Impulse response model in reconstruction of insulin secretion by deconvolution: Role of input design in the identification experiment

Insulin secretion rate (ISR)in vivo can be reconstructed by deconvolution of plasma concentration of C-peptide (CP), a peptide co-secreted with insulin but not extracted by the liver and exhibiting linear kinetics. Deconvolution requires the knowledge of the CP impulse response. A two exponential model is usually chosen to describe the CP impulse response but three exponential and one exponential models have also been used. The purpose of this paper is to investigate the role of the CP impulse response model order in reconstructing ISR by deconvolution in three standard physiological/clinical situations: ultradian oscillations, rapid pulses, and biphasic response to a glucose stimulus. By resorting to simulation, we first show that, in each situation, the validity of impulse response models with different orders depends on the input chosen in the impulse response identification experiment. Real data are then used which support the simulation results.     

Insulin secretion rate during glucose stimuli: alternative analyses of C-peptide data

The ability to evaluate the pancreatic insulin secretion rate (ISR) is essential for a quantitative understanding of the glucose regulation system in man. Various approaches have been developed for evaluation of the ISR in vivo. The aim of this study was to compare input/output and compartmental models of C-peptide to reconstruct the ISR in response to both physiological and nonphysiological glucose stimuli in healthy humans. In particular we applied the nonparametric stochastic deconvolution and the C-peptide minimal model approaches to the graded up&down glucose infusion protocol, where glucose was infused at progressively increasing and then decreasing rates, and to the intravenous glucose tolerance test (IVGTT), where an impulse dose of glucose was administered. Our results show that the two models give virtually identical results when glucose and C-peptide (and thus ISR) profiles are smooth and regular, but when vigorous nonstationarities are present, like during the first 4 min of the IVGTT, the two ISR profiles are different (but not their areas under the curve). The C-peptide minimal model, albeit requiring, at variance with deconvolution, the knowledge of glucose data, has the advantage of providing quantitative indices of the -cell function, which is important in the parametric definition of different physiopathological states. © 2001 Biomedical Engineering Society. PAC01: 8715Rn, 8714Ee, 8716Ac     

Bayesian Identification of a Population Compartmental Model of C-Peptide Kinetics

When models are used to measure or predict physiological variables and parameters in a given individual, the experiments needed are often complex and costly. A valuable solution for improving their cost effectiveness is represented by population models. A widely used population model in insulin secretion studies is the one proposed by Van Cauter et al. (Diabetes 41:368–377, 1992), which determines the parameters of the two compartment model of C-peptide kinetics in a given individual from the knowledge of his/her age, sex, body surface area, and health condition (i.e., normal, obese, diabetic). This population model was identified from the data of a large training set (more than 200 subjects) via a deterministic approach. This approach, while sound in terms of providing a point estimate of C-peptide kinetic parameters in a given individual, does not provide a measure of their precision. In this paper, by employing the same training set of Van Cauter et al., we show that the identification of the population model into a Bayesian framework (by using Markov chain Monte Carlo) allows, at the individual level, the estimation of point values of the C-peptide kinetic parameters together with their precision. A successful application of the methodology is illustrated in the estimation of C-peptide kinetic parameters of seven subjects (not belonging to the training set used for the identification of the population model) for which reference values were available thanks to an independent identification experiment. © 2000 Biomedical Engineering Society. PAC00: 8715Aa, 0250Ga, 8714-g     

Comparison of alpha/beta estimates from homogeneous (individual) and heterogeneous (population) tumor control models for early stage prostate cancer

Radiobiological parameter estimates for prostate cancer are obtained from both a homogeneous (individual) and heterogeneous (population) tumor control model based on Poisson statistics and the linear quadratic model of cell survival. Parameter estimates for both models are highly correlated: statistically equivalent fits are achievable using either (1) linear quadratic (LQ) parameters with low numbers of radioresistant tumor stem cells, or (2) LQ parameters with corresponding larger number of radiosensitive tumor stem cells. A theoretical framework is developed to explain this correlation. A Monte Carlo error analysis based on binomial statistics is used to estimate confidence intervals for all parameter estimates. It was found that both the homogeneous and heterogeneous models produce approximately equivalent estimates of radiobiological parameters, including the alpha/beta ratio. However, the 95% confidence interval for the alpha/beta ratio derived from the heterogeneous model are considerably larger than those derived from the homogeneous model, which indicate the homogeneous model overestimates the statistical significance of the alpha/beta estimate.     

Imputation of missing values of tumour stage in population-based cancer registration

Background  

Previous studies have proposed a simple product-based estimator for calculating exposure-specific risks (ESR), but the methodology has not been rigorously evaluated. The goal of our study was to evaluate the existing methodology for calculating the ESR, propose an improved point estimator, and propose variance estimates that will allow the calculation of confidence intervals (CIs).     

Atypical diabetes associated with inclusion formation in the R6/2 mouse model of Huntington’s disease is not improved by treatment with hypoglycaemic agents

The R6/2 transgenic mouse model of Huntingtons disease (HD) develops a progressive neurological phenotype that involves severe motor and cognitive dysfunctions. Although not a cardinal sign, diabetes has been described in R6/2 mice. It is not clear, however, whether the diabetes contributes to the HD-like phenotype of R6/2 mice. In our study we found that the severity of diabetes in R6/2 mice was associated with the progressive formation of ubiquinated inclusions in pancreatic beta cells. Diabetes is dissociated from early motor and cognitive dysfunctions and did not correlate with motor impairment and survival of R6/2 mice. However, chronic behavioural testing (at a level higher than that which is reported to improve several aspects of the R6/2 phenotype) exacerbated the onset of diabetes. Pharmacological treatment of the diabetes was attempted using two oral hypoglycaemic agents commonly used by diabetics. The mice responded acutely to glibenclamide (which induces exocytosis of insulin) but not to rosiglitazone (which induces sensitization to insulin). This supports the suggestion that the diabetes in R6/2 mice is caused by an impairment in insulin release rather than insulin insensitivity. However, chronic treatment with these hypoglycaemic agents had no effect on either the course of the diabetes or the disease in R6/2 mice.     

Evidence for genetic epistasis in human insulin resistance: the combined effect of PC-1 (K121Q) and PPARgamma2 (P12A) polymorphisms

Insulin resistance is believed to be under the control of several genes often interacting each other. However, whether genetic epistasis does in fact modulate human insulin sensitivity is unknown. In 338 healthy unrelated subjects from Sicily, all nondiabetic and not morbidly obese, we investigated whether two gene polymorphisms previously associated with insulin resistance (namely PC-1 K121Q and PPAR2 P12A) affect insulin sensitivity by interacting. PC-1 X121Q subjects showed higher level of fasting glucose, lower insulin sensitivity (by both the Matsuda insulin sensitivity index and M values at clamp, the latter performed in a subgroup of 113 subjects representative of the overall cohort) and higher insulin levels during the oral glucose tolerance test (OGTT) than PC-1 K121K subjects. In contrast, no difference in any of the measured variables was observed between PPAR2 P12P and X12A individuals. The deleterious effect of the PC-1 X121Q genotype on each of these three variables was significant and entirely dependent upon the coexistence of the PPAR2 P12P genotype. Among PPAR2 P12P carriers also fasting insulin and glucose levels during OGTT were higher in PC-1 X121Q than in K121K individuals. In contrast, no deleterious effect of the PC-1 X121Q genotype was observed among PPAR2 X12A carriers; rather, in these subjects a lower body mass index and consequently lower fasting insulin level was observed in PC-1 X121Q than in K121K carriers. Overall, a significant interaction between the two genes was observed on body mass index, insulin levels (both fasting and after OGTT) and both insulin sensitivity (i.e., insulin sensitivity index and M value) and insulin secretion (i.e., HOMA-B%) indexes.Abbreviations AUC Area under the curve - BMI Body mass index - HOMA-B% Homeostasis model assessment of percent -cell function - HOMA _IR Homeostasis model assessment of insulin resistance - ISI Insulin sensitivity index - OGTT Oral glucose tolerance test - PC-1 Plasma cell-1 glycoprotein - PPAR Peroxisome proliferator activated receptor     

Molecular biomarkers in malignant mesothelioma: state of the art

Malignant mesothelioma (MM) is an aggressive tumour affecting the mesothelial surfaces of the pleural and peritoneal cavities and, rarely, the pericardium and the tunica vaginalis testis. Despite a ban of asbestos in many industrialised nations, the present high incidence of MM is expected to continue, due to the long latency period between first asbestos exposure and occurrence of disease, making it an important health issue for the future. The diagnosis of MM can be difficult, both from a clinical and pathological perspective. It is not unusual for patients to undergo several medical investigations without definitive diagnosis early in their course of illness. Understandably, there is intense interest in the discovery of markers that can be assessed in pleural effusions, histological specimens, and serum to assist with the difficult early diagnosis of MM. Considering the primary aetiological role of asbestos, there is theoretically an easily identifiable target population for screening with a biomarker with adequate sensitivity and specificity or with a combination of biomarkers. In this review we focus on biomarkers that have been examined in the setting of either early diagnosis of MM in symptomatic patients or screening of asbestos-exposed individuals.     

Effect of opiate receptor blockade on the insulin response to oral glucose load in polycystic ovarian disease.

In order to test the hypothesis that endogenous opiates are at least partially responsible for hyperinsulinaemia in patients with polycystic ovarian disease (PCOD), the effect of naloxone (an opiate receptor blocker) on the insulin response to oral glucose load (OGTT) was studied in 20 women with PCOD and 17 control subjects at days 5-8 of their follicular phase. After fasting overnight for 10-12 h, each woman received an i.v. bolus injection (2 mg) of naloxone or an equal volume of saline infusion followed by a constant infusion of naloxone or saline solution at a rate of 8 ml/h (1 mg/h of naloxone) for 5 h. OGTT (75 g) was performed 1 h after the bolus injection. The naloxone study was performed 48 h after the saline study. Naloxone did not modify the insulin response to OGTT in either group. When the data were related to the insulin response, in PCOD hyperinsulinaemic patients, naloxone significantly reduced (P less than 0.02) the insulin response to OGTT without any change in glycaemic response curves. In control and PCOD normoinsulinaemic patients, naloxone did not change significantly either the glycaemia or the insulin levels after OGTT. No change of gonadotrophin and steroid secretion was found in any patient receiving naloxone. In conclusion, endogenous opiates may play a significant role in hyperinsulinaemia in PCOD.     

Effect of prior heavy exercise on muscle deoxygenation kinetics at the onset of subsequent heavy exercise

This study examines the effect of prior heavy exercise on muscle deoxygenation kinetics at the onset of heavy-intensity cycling exercise. Ten young male adults (20 +/- 2 years) performed two repetitions of step transitions (6 min) from 35 W to heavy-intensity exercise preceded by either no warm-up or by a heavy-intensity exercise. VO2 was measured breath-by-breath, and muscle deoxygenation (HHb) and total hemoglobin (Hb(tot)) were monitored continuously by near-infrared spectroscopy. We used a two-exponential model to describe the VO2 kinetics and a mono-exponential model for the HHb kinetic. The parameters of the phase II VO2 kinetics (TD1 VO2, tau1 VO2 and A1 VO2) were unaffected by prior heavy exercise, while some parameters of local muscle deoxygenation kinetics were significantly faster (TD HHb: 7 +/- 2 vs. 5 +/- 2 s; P < 0.001, MRT HHb: 20 +/- 3 vs. 15+/- 4 s; P < 0.05). Blood lactate, heart rate and Hb(tot) values were significantly higher before the second bout of heavy exercise. These results collectively suggest that the prior heavy exercise probably increased muscle O2 availability and improved O2 utilization at the onset of a subsequent bout of heavy exercise.     

Physiological responses at five estimates of critical velocity

The purpose of this study was to compare critical velocity (CV) estimates from five mathematical models, and to examine the oxygen uptake (VO(2)) and heart rate (HR) responses during treadmill runs at the five estimates of CV. Ten subjects (six males and four females) performed one incremental test to determine maximal oxygen consumption (VO(2max)) and four or five randomly ordered constant-velocity trials on a treadmill for the estimation of CV. Five mathematical models were used to estimate CV for each subject including two linear, two nonlinear, and an exponential model. Up to five randomly ordered runs to exhaustion were performed by each subject at treadmill velocities that corresponded to the five CV estimates, and VO(2) and HR responses were monitored throughout each trial. The 3-parameter, nonlinear (Non-3) model produced CV estimates that were significantly (P < 0.05) less than the other four models. During runs at CV estimates, five subjects did not complete 60 min at the their estimate from the Non-3 model, nine did not complete 60 min at their estimate from the Non-2 model, and no subjects completed 60 min at any estimate from the other three models. The mean HR value (179 +/- 18 beats min(-1), HR(peak)) at the end of runs at CV using the Non-3 model was significantly less than the maximal HR (195 +/- 7 beats min(-1), HR(max)) achieved during the incremental trial to exhaustion. However, mean HR(peak) values from runs at all other CV estimates were not significantly different from HR(max). Furthermore, data indicated that mean HR(peak) values increased during runs at CV estimates from the third minute to the end of exercise for all models, and that these increases in VO(2) (range = 367-458 ml min(-1)) were significantly greater than that typically associated with O(2) drift ( approximately 200 ml min(-1)) for all but the exponential model, indicating a VO(2) slow component associated with CV estimates from four of the five models. However, the mean VO(2) values at the end of exercise during the runs at CV estimates for all five mathematical models were significantly less than the mean VO(2max) value. These results suggest that, in most cases, CV estimated from the five models does not represent a fatigueless task. In addition, the mean CV estimates from the five models varied by 18%, and four of the five mean CV estimates were within the heavy exercise domain. Therefore, CV would not represent the demarcation point between heavy and severe exercise domains.     

Glucose dynamics in Type I diabetes: insights from the classic and linear minimal models

This study demonstrates that the classic minimal model (MM) and the linear minimal model (LMM) are able to follow the dynamics of glucose in Type I diabetes. LMM precision is better than the MM with systematic lower mean values for the coefficient of variation (CV) in all characteristic model parameters. LMM S(I)(L)=7.40 is not significantly different from MM S(I)=10.71 (units 1/min per muU/ml, alpha=0.001) with a strong correlation (R(s) = 0.83, alpha=0.01). LMM S(G)(L)=0.0407 appears to be significantly different to S(G)=0.0266 (units 1/min, alpha=0.001) but correlates very well (R(s)=0.91,alpha=0.01). Since residuals appear to be heteroscedastic, further work is required to address the effect of modeling and signal processing on them. For the data under study, the models are not able to fit two-thirds of the data windows available. This is because none of the models are able to follow complex situations such as the presence of several bolus injections, the absence of insulin supply or inappropriate insulin dosage. A synthesis of the patterns found in these windows is presented which would be useful for the development of new models for fitting these data.     

The defect in peripheral blood B-cell activation in patients with multiple myeloma is not due to a deficiency in the production of B-cell growth and differentiation factors

The suppression of B lymphopoiesis is a major feature of multiple myeloma (MM). In this disease, there is a striking defect in the response of peripheral blood B cells to pokeweed mitogen (PWM). Normally, B-cell activation depends on B-cell growth factors (BCGFs) and B-cell differentiation factors (BCDFs), produced by peripheral blood mononuclear cells. We therefore evaluated whether the production of these cytokines was defective in patients with MM. We have studied the production of BCGFs (using the anti- assay) and, particularly, interleukin-2 and interferon-, two well-documented BCGFs. No defect in the production of BCGFs, interleukin-2, and interferon- was found in patients with active (N=14) or stable (N=10) MM, compared with healthy donors (N=13). The production of BCDFs (i.e., overall activity) was also evaluated and, more particularly, that of interleukin-6 (IL-6). This cytokine is a potent BCDF which is essential in the PWM-induced activation of B cells, acting at the terminal stages of B-cell differentiation. Again, no defect in the production of BCDFs and IL-6 was found in patients with MM. Therefore, the ability to secrete cytokines controlling the process of B-cell activation is not affected in such patients. This indicates that the profound failure of humoral immune response is not due to deficiency of peripheral blood mononuclear cells producing these factors.     

Hypothalamic-pituitary activation does not differ during human and porcine insulin-induced hypoglycemia in insulin-dependent diabetes mellitus

Summary Although pituitary hormones play only a minor role in acute hormonal counterregulation during insulin-induced hypoglycemia, their concomitant secretion with the profound sympathoadrenal response provides an indicator of hypothalamic-pituitary activation. The release of different amounts of -endorphin, growth hormone, and adrenocorticotropin during human (HI) and porcine (PI) insulin-induced hypoglycemia would serve as a pointer to a different insulin species effect on hypothalamic-pituitary response. We performed a controlled, double-blind study with randomization to either HI or PI to compare insulin effects during developing and established hypoglycemia. The glucose clamp technique was used to lower the blood glucose concentration stepwise (3.3, 2.2, 1.7 mmol/1) over similar periods in ten patients with insulin-dependent diabetes mellitus. -endorphin, growth hormone, and adrenocorticotropin levels were determined by radioimmunoassay from arterialized blood at the above plateaus. A different action of HI or PI on peripheral glucose metabolism was not found. Pituitary hormones increased significantly during hypoglycemia (analysis of variance for hypoglycemic effects: -endorphin, P < 0.02; growth hormone, P < 0.04; adrenocorticotropin, P < 0.05). No insulin species effect was detected. Hypothalamic-pituitary activation during insulin-induced hypoglycemia is independent of the insulin species used, which supports earlier observations of an identical sympathoadrenal response during HI- and PI-induced hypoglycemia.Abbreviations HI human insulin - PI porcine insulin     

Accurate confidence intervals for binomial proportion and Poisson rate estimation

Estimates of proportion and rate-based performance measures may involve discrete distributions, small sample sizes, and extreme outcomes. Common methods for uncertainty characterization have limited accuracy in these circumstances. Accurate confidence interval estimators for proportions, rates, and their differences are described and MATLAB programs are made available. The resulting confidence intervals are validated and compared to common methods. The programs search for confidence intervals using an integration of the Bayesian posterior with diffuse priors to measure the confidence level. The confidence interval estimators can find one or two-sided intervals. For two-sided intervals, either minimal-length, balanced-tail probabilities, or balanced-width can be selected.     

Randomized, controlled trials, observational studies, and the hierarchy of research designs

BACKGROUND: In the hierarchy of research designs, the results of randomized, controlled trials are considered to be evidence of the highest grade, whereas observational studies are viewed as having less validity because they reportedly overestimate treatment effects. We used published meta-analyses to identify randomized clinical trials and observational studies that examined the same clinical topics. We then compared the results of the original reports according to the type of research design. METHODS: A search of the Medline data base for articles published in five major medical journals from 1991 to 1995 identified meta-analyses of randomized, controlled trials and meta-analyses of either cohort or case-control studies that assessed the same intervention. For each of five topics, summary estimates and 95 percent confidence intervals were calculated on the basis of data from the individual randomized, controlled trials and the individual observational studies. RESULTS: For the five clinical topics and 99 reports evaluated, the average results of the observational studies were remarkably similar to those of the randomized, controlled trials. For example, analysis of 13 randomized, controlled trials of the effectiveness of bacille Calmette-Guérin vaccine in preventing active tuberculosis yielded a relative risk of 0.49 (95 percent confidence interval, 0.34 to 0.70) among vaccinated patients, as compared with an odds ratio of 0.50 (95 percent confidence interval, 0.39 to 0.65) from 10 case-control studies. In addition, the range of the point estimates for the effect of vaccination was wider for the randomized, controlled trials (0.20 to 1.56) than for the observational studies (0.17 to 0.84). CONCLUSIONS: The results of well-designed observational studies (with either a cohort or a case-control design) do not systematically overestimate the magnitude of the effects of treatment as compared with those in randomized, controlled trials on the same topic.     

Rapid effect of insulin on labelling of bis-phosphoenolpyruvate

Summary The time course of the insulin effect on 1,2-bis-phosphoenolpyruvate (bis-PEP), a glucose metabolite, has been investigated. Within 30 sec insulin causes an increase of 60% in the amount of bis-PEP accumulated in incubation media of rat diaphragms.     

Polymorphism in the peroxisome proliferator-activated receptor-gamma gene in women with polycystic ovary syndrome

BACKGROUND: In view of the strong evidence implicating peroxisome proliferator-activated receptor-gamma (PPARgamma) in adiposity and insulin resistance a study was carried out to investigate PPARgamma genotype frequencies in women with polycystic ovary syndrome (PCOS) and to elucidate its role in the pathogenesis of the syndrome. METHODS: The study involved 135 women with PCOS and 115 healthy control women who were genotyped for a known functional variant of the PPARgamma gene using single strand conformation polymorphism (SSCP) analysis. RESULTS: A significantly different allele distribution of the Pro12 Ala polymorphism of the PPARgamma gene was observed between the two groups, with the frequency of the variant Ala isoform being significantly reduced in the PCOS group (12.6%) when compared with the control group (19.1%) (P = 0.045), at an odds ratio of 0.609 (95% confidence interval: 0.374-0.991). The genotype distributions of the Pro12 Ala polymorphism in the PCOS and control groups were different with borderline significance (P = 0.051). CONCLUSIONS: Our data support a role for PPARgamma gene polymorphism in the pathogenesis of PCOS, the presence of the Ala isoform being protective against the development of PCOS.