Minimal Model Of Glucose Kinetics Research Articles

Control of Augmented Minimal Model for Glucose Insulin Pump

A control system can only be used in the form of closed-loop control to stabilize the system. The concept of controllability and observability for the linearized control system of human glucose insulin systems is used so that we can have a feedback control. We have treated an existing model i.e. Augmented minimal model of glucose kinetics for type 1 diabetes.

C-Peptide-based assessment of insulin secretion in the Zucker Fatty rat: a modelistic study.

A C-peptide-based assessment of β-cell function was performed here in the Zucker fatty rat, a suitable animal model of human metabolic syndrome. To this aim, a 90-min intravenous glucose tolerance test (IVGTT) was performed in seven Zucker fatty rats (ZFR), 7-to-9week-old, and seven age-matched Zucker lean rats (ZLR). The minimal model of C-peptide (CPMM), originally introduced for humans, was adapted to Zucker rats and then applied to interpret IVGTT data. For a comprehensive evaluation of glucose tolerance in ZFR, CPMM was applied in combination with the minimal model of glucose kinetics (GKMM). Our results showed that the present CPMM-based interpretation of data is able to: 1) provide a suitable fit of C-Peptide data; 2) achieve a satisfactory estimation of parameters of interest 3) quantify both insulin secretion by estimating the time course of pre-hepatic secretion rate, SR(t), and total insulin secretion, TIS, and pancreatic sensitivity by means of three specific indexes of β-cell responsiveness to glucose stimulus (first-phase, Ф1, second-phase, Ф2, and steady-state, Фss, never assessed in Zucker rats before; 4) detect the significant enhancement of insulin secretion in the ZFR, in face of a severe insulin-resistant state, previously observed only using a purely experimental approach. Thus, the methodology presented here represents a reliable tool to assess β-cell function in the Zucker rat, and opens new possibilities for the quantification of further processes involved in glucose homeostasis such as the hepatic insulin degradation.

Assessment of hepatic insulin degradation, in normoglycemic hypertensive patients, by minimal modelling of standard intravenous glucose tolerance test data

Role of hepatic insulin degradation in modulating insulin delivery to peripheral circulation, in insulin-resistant hypertensive patients, is not yet fully understood. This issue was investigated here by a novel application to hypertension of a previously proposed minimal modelling of insulin and C-peptide data, using population values for insulin and C-peptide kinetics parameters. Data, from frequently sampled intravenous glucose tolerance test (FSIGTT), were analysed in ten normoglycemic, hypertensive patients (H-group), compared with eight normoglycemic, normotensive subjects (N-group), matched for age, gender and body mass index. Minimal modelling of C-peptide and insulin data provided β-cell responsiveness to glucose perturbation (first, Φ 1, second, Φ 2, and basal, Φ b , phase), insulin secretion rate, ISR( t) and total pre-hepatic insulin secretion, TIS, as well as insulin delivery rate, IDR( t), and total insulin delivery, TID, into plasma, over 5-h test. Instantaneous normalized hepatic insulin degradation rate was computed as HIDR( t) = 1 − [ IDR( t)/ ISR( t)]. In our H-group, insulin sensitivity, S I , assessed by minimal model of glucose kinetics, showed a 56% reduction, which confirmed deterioration of insulin action in hypertension. This was associated with significant increase in Φ 1 (105%), TIS (55%) and TID (62%). No significant alterations were observed in other characteristic parameters of secretion and hepatic degradation of insulin, such that no significant difference was observed in HIDR( t) between our H and N groups. In conclusion, an increase of first phase and total insulin secretion occurring, in our H-group, in the presence of no alteration of hepatic insulin degradation, resulted in up-regulation of total insulin delivered to plasma ( TID) for insulin-resistance compensation.

Hostility and Minimal Model of Glucose Kinetics in African American Women

To explore the underlying physiology of hostility (HOST) and to test the hypothesis that HOST has a greater impact on fasting glucose in African American (AA) women than it does on AA men or white men or women, using an intravenous glucose tolerance test (IVGTT) and the minimal model of glucose kinetics. A total of 115 healthy subjects selected for high or low scores on the 27 item Cook Medley HOST Scale underwent an IVGTT. Fasting nonesterified fatty acids (NEFA) levels were measured before the IVGTT. Catecholamine levels were measured 10 minutes into the IVGTT. Moderation by group (AA women versus others) of HOST was found for glucose effectiveness (Sg, p = .02), acute insulin response (AIRg, p = .02), and disposition index (DI, p = .02). AA women showed a negative association between HOST and both Sg (beta = -0.45, p = .04) and DI (beta = -0.49, p = .02), controlling for age and body mass index. HOST was also associated with changes in epinephrine (beta = 0.39, p = .05) and fasting NEFA (beta = 0.44, p = .02) in the AA women. Controlling for fasting NEFA reduced the effect of HOST on both Sg and DI. This study shows that HOST is related to decreased DI, a measure of pancreatic compensation for increased insulin resistance as well as decreased Sg, a measure of noninsulin-mediated glucose transport compared in AA women. These effects are partly mediated by the relationship of HOST to fasting NEFA.

The Effect of Age on Insulin Sensitivity and Insulin Secretion in First-Degree Relatives of Type 1 Diabetic Patients: A Population Analysis

Understanding the role of insulin resistance in type 1 diabetes may lead to new prevention strategies. Estimates of insulin resistance in first-degree relatives of those with type 1 diabetes may be obtained using the minimal model of glucose kinetics incorporating a population approach. The objective of the study was to explore parameters contributing to glucose homeostasis in a cross-sectional study of first-degree relatives across a wide age range. Insulin sensitivity (SI) was assessed using the minimal model of glucose kinetics after an oral glucose tolerance test combined with nonlinear mixed-effects modeling. Beta-cell function was measured from the insulinogenic index at 30 min (IGI(30)). Disposition index (DI) was estimated as the product of SI and IGI(30). The study was conducted at an academic center. Subjects included 1241 first-degree relatives (aged 2-75 yr). SI was found to be negatively correlated with age, whereas IGI(30) increased until young adulthood. The increase IGI(30) was apparently insufficient to compensate for the insulin resistance because DI decreased linearly at the rate of 0.035 (10(-2) min(-1) mmol(-1) liter per year) after young adulthood. Both IGI(30) and DI were significantly lower in those with vs. without autoantibodies, whereas there was no difference between these groups with respect to SI. Beta-cell function, adjusted for age-related insulin resistance, decreases throughout life in first-degree relatives. This deterioration may be exacerbated in the presence of autoantibodies. Oral glucose tolerance test data combined with a nonlinear mixed-effect modeling population approach may be a useful technique to evaluate SI and secretion in a population.

Age‐related analysis of insulin resistance, body weight and arterial pressure in the Zucker fatty rat

The evolution with ageing of insulin resistance, body weight (BW) and mean arterial pressure (MAP) was studied in a group of Zucker fatty rats (ZFRs, n = 22), between 7 and 16 weeks of age, compared with an age-matched control group of Zucker lean rats (ZLRs, n = 22). The minimal model of glucose kinetics was applied to estimate glucose effectiveness, S(G), and insulin sensitivity, S(I), from insulinaemia and glycaemia measured during a 70 min intravenous glucose tolerance test. No correlation was found between S(G) and age in both ZFR and ZLR groups. No significant changes in mean S(G) between the two groups indicated no alteration of glucose-mediated glucose disposal. Estimates of S(I) from individual ZFRs were independent of age and, on average, showed 83% reduction (P < 0.001) compared with the ZLR group. Despite the lack of alteration of S(I) with age, the ZFR group showed an age-related increase of MAP, which correlated with increasing BW (r = 0.71 and P < 0.001). These results support the hypothesis that in our ZFRs, as a suitable genetic model of obesity and hypertension, insulin resistance is fully established at the age of 7 weeks and remains practically unaltered until at least the sixteenth week. An age-related increase in arterial pressure, observed in this strain, relates more properly to increasing BW, rather than insulin resistance. Development of hypertension with increasing age and BW may result from an enhanced insulin-mediated activity of the sympathetic nervous system, as observed in our previously reported study.

Use of oral glucose minimal model–derived index of insulin sensitivity in subjects with early type 1 diabetes mellitus

Insulin resistance plays an important role during various stages of the type 1 diabetes mellitus disease process. Unfortunately, many of the techniques used to measure insulin sensitivity are experimentally laborious and time-consuming and are thus impractical for larger clinical and population studies. Therefore, in this study, we obtain estimates of insulin sensitivity from a simpler experiment, the oral glucose tolerance test (OGTT), and compare them with those from a frequently sampled intravenous glucose tolerance test (FSIGT) in a population of subjects defined as having early type 1 diabetes mellitus (abnormal 2-hour glucose on OGTT) and a group of healthy controls. A total of 19 subjects were studied. Eight antibody-positive first- or second-degree relatives of patients with type 1 diabetes mellitus and 11 healthy controls underwent both a 3-hour OGTT and an insulin-modified FSIGT on separate days. Indices of insulin sensitivity ( S I) were estimated from the recently derived oral glucose minimal model and the original minimal model of glucose kinetics for the OGTT and FSIGT, respectively. Estimates of S I from the OGTT correlated closely with those from the FSIGT in both early type 1 diabetes mellitus ( r s=0.76, P = .04) and healthy control ( r s = 0.67, P = .03) populations. This preliminary study demonstrates the usefulness of OGTT-derived estimates of insulin sensitivity in an early type 1 diabetes mellitus population. Given the simplicity of the OGTT relative to the traditional methods of measuring S I, the oral glucose minimal model may be appropriate for large population studies and clinical trials.

Physical activity-the major unaccounted impediment to closed loop control.

This article presents a mathematical model of glucose homeostasis that is valid during physical activity. Known changes in glucose dynamics during exercise were accounted for in the model, and exercise itself was detected and quantified through heart rate (beats per minute). The model was successfully fit to 21 type 1 diabetic subjects during a hyperinsulemic clamp protocol, and performance of the new model was compared with the standard minimal model of glucose kinetics that it was derived from.

Grey-box Modelling of Pharmacokinetic /Pharmacodynamic Systems

Grey-box pharmacokinetic/pharmacodynamic (PK/PD) modelling is presented as a promising way of modelling PK/PD systems. The concept behind grey-box modelling is based on combining physiological knowledge along with information from data in the estimation of model parameters. Grey-box modelling consists of using stochastic differential equations (SDEs) where the stochastic term in the differential equations represents unknown or incorrectly modelled dynamics of the system. The methodology behind the grey-box PK/PD modelling framework for systematic model improvement is illustrated using simulated data and furthermore applied to Bergman's minimal model of glucose kinetics using clinical data from an intravenous glucose tolerance test (IVGTT). The grey-box estimates of the stochastic system noise parameters indicate that the glucose minimal model is too simple and should preferably be revised in order to describe the complicated in vivo system of insulin and glucose following an IVGTT.

Population and individual minimal modeling of the frequently sampled insulin-modified intravenous glucose tolerance test

Population approaches are more robust estimators of insulin sensitivity (S I) and glucose effectiveness (S G) with the minimal model of glucose kinetics during an intravenous glucose tolerance test (IVGTT). We assessed the performance of 3 population methods, iterative two-stage (ITS), Bayesian hierarchical Markov chain Monte Carlo (MCMC), and NONMEM first-order conditional estimation (FOCE) with interaction (NM), and made a comparison with the standard two-stage method (STS) employing the weighted nonlinear regression analysis. To evaluate accuracy of individual and population estimates, 40 simulated insulin-modified frequently sampled IVGTTs (IM-FSIVGTT) were derived from real IM-FSIVGTTs (0.3 g glucose per kg body weight with 0.02 U/kg insulin at 20 minutes; 30 samples over 180 minutes) performed in 40 healthy Caucasian subjects (male/female, 22/18; age, 46 ± 9 years; body mass index [BMI], 26.7 ± 5.7 kg · m −2; mean ± SD). The population methods assumed a log-normal population distribution of parameters. All methods gave a similar but overestimated population S G by 9% to 13%. Population S I was underestimated to a different degree by the methods (STS 6%, ITS 10%, MCMC 13%, and NM 7%). The between-subject variability of S G was overestimated by STS and underestimated by the population methods (true 33%, STS 40%, ITS 19%, MCMC 24%, NM 24%; coefficient of variation). For S I, this quantity was well estimated by all methods (true 79%, STS 80%, ITS 82%, MCMC 83%, NM 82%). The results for individual estimates indicate that STS performs better than the population methods when estimating S I (STS 12%, ITS 16%, MCMC 16%, NM 16%; 1 outlying subject excluded; root mean squared error expressed as percent of mean) but worse for S G (STS 28%, ITS 21%, MCMC 20%, NM 19%). We conclude that the robust performance of population approaches, preventing parameter estimation failures associated with the nonlinear regression analysis, is not required with IM-FSIVGTT in subjects with normal glucose tolerance. The standard two-stage technique is the preferred method under such circumstances.

Dietary Restriction and Beta-Cell Sensitivity to Glucose in Adult Male Rhesus Monkeys

We examined the effects of dietary restriction (DR) and age on ss-cell function and peripheral insulin sensitivity in rhesus monkeys. A semipurified diet was provided either ad libitum for approximately 8 hours/day to controls (C) or as approximately 70% of baseline intake to restricted (R) animals for 10 years. The minimal model of C-peptide secretion and kinetics and the labeled 2-compartment minimal model of glucose kinetics were identified using plasma glucose, C-peptide, and insulin concentrations during an intravenous glucose tolerance test. R monkeys had less body fat, lower basal ss-cell sensitivity to glucose (Ø(b)), greater insulin sensitivity, and lower first-phase plasma insulin response. DR did not significantly affect first-phase and second-phase ss-cell sensitivity to glucose. Indices of body fatness were highly predictive of the effect of DR on Ø(b), fasting insulin concentration and insulin responses to glucose. Enhanced peripheral insulin sensitivity among R monkeys was strongly correlated with lower Ø(b).

Numerical non-identifiability regions of the minimal model of glucose kinetics: superiority of Bayesian estimation

The so-called minimal model (MM) of glucose kinetics is widely employed to estimate insulin sensitivity ( S I) both in clinical and epidemiological studies. Usually, MM is numerically identified by resorting to Fisherian parameter estimation techniques, such as maximum likelihood (ML). However, unsatisfactory parameter estimates are sometimes obtained, e.g. S I estimates virtually zero or unrealistically high and affected by very large uncertainty, making the practical use of MM difficult. The first result of this paper concerns the mathematical demonstration that these estimation difficulties are inherent to MM structure which can expose S I estimation to the risk of numerical non-identifiability. The second result is based on simulation studies and shows that Bayesian parameter estimation techniques are less sensitive, in terms of both accuracy and precision, than the Fisherian ones with respect to these difficulties. In conclusion, Bayesian parameter estimation can successfully deal with difficulties of MM identification inherently due to its structure.

Age‐Related Analysis of Glucose Metabolism in Spontaneously Hypertensive and Normotensive Rats

This study was designed to investigate the effect of both hypertension and ageing on the efficiency of glucose metabolism. A 12-sample, 120 min intravenous glucose tolerance test (IVGTT) was applied to 36 rats: two groups of nine young (12 weeks) spontaneously hypertensive and Wistar Kyoto rats (Y-SHR and Y-WKY group, respectively) and two groups of nine old (40 weeks) SHR and WKY rats (O-SHR and O-WKY group, respectively). Insulinaemia and glycaemia data were interpreted in terms of estimates of glucose effectiveness, S(G), and insulin sensitivity, S(I), provided by the minimal model of glucose kinetics. The possible link between insulin resistance and hypertension was investigated by comparing Y-SHR vs. Y-WKY and O-SHR vs. O-WKY groups. Comparison of O-SHR vs. Y-SHR and O-WKY vs. Y-WKY groups enabled us to investigate the role of age in the development of abnormalities in glucose metabolism. No significant differences (P > 0.05) were observed in the mean S(G) and S(I) estimates between SHR and age-matched WKY groups. This finding indicates that exposure of SHR to high blood pressure levels does not necessarily lead to the development of insulin resistance and impaired glucose effectiveness. Similarly, no significant differences (P > 0.05) were observed in S(G) and S(I) estimates between old and young SHR and WKY groups. This finding indicates that, in this animal model of hypertension, insulin sensitivity and glucose effectiveness do not even deteriorate with ageing.

Effects of GLP-1-(7-36)NH2, GLP-1-(7-37), and GLP-1- (9-36)NH2 on intravenous glucose tolerance and glucose-induced insulin secretion in healthy humans.

Glucagon-like peptide 1 (GLP-1) is an insulin secretagogue synthesized in the intestine and released in response to meal ingestion. It is secreted primarily in two forms, GLP-1-(7-37) and GLP-1-(7-36)NH(2), both of which bind to a specific GLP-1 receptor (GLP-1r) on the pancreatic beta-cell and augment glucose-stimulated insulin secretion. Once secreted, GLP-1-(7-36)NH(2) is rapidly metabolized to GLP-1-(9-36)NH(2), which is the predominant form of GLP-1 in postprandial plasma because of its relatively slower clearance. Although no clear biological role for GLP-1-(9-36)NH(2) in humans has been identified, recent studies in animals suggest two potential effects: to antagonize the effects of intact GLP-1 and to promote glucose disappearance in peripheral tissues. In the studies reported here we compared the independent effects of GLP-1-(7-36)NH(2), GLP-1-(7-37), and GLP-1-(9-36)NH(2) on parameters of iv glucose tolerance and determined whether GLP-1-(9-36)NH(2) inhibits the insulinotropic actions of GLP-1. Ten healthy subjects underwent 4 separate frequently sampled iv glucose tolerance tests during infusions of GLP-1-(7-37), GLP-1-(7-36)NH(2), GLP-1-(9-36)NH(2), or saline. Results from the iv glucose tolerance test were used to obtain indexes of beta-cell function (acute insulin response to glucose) and iv glucose tolerance (glucose disappearance constant), and the minimal model of glucose kinetics was used to obtain indexes of glucose effectiveness and insulin sensitivity. Compared with control studies, both GLP-1-(7-36)NH(2) and GLP-1-(7-37) significantly increased acute insulin response to glucose, glucose disappearance constant, glucose effectiveness, and glucose effectiveness at zero insulin, but did not change the insulin sensitivity index. In contrast, none of the parameters of glucose tolerance was measurably affected by GLP-1-(9-36) amide. In a second set of experiments, 10 healthy subjects had glucose-stimulated insulin secretion measured during an infusion of GLP-1-(7-36)NH(2) alone or with a simultaneous infusion of GLP-1-(9-36)NH(2) that increased plasma levels approximately 10-fold over those produced by unmetabolized GLP-1. Augmentation of glucose-stimulated insulin secretion by GLP-1-(7-36)NH(2) was not altered by the coadministration of GLP-1-(9-36)NH(2). Based on these results we conclude that GLP-1-(9-36)NH(2) does not regulate insulin release or glucose metabolism in healthy humans.

Measurement of insulin sensitivity indices using 13C-glucose and gas chromatography/combustion/isotope ratio mass spectrometry.

Important aspects of glucose metabolism can be quantified by using the minimal model of glucose kinetics to interpret the results of intravenous glucose tolerance tests. The power of this methodology can be greatly increased by the addition of stable isotopically labelled tracer to the glucose bolus dose. This allows the separation of glucose disposal from endogenous glucose production and also increases the precision of the estimates of the physiological parameters measured. Until now the tracer of choice has been deuteriated glucose and the analytical technique has been gas chromatography/mass spectrometry (GC/MS). The consequence of this choice is that nearly 2 g of labelled material are needed and this makes the test expensive. We have investigated the use of (13)C-labelled glucose as the tracer in combination with gas chromatography/combustion/isotope ratio mass spectrometry (GC/C/IRMS) as the analytical technique. This methodology offers superior analytical precision when compared with the conventional method and so the amount of tracer used, and hence the cost, can be reduced considerably. Healthy non-obese male volunteers were recruited for a standard intravenous glucose tolerance test (IVGTT) protocol but 6,6-(2)H-glucose and 1-(13)C-glucose were administered simultaneously. Tracer/tracee ratios were derived from isotope ratio measurements of plasma glucose using both GC/MS and GC/C/IRMS. The results of these determinations indicated that the two tracers behaved identically under the test protocol. The combination of these results with plasma glucose and insulin concentration data allowed determination of the minimal model parameters S*g and S*i. The parameter relating to insulin-assisted glucose disposal, S*i, was found to be the same in the two techniques, but this was not the case for the non-insulin-dependent parameter S*g.

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.

Insulin Sensitivity and Glucose Effectiveness Estimated by the Minimal Model Technique in Spontaneously Hypertensive and Normal Rats

This study was performed to compare glucose metabolism in anaesthetised spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY) in an attempt to clarify whether this animal model of hypertension approximates the insulin-resistant state seen in human hypertension. With this aim the minimal model of glucose kinetics was applied to glucose and insulin data derived from a 12-sample, 120 min intravenous glucose tolerance test (IVGTT) performed in ten SHR and nine WKY rats under pentobarbital anaesthesia. This method provided two metabolic indices: the glucose effectiveness, SG, which quantifies the ability of glucose per se to enhance its rate of disappearance and to inhibit hepatic glucose production, and the insulin sensitivity, SI, which measures the ability of insulin to enhance plasma glucose disappearance and to inhibit hepatic glucose production. Systolic and diastolic arterial pressures in the SHR group were significantly higher (P < 0.0005) than in the WKY group. Mean SG and SI estimates from the SHR group (SG = 16.2 (± 2.0) × 10-2 dl min-1 kg-1 and SI = 12.5 (± 1.9) × 10-4 dl min-1 kg-1 (μU ml-1)-1) were not significantly different (P > 0.05) from mean estimates that characterised the WKY group (SG = 13.1 (± 1.5) × 10-2 dl min-1 kg-1 and SI = 15.8 (± 4.3) × 10-4 dl min-1 kg-1 (μU ml-1)-1). This result is in contrast with reported findings from humans in which insulin sensitivity is significantly reduced in the presence of hypertension.

Insulin sensitivity and glucose effectiveness estimated by the minimal model technique in spontaneously hypertensive and normal rats.

This study was performed to compare glucose metabolism in anaesthetised spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY) in an attempt to clarify whether this animal model of hypertension approximates the insulin-resistant state seen in human hypertension. With this aim the minimal model of glucose kinetics was applied to glucose and insulin data derived from a 12-sample, 120 min intravenous glucose tolerance test (IVGTT) performed in ten SHR and nine WKY rats under pentobarbital anaesthesia. This method provided two metabolic indices: the glucose effectiveness, S(G), which quantifies the ability of glucose per se to enhance its rate of disappearance and to inhibit hepatic glucose production, and the insulin sensitivity, S(I), which measures the ability of insulin to enhance plasma glucose disappearance and to inhibit hepatic glucose production. Systolic and diastolic arterial pressures in the SHR group were significantly higher (P < 0.0005) than in the WKY group. Mean S(G) and S(I) estimates from the SHR group (S(G) = 16.2 (+/- 2.0) x 10(-2) dl x min(-1) x kg(-1) and S(I) = 12.5 (+/- 1.9) x 10(-4) dl x min(-1) x kg(-1) (microU ml(-1))(-1)) were not significantly different (P > 0.05) from mean estimates that characterised the WKY group (S(G) = 13.1 (+/- 1.5) x 10(-2) dl x min(-1) x kg(-1) and S(I) = 15.8 (+/- 4.3) x 10(-4) dl x min(-1) x kg(-1) (microU ml(-1))(-1)). This result is in contrast with reported findings from humans in which insulin sensitivity is significantly reduced in the presence of hypertension.

A fasting glucose to insulin ratio is a useful measure of insulin sensitivity in women with polycystic ovary syndrome.

Women with polycystic ovary syndrome (PCOS) are profoundly insulin resistant, and the resultant hyperinsulinemia exacerbates the reproductive abnormalities of the syndrome. Agents that ameliorate insulin resistance and reduce circulating insulin levels could provide a new therapeutic modality for PCOS. Identifying the subset of PCOS women who are most insulin resistant may therefore be useful for selecting women who will respond to this therapy. We examined the correlation of basal and oral glucose-stimulated glucose and insulin levels and fasting and stimulated glucose/insulin (G:I) ratios with parameters of insulin sensitivity obtained by frequently sampled i.v. glucose tolerance test (FSIGT) to assess whether there is a simple screening test for insulin resistance in PCOS. Forty PCOS women (aged 18-40 yr; body mass index, >26 kg/m2) and 15 control women matched for age, weight, and ethnicity underwent both a 75-g oral glucose tolerance test (OGTT) and a FSIGT. The insulin sensitivity index (S(I)) was calculated by application of the minimal model of glucose kinetics to the dynamics of plasma glucose and insulin levels during the FSIGT. The best correlation in PCOS between S(I) and a fasting level was found with fasting G:I ratios (r = 0.73; P < 0.0001). A less substantial, but significant, correlation was found with fasting insulin levels (r = 0.50; P < 0.001), and no significant correlation was found with fasting glucose levels (r = 0.24; P = NS). The fasting G:I was more strongly correlated with S(I) than with integrated glucose and insulin responses during the OGTT. The only stronger correlation was with the OGTT 2 h G:I ratio (r = 0.74; P < 0.001). Stepwise regression analysis with S(I) as the dependent variable and fasting glucose and insulin levels, area under the curve for glucose and insulin, and a fasting G:I ratio showed that only the fasting G:I ratio was significantly predictive of S(I) in the model (F to remove value = 38.1; P < 0.001). When viewed as a screening test for insulin resistance in PCOS, setting a value of the fasting G:I ratio of less than 4.5 as abnormal (using an S(I) value below the 10th percentile of our control population as evidence for insulin resistance), the sensitivity of a fasting G:I ratio was 95%, the specificity was 84%, the positive predictive value was 87%, and the negative predictive value was 94%. Receiver operator curve analysis showed that this fasting G:I ratio was the single best screening measure for detecting insulin resistance. We conclude that a fasting G:I ratio may be useful as a screening test for insulin resistance in obese non-Hispanic white PCOS women. This may be a clinically useful parameter for selecting PCOS women most likely to respond to therapeutic interventions that improve insulin sensitivity.

Changes in insulin sensitivity, glucose effectiveness, and B-cell function in regularly exercising subjects

To determine the relative contributions of changes in glucose effectiveness, B-cell function, and insulin sensitivity to changes in glucose tolerance upon exercise cessation in regularly exercising individuals, we studied seven young subjects who were performing aerobic exercise on a regular schedule. Each subject was studied 12 and 84 hours after the last bout of exercise with an intravenous glucose tolerance test (IVGTT) to quantify insulin sensitivity and glucose effectiveness at zero insulin (GEZI) using the minimal model of glucose kinetics. Additionally, B-cell function was quantified as the acute insulin response to glucose (AIRglucose), and intravenous glucose tolerance as the glucose disappearance constant ( K g ). Twelve hours after the last bout of exercise, S l was 8.47 ± 1.12 × 10 −5 min −1/pmol/L, as compared with 6.98 ± 1.17 × 10 −5 min −1/pmol/L 84 hours after exercise (mean ± SE, P = .005). No change was observed in GEZI (0.020 ± 0.004 min −1 at 12 hours v 0.019 ± 0.002 min −1 at 84 hours, P = NS) or AIRglucose (588 ± 213 pmol/L at 12 hours v 687 ± 271 pmol/L at 84 hours, P = NS). Thus, the difference in intravenous glucose tolerance observed 12 hours after exercise as compared with 84 hours after the last bout of exercise ( K g , 2.91 ± 0.70 %/min at 12 hours v 2.23 ± 0.60 %/min at 84 hours, P < .05) would appear to be entirely related to a difference in S l and not to differences in glucose effectiveness or B-cell function.