Biomedical subjects

Claudio Cobelli

Publications and source records attributed to Claudio Cobelli.

At least 55 records · Page 3Linked to original sources

PubMed2003

Bayesian two-compartment and classic single-compartment minimal models: comparison on insulin modified IVGTT and effect of experiment reduction.

Models describing plasma glucose and insulin concentration of an intravenous glucose tolerance test (IVGTT) allow a noninvasive cost-effective approach to estimate important indexes characterizing the efficiency of glucose-insulin control system, i.e., glucose effectiveness (S(G)) and insulin sensitivity (S(I)). To overcome some limitations of the classic single compartment minimal model (1CMM) of glucose kinetics , a two-compartment Bayesian minimal model (2CBMM) has been recently proposed for the standard IVGTT. This study aims to assess 2CBMM ability to describe the insulin-modified IVGTT (IM-IVGTT) which is the protocol of choice since it allows to study insulinopenic states. Both a full-length IM-IVGTT (240 min) as well as a reduced version (90 min) of it are studied. Results of the maximum a posteriori identification of IM-IVGTT (240 min) in 13 normals agree with those of standard IVGTT, i.e., a 42% decrease (P < 0.002) of S(G) and a 13% increase (P < 0.006) of S(I) with respect to ICMM. When identified from IM-IVGTT (90 min), 2CBMM not only provides S(G) and S(I) estimates 46% lower (P < 0.002) and 41% higher (P < 0.002) than 1CMM ones respectively, but also seems to overcome some limitations of the 240 min-based identification that probably arise because the minimal model is unable to properly account for the hyperglycemic hormonal response taking place in the second half of IM-IVGTT.

Bayes Theorem↗

PubMed2003

Model to assess muscle protein turnover: domain of validity using amino acyl-tRNA vs. surrogate measures of precursor pool.

Current models to measure protein turnover across muscle bed are based on many surrogate measures of amino acyl-tRNA. We measured muscle protein turnover based on tracer-to-tracee ratios of the stable isotopes of leucine, phenylalanine, and ketoisocaproate (KIC) in artery and vein and muscle amino acyl-tRNA and muscle tissue fluid (TF) in 26 healthy subjects. A three-compartment model calculation based on arteriovenous and tRNA measurements was first performed and its domain of validity assessed. The results were then compared with those using simpler approaches based on surrogate measures of tRNA such as those of TF and KIC and a one-compartment model based on arteriovenous amino acids. In 96% of cases, the model using tRNA was applicable, but only in a lower percentage of cases were the results using surrogate measures applicable. Protein breakdown, protein synthesis, and shunting of amino acids from artery to vein were consistently underestimated, and fluxes of amino acid from artery to intracellular compartment and from intracellular compartment to vein were overestimated, when surrogate measures were used. The one-compartment model also underestimated protein breakdown and synthesis. Measurements using tissue fluid gave results closer to those based on tRNA. In conclusion, a three-compartment model using arteriovenous samples and amino acyl-tRNA provides measurements of muscle protein turnover of acceptable precision in 96% of cases. The precision was unacceptable in a substantial percentage of cases, and the accuracy of the estimation of protein fluxes was significantly affected when surrogate measures were used.

Adult↗

PubMed2003

Use of a novel triple-tracer approach to assess postprandial glucose metabolism.

Numerous studies have used the dual-tracer method to assess postprandial glucose metabolism. The present experiments were undertaken to determine whether the marked tracer nonsteady state that occurs with the dual-tracer approach after food ingestion introduces error when it is used to simultaneously measure both meal glucose appearance (R(a meal)) and endogenous glucose production (EGP). To do so, a novel triple-tracer approach was designed: 12 subjects ingested a mixed meal containing [1-(13)C]glucose while [6-(3)H]glucose and [6,6-(2)H(2)]glucose were infused intravenously in patterns that minimized the change in the plasma ratios of [6-(3)H]glucose to [1-(13)C]glucose and of [6,6-(2)H(2)]glucose to endogenous glucose, respectively. R(a meal) and EGP measured with this approach were essentially model independent, since non-steady-state error was minimized by the protocol. Initial splanchnic glucose extraction (ISE) was 12.9% +/- 3.4%, and suppression of EGP (EGPS) was 40.3% +/- 4.1%. In contrast, when calculated with the dual-tracer one-compartment model, ISE was higher (P < 0.05) and EGPS was lower (P < 0.005) than observed with the triple-tracer approach. These errors could only be prevented by using time-varying volumes different for R(a meal) and EGP. Analysis of the dual-tracer data with a two-compartment model reduced but did not totally avoid the problems associated with marked postprandial changes in the tracer-to-tracee ratios. We conclude that results from previous studies that have used the dual-tracer one-compartment model to measure postprandial carbohydrate metabolism need to be reevaluated and that the triple-tracer technique may provide a useful approach for doing so.

Adult↗

PubMed2003

Glucose transport and phosphorylation in skeletal muscle in obesity: insight from a muscle-specific positron emission tomography model.

A controversial area in understanding the contribution of obesity to skeletal muscle insulin resistance is the distribution of control of glucose metabolism across proximal steps of glucose delivery, trans-membrane transport, and intracellular trapping via phosphorylation. Dynamic positron emission tomography (PET) imaging of skeletal muscle [(18)F]2-deoxy-2-D-glucose ((18)F-FDG) uptake provides an in vivo method for assessment of these steps in humans. In the current study we have examined the application of a four-compartment skeletal muscle-specific model for assessment of (18)F-FDG metabolism that takes interstitial (18)F-FDG kinetics into account and compared this to the classic three-compartment model in lean and obese volunteers. We assessed the effects of insulin infusions at three rates (0, 40, and 120 mU/m(2).min). In comparison with the classic model, the skeletal muscle-specific model reveals more clearly definable effects of insulin on transmembrane glucose transport and an impairment of this response in obesity. Compared with the classic model for assessment of (18)F-FDG metabolism, both the skeletal muscle-specific and the classic model indicate that, with respect to distribution of control, glucose phosphorylation has an important effect at low to moderate levels of insulin stimulation in both lean and obese subjects.

Biological Transport↗

PubMed2003

L-arginine-nitric oxide kinetics in normal and type 2 diabetic subjects: a stable-labelled 15N arginine approach.

Defective endothelium is a key event in the development of atherosclerosis in diabetes: alteration of the L-arginine-nitric oxide (NO) pathway has been suggested. We propose a modeling approach of the L-arginine-NO pathway in vivo in both control and type 2 diabetic subjects based on the intravenous bolus injection of L-[(15)N]arginine and subsequent noncompartmental and compartmental model analysis of L-[(15)N] arginine in plasma and [(15)N]nitrate in the urine. No differences in arginine kinetics were observed between normal subjects and diabetic patients. [(15)N]nitrates were detectable up to 48 h from the L-(15)[N]arginine administration; no differences were found in the tracer-to-tracee ratio in each urine collection. However, the NO synthesis in plasma from arginine was lower (P = 0.05 for the noncompartmental and 0.1208 for the compartmental analysis, by Mann-Whitney test) in diabetic patients than in control subjects when expressed both in absolute terms (50% decrease) and as percentage of NO turnover (30% decrease). This new modeling approach of L-arginine-NO pathway provides a detailed picture of arginine kinetics and nitrate metabolism. From our data, it appears that noncomplicated type 2 diabetic patients have a decreased conversion of arginine to NO.

Arginine↗

PubMed2003

Weight loss-induced plasticity of glucose transport and phosphorylation in the insulin resistance of obesity and type 2 diabetes.

We tested the hypothesis that weight loss alleviates insulin resistance in skeletal muscle within the proximal steps of glucose metabolism, namely substrate delivery, glucose transport, and glucose phosphorylation. In obese subjects with and without type 2 diabetes, in vivo skeletal muscle assessments were obtained with dynamic positron emission tomography (PET) imaging performed during euglycemic clamps at moderate hyperinsulinemia (40 mU x min(-1) x m(-2)), using [(15)O]H(2)O and [(18)F]fluoro-deoxyglucose ([(18)F]FDG) to quantify tissue perfusion and glucose metabolism. Dynamic [(18)F]FDG PET data were analyzed using both a novel muscle-specific compartmental model and a compartmental model originally developed for the brain and often used for [(18)F]FDG muscle image quantification. Weight loss in obese subjects with (n = 9) and without (n = 9) type 2 diabetes over a 4-month intervention was substantial (14 +/- 2 kg, P < 0.05). Muscle insulin resistance, assessed by insulin-stimulated [(18)F]FDG uptake, decreased threefold in diabetic subjects and twofold in nondiabetic subjects (P < 0.001). Kinetic parameters for [(18)F]FDG transport and phosphorylation improved substantially in both groups, whereas tissue blood flow did not change. In particular, clinically significant weight loss fully corrected insulin resistance in type 2 diabetes at the step of glucose phosphorylation and largely, but incompletely, corrected insulin resistance at the glucose transport step.

Biological Transport↗

PubMed2003

Mechanisms of the age-associated deterioration in glucose tolerance: contribution of alterations in insulin secretion, action, and clearance.

Glucose tolerance decreases with age. For determining the cause of this decrease, 67 elderly and 21 young (70.1 +/- 0.7 vs. 23.7 +/- 0.8 years) participants ingested a mixed meal and received an intravenous injection of glucose. Fasting glucose and the glycemic response above basal were higher in the elderly than in the young participants after either meal ingestion (P < 0.001) or glucose injection (P < 0.01). Insulin action (Si), measured with the meal and intravenous glucose tolerance test models, was highly correlated (r = 0.72; P < 0.001) and lower (P <or= 0.002) in the elderly than in the young participants. However, when adjusted for differences in percentage body fat and visceral fat, Si no longer differed between groups. When considered in light of the degree of insulin resistance, all indexes of insulin secretion were lower (P < 0.01) in the elderly participants, indicating impaired beta-cell function. Hepatic insulin clearance was increased (P < 0.002), whereas total insulin clearance was decreased (P < 0.002) in the elderly subjects. Multivariate analysis (r = 0.70; P < 0.001) indicated that indexes of insulin action (Si) and secretion (Phi(total)) but not age, peak oxygen uptake, fasting glucose, degree of fatness, or hepatic insulin clearance predicted the postprandial glycemic response. We conclude that the deterioration in glucose tolerance that occurs in healthy elderly subjects is due to a decrease in both insulin secretion and action with the severity of the defect in insulin action being explained by the degree of fatness rather than age per se.

Adult↗

PubMed2002

The hot IVGTT two-compartment minimal model: an improved version.

The two-compartment minimal model (2CMM) interpretation of a labeled intravenous glucose tolerance test (IVGTT) is a powerful tool to assess glucose metabolism in a single individual. It has been reported that a derived 2CMM parameter describing the proportional effect of glucose on insulin-independent glucose disposal can take physiologically unplausible negative values. In addition, precision of 2CMM parameter estimates is sometimes not satisfactory. Here we resolve the above issues by presenting an improved version of 2CMM that relies on a new assumption on the constant component R(d0) of insulin-independent glucose disposal. Here R(d0) is not fixed to 1 mg x kg(-1) x min(-1) but instead is expressed as a fraction of steady-state glucose disposal. The new 2CMM is identified on the same stable labeled IVGTT data base on which the original 2CMM was formulated. A more reliable insulin-independent glucose disposal portrait is obtained while that of insulin action remains unchanged. The new 2CMM also improves the precision with which model parameters and metabolic indexes are estimated.

Diabetes Mellitus↗

PubMed2002

WINSTODEC: a stochastic deconvolution interactive program for physiological and pharmacokinetic systems.

Deconvolution allows the reconstruction of non-accessible inputs (e.g. hormone secretion rate) from their causally-related measurable effects (e.g. hormone plasma concentration). Deconvolution is challenging under several aspects both general (e.g. determination of a suitable trade-off between data fit and solution smoothness in order to contrast ill-conditioning, assessment of the confidence intervals) as well as specific of physiological systems (e.g. non-uniform and infrequent data sampling). Recently, a stochastic regularization approach has been proposed and validated to handle these difficulties (De Nicolao et al., Automatica 33 (1997) 851-870). In this paper, an interactive program, WINSTODEC, is presented to allow the clinical investigator to easily obtain the solution of a deconvolution problem by this approach.

Humans↗

PubMed2002

A Bayesian approach to estimate evoked potentials.

Several approaches, based on different assumptions and with various degree of theoretical sophistication and implementation complexity, have been developed for improving the measurement of evoked potentials (EP) performed by conventional averaging (CA). In many of these methods, one of the major challenges is the exploitation of a priori knowledge. In this paper, we present a new method where the 2nd-order statistical information on the background EEG and on the unknown EP, necessary for the optimal filtering of each sweep in a Bayesian estimation framework, is, respectively, estimated from pre-stimulus data and obtained through a multiple integration of a white noise process model. The latter model is flexible (i.e. it can be employed for a large class of EP) and simple enough to be easily identifiable from the post-stimulus data thanks to a smoothing criterion. The mean EP is determined as the weighted average of the filtered sweeps, where each weight is inversely proportional to the expected value of the norm of the correspondent filter error, a quantity determinable thanks to the employment of the Bayesian approach. The performance of the new approach is shown on both simulated and real auditory EP. A signal-to-noise ratio enhancement is obtained that can allow the (possibly automatic) identification of peak latencies and amplitudes with less sweeps than those required by CA. For cochlear EP, the method also allows the audiology investigator to gather new and clinically important information. The possibility of handling single-sweep analysis with further development of the method is also addressed.

Bayes Theorem↗

PubMed2002

Comparison of insulin sensitivity and glucose effectiveness determined by the one- and two-compartment-labeled minimal model in late prepubertal children and early adolescents.

Multiple methods are used to determine insulin sensitivity. Most commonly used in children are euglycemic-hyperinsulinemic clamp and frequently sampled intravenous glucose tolerance (FSIVGTT) with minimal modeling (MinMod). The parameters S(G) and S(I) of MinMod are related to insulin sensitivity and glucose effectiveness, respectively, but inappropriate modeling of glucose kinetics causes inaccuracies. Glucose tracer use may mitigate such inaccuracies, allowing use of multiple modeling approaches, including a 2-compartment model (2CMM). This study was designed to compare the 1-compartment model (1CMM) and 2CMM in a pediatric population. Twenty-three children were studied 4 times using FSIVGTT with [6,6] D(2) glucose. Glucose effectiveness and insulin sensitivity were calculated by 1CMM (S*(G1) and S*(I1)) and 2CMM (S*(G2) and S*(I2)). Indices were reliably estimated in 86 of 87 tests for 1CMM, but only in 49 for 2CMM. S*(G1) overestimated S*(G2), but they were positively related. S*(I1) and S*(12) were not different and were positively related. This suggests that inadequate modeling by the 1CMM has a smaller impact on glucose tolerance indices in children than in adults. Comparison with classical MinMod gave results analogous to those in adults (MinMod S(G) was larger than S*(G1), MinMod S(I) was smaller than S*(I1)). These results demonstrate significant differences in glucose effectiveness, but not insulin sensitivity, as measured by 1CMM and 2CMM in early adolescents. Thus, when insulin sensitivity is the primary interest, the 1CMM is more robust because its parameters are more reliably estimated than those of 2CMM and is the logical choice in pediatric population-based studies.

Child↗

PubMed2002

The oral glucose minimal model: estimation of insulin sensitivity from a meal test.

Recently, a new approach has been proposed to estimate insulin sensitivity (S(I)) from an oral glucose tolerance test or a meal using an "integral equation". Here, we improve on the "integral equation" by resorting to a "differential equation" approach. The classic glucose kinetics minimal model was used with the addition of a parametric model for the rate of appearance into plasma of oral glucose (Ra). Three behavioral models of Ra were proposed: piecewise-linear (P), spline (S) and dynamic (D). All three models performed satisfactorily allowing a precise estimation of S(I) and a plausible reconstruction of Ra. Mean S(I) estimates were virtually identical: S(I)P = 6.81 +/- 0.87 (SE); S(I)S = 6.53 +/- 0.80; and S(I)D = 6.62 +/- 0.79. S(I) strongly correlated with the integral-equation index (I) S(I)I: r = 0.99, p < 0.01 for models D and S, and r 0.97, p < 0.01 for P. Also, SI compared well with insulin sensitivity estimated from intravenous glucose tolerance test in the same subjects (r = 0.75, p < 0.01; r = 0.71, p < 0.01; r = 0.73, p < 0.01, respectively, for P, S, and D models versus s(I)IVGTT). Finally, the novel approach allows estimation of SI from a shorter test (120 min): model P yielded S(I)R = 7.16 +/- 1.0 (R for reduced) which correlated very well with S(I)P and S(I)I (respectively, r = 0.94, p < 0.01; r = 0.95, p < 0.01) and still satisfactorily with S(I)IVGTT (r = 0.77, p < 0.01).

Blood Glucose↗

PubMed2002

Handling non-negativity in deconvolution of physiological signals: a nonlinear stochastic approach.

A stochastic interpretation of Tikhonov regularization has been recently proposed to attack some open problems of deconvolution when dealing with physiological systems, i.e., in addition to ill-conditioning, infrequent and nonuniform sampling and necessity of having credible confidence intervals. However, the possible violation of the non-negativity constraint cannot be dealt with on firm statistical grounds, since the model of the unknown signal is compatible with negative realizations. In this paper, we propose a new model of the unknown input which excludes negative values. The model is embedded within a Bayesian estimation framework to calculate, by resorting to a Markov chain Monte Carlo algorithm, a nonlinear estimate of the unknown input given by its a posteriori expected value. Applications to simulated and real hormone secretion/pharmacokinetic problems are presented which show that this nonlinear approach is more accurate than the linear one. In addition, more realistic confidence intervals are obtained.

Algorithms↗

PubMed2002

Double isotope tracer method for measuring fractional zinc absorption: theoretical analysis.

Several approaches for estimation of fractional zinc absorption (FZA) by calculating the ratio of oral to intravenous stable isotopic tracer concentrations (at an appropriate time) in urine or plasma after their simultaneous administration have been proposed in the last decade. These simple-to-implement approaches, often referred to as the double isotopic tracer ratio (DITR) method, are more attractive than the classical "deconvolution" method and the more commonly used single-tracer methods based on fecal monitoring and indicator dilution, after oral or intravenous tracer administration, respectively. However, the domain of validity of DITR for measuring FZA has recently been questioned. In this paper, we provide a theoretical justification of the validity of four different "approximate" formulations of the DITR technique by demonstrating mathematically that their accuracy is a consequence of the particular properties of zinc kinetics.

Absorption↗

PubMed2002

Regulation of endogenous glucose production after a mixed meal in type 2 diabetes.

The extent and time course of suppression of endogenous glucose production (EGP) in type 2 diabetes after a mixed meal have been determined using a new tracer methodology. Groups of age-, sex-, and weight-matched normal controls (n = 8) and diet-controlled type 2 diabetic subjects (n = 8) were studied after ingesting a standard mixed meal (550 kcal; 67% carbohydrate, 19% fat, 14% protein). There was an early insulin increment in both groups such that, by 20 min, plasma insulin levels were 266 +/- 54 and 190 +/- 53 pmol/l, respectively. EGP was similar basally [2.55 +/- 0.12 mg x kg(-1) x min(-1) in control subjects vs. 2.92 +/- 0.16 mg x kg(-1) x min(-1) in the patients (P = 0.09)]. After glucose ingestion, EGP declined rapidly in both groups to approximately 50% of basal within 30 min of the meal. Despite the initial rapid decrease, the EGP was significantly greater in the diabetic group at 60 min (1.75 +/- 0.12 vs. 1.05 +/- 0.14 mg x kg(-1) x min(-1); P < 0.01) and did not reach nadir until 210 min (0.96 +/- 0.17 mg x kg(-1) x min(-1)). Between 60 and 240 min, EGP was 47% higher in the diabetic group (0.89 +/- 0.09 vs. 1.31 +/- 0.13 mg x kg(-1) x min(-1), P < 0.02). These data quantitate the initial rapid suppression of EGP after a mixed meal in type 2 diabetes and the contribution of continuing excess glucose production to subsequent hyperglycemia.

Blood Glucose↗

PubMed2002

Epinephrine effects on insulin-glucose dynamics: the labeled IVGTT two-compartment minimal model approach.

The hyperglycemic effects of epinephrine (Epi) are established; however, the modulation of Epi-stimulated endogenous glucose production (EGP) by glucose and insulin in vivo in humans is less clear. Our aim was to determine the effect of exogenously increased plasma Epi concentrations on insulin and glucose dynamics. In six normal control subjects, we used the labeled intravenous glucose tolerance test (IVGTT) interpreted with the two-compartment minimal model, which provides not only glucose effectiveness (S(G)(2*)), insulin sensitivity (S(I)(2*)), and plasma clearance rate (PCR) at basal state, but also the time course of EGP. Subjects were randomly studied during either saline or Epi infusion (1.5 microg/min). Exogenous Epi infusion increased plasma Epi concentration to a mean value of 2,034 +/- 138 pmol/l. During the stable-label IVGTT, plasma glucose, tracer glucose, and insulin concentrations were significantly higher in the Epi study. The hormone caused a significant (P < 0.05) reduction in PCR in the Epi state when compared with the basal state. The administration of Epi has a striking effect on EGP profiles: the nadir of the EGP profiles occurs at 21 +/- 7 min in the basal state and at 55 +/- 13 min in the Epi state (P < 0.05). In conclusion, we have shown by use of a two-compartment minimal model of glucose kinetics that elevated plasma Epi concentrations have profound effects at both hepatic and tissue levels. In particular, at the liver site, this hormone deeply affects, in a time-dependent fashion, the inhibitory effect of insulin on glucose release. Our findings may explain how even a normal subject may have the propensity to develop glucose intolerance under the influence of small increments of Epi during physiological stress.

Adult↗

PubMed2002

Minimal model S(I)=0 problem in NIDDM subjects: nonzero Bayesian estimates with credible confidence intervals.

The minimal model of glucose kinetics, in conjunction with an insulin-modified intravenous glucose tolerance test, is widely used to estimate insulin sensitivity (S(I)). Parameter estimation usually resorts to nonlinear least squares (NLS), which provides a point estimate, and its precision is expressed as a standard deviation. Applied to type 2 diabetic subjects, NLS implemented in MINMOD software often predicts S(I)=0 (the so-called "zero" S(I) problem), whereas general purpose modeling software systems, e.g., SAAM II, provide a very small S(I) but with a very large uncertainty, which produces unrealistic negative values in the confidence interval. To overcome these difficulties, in this article we resort to Bayesian parameter estimation implemented by a Markov chain Monte Carlo (MCMC) method. This approach provides in each individual the S(I) a posteriori probability density function, from which a point estimate and its confidence interval can be determined. Although NLS results are not acceptable in four out of the ten studied subjects, Bayes estimation implemented by MCMC is always able to determine a nonzero point estimate of S(I) together with a credible confidence interval. This Bayesian approach should prove useful in reanalyzing large databases of epidemiological studies.

Bayes Theorem↗

PubMed2002

Effects of dietary macronutrient content on glucose metabolism in children.

Effects of carbohydrate, fat, and fructose intake on substrate and hormone concentrations, glucose production, gluconeogenesis, and insulin sensitivity were determined in healthy, nonobese prepubertal children (n = 12) and adolescents (n = 24) using a cross-over design. In one group (12 prepubertal children and 12 adolescents), subjects were studied after 7 d of isocaloric, isonitrogenous diets providing either 60% carbohydrate and 25% fat [high carbohydrate (H(CHO))/low fat (L(F))] or 30% carbohydrate and 55% fat [low carbohydrate (L(CHO))/high fat (H(F))], and in a second group (12 adolescents) H(CHO)/L(F) diets containing either 40% or 10% fructose was used. All subjects adapted to changes in carbohydrate and fat intakes primarily by appropriately adjusting their substrate oxidation rates to match the intakes, with only minor changes in parameters of glucose metabolism. Changing from a L(CHO)/H(F) to H(CHO)/L(F) diet resulted in increased insulin sensitivity (stable labeled iv glucose tolerance test) in adolescents [from 3.2 +/- 0.7 x 10(-4) to 5.0 +/- 1.4 x 10(-4) (min(-1))/( micro U.ml(-1)) (mean +/- SE)] but not in prepubertal children [9.4 +/- 2.5 x 10(-4) to 9.9 +/- 1.5 x 10(-4) (min(-1))/( micro U.ml(-1))], whereas beta-cell sensitivity was unaffected in both groups. Insulin sensitivity was higher in prepubertal children than in adolescents (P < 0.05). The dietary fructose content did not affect any measured parameter. We conclude that in the short term, dramatic changes in fat and carbohydrate intakes (regardless of fructose content) did not adversely affect glucose and lipid metabolism in healthy nonobese children. In the adolescents, the high carbohydrate diet resulted in increased insulin sensitivity, thus facilitating insulin-mediated glucose uptake.

Adolescent↗