein synthesis) and leucine metabolic clearance rate and decreased leucine oxidation in the GH group (P < 0.05) but no change in the placebo group. After the meal, there was an increase in NOLD and oxidation in all studies (P < 0.05), but the increase in NOLD, measured as area under the curve, was greater in the GH group (P < 0.05). This study clearly demonstrates for the first time that the increase in protein synthesis in the postabsorptive state after GH treatment of GH-deficient adults is maintained in the postprandial state.

Adult↗

PubMed1998

Pancreatic beta-cell responsiveness during meal tolerance test: model assessment in normal subjects and subjects with newly diagnosed noninsulin-dependent diabetes mellitus.

A model-based method was developed to quantify pancreatic beta-cell responsiveness during a meal tolerance test (MTT). C peptide secretion was related in a linear fashion to glucose concentration, whereas the standard population model was used to derive transfer rate constants of the two compartmental model of C peptide kinetics. Two indexes of pancreatic beta-cell responsiveness were defined: 1) postprandial sensitivity M(I) (ability of postprandial glucose to stimulate beta-cell), and 2) basal sensitivity M0 (ability of fasting glucose to stimulate beta-cell). The method was evaluated using plasma glucose and C peptide measured over 180 min with a 10- to 30-min sampling interval during a MTT (75 g carbohydrates; 500 Cal) performed in 16 normal subjects (7 men and 9 women; age, 50 +/- 10 yr; body mass index, 29.2 +/- 3.6 kg/m2; fasting plasma glucose, 5.1 +/- 0.5 mmol/L; mean +/- SD) and 16 body mass index-matched subjects with newly diagnosed noninsulin-dependent diabetes mellitus (NIDDM; 15 men and 1 woman; age, 50 +/- 9 yr; body mass index, 29.3 +/- 3.7 kg/m2; fasting plasma glucose, 12.6 +/- 3.2 mmol/L). M(I) and M0 indexes were estimated with very good precision (coefficient of variation, < 15%). Subjects with NIDDM demonstrated lower postprandial sensitivity M(I) (17.7 +/- 11.4 vs. 90.0 +/- 43.3 x 10(-9)/min; NIDDM vs. normal, P < 0.001) and basal sensitivity M0 (5.4 +/- 2.2 vs. 10.3 +/- 4.9 x 10(-9)/min; P < 0.005). Deconvolution analysis documented that the relationship between C peptide secretion and glucose concentration is approximately linear during MTT in both normal subjects (plasma glucose range, 5-8 mmol/L) and subjects with NIDDM (12-17 mmol/L). We conclude that pancreatic responsiveness during glucose stimulation (M(I)) and under basal conditions (M0) can be obtained from this novel method during MTT in healthy and disease states.

Adult↗

PubMed1997

DIAS--the diabetes advisory system: an outline of the system and the evaluation results obtained so far.

The present paper gives a description of the Diabetes Advisory System (DIAS), and the evaluation results obtained so far. DIAS is a decision support system for the management of insulin dependent diabetes. The core of the system is a compartment model of the human carbohydrate metabolism implemented as a causal probabilistic network (CPN or Bayesian network), which gives it the ability to handle the uncertainty, for example, in blood glucose measurements or physiological variations in glucose metabolism. The evaluation results suggest that, at least in our hands, DIAS can generate advice that is safe and of a quality that is at least comparable to what is available from experienced clinicians.

Bayes Theorem↗

PubMed1997

Constant infusion and bolus injection of stable-label tracer give reproducible and comparable fasting HGO.

We have investigated the reproducibility of fasting hepatic glucose output (HGO) estimates by use of isotope dilution methodology of stable-label tracers. Six normal subjects were studied on two occasions 1 wk apart. After an overnight fast, the subjects received a bolus injection of 7 mg/kg of [U-13C]glucose and, simultaneously, a primed constant infusion of 0.05 mg.kg-1.min-1 of [6,6(-2)H]glucose. The bolus injection provided one estimate of HGO (HGOBOL), and the constant infusion provided two estimates of HGO, namely, HGO at 2 h (HGOINF2) and HGO at 4 h (HGOINF4), both with the assumption of steady-state conditions. All estimates were similar in value; HGOBOL was highest, followed by HGOINF2 and HGOINF4 [2.30 +/- 0.11 (SE), 2.17 +/- 0.12, and 2.01 +/- 0.13 mg.kg-1.min-1]. The constant infusion gave highly reproducible results. In the case of HGOINF2, the within-subject coefficient of variation (CV) was only 3% compared with 5% of HGOINF4. The reproducibility of HGOBOL was comparable with the within-subject CV of 7%. We conclude that a constant infusion and a bolus injection of stable-label tracer give reproducible and comparable estimates of HGO.

Adult↗

PubMed1996

Quantitative measurement of 3-O-methyl-D-glucose by gas chromatography-mass spectrometry as a measure of glucose transport in vivo.

Existing methods of measuring glucose kinetics are subject to errors. There is considerable interest in improved methods of measuring glucose kinetics to allow the development of new regimes for the treatment of diabetes mellitus. 3-O-Methyl-D-glucose is transported but not metabolized and therefore allows independent estimation of transport parameters. We describe a method by which 3-O-methyl-D-glucose in plasma samples can be measured in protocols during which glucose flux is assessed with simultaneous use of two isotopically labeled glucoses to quantitate and validate measurements of the rate of glucose appearance and disappearance. Quantitative gas chromatographic/mass spectrometric (GC/MS) analysis of 3-O-methyl-D-glucose, D-glucose, D-[U-13C] glucose and D-[6,6-2H2] glucose in human plasma using methoxime-trimethylsilyl ether derivatives is described. Measurements of all four derivatives were performed together in a small sample volume (50 microliters) with high precision. The intra-assay (inter-assay) coefficients of variation at an isotope content of 0.25 atom% excess for D-[6,6-2H2] glucose, D-[U-13C] glucose and 3-O-methyl-D-glucose were 0.8% (1.0%), 0.5% (4.0%) and 0.1% (3.7%), respectively. This method provides the basis for quantitative estimation of parameters of glucose kinetics in man and the rates of glucose flux across the cell membrane.

3-O-Methylglucose↗

PubMed1996

A comparison of six deconvolution techniques.

We present results for the comparison of six deconvolution techniques. The methods we consider are based on Fourier transforms, system identification, constrained optimization, the use of cubic spline basis functions, maximum entropy, and a genetic algorithm. We compare the performance of these techniques by applying them to simulated noisy data, in order to extract an input function when the unit impulse response is known. The simulated data are generated by convolving the known impulse response with each of five different input functions, and then adding noise of constant coefficient of variation. Each algorithm was tested on 500 data sets, and we define error measures in order to compare the performance of the different methods.

Algorithms↗

PubMed1996

Analysing the hypoglycaemic counter-regulation: a clinically relevant phenomenon?

This paper describes an analysis of the temporal relation between episodes of low blood glucose (hypoglycaemia) and counter-regulations, i.e., episodes of elevated blood glucose (hyperglycaemia), in patients with insulin dependent diabetes. The relation was assessed by statistical methods based on a metabolic computer model of the human glucose metabolism. The study material was standard collected clinical data on meals, insulin injections, and measured blood glucose from hospitalised patients. We have found that a typical hypoglycaemic counter-regulation begins 6-8 h after the hypoglycaemia, that it lasts 16-18 h, giving a total duration of 24 h, and that it elevates the blood glucose by 4-10 mmol/l. The phenomenon was demonstrated in the data from more than half of the patients with hypoglycaemic episodes.

Blood Glucose↗

PubMed1996

Use of the DIAS model to predict unrecognised hypoglycaemia in patients with insulin-dependent diabetes.

The Diabetes Advisory System (DIAS) is a model of human glucose metabolism implemented in a causal probabilistic network. It handles data on insulin dose, carbohydrate intake and blood glucose concentration to predict hourly blood glucose concentrations and thus provide an indication of blood glucose values between home blood tests. DIAS was used to predict blood glucose profiles in eight patients with well-controlled insulin-dependent diabetes, who are at increased risk of hypoglycaemia (abnormally low blood glucose levels). DIAS predicted nocturnal hypoglycaemia in six patients and daytime hypoglycaemia in one patient. The occurrence of nocturnal hypoglycaemia was not recognised by the patient or suspected by their doctor but was subsequently confirmed by blood testing in five patients. It is known that unrecognised nocturnal hypoglycaemia is common in patients with well-controlled diabetes. The ability of DIAS to identify such periods of hypoglycaemia with reasonable accuracy illustrates how the advanced technology it employs may provide reliable decision support to clinicians.

Adolescent↗

PubMed1996

ISEC: a program to calculate insulin secretion.

ISEC (Insulin SECretion) is a computer program which calculates pre-hepatic insulin secretion from plasma C-peptide measurements. The program uses a regression (population) model to derive parameters of C-peptide kinetics from subject's gender, type (normal, obese, non-insulin dependent diabetes mellitus), age, weight, and height. Insulin secretion is calculated as a piece-wise constant (step) function with flexible step length allowing for a fine resolution of the secretion profile between measurements. A constrained regularisation method of deconvolution is employed to carry out the calculations. The calculated profile satisfies three properties: (i) it fits the measurement within the given level of the measurement error, (ii) it is non-negative, and (iii) it has a minimum value of a regularisation criterion (norm of second differences) which quantifies the degree of deviation of the secretion profile from a straight line. Both theoretical aspects and specific features related to ISEC are considered. To exemplify the use of ISEC, pre-hepatic insulin secretion is calculated during meal tolerance test, frequently sampled intravenous glucose tolerance test, hyperinsulinaemic euglycaemic glucose clamp, and basal conditions with frequent sampling.

Adult↗

PubMed1996

Acid-base chemistry of the blood--a general model.

This paper describes a general model of acid-base chemistry of the blood which can be used to simulate physiological perturbation of acid-base chemistry on addition or removal of any buffer acid or base. In particular, it is shown how this model can be used to estimate the concentrations of buffer acid or base. In particular, it is shown how this model can be used to estimate the concentrations of buffer acids and bases when blood is equilibrated to a new pCO2, when hydrogen ions H+ are added to the blood, or when two pools of blood with different concentrations of buffer acids and bases are mixed. The ability of the model to represent the addition or removal of any acid or base is a significant increase in functionality above the Siggaard-Andersen nomogram which is limited to simulating the effects of equilibrating the blood to a new pCO2. When used to represent the situation where blood is equilibrated at a new pCO2 the model enables calculation of the amount CO2 removed during equilibration, a further increase in functionality above the Siggaard-Andersen nomogram. In two experimental situations, equilibrating blood to a new pCO2 and addition of H+ ions, the model predictions are shown to be consistent with existing experimental data in the form of the Siggaard-Andersen nomogram.

Acid-Base Equilibrium↗

PubMed1996

Effects of intravenous infusion of lipid-free apo A-I in humans.

Apolipoprotein (apo) A-I is the principal protein component of the plasma high density lipoproteins (HDLs). Tissue culture studies have suggested that lipid-free apo A-I may, by recruiting phospholipids (PLs) and unesterified cholesterol from cell membranes, initiate reverse cholesterol transport and provide a nidus for the formation, via lipid-poor, pre-beta-migrating HDLs, of spheroidal alpha-migrating HDLs. Apo A-I has also been shown to inhibit hepatic lipase (HL) and lipoprotein lipase (LPL) in vitro. To further study its functions and fate in vivo, we gave lipid-free apo A-I intravenously on a total of 32 occasions to six men with low HDL cholesterol (30 to 38 mg/dL) by bolus injection (25 mg/kg) and/or by infusion over 5 hours (1.25, 2.5, 5.0, and 10.0 mg.kg-1.h-1). The procedure was well tolerated: there were no clinical, biochemical, or hematologic changes, and there was no evidence of allergic, immunologic, or acute-phase responses. The 5-hour infusions increased plasma total apo A-I concentration in a dose-related manner by 10 to 50 mg/dL after which it decreased, with a half-life of 15 to 54 hours. Coinfusion of Intralipid reduced the clearance rate. The apparent volume of distribution exceeded the known extracellular space in humans, suggesting extensive first-pass clearance by one or more organs. No apo A-I appeared in the urine. Increases in apo A-I mass were confined to the pre-beta region on crossed immunoelectrophoresis of plasma and to HDL-size particles on size exclusion chromatography. Increases were recorded in HDL PL, but not in HDL unesterified or esterified cholesterol. Increases also occurred in LDL PL and in very low density lipoprotein cholesterol, triglycerides, and PL but not in plasma total apo B concentration. These results can all be explained by combined inhibition of HL and LPL activities. Owing to the effects that this would have had on HDL metabolism, no conclusions can be drawn from these data about the role of lipid-free apo A-I in the removal of PL and cholesterol from peripheral tissues in humans. The kinetic data suggest that the fractional catabolic rate of lipid-free apo A-I exceeds that of spheroidal HDLs and is reduced in the presence of surplus PL.

Aged↗

PubMed1995

Retrospective testing of an insulin advisory system.

A retrospective analysis of the function of adaptive model based consultation system for insulin therapy was performed. The program proved good adaptation ability with improving blood glucose level prediction. In a group of 12 brittle type 1 diabetic patients individual analysis showed problems resulting from retrospective testing of dynamic systems, when treatment is determined only by the physician.

Blood Glucose↗