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

2003 ◽  
Vol 284 (2) ◽  
pp. E317-E321 ◽  
Author(s):  
Gianna Toffolo ◽  
Claudio Cobelli
Keyword(s):  
Minimal Model ◽  
Tolerance Test ◽  
Intravenous Glucose Tolerance Test ◽  
Glucose Disposal ◽  
Parameter Estimates ◽  
Model Parameters ◽  
Single Individual ◽  
Intravenous Glucose ◽  
Proportional Effect ◽  
Effect Of Glucose

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 Rd0 of insulin-independent glucose disposal. Here Rd0 is not fixed to 1 mg · kg−1 · min−1but 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.

Reduced sampling schedule for the glucose minimal model: importance of Bayesian estimation

2006 ◽  
Vol 290 (1) ◽  
pp. E177-E184 ◽  
Author(s):  
Paolo Magni ◽  
Giovanni Sparacino ◽  
Riccardo Bellazzi ◽  
Claudio Cobelli
Keyword(s):  
Minimal Model ◽  
Large Scale ◽  
Accurate Determination ◽  
Normal Subjects ◽  
Tolerance Test ◽  
Intravenous Glucose Tolerance Test ◽  
Parameter Estimates ◽  
Single Individual ◽  
Intravenous Glucose ◽  
Sampling Schedule

The minimal model (MM) of glucose kinetics during an intravenous glucose tolerance test (IVGTT) is widely used in clinical studies to measure metabolic indexes such as glucose effectiveness (SG) and insulin sensitivity (SI). The standard (frequent) IVGTT sampling schedule (FSS) for MM identification consists of 30 points over 4 h. To facilitate clinical application of the MM, reduced sampling schedules (RSS) of 13–14 samples have also been derived for normal subjects. These RSS are especially appealing in large-scale studies. However, with RSS, the precision of SG and SI estimates deteriorates and, in certain cases, becomes unacceptably poor. To overcome this difficulty, population approaches such as the iterative two-stage (ITS) approach have been recently proposed, but, besides leaving some theoretical issues open, they appear to be oversized for the problem at hand. Here, we show that a Bayesian methodology operating at the single individual level allows an accurate determination of MM parameter estimates together with a credible measure of their precision. Results of 16 subjects show that, in passing from FSS to RSS, there are no significant changes of point estimates in nearly all of the subjects and that only a limited deterioration of parameter precision occurs. In addition, in contrast with the previously proposed ITS method, credible confidence intervals (e.g., excluding negative values) are obtained. They can be crucial for a subsequent use of the estimated MM parameters, such as in classification, clustering, regression, or risk analysis.

scholarly journals Measurement of selective effect of insulin on glucose disposal from labeled glucose oral test minimal model

2005 ◽  
Vol 289 (5) ◽  
pp. E909-E914 ◽  
Author(s):  
Chiara Dalla Man ◽  
Andrea Caumo ◽  
Rita Basu ◽  
Robert Rizza ◽  
Gianna Toffolo ◽  
...  
Keyword(s):  
Minimal Model ◽  
Glucose Production ◽  
Tolerance Test ◽  
Intravenous Glucose Tolerance Test ◽  
Glucose Disposal ◽  
Oral Glucose ◽  
Intravenous Glucose ◽  
Selective Effect ◽  
Clamp Technique ◽  
Model Independent

The oral glucose minimal model (OMM) measures insulin sensitivity (SI) and the glucose rate of appearance (Ra) of ingested glucose in the presence of physiological changes of insulin and glucose concentrations. However, SI of OMM measures the overall effect of insulin on glucose utilization and glucose production. In this study we show that, by adding a tracer to the oral dose, e.g., of a meal, and by using the labeled version of OMM, OMM* to interpret the data, one can measure the selective effect of insulin on glucose disposal, [Formula: see text]. Eighty-eight individuals underwent both a triple-tracer meal with the tracer-to-tracee clamp technique, providing a model-independent reference of the Ra of ingested glucose ([Formula: see text]) and an insulin-modified labeled intravenous glucose tolerance test (IVGTT*). We show that OMM* provides not only a reliable means of tracing the Ra of ingested glucose (Ra meal) but also accurately measures [Formula: see text]. We do so by comparing OMM* Ra meal with the model-independent [Formula: see text] provided by the tracer-to-tracee clamp technique, while OMM* [Formula: see text] is compared with both [Formula: see text], obtained by using as known input [Formula: see text], and with [Formula: see text] measured during IVGTT*.

NONMEM improves group parameter estimation for the minimal model of glucose kinetics

1996 ◽  
Vol 271 (5) ◽  
pp. E932-E937 ◽  
Author(s):  
A. De Gaetano ◽  
G. Mingrone ◽  
M. Castageneto
Keyword(s):  
Blood Glucose ◽  
Minimal Model ◽  
Classical Method ◽  
Intravenous Glucose Tolerance Test ◽  
Glucose Disposal ◽  
Parameter Estimates ◽  
Glucose Kinetics ◽  
Intravenous Glucose ◽  
Group Parameter ◽  
Coefficients Of Variation

The minimal model of glucose kinetics interprets blood glucose and insulin concentrations after an interprets blood glucose and insulin concentrations after an intravenous glucose tolerance test (IVGTT) and provides parameters describing tissue insulin sensitivity and glucose-dependent tissue glucose disposal. In the standard application, the model is fitted to each experimental subject's points by nonlinear least squares, with suitable weighing. The variability of parameter estimates may, however, represent a problem, making the model in practice unidentifiable on a group of experimental subjects undergoing some treatment of interest. To obviate this problem, a specific modification to the original protocol has been introduced: administering tolbutamide 20 min after the glucose bolus has been shown to improve parameter stability. With this modification, however, the converse model of pancreatic secretion can no more be fitted on the collected series of concentrations. The application of the nonlinear mixed effects model (NONMEM) loss function allows estimation of parameter population means, variances, and covariances to be made on all sampled subjects simultaneously. Although this procedure does not allow an individual subject's parameters to be estimated, the variability of the group parameter estimates is greatly reduced compared with the standard method. In the present work, 20 healthy volunteers have been studied with an IVGTT, and group parameters have been computed in both standard and NONMEM ways: asymptotic parameter coefficients of variation with NONMEM were at least twenty times smaller than the corresponding sample parameter coefficients of variation obtained with the classical method.

Estimation of insulin sensitivity and glucose clearance from minimal model: new insights from labeled IVGTT

1986 ◽  
Vol 250 (5) ◽  
pp. E591-E598 ◽  
Author(s):  
C. Cobelli ◽  
G. Pacini ◽  
G. Toffolo ◽  
L. Sacca
Keyword(s):  
Insulin Sensitivity ◽  
Minimal Model ◽  
Glucose Production ◽  
Tolerance Test ◽  
Intravenous Glucose Tolerance Test ◽  
Glucose Disposal ◽  
Model Estimate ◽  
Intravenous Glucose ◽  
Glucose Inhibition ◽  
Glucose Clearance

The "minimal model" of glucose disappearance provides noninvasive estimates of insulin sensitivity and glucose effectiveness from an intravenous glucose tolerance test (IVGTT). However, this model does not allow the separation of glucose production from utilization. To overcome this limitation, labeled glucose was injected along with cold glucose in six normal dogs, and both cold and labeled glucose time courses were monitored along with insulin concentration. A revised minimal model was fitted to tracer data to obtain new measures of insulin sensitivity (SI* = 6.41 +/- 0.91 10(-4) min-1 X microU-1 X ml-1) and fractional glucose clearance (SG* = 0.0092 +/- 0.0009 min-1). SG* was compared with a direct measure obtained by a hepatic arterial-venous difference technique, which yielded a value of 0.0097 +/- 0.0002, virtually identical to SG*, thereby validating the model estimate. When the original minimal model was identified from cold data, we obtained S1 = 4.52 +/- 1.39 and SG = 0.042 +/- 0.009. SI* and SG* were different from SI and SG, respectively. In particular SG overestimates fractional glucose clearance by approximately five times. The revised minimal model yields glucose disposal parameters SI* and SG* that are not affected by the confounding effect of insulin and glucose inhibition of glucose production. Limitations inherent in cold IVGTT and original minimal model are overcome by labeled IVGTT and the revised minimal model, while test simplicity remains.

Modified protocols improve insulin sensitivity estimation using the minimal model

1987 ◽  
Vol 253 (6) ◽  
pp. E595-E602 ◽  
Author(s):  
Y. J. Yang ◽  
J. H. Youn ◽  
R. N. Bergman
Keyword(s):  
Standard Deviation ◽  
Insulin Sensitivity ◽  
Minimal Model ◽  
Insulin Response ◽  
Tolerance Test ◽  
Intravenous Glucose Tolerance Test ◽  
Improve Insulin Sensitivity ◽  
Intravenous Glucose ◽  
Sensitivity Estimation ◽  
Model Technique

We attempted to improve the precision of the estimation of insulin sensitivity (S1) from the minimal model technique by modifying insulin dynamics during a frequently sampled intravenous glucose tolerance test (FSIGT). Tolbutamide and somatostatin (SRIF) were used to change the insulin dynamics without directly affecting insulin sensitivity. Injection of tolbutamide (100 mg) at t = 20 min provoked an immediate secondary peak in insulin response, resulting in a greater integrated incremental insulin than the standard FSIGT. SRIF, injected at t = -1 min, delayed insulin secretion in proportion to the dose without any change in magnitude. Computer simulation was used to assess the precision of S1 estimation. Insulin dynamics from both standard and modified protocols were adjusted in magnitude, with the shape unchanged and analyzed to determine the effect of the magnitude of insulin response. Fractional standard deviation was reduced from 73% with the standard insulin profile to 23% with tolbutamide and 18% with the highest dose of SRIF. In addition, the fractional standard deviation of S1 estimates decreased exponentially with increasing magnitude of insulin response. Modified FSIGTs require a smaller insulin response than the standard protocol to achieve the same precision.

Assessment of Insulin Sensitivity in Man: A Comparison of Minimal Model- and Euglycaemic Clamp-Derived Measures in Health and Heart Failure

1994 ◽  
Vol 86 (3) ◽  
pp. 317-322 ◽  
Author(s):  
Jonathan W. Swan ◽  
Christopher Walton ◽  
Ian F. Godsland
Keyword(s):  
Heart Failure ◽  
Insulin Sensitivity ◽  
Minimal Model ◽  
Glucose Tolerance Test ◽  
Tolerance Test ◽  
Intravenous Glucose Tolerance Test ◽  
High Dose ◽  
Sensitivity Index ◽  
Intravenous Glucose ◽  
Intravenous Glucose Tolerance

1. Simplified protocols for the measurement of insulin resistance will facilitate studies of this potentially important variable. 2. Using the euglycaemic clamp as the reference technique, we have assessed the validity of the insulin sensitivity index (inversely related to insulin resistance) obtained using a high-dose (500 mg/kg), unmodified intravenous glucose tolerance test with a 16 point sampling schedule and analysis using the minimal model of glucose disappearance. The two methods were compared in 10 clinically normal subjects and five patients with severe heart failure secondary to coronary heart disease. 3. The insulin sensitivity index of the minimal model was compared with four clamp-derived measures. Correlation coefficients of 0.72–0.92 (P < 0.01−P < 0.001) were obtained between the two methods over a wide range of insulin sensitivity [model values 1.03–14.63 min−1/(pmol/l) × 10−5]. Patients with heart failure had the lowest measures of insulin sensitivity. 4. The high-dose, unmodified intravenous glucose tolerance test with minimal model analysis is a straightforward and economical clinical procedure and provides a valid measure of insulin sensitivity, in health and disease.

Glucose effectiveness is the major determinant of intravenous glucose tolerance in the rat

1999 ◽  
Vol 276 (4) ◽  
pp. E739-E746 ◽  
Author(s):  
M. Dawn McArthur ◽  
Dan You ◽  
Kim Klapstein ◽  
Diane T. Finegood
Keyword(s):  
Glucose Tolerance ◽  
Bolus Injection ◽  
Insulin Response ◽  
Tolerance Test ◽  
Physiological Effect ◽  
Intravenous Glucose Tolerance Test ◽  
Glucose Disposal ◽  
Disappearance Rate ◽  
Intravenous Glucose ◽  
Intravenous Glucose Tolerance

To determine the importance of insulin for glucose disposal during an intravenous glucose tolerance test in rats, experiments were performed in four cohorts of conscious unrestrained rats fasted overnight. In cohorts 1- 3, a bolus of tracer ([3-3H]glucose, 50 μCi) was given alone, with glucose (0.3 g/kg) to induce an endogenous insulin response (∼1,100 pmol/l), or with exogenous insulin to give physiological (1,700 pmol/l) or supraphysiological (12,000 pmol/l) plasma levels. Raising plasma insulin within the physiological range had no effect ( P > 0.05), but supraphysiological levels induced hypoglycemia (7.3 ± 0.2 to 3.6 ± 0.2 mmol/l) and increased [3H]glucose disappearance rate ( P < 0.001). In cohort 4, a primed, continuous tracer infusion was started 120 min before saline or glucose bolus injection. [3H]glucose levels fell 15–20%, and the disappearance rate rose 36% ( P < 0.05) after glucose injection. These results indicate that in fasted rats a tracer bolus injection protocol is not sufficiently sensitive to measure the physiological effect of insulin released in response to a bolus of glucose because this effect of insulin is small. Glucose itself is the predominant mediator of glucose disposal after a bolus of glucose in the fasted rat.

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