Search

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.

We have separated the effect of insulin on glucose distribution/transport, glucose disposal, and endogenous production (EGP) during an intravenous glucose tolerance test (IVGTT) by use of a dual-tracer dilution methodology. Six healthy lean male subjects (age 33 ± 3 yr, body mass index 22.7 ± 0.6 kg/m2) underwent a 4-h IVGTT (0.3 g/kg glucose enriched with 3–6% d-[U-13C]glucose and 5–10% 3- O-methyl-d-glucose) preceded by a 2-h investigation under basal conditions (5 mg/kg ofd-[U-13C]glucose and 8 mg/kg of 3- O-methyl-d-glucose). A new model described the kinetics of the two glucose tracers and native glucose with the use of a two-compartment structure for glucose and a one-compartment structure for insulin effects. Insulin sensitivities of distribution/transport, disposal, and EGP were similar (11.5 ± 3.8 vs. 10.4 ± 3.9 vs. 11.1 ± 2.7 × 10−2ml · kg−1· min−1per mU/l; P = nonsignificant, ANOVA). When expressed in terms of ability to lower glucose concentration, stimulation of disposal and stimulation of distribution/transport accounted each independently for 25 and 30%, respectively, of the overall effect. Suppression of EGP was more effective ( P < 0.01, ANOVA) and accounted for 50% of the overall effect. EGP was suppressed by 70% (52–82%) (95% confidence interval relative to basal) within 60 min of the IVGTT; glucose distribution/transport was least responsive to insulin and was maximally activated by 62% (34–96%) above basal at 80 min compared with maximum 279% (116–565%) activation of glucose disposal at 20 min. The deactivation of glucose distribution/transport was slower than that of glucose disposal and EGP ( P < 0.02) with half-times of 207 (84–510), 12 (7–22), and 29 (16–54) min, respectively. The minimal-model insulin sensitivity was tightly correlated with and linearly related to sensitivity of EGP ( r = 0.96, P < 0.005) and correlated positively but nonsignificantly with distribution/transport sensitivity ( r = 0.73, P = 0.10) and disposal sensitivity ( r = 0.55, P = 0.26). We conclude that, in healthy subjects during an IVGTT, the two peripheral insulin effects account jointly for approximately one-half of the overall insulin-stimulated glucose lowering, each effect contributing equally. Suppression of EGP matches the effect in the periphery.

The minimal model method is widely used to estimate glucose effectiveness (SG) and insulin sensitivity (SI) from intravenous glucose tolerance test (IVGTT) data. In the standard protocol (sIVGTT, 0.33 g/kg glucose bolus given at time 0), which allows the simultaneous assessment of β-cell function, the precision of the individualized estimates often degrades and particularly so in the presence of reduced sampling schedules. Here, we investigated the use of a population approach, the iterative two-stage (ITS) approach, to analyze 16 sIVGTTs in healthy subjects and to obtain refined estimates of SG and SI in the population and in the individual subjects. The ITS is based on calculation of the population mean and standard deviation of the parameters at each iteration and then use of them as prior information for the individual analyses. Theoretically, the use of a prior in the ITS should improve the precision of the individual estimates. The customary approach (standard two stage, STS), where modeling is performed separately for each individual subject, does not take the population knowledge into account. We used both frequent (FSS, 30 samples) and (quasi-optimally) reduced (RSS, 14 samples) sampling schedules. For the FSS, STS gave estimates (mean ± SD) for SG = 2.66 ± 1.09 × 10−2 · min−1 and SI = 6.46 ± 6.99 10−4 · min−1 · μU−1 · ml, with an average precision of 51 (range 5–176) and 33% (3–91), respectively. RSS radically worsened the precision of both SG and SI. However, RSS and ITS gave SG = 2.59 ± 0.73 and SI = 6.06 ± 7.28, with an average precision of 23 (12–42) and 27% (), respectively. In conclusion, population minimal modeling of sIVGTT data improves the precision of individual estimates of glucose effectiveness and insulin sensitivity, as the theory predicts, and, even with reduced sampling, the improvement is substantial.

The aim of the present study was to determine the effects of feeding various dietary proteins on insulin sensitivity and glucose tolerance in rats. Male Wistar rats were fed for 28 days with isoenergetic diets containing either casein, soy protein, or cod protein. Cod protein-fed and soy protein-fed rats had lower fasting plasma glucose and insulin concentrations compared with casein-fed animals. After intravenous glucose bolus, cod protein- and soy protein-fed rats induced lower incremental areas under glucose curves compared with casein-fed animals. Improved peripheral insulin sensitivity was confirmed by higher glucose disposal rates in cod protein- and soy protein-fed rats (15.2 ± 0.3 and 13.9 ± 0.6 mg ⋅ kg−1⋅ min−1, respectively) compared with casein-fed animals (6.5 ± 0.7 mg ⋅ kg−1⋅ min−1, P < 0.05). Moreover, test meal experiments revealed that, in the postprandial state, the lower plasma insulin concentrations in cod protein- and soy protein-fed animals could be also due to decreased pancreatic insulin release and increased hepatic insulin removal. In conclusion, the metabolic responses to three common dietary proteins indicate that cod and soy proteins, when compared with casein, improve fasting glucose tolerance and peripheral insulin sensitivity in rats.

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.

Glucose effectiveness is an important determinant of glucose tolerance that can be derived from minimal model analysis of an intravenous glucose tolerance test (IVGTT). However, recent evidence suggests that glucose effectiveness is overestimated by minimal model analysis. Here we compare a new model-independent estimate of glucose effectiveness with the minimal model estimate by reanalyzing published data in which insulin-dependent diabetic subjects were each given IVGTTs under two conditions (Quon, M. J., C. Cochran, S. I. Taylor, and R. C. Eastman. Diabetes 43: 890–896, 1994). In one case, a basal insulin level was maintained (BI-IVGTT). In the second case, a dynamic insulin response was recreated (DI-IVGTT). Our results show that minimal model glucose effectiveness is very similar to the model-independent measurement during a BI-IVGTT but is three times higher during a DI-IVGTT. To investigate the causes of minimal model overestimation in the presence of a dynamic insulin response, Monte Carlo simulation studies on a two-compartment model of glucose kinetics with various insulin response patterns were performed. Results suggest that minimal model overestimation is due to single-compartment representation of glucose kinetics that results in a critical oversimplification in the presence of increasingly dynamic insulin secretion patterns.

Insulin sensitivity is frequently assessed with the minimal model (MM) and the insulin-modified intravenous glucose tolerance test (MIVGTT). To ascertain the validity of this approach, the mechanisms by which the MM estimates glucose effectiveness and insulin sensitivity (SG and SI, respectively) from the data are analyzed theoretically. Published data and new labeled MIVGTTs in normal and non-insulin-dependent diabetic (NIDDM) subjects are used as reference data. One reason for the reported difficulty in estimating SI in NIDDM is the inadequacy of the MM to describe the data. SG is a biased estimate of the fractional glucose clearance (FGC) at basal insulin, and SI is a biased estimate of the average slope of the insulin concentration-FGC curve. The monocompartmental assumption and the role of glucose production in the MM are causes of bias. The bias is fairly constant across the spectrum of glucose tolerance (SG: approximately 150% overestimate; SI: approximately 30% underestimate). Also, SI is not expected to account satisfactorily for hepatic insulin sensitivity. Finally, by the use of SG and SI, FGC at a target insulin level (FGCMM) can be estimated. FGCMM agrees well with the analogous clamp index (difference 10%; correlation: r = 0.88, P < 0.002) and, in NIDDM, has a lower coefficient of variation than SI (57 vs. 82%). In conclusion, this analysis indicates that the MM is a sufficiently reliable method for the assessment of insulin sensitivity if it is used cautiously.

We previously demonstrated that minimal model-derived estimates of glucose effectiveness (SG), based on the frequently sampled intravenous glucose tolerance test (SGFSIGT), were reduced in islet-transplanted or streptozotocin-treated dogs and in patients with insulin-dependent diabetes mellitus. To ascertain the validity of our observations, we compared SGFSIGT with estimates based on a basal hormone replacement glucose clamp (SGBRCLAMP) and a basal hormone replacement glucose tolerance test (SGBRGTT) in normal control (CNTL, n = 12) and streptozotocin-treated dogs with normal fasting plasma glucose (STZ-Rx, n = 9). SGFSIGT was reduced in STZ-Rx compared with CNTL (P < 0.05). However, neither SGBRCLAMP nor SGBRGTT was reduced in the STZ-Rx group (P > 0.05). Comparison of protocols for each subject indicated that SGFSIGT was greater than either SGBRCLAMP or SGBRGTT in control (P < 0.002) but not in STZ-Rx dogs (P > 0.1). The relationship of SGFSIGT to insulin secretory function suggests that our previous conclusion that SGFSIGT was reduced in subjects with limited insulin release may be an artifact of the minimal-model method. Our results suggest that caution must be exercised in the interpretation of differences in minimal-model estimates of SG between subject groups with significantly different levels of insulin secretory function.

Glucose effectiveness (SG) and insulin sensitivity of sedentary and physically trained males were estimated by the minimal model approach. Trained subjects, who ran 86 +/- 10 km/wk and had 37% higher maximal oxygen consumption than that of sedentary subjects (56.2 +/- 1.2 vs. 40.9 +/- 1.4 ml.kg-1 x min-1, P < 0.01), were studied 16 h and 1 wk after their last training session. After overnight fasting, glucose was administered intravenously (300 mg/kg body wt) within 2 min, and insulin was infused (approximately 13-20 mU/kg given over 5 min) from 20 to 25 min after administration of glucose. Glucose disappearance constant values as an estimate of glucose tolerance were significantly higher in trained subjects after 16 h and 1 wk of their training session (3.29 +/- 0.48 and 3.60 +/- 0.64%/min) than in sedentary subjects (1.92 +/- 0.30%/min, P < 0.05). Insulin sensitivity in trained subjects measured after 16 h and 1 wk of their last training session (26.2 +/- 4.4 and 24.3 +/- 6.0 x 10(-5) min-1 x pM-1) was also higher than that of sedentary subjects (10.3 +/- 1.2 x 10(-5) min-1 x pM-1, P < 0.05). SG, the ability of glucose itself to increase peripheral glucose uptake and suppress hepatic glucose output, was significantly higher in trained subjects after 16 h and 1 wk of their last training session (0.028 +/- 0.003 and 0.030 +/- 0.004/min) than in sedentary subjects (0.017 +/- 0.002/min, P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)