Biomedical subjects

C Cobelli

Publications and source records attributed to C Cobelli.

At least 37 records · Page 2Linked to original sources

PubMed2000

Evidence for impaired glucose effectiveness in cirrhotic patients after liver transplantation.

To evaluate the impact of acute and chronic liver disease and single immunosuppression (cyclosporine A [CSA] or FK506) on insulin sensitivity and glucose effectiveness in liver-grafted patients, we performed a frequently sampled intravenous glucose tolerance test (FSIGTT) in nondiabetic patients after orthotopic liver transplantation (OLT) with acute liver failure ([ALF] group, n = 9, with CSA therapy), in patients after OLT with chronic liver disease (CSA group, n = 8; FK506 group, n = 8), and in 9 healthy control subjects. Insulin sensitivity and glucose effectiveness were determined by analyzing glucose and insulin data from the FSIGTT with Bergman's minimal model technique for glucose. The intravenous glucose tolerance index ([KG] ie, the slope of the regression of the logarithm of blood glucose concentration) was not different between the ALF group (2.17 +/- 0.16 min(-1)) and controls (2.29 +/- 0.13 min(-1)), but was lower (P < .05) in both groups with chronic liver disease (CSA group, 1.46 +/- 0.1; FK506 group, 1.61 +/- 0.11 min(-1)) compared with the ALF group (P < .05). A positive relation for the KG and glucose effectiveness was found in all liver-grafted patients and controls. Insulin sensitivity was not different between all liver-grafted patients and controls. The body mass index (BMI) was the overall determinant of insulin sensitivity in all groups. Single immunosuppressive therapy does not impair insulin sensitivity in liver-grafted patients. The lower glucose effectiveness in liver-grafted patients with chronic liver disease but not in patients after ALF points to a defect in the regulation of glucose-mediated glucose uptake in peripheral tissue.

Adult↗

PubMed2000

Models of subcutaneous insulin kinetics. A critical review.

Subcutaneous insulin kinetics is a complex process whose quantitation is needed for a reliable glycemic control in the conventional therapy of insulin-dependent diabetes. The major difficulties in modeling include accounting for the distribution in the subcutaneous depot and transport to plasma. A single model describing in detail the various processes for all the commercially available insulin preparations is not available. Several models however have been proposed which vary in the degree of complexity. Virtually all of them handle the regular insulin preparation while a few handle the intermediate acting and the novel insulin analogues. In this paper we critically review these models.

Absorption↗

PubMed2000

Evaluation of factors controlling glucose tolerance in patients with HCV infection before and after 4 months therapy with interferon-alpha.

BACKGROUND: Epidemiological data suggest that chronic hepatitis C virus (HCV) infection may contribute to the development of diabetes mellitus. Therapy of HCV infection with recombinant interferon-alpha (r-IFN-alpha) can also impair of glucose metabolism. METHODS: To investigate the impact of HCV infection and the therapy with r-IFN-alpha on glucose metabolism we measured insulin sensitivity, glucose effectiveness, and first and second phase insulin secretion, using the minimal modelling analysis of frequently sampled intravenous glucose tolerance tests in 13 nondiabetic patients with HCV-induced liver disease before and after therapy with r-INF-alpha (6 x 106 U, subcutaneously, three times a week over 4 months). Liver biopsy was performed to evaluate and score liver fibrosis as a marker of HCV-induced cell injury. RESULTS: Insulin sensitivity (r = - 0.59, P < 0.05) and first phase insulin secretion (r = - 0.66, P < 0.03) were negatively related to the fibrosis score. Insulin sensitivity rose from 1.96 (SEM 0.37, n = 8) to 5.69 (SEM 0.99, n = 8) 10-4 min-1 per microU mL-1 (P < 0.01) in responders and from 2.51 (SEM 0.61, n = 5) to 6.95 (SEM 1.99, n = 5) in nonresponders after 4 months r-INF-alpha therapy. Fasting free fatty acids decreased significantly to about 50% (P < 0.01) in patients with and without therapy response after 4 months, whereas first phase insulin secretion did not change. CONCLUSIONS: HCV-induced liver injury is related to the deterioration of insulin sensitivity and first phase insulin response, thus impairing glucose homeostasis in these HCV-infected patients. The administration of r-INF-alpha three times a week over 4 months is not associated with an impairment of glucose homeostasis.

Blood Glucose↗

PubMed2000

Maximum-likelihood versus maximum a posteriori parameter estimation of physiological system models: the C-peptide impulse response case study.

Maximum-likelihood (ML), also given its connection to least-squares (LS), is widely adopted in parameter estimation of physiological system models, i.e., assigning numerical values to the unknown model parameters from the experimental data. A more sophisticated but less used approach is maximum a posteriori (MAP) estimation. Conceptually, while ML adopts a Fisherian approach, i.e., only experimental measurements are supplied to the estimator, MAP estimation is a Bayesian approach, i.e., a priori available statistical information on the unknown parameters is also exploited for their estimation. In this paper, after a brief review of the theory behind ML and MAP estimators, we compare their performance in the solution of a case study concerning the determination of the parameters of a sum of exponential model which describes the impulse response of C-peptide (CP), a key substance for reconstructing insulin secretion. The results show that MAP estimation always leads to parameter estimates with a precision (sometimes significantly) higher than that obtained through ML, at the cost of only a slightly worse fit. Thus, a three exponential model can be adopted to describe the CP impulse response model in place of the two exponential model usually identified in the literature by the ML/LS approach. Simulated case studies are also reported to evidence the importance of taking into account a priori information in a data poor situation, e.g., when a few or too noisy measurements are available. In conclusion, our results show that, when a priori information on the unknown model parameters is available, Bayes estimation can be of relevant interest, since it can significantly improve the precision of parameter estimates with respect to Fisher estimation. This may also allow the adoption of more complex models than those determinable by a Fisherian approach.

Bayes Theorem↗

PubMed2000

Bayesian identification of a population compartmental model of C-peptide kinetics.

When models are used to measure or predict physiological variables and parameters in a given individual, the experiments needed are often complex and costly. A valuable solution for improving their cost effectiveness is represented by population models. A widely used population model in insulin secretion studies is the one proposed by Van Cauter et al. (Diabetes 41:368-377, 1992), which determines the parameters of the two compartment model of C-peptide kinetics in a given individual from the knowledge of his/her age, sex, body surface area, and health condition (i.e., normal, obese, diabetic). This population model was identified from the data of a large training set (more than 200 subjects) via a deterministic approach. This approach, while sound in terms of providing a point estimate of C-peptide kinetic parameters in a given individual, does not provide a measure of their precision. In this paper, by employing the same training set of Van Cauter et al., we show that the identification of the population model into a Bayesian framework (by using Markov chain Monte Carlo) allows, at the individual level, the estimation of point values of the C-peptide kinetic parameters together with their precision. A successful application of the methodology is illustrated in the estimation of C-peptide kinetic parameters of seven subjects (not belonging to the training set used for the identification of the population model) for which reference values were available thanks to an independent identification experiment.

Adult↗

PubMed2000

Approximate entropy studies of hormone pulsatility from plasma concentration time series: influence of the kinetics assessed by simulation.

Approximate entropy (ApEn) is a method developed in the early nineties to quantify the "regularity" of a time series. In recent years, it has been vigorously employed to study the oscillatory/pulsatile secretory behavior of many hormones and found capable of successfully identifying pathological or prepathological states characterized by an enhanced secretion irregularity. Since hormone secretion rate is nonaccessible to direct measurement, ApEn is usually calculated from the time series of the hormone concentrations in plasma. However, the plasma concentration time course also reflects the whole-body kinetics of the hormone and can thus only provide a distorted portrait of the secretion rate at the gland level. In this paper, we investigate by simulation whether and how this distortion can influence the study of the regularity of hormone pulsatility by ApEn. Pulsatile secretion time series with different degrees of irregularity are simulated by varying the statistics of the random parameters which describe the secretory pulses. Then, plasma concentration time series are obtained by convolution with the hormone impulse response. Different degrees of impulse response smoothness are also considered in order to vary the amount of the distortion introduced. Results show that ApEn computed from secretion time series consistently discriminated better than ApEn calculated from plasma concentration time series among processes with different degrees of regularity. In addition, smoother impulse responses decreased the ApEn differences between plasma concentration time series corresponding to different degrees of secretion regularity. Therefore, the power of the ApEn index in the study of hormone pulsatility can potentially be enhanced by applying it to the hormone secretion time series.

Algorithms↗

PubMed2000

Direct measurement of the lumped constant for 2-deoxy-[1-(14)C]glucose in vivo in human skeletal muscle.

The lumped constant (LC) is used to convert the clearance rate of 2-deoxy-D-glucose (2-DG(CR)) to that of glucose (Glc(CR)). There are currently no data to validate the widely used assumption of an LC of 1.0 for human skeletal muscle. We determined the LC for 2-deoxy-[1-(14)C]glucose (2-DG) in 18 normal male subjects (age, 29+/- 2 yr; body mass index, 24.8+/-0.8 kg/m(2)) after an overnight fast and during physiological (1 mU x kg(-1) x min(-1) insulin infusion for 180 min) and supraphysiological (5 mU x kg(-1) x min(-1) insulin infusion for 180 min) hyperinsulinemic conditions. Normoglycemia was maintained with the euglycemic clamp technique. The LC was measured directly with the use of a novel triple tracer-based method. [3-(3)H]glucose, 2-[1-(14)C]DG, and [(12)C]mannitol (Man) were injected as a bolus into the brachial artery. The concentrations of [3-(3)H]glucose and 2-[1-(14)C]DG (dpm/ml plasma) and of Man (micromol/l) were determined in 50 blood samples withdrawn from the ipsilateral deep forearm vein over 15 min after the bolus injection. The LC was calculated by a formula involving blood flow calculated from Man and the Glc(CR) and 2-DG(CR). The LC averaged 1.26+/-0.08 (range 1.06-1.43), 1.15+/-0.05 (0.99-1.39), and 1.18+/-0.05 (0.97-1.37) under fasting conditions and during the 1 and 5 mU x kg(-1). min(-1) insulin infusions (not significant between the different insulin concentrations, mean LC = 1.2, P<0.01 vs. 1.0). We conclude that, in normal subjects, the LC for 2-DG in human skeletal muscle is constant over a wide range of insulin concentrations and averages 1. 2.

Adult↗

PubMed2000

On-line monitoring of intrinsic PEEP in ventilator-dependent patients.

Measurement of the intrinsic positive end-expiratory pressure (PEEP(i)) is important in planning the management of ventilated patients. Here, a new recursive least squares method for on-line monitoring of PEEP(i) is proposed for mechanically ventilated patients. The procedure is based on the first-order model of respiratory mechanics applied to experimental measurements obtained from eight ventilator-dependent patients ventilated with four different ventilatory modes. The model PEEP(i) (PEEP(i,mod)) was recursively constructed on an inspiration-by-inspiration basis. The results were compared with two well-established techniques to assess PEEP(i): end-expiratory occlusion to measure static PEEP(i) (PEEP(i, st)) and change in airway pressure preceding the onset of inspiratory airflow to measure dynamic PEEP(i) (PEEP(i,dyn)). PEEP(i, mod) was significantly correlated with both PEEP(i,dyn) (r = 0.77) and PEEP(i,st) (r = 0.90). PEEP(i,mod) (5.6 +/- 3.4 cmH(2)O) was systematically >PEEP(i,dyn) and PEEP(i,st) (2.7 +/- 1.9 and 8.1 +/- 5.5 cmH(2)O, respectively), in all the models without external PEEP. Focusing on the five patients with chronic obstructive pulmonary disease, PEEP(i,mod) was significantly correlated with PEEP(i,st) (r = 0.71), whereas PEEP(i,dyn) (r = 0.22) was not. When PEEP was set 5 cmH(2)O above PEEP(i,st), all the methods correctly estimated total PEEP, i.e., 11.8 +/- 5.3, 12.5 +/- 5.0, and 12.0 +/- 4.7 cmH(2)O for PEEP(i,mod), PEEP(i,st), and PEEP(i,dyn), respectively, and were highly correlated (0.97-0.99). We interpreted PEEP(i,mod) as the lower bound of PEEP(i,st) and concluded that our method is suitable for on-line monitoring of PEEP(i) in mechanically ventilated patients.

Adult↗

PubMed2000

Severity of HCV-induced liver damage alters glucose homeostasis in noncirrhotic patients with chronic HCV infection.

BACKGROUND/AIMS: To investigate the link between hepatitis C infection and glucose intolerance, we measured insulin sensitivity, glucose effectiveness and beta-cell secretion in noncirrhotic HCV-infected patients with normal glucose tolerance according to WHO criteria as assessed by oral glucose tolerance tests. METHODS: Glucose, insulin and C-peptide data from frequently sampled intravenous glucose tolerance tests were analyzed using the minimal modeling technique for glucose and C-peptide to determine insulin sensitivity, glucose effectiveness, first and second phase insulin secretion in noncirrhotic HCV-infected patients (n = 10) and in healthy control subjects (n = 10). Histological activity index (HAI) as well as the extent of fibrosis were evaluated by scoring liver biopsies. RESULTS: Insulin sensitivity (2.72 +/- 1.63 vs. 6.84 +/- 1. 20 10(-4) min(-1) per microU/ml, p < 0.01) and glucose effectiveness (2.29 +/- 0.45 vs. 2.89 +/- 0.39 10(-2) min(-1), p < 0.05) ere significantly lower in patients with HCV-induced liver disease. Insulin sensitivity was negatively related to serum alanine aminotransferase (r = -0.47, p < 0.05) and aspartate aminotransferase concentrations (r = -0.65, p < 0.05). Multiple linear regression analysis revealed a strong relation of insulin sensitivity with fibrosis score and HAI (r = -0.82, p < 0.02 for both). Second phase insulin secretion was significantly enhanced in HCV-infected patients (14.30 +/- 2.04 vs. 8.29 +/- 1.65 min(-1), p < 0.05). CONCLUSIONS: HCV-infected patients with normal glucose tolerance are insulin and glucose resistant. The impairment of glucose tolerance appears to be closely related with the severity of HCV-induced liver damage.

Adult↗

PubMed2000

Pubertal adolescent male-female differences in insulin sensitivity and glucose effectiveness determined by the one compartment minimal model.

Most studies of insulin sensitivity in puberty have been cross-sectional and have not been able to longitudinally address changes that might occur. In addition, these studies were unable to separate out glucose's ability to stimulate its own disposal (glucose effectiveness, S(G)) from insulin sensitivity (S(I)) or to separate the hepatic and peripheral effects of insulin. To address these problems, we used the frequently sampled i.v. glucose tolerance test with [6,6]D2 glucose to study S(G)* and S(I)* in 24 children (Tanner stage 1-3) at 6-mo intervals over an 18-mo period. Mean overnight GH and fasting GH binding protein (GHBP), IGF-1, and leptin levels were also measured. S(G)* did not differ between the sexes or Tanner stages. S(I)* did not differ between Tanner stages for either sex and was higher in boys than in girls. Hepatic insulin resistance did not differ between sexes or Tanner stages. S(G)* was not related to any of the other variables measured. S(I)* was negatively related to BMI, GHBP, IGF1, and leptin. These results demonstrate that insulin sensitivity is greater in prepubertal and early pubertal boys than in girls and is primarily determined by body mass effects.

Adolescent↗

PubMed2000

Insulin sensitivity from meal tolerance tests in normal subjects: a minimal model index.

In this report a new approach is introduced that allows estimation of insulin sensitivity (S(I)) from orally ingested glucose during an oral glucose tolerance test (OGTT) or a meal glucose tolerance test (MGTT) in normal subjects. The method hinges on the classic minimal model of glucose kinetics that is coupled with an equation describing the rate of appearance of glucose into the circulation after oral glucose ingestion. The model provides an estimate of S(I) in a given individual based on simple area under the curve type of calculations. To prove the reliability of the new approach, MGTT studies performed in 10 normal subjects were analyzed and the S(I) index from the MGTT was compared with the S(I) index obtained in the same subjects from an insulin-modified, frequently sampled iv glucose test (FSIGT). S(I) from the MGTT was 13.6+/-3.9 x 10(-4) dL/kg x min/microU x mL and was strongly correlated to the S(I) from the FSIGT (rs = 0.89; P < 0.01). In conclusion, this study shows that in normal subjects the minimal model can be applied to a MGTT/OGTT to derive an index of insulin sensitivity that is in good agreement with the one estimated from the FSIGT. Due to its simplicity, this method has potential for use in population studies, but further investigation is required to ascertain its applicability to subjects with severe insulin resistance and impaired secretory function.

Area Under Curve↗

PubMed2000

Prandial glucose effectiveness and fasting gluconeogenesis in insulin-resistant first-degree relatives of patients with type 2 diabetes.

Impaired glucose effectiveness (i.e., a diminished ability of glucose per se to facilitate its own metabolism), increased gluconeogenesis, and endogenous glucose release are, together with insulin resistance and beta-cell abnormalities, established features of type 2 diabetes. To explore aspects of the pathophysiology behind type 2 diabetes, we assessed in a group of healthy people prone to develop type 2 diabetes (n = 23), namely first-degree relatives of type 2 diabetic patients (FDR), 1) endogenous glucose release and fasting gluconeogenesis measured using the 2H2O technique and 2) glucose effectiveness. The FDR group was insulin resistant when compared with an age-, sex-, and BMI-matched control group without a family history of type 2 diabetes (n = 14) (M value, clamp: 6.07 +/- 0.48 vs. 8.06 +/- 0.69 mg x kg(-1) lean body weight (lbw) x min(-1); P = 0.02). Fasting rates of gluconeogenesis (1.28 +/- 0.06 vs. 1.41 +/- 0.07 mg x kg(-1) lbw x min(-1); FDR vs. control subjects, P = 0.18) did not differ in the two groups and accounted for 53 +/- 2 and 60 +/- 3% of total endogenous glucose release. Glucose effectiveness was examined using a combined somatostatin and insulin infusion (0.17 vs. 0.14 mU x kg(-1) x min(-1), FDR vs. control subjects), the latter replacing serum insulin at near baseline levels. In addition, a 360-min labeled glucose infusion was given to simulate a prandial glucose profile. After glucose infusion, the integrated plasma glucose response above baseline (1,817 +/- 94 vs. 1,789 +/- 141 mmol/l per 6 h), the ability of glucose to simulate its own uptake (1.50 +/- 0.13 vs. 1.32 +/- 0.16 ml x kg(-1) lbw x min(-1)), and the ability of glucose per se to suppress endogenous glucose release did not differ between the FDR and control group. In conclusion, in contrast to overt type 2 diabetic patients, healthy people at high risk of developing type 2 diabetes are characterized by normal glucose effectiveness at near-basal insulinemia and normal fasting rates of gluconeogenesis.

Adult↗

PubMed1999

Beta-cell function during insulin-modified intravenous glucose tolerance test successfully assessed by the C-peptide minimal model.

The insulin-modified intravenous glucose tolerance test (IM-IVGTT) is increasingly used to measure insulin sensitivity. However, the assessment of beta-cell secretion is usually made using rough indices. The aim here is to evaluate the ability of the minimal model of C-peptide secretion and kinetics recently proposed for the standard IVGTT (S-IVGTT) to also assess beta-cell function during the IM-IVGTT. C-peptide and glucose data from the IM-IVGTT in 15 normal humans were analyzed. The results show that the same rich beta-cell picture from the S-IVGTT can be obtained during an IM-IVGTT. In particular, in each individual, the time course of beta-cell secretion can be reconstructed and the functional indices of glucose control on first-phase (phi1), second-phase (phi2), and basal (phi(b)) insulin secretion can be estimated (phi1 = 191 +/- 29, phi2 = 10.9 +/- 1.4 x 10(-9) x min(-1), and phi(b) = 5.7 +/- 1.0 x 10(-9) x min(-1), mean +/- SE). Finally, the comparison between IM-IVGTT and S-IVGTT phi1, phi2, and phi(b) values suggest they are not affected by insulin administration.

C-Peptide↗

PubMed1999

The monoethylglycinexylidide test for grading of liver cirrhosis.

BACKGROUND: Monoethylglycinexylidide (MEGX) formation following lignocaine injection has recently been proposed as a simple dynamic liver function test based on a single measurement of its serum concentration. AIM: To determine the optimal sampling time for MEGX determination. METHODS: A modelling analysis of lignocaine and MEGX kinetics was performed in seven normals and in four patients with compensated liver cirrhosis; a similar study was performed in 74 cirrhotic patients, divided into two groups according to disease severity (Pugh score). RESULTS: Only the MEGX fractional formation rate (kf) and formation delay (tau) were significantly altered in cirrhotic patients compared to normals: kf = 0.15 +/- 0.03 vs. 0.32 +/- 0.10 min-1 (mean +/- s.d.); tau = 7.7 +/- 2.0 vs. 3.9 +/- 2.9 min-1. A good correlation was found between kf and late (r = 0.82) but not early (r = 0.63) serum MEGX formation, suggesting that late measurements for the clinical MEGX test are preferred. In the second part of our investigation, by discriminant analysis of MEGX test data for 74 cirrhotic patients, the late MEGX concentrations gave the best discrimination between the two classes. In particular, the 60 min MEGX concentration showed the best diagnostic accuracy (81%), sensitivity (75%) and specificity (84%). The association of this with other MEGX parameters, either singly or derived from the whole curve measurements, did not improve the performance of the method. CONCLUSION: The MEGX test, based on a single determination 60 min after lignocaine injection, may be regarded as a simple and sensitive quantitative liver function test.

Adult↗

PubMed1999

Interferon-alpha improves glucose tolerance in diabetic and non-diabetic patients with HCV-induced liver disease.

This pilot study was initiated to evaluate factors controlling glucose tolerance in patients with hepatitis C virus-induced liver disease before and after therapy with recombinant interferon-alpha (r-INF-alpha). Fifteen patients with histologically and serologically proven hepatitis C infection underwent oral and frequently sampled intravenous glucose tolerance tests (FSIGTT) before and after four months of therapy (6 x 106 U r-INF-alpha, subcutaneously, three times a week). Glucose, insulin and C-peptide data from FSIGTT were analysed using the minimal modeling technique to determine insulin sensitivity, glucose effectiveness and first and second phase insulin secretion. According to the WHO criteria 13 patients, had normal glucose tolerance; diabetes mellitus was diagnosed in 2 patients. In the morning following the last r-INF-alpha injection four months later, insulin sensitivity improved significantly in hepatitis C virus-infected patients with normal glucose tolerance (2.17 +/- 0.37 vs. 6.18 +/- 0.94 10(-4) min(-1) per microU/ml, p < 0.001) and with diabetes mellitus (0.86 to 2.61; 0.46 to 1.06 10(-4) min(-1) per microU/ml). This effect was independent of the extent of fibrosis, virus load before treatment and therapy response. First phase insulin secretion increased in non-diabetic (139.2 +/- 17.1 vs. 200.0 +/- 32.7, p < 0.05) and diabetic patients with HCV infection (55.24 to 118.5; 84.23 to 261.1). Moreover, free fatty acid concentrations in all HCV-infected patients were significantly reduced (0.48 +/- 0.01 vs 0.21 +/- 0.03 mmol/l, p < 0.01). Therapy with recombinant interferon-alpha is associated with an amelioration of glucose tolerance in non-diabetic and diabetic HCV-infected patients.

Adult↗

PubMed1999

Glucose effectiveness and insulin sensitivity from the minimal models: consequences of undermodeling assessed by Monte Carlo simulation.

The unlabeled (cold) minimal model (MM) and the labeled (hot) minimal model (HMM) are a powerful tool to investigate in vivo metabolism from a standard intravenous glucose tolerance test (IVGTT) or hot IVGTT (HIVGTT). They allow to estimate metabolic indexes of the glucose-insulin system, namely glucose effectiveness (GE) and insulin sensitivity (IS) (of uptake and production those of MM, and of uptake only those of HMM). Here, the consequences of the single-compartment glucose kinetics approximation used in the MM's are investigated via Monte Carlo simulation, using a physiologic reference model (RM) of the system. RM allows to generate noisy synthetic plasma concentrations of glucose, tracer glucose, and insulin during IVGTT and HIVGTT, which are then analyzed with MM and HMM. The MM and HMM GE and IS are then compared with the RM ones. Results of 400 runs show that: 1) correlation of MM GE with the RM index is weak; 2) MM IS is well correlated with the RM index, but severely underestimates it; 3) HMM clearance rate is correlated with RM clearance; and 4) HMM IS is well correlated and only slightly overestimates the RM index. These results demonstrate that GE of MM is most affected by the single-compartment approximation and the indexes of HMM are more robust than those of MM.

Blood Glucose↗

PubMed1999

Glucose production during an IVGTT by deconvolution: validation with the tracer-to-tracee clamp technique.

Recently, a new method, based on a two-compartment minimal model and deconvolution [A. Caumo and C. Cobelli. Am. J. Physiol 264 (Endocrinol. Metab. 37): E829-E841, 1993; P. Vicini, G. Sparacino, A. Caumo, and C. Cobelli. Comput. Meth. Prog. Biomed. 52: 147-156, 1997], has been proposed to estimate endogenous glucose production (EGP) from labeled intravenous glucose tolerance test (IVGTT) data. Our aim here is to compare this EGP profile with that independently obtained with the reference method, based on the tracer-to-tracee ratio (TTR) clamp. An insulin-modified (0.03 U/kg body wt infused over 5 min) [6,6-2H2]glucose-labeled IVGTT (0.33 g/kg of glucose) was performed in 10 normal subjects. A second tracer ([U-13C]glucose) was also infused during the test in a variable fashion to clamp endogenous glucose TTR. The TTR clamp was quite successful. As a result, the EGP profile, reconstructed from [U-13C]glucose data with the models of Steele and Radziuk, were almost superimposable. The deconvolution-obtained EGP profile, calculated from [6,6-2H2]glucose data, showed remarkable agreement with that obtained from the TTR clamp. Some differences between the two profiles were noted in the estimated basal EGP and in the initial modalities of EGP inhibition. A high interindividual variability was also observed with both methods in the resumption of EGP to baseline; variability was high in both the timing and the extent of resumption. In conclusion, the use of the two-compartment minimal model of the IVGTT and deconvolution allows the estimation of a profile of EGP that is in very good agreement with that independently obtained with a TTR clamp.

Adult↗

PubMed1999

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

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 (SG*) and insulin sensitivity (SI*) 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*, and 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.

Glucose↗