An islet population model is proposed for pancreatic insulin secretion. Without detailing the chain of biochemical events giving rise to the delivery of insulin packets, the effect of the islets' bursting response to varying glucose concentration is described by a simple second order nonlinear model, of the same functional form for all islets, but with a random distribution of parameter values over the one million islets considered. The islet equations are coupled to a traditional model of the glucose/insulin dynamics to complete a description of the feed-back control of the glucose/insulin system. The model is thus based upon the completely random cooperation of a large number of independent controllers, all reacting to the same prevailing plasma glucose concentrations, but with distributed reaction characteristics. It is shown that the proposed model is able to replicate in silico different observed phenomena such as low frequency glycemia-insulinemia oscillations (ultradian oscillations, with a period between 50 and 150 min, amplified by constant glucose administration and entrained by an oscillating exogenous glucose infusion), as well as concordant induction of high-frequency insulin oscillations by a rapid periodic pulsatile glucose infusion. In order to reproduce by simulation all of the above observed phenomena, a single set of (hyper-)parameters has been used throughout, showing that it is indeed possible that a single model may explain the results of several published experimental protocols.

PURPOSE: Given the high cost and side effects of radioprotective agents such as amifostine, attention has been focused on potentially equally effective but less expensive and toxic natural substances. We evaluated the potential radioprotective effects of wine in preventing skin toxicity in patients with breast cancer. METHODS AND MATERIALS: Before treatment, the medical history and habits of patients were assessed and the information recorded in their clinical folders. Patients were divided into three groups based on the dose/fractionation scheme used: control group, 60.4 Gy (standard technique); Modulated Accelerated Radiotherapy in Adjuvant treatment of breast cancer (MARA)-1 protocol group, 44 Gy (concomitant boost to tumoral bed); and MARA-2 protocol group, 60 Gy (concomitant boost to tumoral bed). The impact of the following variables on acute skin toxicity was evaluated by chart review: radiotherapy protocol, planning target volume (PTV), comorbidity (e.g., hypertension and diabetes), hemoglobin level before therapy, adjuvant hormone therapy, adjuvant chemotherapy, cigarette smoking, and drinking habits. RESULTS: The study population consisted of 348 patients. More severe skin toxicity was significantly associated with the radiotherapy protocol (p < 0.001) and median PTV (p = 0.005). In addition, the incidence of acute toxicity of Grade 2 or greater was higher in patients without alcohol intake (38.4% vs. 22.3%, p = 0.021). The daily amount of alcohol intake also influenced the incidence of skin toxicity, with an incidence of 38.4% in patients with no wine intake, 31.8% in patients drinking half a glass per day, 13.6% in patients drinking one glass per day, and 35.0% in patients drinking two glasses per day. Multivariate analysis showed that wine intake, PTV, and radiotherapy protocol were all significantly correlated with acute toxicity. CONCLUSIONS: Our results indicate that wine may have a radioprotective effect; however, prospective studies are needed to confirm this beneficial effect of wine and its components.

Few attempts have been made to model mathematically the progression of Type 2 diabetes. A realistic representation of the long-term physiologic adaptation to developing insulin resistance is necessary for effectively designing clinical trials and evaluating diabetes prevention or disease modification therapies. Writing a good model for diabetes progression is difficult, because the long time-span of the disease makes experimental verification of modeling hypotheses extremely awkward. In this context, it is of primary importance that the assumptions underlying the model equations properly reflect established physiology and that the mathematical formulation of the model give rise only to physically plausible behavior of the solutions. In the present work, a model of the pancreatic islet compensation is formulated, its physiological assumptions are presented, some fundamental qualitative characteristics of its solutions are established, the numerical values assigned to its parameters are extensively discussed (also with reference to available cross-sectional epidemiologic data), and its performance over the span of a lifetime is simulated under various conditions including worsening insulin resistance and primary replication defects. The differences with respect to two previously proposed models of diabetes progression are highlighted, and the model is therefore proposed as a realistic, robust description of the evolution of the compensation of the glucose-insulin system in healthy and diabetic individuals. Model simulations can be run from the Authors' webpage. Key words: Type 2 Diabetes Mellitus, Mathematical Models, Insulin resistance, Beta-cell mass, glucose-insulin control.

Objective: In this article we provide evidence of a significant spontaneous humoral response in cancer patients. Methods: A panel of tumor-associated antigens, previously identified through serological screening of phage-displayed cDNA libraries from solid human tumors, breast carcinoma cell lines and human testis by employing breast cancer patient sera, was used in this study to survey sera from 182 patients with known disease histories and clinical stages. Results: This analysis reveals a statistically significant association between tumor disease and presence in peripheral blood of IgG antibodies against four autoantigens. One of these antigens (D7-1) is particularly interesting in that the antibody response against it grows with cancer progression from stages I through IV, with an incidence of 13.2, 13.5, 18.2 and 27%, respectively. The significance of this stage-dependent increase in the incidence is confirmed by the Mantel-Haenszel Chi-squared test (P=0.001). Conclusions: Our data confirm association between breast cancer diagnosis of patients and presence in their peripheral blood of antibodies against several autoantigens identified by phage display.

BACKGROUND: Abnormally low plasma levels of coenzyme Q10 (CoQ10) have been found in patients with cancer of the breast, lung, or pancreas. OBJECTIVE: A prospective study of patients with melanoma was conducted to assess the usefulness of CoQ10 plasma levels in predicting the risk of metastasis and the duration of the metastasis-free interval. METHODS: Between January 1997 and August 2004, plasma CoQ10 levels were measured with high-performance liquid chromatography in 117 consecutive melanoma patients without clinical or instrumental evidence of metastasis according to American Joint Committee on Cancer criteria and in 125 matched volunteers without clinically suspect pigmented lesions. Patients taking CoQ10 or cholesterol-lowering medications and those with a diagnosis of diabetes mellitus were excluded from the study. Multiple statistical methods were used to evaluate differences between patients and control subjects and between patients who did (32.5%) and did not (67.5%) develop metastases during follow-up. RESULTS: CoQ10 levels were significantly lower in patients than in control subjects (t test: P <.0001) and in patients who developed metastases than in the metastasis-free subgroup (t test: P <.0001). Logistic regression analysis indicated that plasma CoQ10 levels were a significant predictor of metastasis (P =.0013). The odds ratio for metastatic disease in patients with CoQ10 levels that were less than 0.6 mg/L (the low-end value of the range measured in a normal population) was 7.9, and the metastasis-free interval was almost double in patients with CoQ10 levels 0.6 mg/L or higher (Kaplan-Meier analysis: P <.001). LIMITATIONS: A study with a larger sample, which is currently being recruited, and a longer follow-up will doubtlessly increase the statistical power and enable survival statistics to be obtained. CONCLUSIONS: Analysis of our findings suggests that baseline plasma CoQ10 levels are a powerful and independent prognostic factor that can be used to estimate the risk for melanoma progression.

BACKGROUND: The Euglycemic Hyperinsulinemic Clamp (EHC) is the most widely used experimental procedure for the determination of insulin sensitivity, and in its usual form the patient is followed under insulinization for two hours. In the present study, sixteen subjects with BMI between 18.5 and 63.6 kg/m;2 were studied by long-duration (five hours) EHC. RESULTS: From the results of this series and from similar reports in the literature it is clear that, in obese subjects, glucose uptake rates continue to increase if the clamp procedure is prolonged beyond the customary 2 hours. A mathematical model of the EHC, incorporating delays, was fitted to the recorded data, and the insulin resistance behaviour of obese subjects was assessed analytically. Obese subjects had significantly less effective suppression of hepatic glucose output and higher pancreatic insulin secretion than lean subjects. Tissue insulin resistance appeared to be higher in the obese group, but this difference did not reach statistical significance. CONCLUSIONS: The use of a mathematical model allows a greater amount of information to be recovered from clamp data, making it easier to understand the components of insulin resistance in obese vs. normal subjects.

Dicarboxylic acids with an even number of carbon atoms have been proposed as an alternate energy substrate for enteral or parenteral nutrition in the acutely ill patient, due to their water solubility and their yielding TCA cycle intermediates upon beta-oxidation. In the present work, a nonlinear compartmental model of the kinetics of dodecanedioic acid is developed, and its parameters are estimated from time concentration experimental observations obtained from six healthy volunteers undergoing a per os administration of 3 g of the substance. Although the model is linear in the transfer of the free substance from plasma to the tissues, the exchange between gut and plasma compartments is represented as a saturable function. Albumin binding is then incorporated to obtain the final model in terms of the measured total concentrations. Estimates of the model's structural parameters were computed for each experimental subject, and the usual single-subject approximate confidence regions for the parameters were derived by inversion of the Hessian at the optimum. To verify the applicability of this approximation, the nonlinearity of the expectation surface at the optimum was measured by computing the normal (intrinsic) component of curvature. Because the model curvature was excessive in all subjects, the usual approximation could not be trusted to provide acceptable approximations to the parameter confidence regions. A suitable Monte Carlo simulation yielded empirical joint parameter distributions from which the approximate parameter variances could finally be obtained.

BACKGROUND: Polycystic ovary syndrome (PCOS) and menopausal subjects are characterized by an increased cardiovascular and type 2 diabetes mellitus risk, at least partially related to insulin disturbances. The evaluation of insulin resistance in these patients could be useful as primary prevention. The aim of the study was to verify the validity of several indexes of insulin sensitivity in PCOS and menopausal subjects by comparing the data obtained by these indexes to those of euglycemic-hyperinsulinemic clamp studies. METHODS: One hundred PCOS and 110 menopausal subjects were analyzed; all subjects underwent an oral glucose tolerance test (75 g) and euglycemic-hyperinsulinemic clamp study. Seven PCOS patients and 13 menopausal subjects had impaired glucose tolerance or type 2 diabetes mellitus and were excluded from the study. After analysis of correlation coefficients between the evaluated indexes and the clamp studies, the sensitivity and specificity of different cut-off values for each parameter were analyzed by receiver operating characteristic (ROC) curves. RESULTS: The best correlation coefficients with clamp studies were obtained with the Avignon insulin sensitivity index (SiM)(R(s)= 0.7812) in PCOS patients and the Matsuda and De Fronzo index (R(s)= 0.6178) in menopausal patients. The best predictive index of insulin resistance in PCOS was a Avignon insulin sensitivity basal index (SibB) value of 62 or less (78% sensitivity, 95% specificity) and an insulin area under the curve (AUC) of 7,000 microIU/ml or more (>/=50,225 pmol/liter) x 120 min (83% sensitivity, 90% specificity). In the menopausal population, the best predictive performance was obtained by an insulin AUC of 10,000 microIU/ml or more (>/=71,750 pmol/liter) x 240 min (70% sensitivity, 88% specificity). CONCLUSIONS: The presence of high correlation coefficients does not necessarily mean that the indexes of insulin resistance have an optimal predictive performance; this is probably due to the presence of many borderline values. The simple evaluation of insulin AUC seems to effectively replace the euglycemic-hyperinsulinemic clamp in routine clinical practice, allowing results superimposable to those obtained by minimal model analysis.

AIM: Hypertension is common in haemodialysis (HD) patients. Determining the most appropriate method of blood pressure (BP) measurement, representative of target organ damage, is still an issue. BP variations between pre- and post-HD treatment, or between on-dialysis day and off-dialysis day, are common. The aim of this study was to examine the possible differences between pre-HD office BP (OBP) levels, inter-HD (iHD) or HDday 24 h ambulatory BP measurement (ABPM) with 48 h ABPM, where the latter was considered the gold standard. METHODS: 163 HD patients were studied. BP was monitored consecutively for 48 h with a Takeda TM2421 device, then sub-analysed into two periods of 24 h: HD and iHD day. An average of 12 sessions pre-HD OBP measurements was determined. RESULTS: OBP significantly overestimates systolic (SBP) and diastolic BP (DBP) when compared with 48 hABPM. SBP and DBP are significantly higher on iHD day than on HD day: 141.2 1 20.8 versus 137.9 1 20.9, and 77.1 1 11.1 versus 76.1 1 10.9 (P < 0.01). No differences of SBP night/day ratio were reported between 48 hABPM and iHD 24 h ABPM or HD 24 h ABPM. The highest correlations were reported between 48 h SBP/DBP with iHD or HD 24 h ABPM (r 2 = 0.95, P < 0.001), while the lowest between 48 h SBP/DBP and OBP (r 2 = 0.40,P < 0.01, r 2 = 0.12, P < 0.01). The narrowest limits of agreement using the Bland and Altman test were reported between 48 h SBP or DBP and 24 h iHD or HD day ABPM. Considering 48 h ABPM, 80.5% of patients had BP higher than the norm, compared with 61.7% of patients in the case of OBP (c2 = 13.28, P < 0.001). The sensibility for detecting hypertension for iHD day 24 h ABPM was 98.4%, with specificity of 90%. The sensibility of 24 h HDday ABPM was 90.3%, with specificity 96.6%. In the case of OBP, sensibility and specificity were considerably lower, that is, 72.6% and 83.3% respectively. CONCLUSION: Significant differences are shown between OBP and 48 h ABPM in the recognition of a hypertensive state. OBP measurement has a lower sensibility and specificity than 24 h ABPM, which remains a valid alternative approach to 48 h ABPM in HD patients. Errors of OBP estimation should be taken into account, with possible negative impact on treatment strategies and epidemiology studies

Context: The wide family of the phytoestrogens has become an alternative to the classical hormonal therapy in menopause, nevertheless some findings are still conflicting. Objective: To examine the effect of genistein administration on metabolic parameters and vascular reactivity considering the basal endocrine status of the patients. Design: Randomized placebo controlled study. Setting: University Hospital. Participants: 50 postmenopausal women. Intervention(s): Thirty subjects (group A) were randomized to receive 54 mg/day of genistein while twenty subjects (group B) were treated with the placebo for 24 weeks. In the group A we distinguish two subgroups: 14 normoinsulinemic and 12 hyperinsulinemic patients. Main Outcome Measure(s): Antropometric measures, hormonal and lipid assays, OGTT with glycemic, insulin and C-peptide evaluation, indexes of insulin sensitivity and endothelial function, euglycemic hyperinsulinemic clamps were performed. Results: The insulin basal values significantly decreased in group A, where as the homeostasis model index of insulin sensitivity (HOMA-IR) and the fasting glucose levels significantly improved compared to placebo group. The genistein administration decreased fasting glucose and AUC-glucose levels in the normoinsulinemic patients after treatment. In the hyperinsulinemic patients a significant reduction in fasting insulin, fasting C-peptide and AUC-insulin levels as well as an increase in FHIE was shown. In these patients HDL cholesterol levels were significantly improved. The endothelium-dependent and independent dilatation improved in the treated group. Normoinsulinemic patients showed both a significantly enhanced flow mediated and nitrate mediated dilatation, while no significant changes were found in the hyperinsulinemic group. Conclusions: The glycoinsulinemic metabolism and the endothelial function were significantly influenced by genistein. In particular normoinsulinemic patients showed an improvement in glycemic and vascular reactivity indexes. Conversely, an improvement in the insulin sensitivity indexes was noted in hyperinsulinemic patients.

Semi-mechanistic pharmacodynamic (PD) models that capture tumor responses to anticancer agents with fidelity can provide valuable insights that could aid in the optimization of dosing regimens and the development of drug delivery strategies. This study evaluated the utility and potential interchangeability of two transduction-type PD models: a cell distribution model (CDM) and a signal distribution model (SDM). The evaluation was performed by simulating dense and sparse tumor response data with one model and analyzing it using the other. Performance was scored by visual inspection and precision of parameter estimation. Capture of tumor response data was also evaluated for a liposomal formulation of paclitaxel in the paclitaxel-resistant murine Colon-26 model. A suitable PK model was developed by simultaneous fitting of literature data for paclitaxel formulations in mice. Analysis of the simulated tumor response data revealed that the SDM was more flexible in describing delayed drug effects upon tumor volume progression. Dense and sparse data simulated using the CDM were fit very well by the SDM, but under some conditions, data simulated using the SDM were fitted poorly by the CDM. Although both models described the dose-dependent therapeutic responses of Colon-26 tumors, the fit by the SDM contained less bias. The CDM and SDM are both useful transduction models that recapitulate, with fidelity, delayed drug effects upon tumor growth. However, they are mechanistically distinct and not interchangeable. Both fit some types of tumor growth data well, but the SDM appeared more robust, particularly where experimental data are sparse.

AIMS/HYPOTHESIS: Minimal model analysis for insulin sensitivity has been validated against the glucose clamp and is an accepted method for estimating insulin sensitivity from IVGTT. However minimal model analysis requires a 3 h test and relevant expertise to run the mathematical model. The aim of this study was to suggest a simple predictor of minimal model analysis index using only 1 h IVGTT. METHODS: We studied participants with different clinical characteristics who underwent 3 h regular (n = 336) or insulin-modified (n = 160) IVGTT, or 1 h IVGTT and euglycaemic-hyperinsulinaemic clamp (n = 247). Measures of insulin sensitivity were insulin sensitivity index estimated by minimal model analysis (S(I)) and the mean glucose infusion rate (clamp)(M). A calculated S(I)(CS(I)) predictor,[Formula: see text], was suggested, based on the calculation of the rate of glucose disappearance K (G) and the suprabasal AUC of insulin concentration DeltaAUC(INS) over T = 40 min. For all the participants, alpha was assumed equal to the regression line slope between K (G)/(DeltaAUC(INS)/T) and S(I) in control participants. RESULTS: CS(I) and S(I) showed high correlation (R (2)= 0.68-0.96) and regression line slopes of approximately one in the majority of groups. CS(I) tended to overestimate S(I) in type 2 diabetic participants, but results were more reliable when CS(I) was computed with insulin-modified rather than regular IVGTT. CS(I) showed behaviours similar to S(I) as regards relationships with BMI, acute insulin response and sex. CS(I) showed good correlation with M (R (2)= 0.82). CONCLUSIONS/INTERPRETATION: A short test can achieve a good approximation of minimal model analysis and clamp insulin sensitivity. The importance of a method such as CS(I) is that it allows analysis of IVGTT datasets with samples limited to 1 h.

This paper aims to present a mathematical model to describe the plasma glucose and insulin daily variations on normal and diabetic subjects. The proposed model consists of two delay differential equations (DDEs) where five adjustable parameters are used to characterize the respective dynamics and oscillation behavior of normal and diabetic subjects. Several clinical data tests demonstrate that the suggested model is practical to approach the daily-life glucose dynamics on normal, diabetic Type 1 and Type 2 subjects. Moreover, the corresponding parameters are fairly persuasive to identify the patients' conditions of physiological functions.

The sparse distributed memory (SDM) was originally developed to tackle the problem of storing large binary data patterns. The model succeeded well in storing random input data. However, its efficiency, particularly in handling nonrandom data, was poor. In its original form it is a static and inflexible system. Most of the recent work on the SDM has concentrated on improving the efficiency of a modified form of the SDM which treats the memory as a single-layer neural network. This paper introduces an alternative SDM, the SDM signal model which retains the essential characteristics of the original SDM, while providing the memory with a greater scope for plasticity and self-evolution. By removing many of the problematic features of the original SDM the new model is not as dependent upon a priori input values. This gives it an increased robustness to learn either random or correlated input patterns. The improvements in this new SDM signal model should be also of benefit to modified SDM neural network models.

ABSTRACT: BACKGROUND: Due to the increasing importance of identifying insulin resistance, a need exists to have a reliable mathematical model representing the glucose/insulin control system. Such a model should be simple enough to allow precise estimation of insulin sensitivity on a single patient, yet exhibit stable dynamics and reproduce accepted physiological behavior. RESULTS: A new, discrete Single Delay Model (SDM) of the glucose/insulin system is proposed, applicable to Intra-Venous Glucose Tolerance Tests (IVGTTs) as well as to multiple injection and infusion schemes, which is fitted to both glucose and insulin observations simultaneously. The SDM is stable around baseline equilibrium values and has positive bounded solutions at all times. Applying a similar definition as for the Minimal Model (MM) SI index, insulin sensitivity is directly represented by the free parameter KxgI of the SDM. In order to assess the reliability of Insulin Sensitivity determinations, both SDM and MM have been fitted to 40 IVGTTs from healthy volunteers. Precision of all parameter estimates is better with the SDM: 40 out of 40 subjects showed identifiable (CV < 52%) KBxgIB from the SDM, 20 out of 40 having identifiable SBIB from the MM. KBxgIB correlates well with the inverse of the HOMA-IR index, while SBIB correlates only when excluding five subjects with extreme SBIB values. With the exception of these five subjects, the SDM and MM derived indices correlate very well (r = 0.93). CONCLUSION: The SDM is theoretically sound and practically robust, and can routinely be considered for the determination of insulin sensitivity from the IVGTT. Free software for estimating the SDM parameters is available.

OBJECTIVE: To investigate the function of islet beta cells in subjects with normal glucose tolerance (NGT), impaired glucose regulation (IGR), and type 2 diabetes mellitus (T2DM). Different indexes of insulin secretion, including DeltaI30/DeltaG30, AIR or HOMAbeta, were compared. METHODS: 178 subjects without overt diabetes were classified into three groups according to the results of 75 g oral glucose tolerance test (OGTT): NGT group (n = 68), IGR group (n = 75), and T2DM group (n = 35). Intravenous glucose tolerance test (IVGTT) was carried out 1 approximately 3 days later in all participants, with measurement of plasma insulin. The ratio of insulin-to-glucose levels increment during the first 30 min of OGTT (DeltaI30/DeltaG30) and the acute insulin response (AIR) in IVGTT were used as indexes of early insulin secretion. Homeostasis model assessment of insulin secretion (HOMAbeta) was another indicator of insulin secretion. The fasting plasma proinsulin level (FPI) was measured and the ratio fasting proinsulin to fasting insulin (PI/I) was calculated. HOMA insulin resistance index (HOMA IR) was used to assess the insulin resistance. RESULTS: The DeltaI30/DeltaG30 and AIR of the IGR group, adjusted by age, sex, and BMI, were both significantly lower than those of the NGT group. But the HOMAbeta of the IGR group was only slightly lower than that of the NGT group. Compared with the NGT subjects, the T2DM patients had a very severe islet beta cell dysfunction (84% decrease in AIR, 70% decrease in DeltaI30/DeltaG30 and 62% decrease in HOMA beta). When the DeltaI30/DeltaG30 was adjusted by HOMR IR, the extent of impairment in early insulin response was similar to that of AIR (87% versus 84% lower than that of the NGT group). The FPI and ratio of proinsulin to insulin were higher in the T2DM subjects compared with the NGT subjects (24.4 pmol/L +/- 18.0 pmol/L vs 10.9 pmol/L +/- 6.7 pmol/L; and 14.7%+/- 10.5% vs. 10.0%+/- 6.5%, both P < 0.05). There was a significantly positive correlation between DeltaI30/DeltaG30 and AIR (r = 0.75, P < 0.001). CONCLUSION: In the stage of IGR, an evident deficit in phasic insulin secretion after glucose load and a decreasing HOMAbeta are exhibited. In addition to this, qualitative decrease of insulin secretion appears in the DM stage. AIR is a reliable index of isletbeta cell function. DeltaI30/DeltaG30 is an alternative one in the subjects with NGT and IGR. But it should be adjusted by IR in diabetic patients.

BACKGROUND: Glucose intolerance and insulin sensitivity in preadolescent children might predict the risk of developing type 2 diabetes mellitus in adult life in small for gestational age (SGA) children. We aimed to investigate whether reduced birthweight is related to low insulin sensitivity in preadolescence. SUBJECTS AND METHODS: Twenty-five SGA children and 29 appropriate for gestational age children (AGA) children born between 1993 and 1994 were evaluated for insulin sensitivity in preadolescence. At the beginning of the study, body mass index (BMI) was calculated and an oral glucose tolerance test (OGTT) was performed. Blood samples to measure glucose and insulin were taken every 30 minutes during OGTT. Homeostasis of model assessment-insulin resistance (HOMA-IR) and composite index (CI) values were measured to assess insulin sensitivity. RESULTS: On the OGTT, 120-minute glucose and insulin levels were higher in SGA than AGA children (P=0.02 and P=0.001, respectively). Although there was no difference between HOMA-IR values, the mean CI value was lower in SGA than AGA children (P=0.001). There was an inverse correlation between birthweight and 120-minute glucose concentrations (r=-0.30, P=0.02). This correlation was stronger between birthweight and 120-minute insulin concentrations (r=-0.50, P=0.001). BMI was positively correlated with 120-minute insulin (r=0.50, P=0.001). There was no relationship between HOMA-IR values and birth size, but the CI index was positively correlated with birthweight (r=0.40, P=0.002). CONCLUSIONS: Birthweight may be a predictive factor for insulin sensitivity and CI is more reliable than HOMA-IR to assess this sensitivity in preadolescence.

The aim of this study was to evaluate the validity and reliability of homeostasis model assessment-insulin resistance (HOMA-IR) index, its reciprocal (1/HOMA-IR), quantitative insulin sensitivity check index (QUICKI) and McAuley's index in hypertensive diabetic patients. In 78 patients with hypertension and type II diabetes glucose, insulin and triglyceride levels were determined after a 12-h fast to calculate these indices, and insulin sensitivity (IS) was measured with the hyperinsulinemic euglycemic clamp technique. Two weeks later, subjects had again their glucose, insulin and triglycerides measured. Simple and multiple linear regression analysis were applied to assess the validity of these indices compared to clamp IS and coefficients of variation between the two visits were estimated to assess their reproducibility. HOMA-IR index was strongly and inversely correlated with the basic IS clamp index, the M-value (r=-0.572, P<0.001), M-value normalized with subjects' body weight or fat-free mass and every other clamp-derived index. 1/HOMA-IR and QUICKI indices were positively correlated with the M-value (r=0.342, P<0.05 and r=0.456, P<0.01, respectively) and the rest clamp indices. McAuley's index generally presented less strong correlations (r=0.317, P<0.05 with M-value). In multivariate analysis, HOMA-IR was the best fit of clamp-derived IS. Coefficients of variation between the two visits were 23.5% for HOMA-IR, 19.2% for 1/HOMA-IR, 7.8% for QUICKI and 15.1% for McAuley's index. In conclusion, HOMA-IR, 1/HOMA-IR and QUICKI are valid estimates of clamp-derived IS in patients with hypertension and type II diabetes, whereas the validity of McAuley's index needs further evaluation. QUICKI displayed better reproducibility than the other indices.Journal of Human Hypertension advance online publication, 19 April 2007; doi:10.1038/sj.jhh.1002201.

BACKGROUND: Few previous studies have examined the validity of the fasting glucose-to-insulin ratio (FGIR), homeostasis model assessment of insulin resistance (HOMA-IR) and quantitative insulin-sensitivity check index (QUICKI) in pediatric populations. OBJECTIVE: To compare simple indices of insulin resistance calculated from fasting glucose and insulin levels with insulin sensitivity indices (area under the response curve [AUCinsulin], insulin sensitivity index [ISI-compositeL) determined by oral glucose tolerance testing (OGTT) in obese children. METHODS: One hundred and forty-eight obese children and adolescents (86 girls and 62 boys, mean age: 10.86 +/- 3.08 years, mean body mass index (BMI): 27.7 +/- 4.2) participated in the study. OGTT was performed in all participants. After glucose and insulin measurements from OGTT, the children were divided into two groups according to the presence or absence of insulin resistance. Insulin sensitivity indices obtained from the OGTT were compared between the groups. The total plasma glucose response and insulin secretion were evaluated from the AUC estimated by the trapezoid rule. Cut-off points, and sensitivity and specificity calculations were based on insulin resistance with receiver operating characteristic curve (ROC) analysis. RESULTS: The prevalence of insulin resistance, glucose intolerance and dyslipidemia was 37.1%, 24.3% and 54% in obese children, respectively. The groups consisted of 93 children without insulin resistance (54 girls and 39 boys; mean age: 10.5 +/- 3.3 years; mean BMI: 27.0 +/- 4.2) and 55 children with insulin resistance (32 girls and 23 boys; mean age: 11.4 +/- 2.5 years; mean BMI: 27.9 +/- 3.9). There were significant differences in mean FGIR (10.0 +/- 7.2 vs 5.6 +/- 2.8, p < 0.001), HOMA-IR (3.2 +/- 2.3 vs 4.9 +/- 2.3, p < 0.001) and QUICKI (0.33 +/- 0.03 vs 0.30 +/- 0.02, p < 0.001) between the groups. The cut-off points for diagnosis of insulin resistance were < 5.6 for FGIR (sensitivity 61.8, specificity 76.3),> 2.7 for HOMA-IR (sensitivity 80, specificity 59.1), and < 0.328 for QUICKI (sensitivity 80, specificity 60.2). CONCLUSIONS: Indices derived from fasting samples for diagnosis of insulin sensitivity are reliable criteria in obese children and adolescents. HOMA-IR and QUICKI appeared to have similar sensitivity and specificity and to have higher sensitivity than FGIR.

Insulin resistance is the principal cause of glucose intolerance and type 2 diabetes and induces progression of severe atherosclerosis in these patients. Adiponectin, the adipose-specific proteins, is known to correlate negatively with insulin resistance in patients with obesity and type 2 diabetes. The purpose of this study was to evaluate the potential of using serum adiponectin levels as a marker of insulin resistance in various states of insulin resistance. Furthermore, we attempted to establish a modified index of the homeostasis model assessment index (HOMA-IR), calculated from the product of serum insulin and plasma glucose levels divided by serum adiponectin levels (HOMA-AD). We recruited 117 Japanese subjects with various degrees of glucose tolerance and determined serum adiponectin levels and insulin sensitivity (M-value) by using the euglycemic hyperinsulinemic clamp technique. M-value, the gold standard index of insulin resistance, correlates significantly and independently with fasting insulin (r=-0.313, P<0.001), glucose (r=-0.319, P<0.001), and adiponectin (r=0.241, P<0.002) levels. M-values were more significantly correlated with HOMA-AD (r=-0.643, P<0.001) than HOMA-IR values (r=-0.591, P<0.001). In subjects with moderate hyperglycemia (fasting glucose levels>8.0mmol/L, n=30), HOMA-AD showed a more significant correlation with the M-value than HOMA-IR (r=-0.535, P=0.005 versus r=-0.461, P=0.010). We would therefore like to propose a novel index, HOMA-AD, as a simple and adequate index for determining insulin resistance even in diabetic patients with overt hyperglycemia.