scholarly journals Undermodeling affects minimal model indexes: insights from a two-compartment model

1999 ◽  
Vol 276 (6) ◽  
pp. E1171-E1193 ◽  
Author(s):  
Andrea Caumo ◽  
Paolo Vicini ◽  
Jeffrey J. Zachwieja ◽  
Angelo Avogaro ◽  
Kevin Yarasheski ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Minimal Model ◽  
Compartment Model ◽  
Minimal Models ◽  
Intravenous Glucose ◽  
Glucose Effectiveness ◽  
Glucose Disappearance ◽  
Single Compartment ◽  
Two Compartment Model ◽  
The Impact

The classic (hereafter cold) and the labeled (hereafter hot) minimal models are powerful tools to investigate glucose metabolism. The cold model provides, from intravenous glucose tolerance test (IVGTT) data, indexes of glucose effectiveness (SG) and insulin sensitivity (SI) that measure the effect of glucose and insulin, respectively, to enhance glucose disappearance and inhibit endogenous glucose production. The hot model provides, from hot IVGTT data, indexes of glucose effectiveness ([Formula: see text]) and insulin sensitivity ([Formula: see text]) that, respectively, measure the effects of glucose and insulin on glucose disappearance only. Recent reports call for a reexamination of some of the assumptions of the minimal models. We have previously pointed out the criticality of the single-compartment description of glucose kinetics on which both the minimal models are founded. In this paper we evaluate the impact of single-compartment undermodeling on SG, SI,[Formula: see text], and[Formula: see text] by using a two-compartment model to describe the glucose system. The relationships of the minimal model indexes to the analogous indexes measured with the glucose clamp technique are also examined. Theoretical analysis and simulation studies indicate that cold indexes are more affected than hot indexes by undermodeling. In particular, care must be exercised in the physiological interpretation of SG, because this index is a local descriptor of events taking place in the initial portion of the IVGTT. As a consequence, SG not only reflects glucose effect on glucose uptake and production but also the rapid exchange of glucose between the accessible and nonaccessible glucose pools that occurs in the early part of the test.

scholarly journals Minimal model SGoverestimation and SIunderestimation: improved accuracy by a Bayesian two-compartment model

1999 ◽  
Vol 277 (3) ◽  
pp. E481-E488 ◽  
Author(s):  
Claudio Cobelli ◽  
Andrea Caumo ◽  
Matteo Omenetto
Keyword(s):  
Insulin Sensitivity ◽  
Minimal Model ◽  
Compartment Model ◽  
Tolerance Test ◽  
Intravenous Glucose Tolerance Test ◽  
Glucose Kinetics ◽  
Intravenous Glucose ◽  
Glucose Effectiveness ◽  
Normal Humans ◽  
Improved Accuracy

The intravenous glucose tolerance test (IVGTT) single-compartment minimal model (1CMM) method has recently been shown to overestimate glucose effectiveness and underestimate insulin sensitivity. Undermodeling, i.e., use of single- instead of two-compartment description of glucose kinetics, has been advocated to explain these limitations. We describe a new two-compartment minimal model (2CMM) into which we incorporate certain available knowledge on glucose kinetics. 2CMM is numerically identified using a Bayesian approach. Twenty-two standard IVGTT (0.30 g/kg) in normal humans were analyzed. In six subjects, the clamp-based index of insulin sensitivity ([Formula: see text]) was also measured. 2CMM glucose effectiveness ([Formula: see text]) and insulin sensitivity ([Formula: see text]) were, respectively, 60% lower ( P < 0.0001) and 35% higher ( P < 0.0001) than the corresponding 1CMM [Formula: see text] and[Formula: see text] indexes: 2.81 ± 0.29 (SE) vs.[Formula: see text] = 4.27 ± 0.33 ml ⋅ min−1 ⋅ kg−1and [Formula: see text] = 11.67 ± 1.71 vs.[Formula: see text] = 8.68 ± 1.62 102ml ⋅ min−1 ⋅ kg−1per μU/ml. [Formula: see text] was not different from[Formula: see text] = 12.61 ± 2.13 102ml ⋅ min−1 ⋅ kg−1per μU/ml (nonsignificant), whereas [Formula: see text]was 60% lower ( P < 0.02). In conclusion, a new 2CMM has been presented that improves the accuracy of glucose effectiveness and insulin sensitivity estimates of the classic 1CMM from a standard IVGTT in normal humans.

Insulin sensitivity and glucose effectiveness from three minimal models: effects of energy restriction and body fat in adult male rhesus monkeys

2003 ◽  
Vol 285 (6) ◽  
pp. R1340-R1354 ◽  
Author(s):  
Theresa A. Gresl ◽  
Ricki J. Colman ◽  
Thomas C. Havighurst ◽  
Lauri O. Byerley ◽  
David B. Allison ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Body Fat ◽  
Rhesus Monkeys ◽  
Hepatic Glucose Production ◽  
Intravenous Glucose Tolerance Test ◽  
Energy Restriction ◽  
Minimal Models ◽  
Intravenous Glucose ◽  
Glucose Effectiveness ◽  
Male Rhesus

The minimal model of glucose disappearance (MINMOD version 3; MM3) and both the one-compartment (1CMM) and the two-compartment (2CMM) minimal models were used to analyze stable isotope-labeled intravenous glucose tolerance test (IVGTT) data from year 10 of a study of the effect of dietary restriction (DR) in male rhesus monkeys. Adult monkeys were energy restricted (R; n = 12) on a semipurified diet to ∼70% of control (C) intake (ad libitum-fed monkeys; n = 12). Under ketamine anesthesia, fasting insulin levels were greater among C monkeys. Insulin sensitivity estimates from all models were greater in R than C monkeys, whereas glucose effectiveness estimates were not consistently greater in R monkeys. Fasting plasma glucose as well as hepatic glucose production and clearance rates did not differ between groups. Body fat, in part, statistically mediated the effect of DR to enhance insulin sensitivity indexes. Precision of estimation and intermodel relationships among insulin sensitivity and glucose effectiveness estimates were in the ranges of those reported previously for humans and dogs, suggesting that the models may provide valid estimates for rhesus monkeys as well. The observed insulin sensitivity indexes from all models, elevated among R vs. C monkeys, may be explained, at least in part, by the difference in body fat content between these groups after chronic DR.

scholarly journals The hot IVGTT two-compartment minimal model: indexes  of glucose effectiveness and insulin sensitivity

1997 ◽  
Vol 273 (5) ◽  
pp. E1024-E1032 ◽  
Author(s):  
Paolo Vicini ◽  
Andrea Caumo ◽  
Claudio Cobelli
Keyword(s):  
Insulin Sensitivity ◽  
Minimal Model ◽  
Glucose Production ◽  
Normal Subjects ◽  
Tolerance Test ◽  
Intravenous Glucose Tolerance Test ◽  
Distribution Volume ◽  
Intravenous Glucose ◽  
Glucose Effectiveness

A two-compartment minimal model (2CMM) has been proposed [A. Caumo and C. Cobelli. Am. J. Physiol. 264 ( Endocrinol. Metab. 27): E829–E841, 1993] to describe intravenous glucose tolerance test (IVGTT) labeled (hereafter hot) glucose kinetics. This model, at variance with the one-compartment minimal model (1CMM), allows the estimation of a plausible profile of glucose production. The aim of this study is to show that the 2CMM also allows the assessment of insulin sensitivity ([Formula: see text]), glucose effectiveness ([Formula: see text]), and plasma clearance rate (PCR). The 2CMM was identified on stable-isotope IVGTTs performed in normal subjects ( n = 14). Results were (means ± SE) [Formula: see text] = 0.85 ± 0.14 ml ⋅ kg−1 ⋅ min−1, PCR = 2.02 ± 0.14 ml ⋅ kg−1 ⋅ min−1, and [Formula: see text] = 13.83 ± 2.54 × 10−2ml ⋅ kg−1 ⋅ min−1 ⋅ μU−1 ⋅ ml. The 1CMM was also identified; glucose effectiveness and insulin sensitivity indexes were [Formula: see text]V = 1.36 ± 0.08 ml ⋅ kg−1 ⋅ min−1and [Formula: see text] V = 12.98 ± 2.21 × 10−2ml ⋅ kg−1 ⋅ min−1 ⋅ μU−1 ⋅ ml, respectively, where V is the 1CMM glucose distribution volume.[Formula: see text]V was lower than PCR and higher than [Formula: see text] and did not correlate with either [ r = 0.45 (NS) and r = 0.50 (NS), respectively], whereas [Formula: see text]V was not different from and was correlated with[Formula: see text]( r = 0.95; P < 0.001).[Formula: see text] compares well ( r = 0.78; P < 0.001) with PCR normalized by the 2CMM total glucose distribution volume. In conclusion, the 2CMM is a powerful tool to assess glucose metabolism in vivo.

Glucagon-like peptide-1 accelerates the onset of insulin action on glucose disappearance in mice

2007 ◽  
Vol 292 (6) ◽  
pp. E1808-E1814 ◽  
Author(s):  
K. Thomaseth ◽  
A. Pavan ◽  
G. Pacini ◽  
B. Ahrén
Keyword(s):  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Minimal Model ◽  
Insulin Action ◽  
Intravenous Glucose Tolerance Test ◽  
Model Parameters ◽  
Intravenous Glucose ◽  
Glucose Disappearance ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Glucagon-like peptide-1 (GLP-1) plays a significant role in glucose homeostasis through its incretin effect on insulin secretion. However, GLP-1 also exhibits extrapancreatic actions, and in particular its possible influences on insulin sensitivity are controversial. To study the dynamic action of GLP-1 on insulin sensitivity, we applied advanced statistical modeling methods to study glucose disappearance in mice that underwent intravenous glucose tolerance test with administration of GLP-1 at various dose levels. In particular, the minimal model of glucose disappearance was exploited within a population estimation framework for accurate detection of relationships between glucose disappearance parameters and GLP-1. Minimal model parameters were estimated from glucose and insulin data collected in 209 anesthetized normal mice after intravenous injection of glucose (1 g/kg) alone or with GLP-1 (0.03–100 nmol/kg). Insulin secretion markedly increased, as expected, with increasing GLP-1 dose. However, minimal model-derived indexes, i.e., insulin sensitivity and glucose effectiveness, did not significantly change with GLP-1 dose. Instead, fractional turnover rate of insulin action [P2 = 0.0207 ± 24.3% (min) at zero GLP-1 dose] increased steadily with administered GLP-1 dose, with significant differences at 10.4 nmol/kg (P2 = 0.040 ± 15.5%, P = 0.0046) and 31.2 nmol/kg (P2 = 0.050 ± 29.2%, P = 0.01). These results show that GLP-1 influences the dynamics of insulin action by accelerating insulin action following glucose challenge. This is a novel mechanism contributing to the glucose-lowering action of GLP-1.

SG, SI, and EGP of exercise-trained middle-aged men estimated by a two-compartment labeled minimal model

2002 ◽  
Vol 283 (4) ◽  
pp. E809-E816 ◽  
Author(s):  
Yuichiro Nishida ◽  
Kumpei Tokuyama ◽  
Shoichiro Nagasaka ◽  
Yasuki Higaki ◽  
Kanta Fujimi ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
Minimal Model ◽  
Time Course ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Middle Aged ◽  
Intravenous Glucose ◽  
Glucose Effectiveness ◽  
Intravenous Glucose Tolerance Tests

To examine the effects of physical training on glucose effectiveness (SG), insulin sensitivity (SI), and endogenous glucose production (EGP) in middle-aged men, stable-labeled frequently sampled intravenous glucose tolerance tests (FSIGTT) were performed on 11 exercise-trained middle-aged men and 12 age-matched sedentary men. The time course of EGP during the FSIGTT was estimated by nonparametric stochastic deconvolution. Glucose uptake-specific indexes of glucose effectiveness (S[Formula: see text]*× 102: 0.81 ± 0.08 vs. 0.60 ± 0.05 dl · min−1· kg−1, P < 0.05) and insulin sensitivity [S[Formula: see text]*  × 104: 24.59 ± 2.98 vs. 11.89 ± 2.36 dl · min−1· (μU/ml)−1· kg−1, P < 0.01], which were analyzed using the two-compartment minimal model, were significantly greater in the trained group than in the sedentary group. Plasma clearance rate (PCR) of glucose was consistently greater in the trained men than in sedentary men throughout FSIGTT. Compared with sedentary controls, EGP of trained middle-aged men was higher before glucose load. The EGP of the two groups was similarly suppressed by ∼70% within 10 min, followed by an additional suppression after insulin infusion. EGP returned to basal level at ∼60 min in the trained men and at 100 min in the controls, followed by its overshoot, which was significantly greater in the trained men than in the controls. In addition, basal EGP was positively correlated with S[Formula: see text]*. The higher basal EGP and greater EGP overshoot in trained middle-aged men appear to compensate for the increased insulin-independent (S[Formula: see text]*) and -dependent (S[Formula: see text]*) glucose uptake to maintain glucose homeostasis.

scholarly journals Insulin sensitivity and glucose effectiveness: minimal model analysis of regular and insulin-modified FSIGT

1998 ◽  
Vol 274 (4) ◽  
pp. E592-E599 ◽  
Author(s):  
Giovanni Pacini ◽  
Giancarlo Tonolo ◽  
Maria Sambataro ◽  
Mario Maioli ◽  
Milco Ciccarese ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Minimal Model ◽  
Cell Activity ◽  
Early Period ◽  
Normal Subjects ◽  
Model Analysis ◽  
Sensitivity Index ◽  
Intravenous Glucose ◽  
Glucose Effectiveness ◽  
Endogenous Insulin

The minimal model is widely used to evaluate insulin action on glucose disappearance from frequently sampled intravenous glucose tolerance tests (FSIGT). The common protocols are a regular (rFSIGT, single injection of 0.3 g/kg of glucose) and an insulin-modified test (mFSIGT, with an additional insulin administration at 20 min). This study compared the insulin sensitivity index (SI) and glucose effectiveness (SG) obtained in the same individual (16 normal subjects) with the two tests. SI was 7.11 ± 0.80 10−4 ⋅ min−1 ⋅ μU−1 ⋅ ml in rFSIGT and 6.96 ± 0.83 in mFSIGT ( P = 0.656), regression r = 0.92, P < 0.0001; SG was 0.0260 ± 0.0028 min−1 and 0.0357 ± 0.0052, respectively, statistically different ( P = 0.013) but still with a good regression ( r = 0.66, P = 0.0051). SG and insulin amount during the early period correlated ( r = 0.6, P = 0.015 in rFSIGT and r = 0.76, P = 0.0006 in mFSIGT). In summary, both FSIGTs with minimal model analysis provide the same SI, which is a very robust index. SG was different by 28% due probably to the relationship between SG and the amount of circulating insulin. In studies comparing groups, the simpler rFSIGT can still be used with the advantage of accounting for endogenous insulin, thus offering the possibility of direct inferences on the β-cell activity.

Population approaches to estimate minimal model indexes of insulin sensitivity and glucose effectiveness using full and reduced sampling schedules

2006 ◽  
Vol 291 (4) ◽  
pp. E716-E723 ◽  
Author(s):  
Kevin M. Krudys ◽  
Steven E. Kahn ◽  
Paolo Vicini
Keyword(s):  
Insulin Sensitivity ◽  
Minimal Model ◽  
Traditional Approach ◽  
Parameter Estimates ◽  
Two Stage ◽  
Intravenous Glucose ◽  
Individual Parameter ◽  
Glucose Effectiveness ◽  
Population Means ◽  
Subject Variability

The intravenous glucose tolerance test (IVGTT) interpreted with the minimal model provides individual indexes of insulin sensitivity (SI) and glucose effectiveness (SG). In population studies, the traditional approach, the standard two-stage (STS) method, fails to account for uncertainty in individual estimates, resulting in an overestimation of between-subject variability. Furthermore, in the presence of reduced sampling and/or insulin resistance, individual estimates may be unobtainable, biasing population information. Therefore, we investigated the use of two population approaches, the iterative two-stage (ITS) method and nonlinear mixed-effects modeling (NM), in a population ( n = 235) of insulin-sensitive and insulin-resistant subjects under full (FSS, 33 samples) and reduced [RSS(240-min), 13 samples and RSS(180-min), 12 samples] IVGTT sampling schedules. All three population methods gave similar results with the FSS. Using RSS(240), the three methods gave similar results for SI, but SG population means were overestimated. With RSS(180), SI and SG population means were higher for all three methods compared with their FSS counterparts. NM estimated similar between-subject variability (19% SG, 53% SI) with RSS(180), whereas ITS showed regression to the mean for SG (0.01% SG, 56% SI) and STS provided larger population variability in SI (29% SG, 91% SI). NM provided individual estimates for all subjects, whereas the two-stage methods failed in 16–18% of the subjects using RSS(180) and 6–14% using RSS(240). We conclude that population approaches, specifically NM, are useful in studies with a sparsely sampled IVGTT (∼12 samples) of short duration (∼3 h) and when individual parameter estimates in all subjects are desired.

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