Precision and accuracy of hyperglycemic clamps in a multicenter study.

Application of glucose clamp methodologies in multicenter studies brings challenges for standardization. The Restoring Insulin Secretion (RISE) Consortium implemented a hyperglycemic clamp protocol across seven centers using a combination of technical and management approaches to achieve standardization. Two-stage hyperglycemic clamps with glucose targets of 200 mg/dL and >450 mg/dL were performed utilizing a centralized spreadsheet-based algorithm that guided dextrose infusion rates using bedside plasma glucose measurements. Clamp operators received initial and repeated training with ongoing feedback based on surveillance of clamp performance. The precision and accuracy of the achieved stage-specific glucose targets were evaluated, including differences by study center. We also evaluated robustness of the method to baseline physiologic differences and on-study treatment effects. The RISE approach produced high overall precision (3%-9% variance in achieved plasma glucose from target at various times across the procedure) and accuracy (SD < 10% overall). Statistically significant but numerically small differences in achieved target glucose concentrations were observed across study centers, within the magnitude of the observed technical variability. Variation of the achieved target glucose over time in placebo-treated individuals was low (<3% variation), and the method was robust to differences in baseline physiology (youth vs. adult, IGT vs. diabetes status) and differences in physiology induced by study treatments. The RISE approach to standardization of the hyperglycemic clamp methodology across multiple study centers produced technically excellent standardization of achieved glucose concentrations. This approach provides a reliable method for implementing glucose clamp methodology across multiple study centers.NEW & NOTEWORTHY The Restoring Insulin Secretion (RISE) study centers undertook hyperglycemic clamps using a simplified methodology and a decision guidance algorithm implemented in an easy-to-use spreadsheet. This approach, combined with active management including ongoing central data surveillance and routine feedback to study centers, produced technically excellent standardization of achieved glucose concentrations on repeat studies within and across study centers.

Hyperinsulinaemic-hypoglycaemic glucose clamps in human research: a systematic review of the literature.

AIMS/HYPOTHESIS: The hyperinsulinaemic-hypoglycaemic glucose clamp technique has been developed and applied to assess effects of and responses to hypoglycaemia under standardised conditions. However, the degree to which the methodology of clamp studies is standardised is unclear. This systematic review examines how hyperinsulinaemic-hypoglycaemic clamps have been performed and elucidates potential important differences. METHODS: A literature search in PubMed and EMBASE was conducted. Articles in English published between 1980 and 2018, involving adults with or without diabetes, were included. RESULTS: A total of 383 articles were included. There was considerable variation in essential methodology of the hypoglycaemic clamp procedures, including the insulin dose used (49-fold difference between the lowest and the highest rate), the number of hypoglycaemic steps (range 1-6), the hypoglycaemic nadirs (range 2.0-4.3 mmol/l) and the duration (ranging from 5 to 660 min). Twenty-seven per cent of the articles reported whole blood glucose levels, most venous levels. In 70.8% of the studies, a dorsal hand vein was used for blood sampling, with some form of hand warming to arterialise venous blood in 78.8% of these. Key information was missing in 61.9% of the articles. CONCLUSIONS/INTERPRETATION: Although the hyperinsulinaemic-hypoglycaemic clamp procedure is considered the gold standard to study experimental hypoglycaemia, a uniform standard with key elements on how to perform these experiments is lacking. Methodological differences should be considered when comparing results between hypoglycaemic clamp studies. PROSPERO REGISTRATION: This systematic review is registered in PROSPERO (CRD42019120083).

Normalization of metabolic flux data during clamp studies in humans.

BACKGROUND: There is no consensus in the field regarding the optimal method for the expression of metabolic flux data, such as glucose disposal rates during hyperinsulinemic-euglycemic clamp experiments. Several normalization methods are in use today, but their impact on study outcomes is rarely discussed. METHODS: We illustrate this issue using clamp data from 92 lean and 66 obese subjects. Glucose kinetics and insulin sensitivity were determined during hyperinsulinemic-euglycemic clamp studies using [6,6-2H2]glucose. From this single dataset, we calculated 21 expression methods for the glucose disposal rate during hyperinsulinemic conditions. RESULTS AND DISCUSSION: With most normalization methods, the obese subjects demonstrated reduced insulin-stimulated glucose disposal as compared to the lean subjects. However, depending on the normalization method, glucose disposal rates in obese subjects ranged from 26 ±â€¯1% to 207 ±â€¯10% of glucose disposal rates in lean subjects. We conclude that data normalization methods greatly impacted metabolic flux outcomes in our dataset of lean and obese subjects. There is no compelling evidence to select one method over the other, but we encourage authors in the metabolic arena to think about, and provide a rationale for, the best normalization method for their specific research questions.

Screening for a Simple and Effective Indicator of Insulin Resistance in Chinese Reproductive-Aged Women, with the Insulin Clamp Technique as a Reference.

Background: Applying the hyperinsulinemic-euglycemic clamp to estimate insulin resistance (IR) is accurate but time-consuming, so identifying a simple and effective index for IR is vitally important. The present study aimed to compare the lipid accumulation product (LAP), visceral adiposity index (VAI), body mass index (BMI), waist circumference (WC), homeostasis model assessment of insulin resistance (HOMA-IR), and Chinese visceral adiposity index (CVAI) using the hyperinsulinemic-euglycemic clamp as a reference and to screen a simple and effective indicator for IR in Chinese women of childbearing age. Methods: The present study included a cross-sectional study of 537 reproductive-aged women and an interventional study of 90 randomly chosen polycystic ovarian syndrome (PCOS) women. Physical, laboratory, and hyperinsulinemic-euglycemic clamp were completed, and the BMI, WC, LAP, VAI, CVAI, and HOMA-IR were calculated. A linear correlation and a receiver operating characteristic curve were performed. After intervention with metformin, the effects were estimated in the third month. Results: PCOS women had worse glycometabolism, serum lipid metabolism and IR, and higher prevalence rates of metabolic disorders than those without PCOS. The CVAI was strongly associated with the M value (r = -0.6953, P < 0.0001) and outperformed other parameters with the largest area under the curve (0.903) and Youden index (71.07%) for IR diagnosis in Chinese reproductive-aged women, and the diagnostic point was >28.5. After 3 months of metformin therapy, IR improved with remarkable increases in M value and reductions in the CVAI. Conclusion: The CVAI can be used as an appropriate surrogate indicator for the hyperinsulinemic-euglycemic clamp to identify IR in Chinese women of childbearing age. The interventional trial part of this study has been registered as a clinical trial (no. ChiCTR-IIR-16007901).

Assessing the predictive accuracy of oral glucose effectiveness index using a calibration model.

PURPOSE: Current reference methods for measuring glucose effectiveness (GE) are the somatostatin pancreatic glucose clamp and minimal model analysis of frequently sampled intravenous glucose tolerance test (FSIVGTT), both of which are laborious and not feasible in large epidemiological studies. Consequently, surrogate indices derived from an oral glucose tolerance test (OGTT) to measure GE (oGE) have been proposed and used in many studies. However, the predictive accuracy of these surrogates has not been formally validated. In this study, we used a calibration model analysis to evaluate the accuracy of surrogate indices to predict GE from the reference FSIVGTT (SgMM). METHODS: Subjects (n = 123, mean age 48 ± 11 years; BMI 35.9 ± 7.3 kg/m2) with varying glucose tolerance (NGT, n = 37; IFG/IGT, n = 78; and T2DM, n = 8) underwent FSIVGTT and OGTT on two separate days. Predictive accuracy was assessed by both root mean squared error (RMSE) of prediction and leave-one-out cross-validation-type RMSE of prediction (CVPE). RESULTS: As expected, insulin sensitivity, SgMM, and oGE were reduced in subjects with T2DM and IFG/IGT when compared with NGT. Simple linear regression analyses revealed a modest but significant relationship between oGE and SgMM (r = 0.25, p < 0.001). However, using calibration model, measured SgMM and predicted SgMM derived from oGE were modestly correlated (r = 0.21, p < 0.05) with the best fit line suggesting poor predictive accuracy. There were no significant differences in CVPE and RMSE among the surrogates, suggesting similar predictive ability. CONCLUSIONS: Although OGTT-derived surrogate indices of GE are convenient and feasible, they have limited ability to robustly predict GE.

Euglycaemic glucose clamp: what it can and cannot do, and how to do it.

The hyperinsulinaemic-euglycaemic glucose clamp has always been regarded as the "gold standard" for the assessment of pharmacodynamic (PD) properties of insulin preparations; however, there has been controversy over a variety of methodogical details, such as study population, dosing time and the initial stabilization of blood glucose (BG) concentrations at the clamp target level, among clamp groups. As the impact of these details on PD results is unclear, the present review provides an overview of different methodological approaches for both the manual and the automated hyperinsulinaemic-euglycaemic glucose clamp. The advantages and limitations of several methodological details are discussed as well as the relevance of clamp results for the prediction of clinical outcomes. Overall, the best method strongly depends on the exact objective of the trial. If, for instance, duration of action is the primary objective, studies should be carried out in patients with type 1 diabetes to avoid any interference of endogenous insulin. This is less important for variables such as onset of action or early metabolic activity. The hyperinsulinaemic-euglycaemic glucose clamp has a high sensitivity to detect even minor differences between different insulin preparations. The practical relevance of potential differences, however, needs to be investigated in clinical studies. A major prerequisite for obtaining reliable glucose clamp results is the attainment of high clamp quality (i.e. keeping BG concentrations close to the clamp target throughout the experiments). Unfortunately, measures of clamp quality are often under-reported, as is the variability in PD profiles, although these might explain some unconfirmed extreme results obtained in a few clamp studies.

Strong association between insulin-mediated glucose uptake and the 2-hour, not the fasting plasma glucose concentration, in the normal glucose tolerance range.

AIM: The aim of this study was to examine the relationship between whole-body insulin-mediated glucose disposal and the fasting plasma glucose concentration in nondiabetic individuals. RESEARCH DESIGN AND METHODS: Two hundred fifty-three nondiabetic subjects with normal glucose tolerance (NGT), impaired fasting glucose (IFG), impaired glucose tolerance, and combined glucose intolerance received a 75-g oral glucose tolerance test and euglycemic hyperinsulinemic clamp. Total glucose disposal (TGD) during the insulin clamp was compared in IFG and NGT individuals and was related to fasting and 2-hour plasma glucose concentrations in each group. RESULTS: TGD varied considerably between NGT and IFG individuals and displayed a strong inverse relationship with the 2-hour plasma glucose (PG; r = 0.40, P < .0001) but not with the fasting PG. When IFG and NGT individuals were stratified based on their 2-hour PG concentration, the increase in 2-hour PG was associated with a progressive decrease in TGD in both groups, and the TGD was comparable among NGT and IFG individuals. CONCLUSION: The present results indicate the following: 1) as in NGT, insulin-stimulated TGD varies considerably in IFG individuals; 2) the large variability in TGD in IFG and NGT individuals is related to the 2-hour PG concentration; and 3) after adjustment for the 2-hour proglucagon concentration, IFG subjects have comparable TGD with NGT individuals.

Accuracy and precision of commonly used methods for quantifying surgery-induced insulin resistance: Prospective observational study.

BACKGROUND: Insulin resistance develops in the perioperative setting and has an adverse influence on postoperative recovery and well-being. OBJECTIVES: To evaluate the effectiveness of commonly used methods for quantifying surgery-induced insulin resistance. DESIGN: Prospective observational study. SETTING: Surgery department and orthopaedic ward at two regional hospitals. PATIENTS: Twenty-two patients (mean age 68 years) scheduled for elective hip replacement. INTERVENTIONS: A short seven-sample intravenous glucose tolerance test (IVGTT) followed by a euglycaemic hyperinsulinaemic glucose clamp 1 day before and 2 days after the surgery. MAIN OUTCOME MEASURES: Insulin resistance shown by dynamic tests (the IVGTT and the glucose clamp) were compared to static tests [the quantitative insulin sensitivity check index (QUICKI) and the homeostatic model assessment-insulin resistance (HOMA-IR)], which use only the plasma glucose and insulin concentrations at baseline. RESULTS: The linear correlation coefficients for the relationship between insulin resistance as obtained with the glucose clamp and the other methods before or after surgery were 0.76 (IVGTT), 0.58 (QUICKI) and -0.65 (HOMA). The prediction errors (precision) averaged 18, 29 and 31%, respectively. Surgery-induced insulin resistance amounted to 45% (glucose clamp), 26% (IVGTT), 4% (QUICKI) and 3% (HOMA). CONCLUSION: Despite reasonably good linear correlations, the static tests grossly underestimated the degree of insulin resistance that developed in response to surgery.

Modeling hepatic insulin sensitivity during a meal: validation against the euglycemic hyperinsulinemic clamp.

Recently, we proposed a model describing the suppression of endogenous glucose production (EGP) during a meal. It assumes that EGP suppression depends on glucose concentration and its rate of change and on delayed insulin action. Hepatic insulin sensitivity (S(I)(Lmeal)) can be derived from EGP model parameters. This model was shown to adequately describe EGP profiles measured with multiple tracer techniques; however, S(I)(Lmeal) has never been compared directly with its euglycemic hyperinsulinemic clamp counterpart (S(I)(Lclamp)). To do so, 62 subjects with different degrees of glucose tolerance underwent a triple-tracer mixed meal. Fifty-seven subjects also underwent a labeled ([3-(3)H]glucose) euglycemic hyperinsulinemic clamp. From the triple-tracer meal data, virtually model-independent estimates of EGP were obtained using the tracer-to-tracee clamp technique, and the EGP model was identified in each subject. Model fit was satisfactory, and S(I)(Lmeal) was estimated with good precision. Correlation between S(I)(Lclamp) and S(I)(Lmeal) was good (r = 0.72, P < 0.001); however, S(I)(Lmeal) was lower than S(I)(Lclamp) (4.60 ± 0.64 vs. 8.73 ± 1.07 10(-4) dl·kg(-1)·min(-1) per µU/ml, P < 0.01). This difference may be due to different ranges of insulin explored during the two tests (ΔI(clamp) = 15.60 ± 1.61 vs. ΔI(meal)= 83.37 ± 10.71 µU/ml) as well as steady- vs. non-steady-state glucose and insulin profiles. In conclusion, the new EGP model provides an estimate of hepatic insulin sensitivity during a meal that is in good agreement with that derived in the same individuals with a hyperinsulinemic clamp. When used in conjunction with the minimal model, the approach potentially enables estimation of hepatic insulin sensitivity from a single-tracer labeled meal or oral glucose tolerance test.

Pharmacokinetics and pharmacodynamics of basal insulins.

The two basal insulin analogs, insulin glargine and insulin detemir, were developed to ameliorate the well-known limitations of NPH insulin. In contrast to rapid-acting analogs, which differ exclusively in terms of primary structure while sharing similar pharmacokinetics (PK) and pharmacodynamics (PD), the two long-acting insulin analogs are different chemical and structural entities, exhibiting distinct modes of protracting the insulin effect. So far, PK and PD studies of long-acting analogs have often shown conflicting results, pointing out different conclusions, thereby leading to animated controversies. The methods used in the evaluation of basal insulins might have been partially responsible as, although the euglycemic clamp technique has been broadly acknowledged to be the "gold standard" reference to assess the glucose-lowering effect of an insulin preparation, its execution and interpretation might have been substantially different across studies, in various methodological and analytical aspects, ultimately providing an explanation for some of these controversies. This review will present and describe the basic methods used in the evaluation of basal insulins and will critically summarize the points that might have been responsible for the different outcomes. The findings of glucose clamp studies demonstrate that the two long-acting insulin analogs are different, to some extent, in both their PK and PD profiles. These differences should be taken into consideration when the individual analogs are introduced to provide basal insulin supplementation to optimize blood glucose control in patients with type 1 and type 2 diabetes as well.

Measuring insulin sensitivity in youth: How do the different indices compare with the gold-standard method?

AIM: The objective of the study was to examine the correlation between three methods of measuring insulin sensitivity (IS) - namely, the frequently sampled intravenous glucose tolerance test (FSIVGTT), indices derived from the oral glucose tolerance test (OGTT) and fasting indices (HOMA-IR, QUICKI, fasting insulin [INS(0)]) - and the gold-standard method, the hyperinsulinaemic-euglycaemic clamp (HEC) test, in children. METHODS: A total of 20 children [nine boys and 11 girls; mean (SD) age: 9 (2) years] were studied. Their mean (SD) BMI Z score was 1.5 (0.8). All participants had normal glucose metabolism. Each child underwent a 3-h HEC (40 mU/m(2)/min of insulin), an insulin-modified minimal-model FSIVGTT and a 3-h OGTT. The clamp-derived IS was calculated, using DeFronzo's metabolized glucose index and Bergman's IS index. Correlations were established using Spearman's rank correlations. RESULTS: The two clamp-derived measures were highly correlated (r=0.85), and the IS measured from the FSIVGTT was well correlated with both clamp measures [r=0.69, 0.74]. Of the nine indices derived from the OGTT, the three with the highest correlation with clamp results were the ISI Matsuda [r=0.63, 0.68], SI(is)OGTT [r=0.53, 0.65] and log sum insulin [r=-0.64, -0.75]. Fasting indices of IS had similar correlations to clamp results: HOMA-IR [r=-0.55, -0.56]; QUICKI [r=0.55, 0.57]; and INS(0) [r=-0.59, -0.63]. CONCLUSION: While fasting-based indices of IS are a suitable option for large cohorts, OGTT-derived indices may represent a useful compromise for obtaining both clinical (glucose tolerance) and physiological (insulin sensitivity) information, making them particularly useful for large-scale physiological and epidemiological studies.

Repeatability and reproducibility of the hyperinsulinemic-euglycemic clamp and the tracer dilution technique in a controlled inpatient setting.

The objective of the study was to evaluate the reproducibility and repeatability of the combined use of the hyperinsulinemic-euglycemic (H-E) clamp and tracer dilution techniques. Ten nondiabetic men underwent a low-dose (40 mU/[m(2) min]) H-E clamp that was repeated within 3 to 4 days using porcine or human insulin in a double-blinded, randomized, crossover design. Coefficients of variation (CVs) for intraindividual differences and repeatability coefficient were calculated to evaluate reproducibility and repeatability. The Bland and Altman method was used to quantify repeatability. The CVs for intraindividual differences were 5.7% +/- 3.5% for steady-state (SS) insulin; 6.7% +/- 6.2% and 54.2 +/- 38.3% for basal and SS endogenous glucose product (EGP), respectively; and 10.3% +/- 8.5% for total insulin-stimulated glucose disposal (M) values. Basal EGP, SS EGP, and SS glucose and insulin concentrations were similar for the 2 clamps; but glucose infusion rate (P = .02) and M (borderline significant, P = .06) were higher in the first clamp than the second clamp. No significant correlations between mean of differences and average of basal and SS EGP, SS insulin concentration, and M between the 2 clamps were observed. We also found that the different values were less than the repeatability coefficients of these parameters and that the 95% limits of agreement and the interval of repeatability coefficient of these parameters were similar. There were no differences in metabolic responses between clamps when compared by the type of insulin (porcine vs human) infused. Our findings indicate that, although SS EGP has a high CV, the clamp, which measures insulin action (ie, SS insulin, M), and the tracer dilution technique for assessing basal EGP are repeatable and reproducible. Decreased glucose infusion rate and M over a short period in the second clamp may reflect an accumulative effect of continued physical inactivity.

Euglycemic hyperinsulinemic clamp

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Insulin is the principal hormone of glucose metabolic regulation. Reduced glucose responses to insulin constitute an underlying feature of type 2 diabetes. In addition, insulin resistance is a common condition related with the metabolic syndrome and strongly associated with an increased risk of cardiovascular disease. The importance of the insulin-resistant phenotype for the assessment of cardiovascular risk and response to intervention is increasingly being recognized. Therefore, there is a need for an accurate and reproducible method for measuring insulin resistance in vivo. The euglycemic hyperinsulinemic clamp (EHC) is currently the gold standard method available for the determination of whole glucose uptake in response to insulin, from which several derived indices of insulin sensitivity are obtained. The clamp technique is both expensive and complex to undertake and has prompted the use of surrogate methods, notably the insulin tolerance test and frequently sampled intravenous glucose tolerance test. Indices may be derived from these methods and correlate well with those derived from clamp studies. However, important limitations of these procedures are that not only does insulin sensitivity change in pathological situations, but also in normal physiology. Variations also occur in time–depending on the physiological state of the individual or following diurnal rhythms. In conclusion, the quantitative assessment of insulin sensitivity with EHC is not used for routine clinical purposes, but the emerging importance of insulin resistance has led to its wider application to research studies that have examined its pathogenesis, etiology and consequences (AU)

[Critical analysis on the use of the homeostasis model assessment (HOMA) indexes in the evaluation of the insulin resistance and the pancreatic beta cells functional capacity]. / Análise crítica do uso dos índices do Homeostasis Model Assessment (HOMA) na avaliação da resistência à insulina e capacidade funcional das células-beta pancreáticas.

Beta-cell dysfunction and insulin resistance are interrelated metabolic abnormalities in the aetiology of Type 2 Diabetes. In several countries, increases in the prevalence of obesity and diabetes have been observed in association with the presence of insulin resistance. In this context, measurement of insulin resistance and beta-cell function is useful. The HOMA indexes (Homeostasis Model Assessment) have been widely used, representing an alternative for the evaluation of these parameters, particularly as a fast, easy and cheap method. This review discusses the origin and evolution of the HOMA index, as well as details of the method, analyzing features related to its validation and the cutoff limits for its interpretation.

Análise crítica do uso dos índices do Homeostasis Model Assessment (HOMA) na avaliação da resistência à insulina e capacidade funcional das células-beta pancreáticas: [revisão] / Critical analysis on the use of the homeostasis hodel assessment (HOMA) indexes in the evaluation of the insulin resistance and the pancreatic beta cells functional capacity: [review]

A disfunção das células-beta e a resistência insulínica são anormalidades metabólicas inter-relacionadas na etiologia do diabetes tipo 2. Em diversos países, tem sido observado o aumento da prevalência de obesidade e diabetes em associação com a presença da resistência insulínica. Nesse contexto, é útil a mensuração da resistência insulínica e da capacidade funcional das células-beta nos indivíduos. Os índices Homeostasis Model Assessment (HOMA) têm sido amplamente utilizados, representando uma das alternativas para avaliação desses parâmetros, principalmente por figurarem um método rápido, de fácil aplicação e de menor custo. Esta revisão discute sobre a origem e a evolução dos índices HOMA, bem como as particularidades do método, abordando aspectos relacionados à sua validação e aos pontos de corte existentes para sua interpretação.

Beta-cell dysfunction and insulin resistance are interrelated metabolic abnormalities in the aetiology of Type 2 Diabetes. In several countries, increases in the prevalence of obesity and diabetes have been observed in association with the presence of insulin resistance. In this context, measurement of insulin resistance and beta-cell function is useful. The HOMA indexes (Homeostasis Model Assessment) have been widely used, representing an alternative for the evaluation of these parameters, particularly as a fast, easy and cheap method. This review discusses the origin and evolution of the HOMA index, as well as details of the method, analyzing features related to its validation and the cutoff limits for its interpretation.

Impact of lowering the criterion for impaired fasting glucose on identification of individuals with insulin resistance. The GISIR database.

OBJECTIVE: We assessed the accuracy of the American Diabetes Association (ADA)2003 definition of impaired fasting glucose (IFG) in identifying subjects with low insulin sensitivity, and determined cardiovascular risk factors in ADA2003 IFG subjects. RESEARCH DESIGN AND METHODS: This study included 930 non-diabetic Italian Caucasians from the GISIR database in which subjects underwent a hyperinsulinaemic-euglycaemic clamp performed with a standard technique. Low insulin sensitivity was defined as being in the lower quartile of glucose metabolized during the last hour of the clamp (M). Subjects were stratified in the following groups: normal fasting glucose (NFG) (<100 mg/dL), IFG100 (100-109 mg/dL), ADA1997 IFG110 (110-125 mg/dL), and ADA2003 IFG (100-125 mg/dL). RESULTS: The sensitivity of identifying subjects with low insulin sensitivity increased adopting the ADA2003 criterion. After Bonferroni correction for multiple comparisons, both IFG100 and ADA1997 IFG110 showed significantly higher body mass index (BMI), waist, systolic blood pressure (SBP) and diastolic blood pressure (DBP), triglyceride, fasting plasma insulin (FPI) and fasting plasma glucose (FPG), and lower insulin sensitivity as compared with NFG. As compared with IFG100, ADA1997 IFG110 showed significantly higher BMI, waist, SBP, FPI, FPG, and lower insulin sensitivity. ADA2003 IFG group showed significantly higher BMI, waist, SBP and DBP, triglyceride, cholesterol, FPI, and FPG, but lower HDL levels and insulin sensitivity compared with NFG subjects. CONCLUSIONS: Although neither the ADA2003 nor the ADA1997 definition of IFG appears to be particularly efficacious for the identification of subjects' low insulin sensitivity, lowering the criterion to the ADA2003 glucose threshold increased the sensitivity without affecting the specificity. ADA2003 IFG showed a worse cardiovascular risk profile compared with NFG.

Validation of insulin sensitivity indices from oral glucose tolerance test parameters in obese children and adolescents.

Given the extreme increase in prediabetes, type 2 diabetes, and the potential for metabolic syndrome in obese youth, identifying simplified indexes for assessing stimulated insulin sensitivity is critical. The purpose of this study was validation of two surrogate indexes of insulin sensitivity determined from the oral glucose tolerance test (OGTT): the composite whole body insulin sensitivity index (WBISI) and the insulin sensitivity index (ISI). An obese population (aged 8-18 yr) of normal and impaired glucose tolerance individuals was studied. One group (n = 38) performed both the euglycemic-hyperinsulinemic clamp and OGTT for comparison of insulin sensitivity measurements as well as (1)H-magnetic resonance spectroscopy estimates of intramyocellular lipid content. Another larger (n = 368) cohort participated only in an OGTT. Both the WBISI and ISI represented good estimates (r = 0.78 and 0.74; P < 0.0005) for clamp-derived insulin sensitivity (glucose disposed, M-value), respectively. In the large cohort, the surrogate indexes demonstrated the shift toward poorer function and increased risk profile as a function of insulin resistance. Additionally, the WBISI and ISI correlated with intramyocellular lipid content (r = -0.74 and -0.71; P < 0.0001), a tissue marker for insulin resistance. Insulin sensitivity can be estimated using plasma glucose and insulin responses derived from the OGTT in obese youth with normal and impaired glucose tolerance.

Failure of mathematical indices to accurately assess insulin resistance in lean, overweight, or obese women with polycystic ovary syndrome.

Insulin resistance is a common metabolic feature of polycystic ovary syndrome (PCOS). In this study, we examined the validity of the mathematical indices [the quantitative insulin sensitivity check index (QUICKI) and the homeostasis model of assessment (HOMA)] that calculate insulin sensitivity and their correlation to glucose utilization with the insulin infusion rate in 40 mU/m(2).min by the euglycemic clamp (M) in women with PCOS. We studied 59 women with PCOS (20 lean, 16 overweight, and 23 obese subjects). Euglycemic clamp testing was performed, and QUICKI, HOMA, total testosterone, fasting insulin, fasting glucose, and glucose-to-insulin ratio were estimated. No difference was found in testosterone and glucose levels among the three groups. Lean or overweight women compared with obese women differed in insulin levels, glucose-to-insulin ratio, QUICKI, and HOMA (P < 0.01). No statistical difference was found between lean and overweight women in the above parameters. M differed when lean women were compared with overweight (P < 0.002) or obese women (P < 0.0001); however, no statistical difference was observed between overweight and obese women. No significant correlation was found between M and QUICKI or HOMA. We conclude that mathematical indices should be applied with caution in different insulin-resistant populations and should not be considered a priori equivalent to the euglycemic clamp technique.