Surrogate Estimates Research Articles

Surrogate Estimates of Insulin Sensitivity in Obese Youth along the Spectrum of Glucose Tolerance from Normal to Prediabetes to Diabetes

In epidemiological studies of childhood obesity, simple and reliable surrogate estimates of insulin sensitivity are needed because the gold standard, the hyperinsulinemic-euglycemic clamp, is not feasible on a large scale. To examine the correlation of fasting and oral glucose tolerance test (OGTT)-derived surrogate indices of insulin sensitivity with the hyperinsulinemic-euglycemic clamp in obese adolescents with normal glucose tolerance, prediabetes, and diabetes. A total of 188 overweight/obese adolescents (10 to <20 yr old) who completed a standard 2-h OGTT and 3-h hyperinsulinemic-euglycemic clamp were included. Fasting-derived surrogates [fasting glucose (G(F)), fasting insulin (I(F)), 1/I(F), G(F)/I(F), homeostasis model assessment and quantitative insulin sensitivity check index] and OGTT-derived surrogates [whole-body insulin sensitivity index and the ratio of glucose and insulin areas under the curve (Gluc(AUC)/Ins(AUC))] were calculated. We evaluated the correlations between the clamp-measured insulin sensitivity and the surrogate estimates and area under the receiver operating characteristic curves. Fasting indices (1/I(F), G(F)/I(F), homeostasis model assessment of insulin sensitivity, and quantitative insulin sensitivity check index) correlated significantly with clamp insulin sensitivity (r = 0.82, 0.78, 0.81, and 0.80, respectively), with lower correlations between the OGTT surrogates and clamp (whole-body insulin sensitivity index, r = 0.77; Gluc(AUC)/Ins(AUC), r = 0.62). The area under the receiver operating characteristic curves was more than or equal to 0.94 for all surrogates except Gluc(AUC)/Ins(AUC.) Across quartiles of clamp-measured insulin sensitivity, there was a significant overlap in individual values of I(F), 1/I(F), and G(F)/I(F). In obese adolescents with normal or impaired glucose tolerance or diabetes, OGTT-derived surrogates do not offer any advantage over the simpler fasting indices, which correlate strongly with clamp insulin sensitivity. Surrogate indices of insulin sensitivity could be used in epidemiological studies but not to define insulin resistance in individual patients or research subjects.

Evaluating the difference between the normalized difference vegetation index and net primary productivity as the indicators of vegetation vigor assessment at landscape scale

Both the net primary productivity (NPP) and the normalized difference vegetation index (NDVI) are commonly used as indicators to characterize vegetation vigor, and NDVI has been used as a surrogate estimator of NPP in some cases. To evaluate the reliability of such surrogation, here we examined the quantitative difference between NPP and NDVI in their outcomes of vegetation vigor assessment at a landscape scale. Using Landsat ETM+ data and a process model, the Boreal Ecosystem Productivity Simulator, NPP distribution was mapped at a resolution of 90 m, and total NDVI during the growing season was calculated in Heihe River Basin, Northwest China in 2002. The results from a comparison between the NPP and NDVI classification maps show that there existed a substantial difference in terms of both area and spatial distribution between the assessment outcomes of these two indicators, despite that they are strongly correlated. The degree of difference can be influenced by assessment schemes, as well as the type of vegetation and ecozone. Overall, NDVI is not a good surrogate of NPP as the indicators of vegetation vigor assessment in the study area. Nonetheless, NDVI could serve as a fairish surrogate indicator under the condition that the target region has low vegetation cover and the assessment has relatively coarse classification schemes (i.e., the class number is small). It is suggested that the use of NPP and NDVI should be carefully selected in landscape assessment. Their differences need to be further evaluated across geographic areas and biomes.

Estimates of Insulin Secretory Function in Apparently Healthy Volunteers Vary as a Function of How the Relevant Variables Are Quantified

Several surrogate estimates have been used to define relationships between insulin action and pancreatic β-cell function in healthy individuals. Because it is unclear how conclusions about insulin secretory function depend on specific estimates used, we evaluated the effect of different approaches to measurement of insulin action and secretion on observations of pancreatic β-cell function in individuals whose fasting plasma glucose (FPG) was <7.0 mmol/L (126 mg/dL). We determined 2 indices of insulin secretion [homeostasis model assessment of β-cell function (HOMA-β) and daylong insulin response to mixed meals], insulin action [homeostasis model assessment of insulin resistance (HOMA-IR) and steady-state plasma glucose (SSPG) concentration during the insulin suppression test], and degree of glycemia [fasting plasma glucose (FPG) and daylong glucose response to mixed meals] in 285 individuals with FPG <7.0 mmol/L. We compared the relationship between the 2 measures of insulin secretion as a function of the measures of insulin action and degree of glycemia. Assessment of insulin secretion varied dramatically as a function of which of the 2 methods was used and which measure of insulin resistance or glycemia served as the independent variable. For example, the correlation between insulin secretion (HOMA-β) and insulin resistance varied from an r value of 0.74 (when HOMA-IR was used) to 0.22 (when SSPG concentration was used). Conclusions about β-cell function in nondiabetic individuals depend on the measurements used to assess insulin action and insulin secretion. Viewing estimates of insulin secretion in relationship to measures of insulin resistance and/or degree of glycemia does not mean that an unequivocal measure of pancreatic β-cell function has been obtained.

Variance-based sensitivity analysis of model outputs using surrogate models

If a computer model is run many times with different inputs, the results obtained can often be used to derive a computationally cheaper approximation, or surrogate model, of the original computer code. Thereafter, the surrogate model can be employed to reduce the computational cost of a variance-based sensitivity analysis (VBSA) of the model output. Here, we draw attention to a procedure in which an adaptive sequential design is employed to derive surrogate models and estimate sensitivity indices for different sub-groups of inputs. The results of such group-wise VBSAs are then used to select inputs for a final VBSA. Our procedure is particularly useful when there is little prior knowledge about the response surface and the aim is to explore both the global variability and local nonlinear features of the model output. Our conclusions are based on computer experiments involving the process-based river basin model INCA-N, in which outputs like the average annual riverine load of nitrogen can be regarded as functions of 19 model parameters.

Maximal degree of airway narrowing induced by methacholine and adenosine monophosphate: relationship with the decrease in forced vital capacity

Changes in forced vital capacity (FVC) may represent an indirect method for the detection of plateau in response to inhaled bronchoconstrictor agents. To determine the relationship between the level of plateau obtained with either methacholine or adenosine monophosphate (AMP) and the decrease in FVC induced by each bronchoconstrictor agent. Airway responsiveness to high concentrations of methacholine and AMP was determined in patients with intermittent asthma (n = 41) or allergic rhinitis (n = 26). Furthermore, allergen-induced changes in the response to each bronchoconstrictor agent were investigated in 18 pollen-sensitive patients. Concentration-response curves were characterized by the slope of the FVC values recorded at each step of the challenge against the corresponding forced expiratory volume in 1 second (FEV1) values and, if possible, by the level of plateau. The slope FVC vs FEV1 was similar in patients with plateau and in those without plateau. In patients with pollen allergy, the mean (95% confidence interval) for the level of plateau detected with methacholine increased from 16.8% (11.8%-22.0%) before the pollen season to 21.7% (14.8%-28.6%, P = .008) during the pollen season, whereas pollen-induced changes in the slope FVC vs FEV1 were not significant. Similar results were obtained with AMP. In patients with allergic rhinitis or intermittent asthma, methacholine or AMP-induced changes in FVC are not significantly related to the presence or level of plateau. Furthermore, these 2 constituents of the concentration-response curve can be modified independently by a proinflammatory stimulus. These results suggest that the bronchoconstrictor-induced change in FVC cannot be used as a surrogate estimation of the level of plateau.

Evaluating aortic stiffness through an arm cuff oscillometric device: is validation against invasive measurements enough?

Introduction Following the 2006 expert consensus document of the European Network for Noninvasive Investigation of Large Arteries [1], arterial stiffness and central pressure measurements should be considered as recommended tests for the evaluation of cardiovascular risk, particularly in patients in whom target organ damage is not discovered by routine investigations. Within the area of noninvasive methods, pulse wave recording and analysis either from central (ascending aorta, carotid artery) or peripheral (radial artery) sites have become popular, particularly after the release of dedicated commercial devices [2]. Theoretically, pulse wave analysis should allow calculation of at least three parameters related to arterial wall properties: central pulse pressure, central systolic pressure and the augmentation index (Aix). There is large consensus that these parameters should not be considered as direct measures of arterial stiffness, but rather as surrogate estimates. Conversely, most investigators [1] agree that pulse wave velocity (PWV) is the more direct measure of arterial stiffness. Unfortunately there are different definitions of PWV, and different measurement sites have been proposed while, at the same time, the number of published papers on the validity and prognostic value of carotid–femoral, aortic, brachial–ankle and local PWVs is constantly increasing. Carotid–femoral PWV (PWVcf), the ‘gold standard’ of arterial stiffness [1], and aortic PWV (PWVao) are supported by the largest amount of epidemiological evidence on their ability to predict cardiovascular events in specific subgroups of patients and, possibly, in the population at large. However, there is also increasing evidence that central Aix predicts allcause mortality in end-stage renal disease and cardiovascular events in hypertension and coronary artery disease [1].

Quantification and comparison of marijuana smoking practices: Blunts, joints, and pipes

The quantification method for collecting self-reported marijuana use data is not standardized as it is for alcohol or cigarettes, which presents a methodologic challenge for marijuana use disorder treatment studies. Serum and urine markers of marijuana use have a long half-life, limiting their utility as a clinical trial outcome measure. Structured calendar-based interview procedures can accurately measure the frequency of self-reported marijuana use, but are unable to reliably address issues such as quantity of use or potency. This study compared the quantity and assigned-dollar value among users of blunts, joints, and pipes enrolled in two clinical trials testing pharmacotherapies for marijuana dependence. The timeline follow-back method was modified to incorporate using a surrogate substance to represent marijuana to enable participants to estimate the amount and value used. Blunt users were mostly black and Hispanic, while users of joints and pipes were primarily white. Participants reported that they placed 50% more marijuana in blunts than in joints and placed more than twice the amount of marijuana in blunts than in pipes. These findings demonstrate the feasibility of using a surrogate weight estimation procedure to augment calendar-based methods of measuring self-reported marijuana use. Individual variability in use practices limits the utility of this method to estimating within-subject comparisons, rather than between subject comparisons.

Hazard function estimation with cause-of-death data missing at random

Hazard function estimation is an important part of survival analysis. Interest often centers on estimating the hazard function associated with a particular cause of death. We propose three nonparametric kernel estimators for the hazard function, all of which are appropriate when death times are subject to random censorship and censoring indicators can be missing at random. Specifically, we present a regression surrogate estimator, an imputation estimator, and an inverse probability weighted estimator. All three estimators are uniformly strongly consistent and asymptotically normal. We derive asymptotic representations of the mean squared error and the mean integrated squared error for these estimators and we discuss a data-driven bandwidth selection method. A simulation study, conducted to assess finite sample behavior, demonstrates that the proposed hazard estimators perform relatively well. We illustrate our methods with an analysis of some vascular disease data.

The demography of introduction pathways, propagule pressure and occurrences of non‐native freshwater fish in England

Abstract Biological invasion theory predicts that the introduction and establishment of non‐native species is positively correlated with propagule pressure. Releases of pet and aquarium fishes to inland waters has a long history; however, few studies have examined the demographic basis of their importation and incidence in the wild. For the 1500 grid squares (10×10 km) that make up England, data on human demographics (population density, numbers of pet shops, garden centres and fish farms), the numbers of non‐native freshwater fishes (from consented licences) imported in those grid squares (i.e. propagule pressure), and the reported incidences (in a national database) of non‐native fishes in the wild were used to examine spatial relationships between the occurrence of non‐native fishes and the demographic factors associated with propagule pressure, as well as to test whether the demographic factors are statistically reliable predictors of the incidence of non‐native fishes, and as such surrogate estimators of propagule pressure. Principal coordinates of neighbour matrices analyses, used to generate spatially explicit models, and confirmatory factor analysis revealed that spatial distributions of non‐native species in England were significantly related to human population density, garden centre density and fish farm density. Human population density and the number of fish imports were identified as the best predictors of propagule pressure. Human population density is an effective surrogate estimator of non‐native fish propagule pressure and can be used to predict likely areas of non‐native fish introductions. In conjunction with fish movements, where available, human population densities can be used to support biological invasion monitoring programmes across Europe (and perhaps globally) and to inform management decisions as regards the prioritization of areas for the control of non‐native fish introductions. © Crown copyright 2010. Reproduced with the permission of her Majesty's Stationery Office. Published by John Wiley &amp; Sons, Ltd.

Fasting urine pH is independent of insulin sensitivity

It has recently been suggested that a low urine pH be added to the abnormalities linked to insulin resistance. This conclusion is based on the finding of a low urine pH in individuals with clinical syndromes associated with insulin resistance and not on studies in which a direct measure of insulin sensitivity was shown to be significantly related to differences in urine pH. To address this issue, we quantified insulin-mediated glucose uptake (IMGU) by using the insulin suppression test in 96 apparently healthy, nondiabetic individuals and defined its relation to fasting urine pH. Urine samples were collected and analyzed from a cohort of healthy subjects within a narrow body mass index range who were recruited to determine insulin sensitivity. There was an approximate 6-fold variation in values for IMGU in this population, with no relation to urine pH (r = 0.02). Furthermore, there was no relation between body mass index, as a surrogate estimate of insulin resistance, and urine pH (r = 0.06). On the basis of these findings, we question the view that a low urine pH be added to the abnormalities linked to insulin resistance in low-risk populations.

Vitamin D: considerations in the continued development as an agent for cancer prevention and therapy.

Considerable preclinical and epidemiologic data suggest that vitamin D may play a role in the pathogenesis, progression, and therapy for cancer. Numerous epidemiologic studies support the hypothesis that individuals with lower serum vitamin D levels have a higher risk of a number of cancers. Measures of vitamin D level in such studies include both surrogate estimates of vitamin D level (residence in more northern latitudes, history of activity, and sun exposure) as well as measured serum 25(OH) cholecalciferol levels. Perhaps, the most robust of these epidemiologic studies is that of Giovannucci et al, who developed and validated an estimate of serum 25(OH) cholecalciferol level and reported that among >40,000 individuals in the Health Professionals Study, an increase in 25(OH) cholecalciferol level of 62.5 ng/mL was associated with a reduction in the risk of head/neck, esophagus, pancreas cancers, and acute leukemia by >50%. Unfortunately, very limited data are available to indicate whether or not giving vitamin D supplements reduces the risk of cancer. Many preclinical studies indicate that exposing cancer cells, as well as vascular endothelial cells derived from tumors, to high concentrations of active metabolites of vitamin D halts progression through cell cycle, induces apoptosis and will slow or stop the growth of tumors in vivo. There are no data that one type of cancer is more or less susceptible to the effects of vitamin D. Vitamin D also potentiates the antitumor activity of a number of types of cytotoxic anticancer agents in in vivo preclinical models. Vitamin D analogues initiate signaling through a number of important pathways, but the pathway(s) essential to the antitumor activities of vitamin D are unclear. Clinical studies of vitamin D as an antitumor agent have been hampered by the lack of a suitable pharmaceutical preparation for clinical study. All commercially available formulations are inadequate because of the necessity to administer large numbers of caplets and the poor "bioavailability" of calcitriol (the most carefully studied analogue) at these high doses. Preclinical data suggest that high exposures to calcitriol are necessary for the antitumor effects. Clinical data do indicate that high doses of calcitriol (>100 mcg weekly, intravenously, and 0.15 microg /kg weekly, orally) can be given safely. The maximum tolerated dose of calcitriol is unclear. While a 250-patient trial in men with castration-resistant prostate cancer comparing docetaxel (36 mg/sqm weekly) +/- calcitriol 0.15 microg/kg indicated that calcitriol was very safe may have reduced to death rate, an adequately powered (1000 patients) randomized study of weekly docetaxel + calcitriol versus q3 week docetaxel was negative. The limitations of this trial were the unequal chemotherapy arms compared in this study and the failure to use an optimal biologic dose or maximum-tolerated dose of calcitriol. In view of the substantial preclinical and epidemiologic data supporting the potential role of vitamin D in cancer, careful studies to evaluate the impact of vitamin D replacement on the frequency of cancer and the impact of an appropriate dose and schedule of calcitriol or other active vitamin D analogue on the treatment of established cancer are indicated.

Perceived body image in men and women with type 2 diabetes mellitus: correlation of body mass index with the figure rating scale.

BackgroundBody mass index (BMI) is often used as an objective surrogate estimate of body fat. Increased BMI is directly associated with an increase in metabolic disease, such as type 2 diabetes mellitus (T2DM). The Stunkard Figure Rating Scale (FRS) is a subjective measure of body fat, and self-perceptions of body image conceivably impact the development and treatment of T2DM. This study examined the self-perception of body image to various levels of BMI among those with T2DM.MethodsRespondents (n = 13,887) to the US Study to Help Improve Early evaluation and management of risk factors Leading to Diabetes (SHIELD) 2006 survey self-reported their weight and height for BMI calculation. On the gender-specific Stunkard FRS, respondents selected the figure most closely resembling their body image. Spearman correlation was computed between perceived body image and BMI for men and women separately. Student's t-test analysis compared the mean BMI differences between respondents with and without T2DM.ResultsMen with T2DM did not significantly differ from men without diabetes mellitus in mean BMI per body image figure except at the extremes in body figures. Women with T2DM had a significantly higher BMI for the same body figure compared with women without diabetes mellitus for most figures (p < 0.05).ConclusionsIndividuals, particularly women, with T2DM may differ in their perception of body image compared with those without diabetes mellitus. It is unclear if these perceived differences increase the risk of T2DM, or if the diagnosis of T2DM alters body image perceptions.

Usefulness of minimal modelling to assess impaired insulin sensitivity in patients with chronic heart failure

In chronic heart failure (CHF), impaired insulin sensitivity (Si) is frequently observed. It is associated with symptomatic status and poor prognosis suggesting an intrinsic role of Si within CHF pathophysiology. HOmeostasis Model Assessment (HOMA), Fasting Insulin Resistance Index (FIRI), and QUick Insulin CheCK Index (QUICKI) are based on single-time fasting glucose and insulin assessment. Their value and discriminatory power in comparison to dynamic range assessment of Si by minimal modelling are not well established. In 105 patients with stable CHF (mean age 62 ± 1 years, peak VO(2) 18.2 ± 0.7 mL/kg/min, LVEF 28 ± 2%, mean ± SEM) Si was assessed by minimal modelling. HOMA, FIRI, and QUICKI were calculated from single-time point fasting glucose and insulin measurements. Detailed body composition was analyzed using dual-energy X-ray absorptiometry. All assessment methods showed impaired Si in CHF patients compared to healthy controls (n = 25). Yet, only minimal model-derived Si differentiated between NYHA classes (p = 0.0007). Further, minimal modelling was the only method to be directly associated with peak oxygen uptake and skeletal muscle strength. Model-derived Si predicted survival independently of established prognostic markers in CHF (RR 0.30 [95%CI 0.14-0.63]; p = 0.0016). In contrast, HOMA, FIRI and QUICKI did not show any of these qualities. HOMA, FIRI and QUICKI are surrogate estimates of Si with reduced discriminatory power in patients with CHF. While they are suitable to semi-quantitatively categorize impaired Si compared to normal values, the dynamic range assessment of Si by minimal modelling is superior for quantitative assessment of Si in pathophysiological studies.

Response to Letters Regarding Article, “Tissue Doppler Imaging in the Estimation of Intracardiac Filling Pressure in Decompensated Patients With Advanced Systolic Heart Failure”

We thank all the authors for their interest and insightful comments about our article1 and the tremendous contributions of the American Society of Echocardiography/European Association of Echocardiography Diastology Writing Group.2 We believe the many issues raised about the potential inaccuracies of our findings are precisely the factors that may directly influence the reliability of the ratio of early transmitral velocity to tissue Doppler mitral annular early diastolic velocity (E/Ea) to act as the single surrogate estimate of left ventricular filling pressures. In particular, the confounding factors that they addressed (such as the degree of ventricular remodeling, prevalence of mitral regurgitation, presence of dyssynchrony, or previous cardiac resynchronization therapy) are commonly observed in patients presenting with advanced decompensated heart failure. These are the exact patients in whom assessing intracardiac filling pressures may have a major impact on treatment decisions (such as initiation of diuretic therapy to relieve congestion). In essence, their salient points about the limitations of our findings are concordant with our observations on the …

Relationship between body mass index and adiposity in prepubertal children: ethnic and geographic comparisons between New York City and Jinan City (China)

Body mass index (BMI) is often used as a surrogate estimate of percent body fat in epidemiological studies. This study tested the hypothesis that BMI is representative of body fatness independent of age, sex, ethnicity, and geographic location in prepubertal children. The study sample included a total of 605 prepubertal children (275 girls and 330 boys) of which 247 were Chinese from Jinan, Shandong, Mainland China, and 358 children were from various ethnic backgrounds in New York City (NYC): 121 Caucasians, 94 African Americans, and 143 Asians (Chinese and Korean). In this cross-sectional study, dual energy X-ray absorptiometry was used to quantify total body fat (TBF) and percent body fat (PBF). Prepubertal status was assessed by the criteria of Tanner. Multiple regression models were developed with TBF and PBF as the dependent variables and BMI, age, sex, and ethnicity as independent variables. Multiple regression analysis showed that BMI alone explained 85% and 69% of between-subject variance for TBF and PBF, respectively. Sex was a significant contributor to the models (P<0.001) with girls having higher TBF and PBF than boys. Ethnicity and geographic location were significant contributors to the model (P<0.0001) with Asians (Jinan and NYC Asians) having higher PBF than all non-Asian groups (P<0.0001), and Jinan Asians having higher TBF and PBF than NYC-Asians. Among prepubertal children, for the same BMI, Asians have significantly higher PBF compared with African Americans and Caucasians. Caution is warranted when applying BMI across sex and ethnic prepubertal groups.

No Correlation Between Ultrasound Placental Grading at 31–34 Weeks of Gestation and a Surrogate Estimate of Organ Function at Term Obtained by Stereological Analysis

We test the experimental hypothesis that early changes in the ultrasound appearance of the placenta reflect poor or reduced placental function. The sonographic (Grannum) grade of placental maturity was compared to placental function as expressed by the morphometric oxygen diffusive conductance of the villous membrane. Ultrasonography was used to assess the Grannum grade of 32 placentas at 31–34 weeks of gestation. Indications for the scans included a history of previous fetal abnormalities, previous fetal growth problems or suspicion of IUGR. Placentas were classified from grade 0 (most immature) to grade III (most mature). We did not exclude smokers or complicated pregnancies as we aimed to correlate the early appearance of mature placentas with placental function. After delivery, microscopical fields on formalin-fixed, trichrome-stained histological sections of each placenta were obtained by multistage systematic uniform random sampling. Using design-based stereological methods, the exchange surface areas of peripheral (terminal and intermediate) villi and their fetal capillaries and the arithmetic and harmonic mean thicknesses of the villous membrane (maternal surface of villous trophoblast to adluminal surface of vascular endothelium) were estimated. An index of the variability in thickness of this membrane, and an estimate of its oxygen diffusive conductance, were derived secondarily as were estimates of the mean diameters and total lengths of villi and fetal capillaries. Group comparisons were drawn using analysis of variance. We found no significant differences in placental volume or composition or in the dimensions or diffusive conductances of the villous membrane. Subsequent exclusion of smokers did not alter these main findings. Grannum grades at 31–34 weeks of gestation appear not to provide reliable predictors of the functional capacity of the term placenta as expressed by the surrogate measure, morphometric diffusive conductance.

HOMA-beta in the UKPDS and ADOPT. Is the natural history of type 2 diabetes characterised by a progressive and inexorable loss of insulin secretory function? Maybe? Maybe not?

Introduction In 1995 the investigators of the United Kingdom Prospective Diabetes Study (UKPDS) published the results of 6 years of therapy with a variety of blood glucose-lowering drugs in patients with 2DM. Although the major goal of the study was to evaluate the relationship between glycaemic control and the development of diabetic complications, the report contained metabolic data which have had a substantial impact on general views as to the pathophysiology of 2DM. Specifically, using HOMA-beta, a surrogate estimate of pancreatic beta-cell function based on measurements of fasting plasma glucose and insulin concentrations, it was concluded that approximately 50% of insulin secretory capacity had been lost in these patients prior to initiation of the study. Following enrolment, there was a progressive deterioration of glycaemic control over the next 6 years in all groups, including those assigned to ‘intensive’ glycaemic intervention. beta-cell function as estimated by HOMA-beta also decreased continuously over the study period, leading the authors to conclude that ‘progressively increasing hyperglycaemia, associated with decreasing beta-cell function, was a marked feature irrespective of the therapy used.’ HOMA-beta has continued to be used as an estimate of beta-cell function in the years following the publication of the UKPDS report, with essentially similar conclusions as to the progressive loss of insulin secretory function over the natural history of 2DM. For example, HOMA-beta was used in the recent study 3 A Diabetes Outcome Progression Trial (ADOPT) to assess changes in beta-cell function over time in patients with 2DM assigned to monotherapy with rosiglitazone, metformin or glyburide. The major conclusion of ADOPT was that although the three drugs differed in length of time for monotherapy to fail, the data were consistent with the UKPDS results in that the initial improvement in glycaemic control was followed by a progressive increase in glycated haemoglobin and fasting plasma glucose concentration. The effect of treatment on the estimate of beta-cell function was somewhat more complicated than reported by the UKPDS, consisting of an initial improvement following initiation of drug treatment, but after this ‘levels of beta-cell function declined in all three groups.’ The notion of a progressive and inexorable loss of beta-cell function as part of the natural history of 2DM has been buttressed by results suggesting that in order to attain glycaemic control in patients with 2DM over time additional pharmacological agents must continually be added. This point was initially made in one of the reports of the UKPDS, but is echoed in the findings of the ADOPT study. The remainder of this analysis will be devoted to consideration of the appropriateness of HOMA-beta as an assessment of insulin secretory function, as well as the notion that glycaemic control inexorably declines with duration of 2DM.

Elastography for the non-invasive assessment of liver disease: limitations and future developments

Hepatology is still a relatively young discipline in medicine. The birth of hepatology in the 1950s was largely dependent on the introduction of liver biopsy performed with the Menghini’s needle1...

Assessment of the Efficacy of New Anti-Tuberculosis Drugs

The pathology of tuberculosis in humans starts with an initial Ghon focus in the lungs followed by transmission of bacilli though the blood and lymph to other regions in the lungs and to other organs. While these bacilli usually lie latent without causing further disease, some 10% start foci of adult type disease usually starting in the sub-apical regions of the lungs. Bacilli multiply, killing tissue by caseation and then forming colonies within the caseum. Cavities form connecting to the air in whose walls vigorous bacillary multiplication occurs. The history of the development of anti-tuberculosis chemotherapy is described, starting with the use of multi-drug regimens to prevent the emergence of drug resistance and continuing with the shortening of the treatment period to 6 months by the incorporation in the regimens of rifampicin and pyrazinamide, which are the two drug responsible for bactericidal activity during treatment. Prospects for further shortening of treatment rest with the introduction of higher dosage with rifamycins and with new anti-tuberculosis drugs. These new drugs include the 8 methoxyfluoroquinolones moxifloxacin and gatifloxacin which inhibit topoisomerases and protein formation, the diarylquinoline TM-207 which inhibits the mycobacterial ATP synthase and thus energy formation, the nitroimidazopyran PA-824 and the closely related OPC-676832 which are pro-drugs with uncertain modes of action and the pyrrole SQ-109, a cell wall inhibitor. Anti-tuberculosis drugs have widely variable pharmacokinetic characteristics but as they work efficiently together, it is unnecessary to match these when giving drug combinations. The effects of drug-drug interactions are usually small though the interactions with anti-retroviral drugs can pose problems. Dose sizes have usually been chosen to minimize side effects while retaining activity and thus tend to have low therapeutic margins, the exception being the margin of about 20 for isoniazid. The role of high plasma binding, important in limiting the efficacy of rifamycins, is uncertain for the newer drugs. Post antibiotic effects are vital to the prevention of drug resistance and need exploration for new drugs. The main aims of current drug development are (1) to shorten treatment, and (2) to make it more convenient, by for instance using widely intermittent regimens. The current techniques for measuring efficacy during drug development start with in vitro models, including the Hu/Coates models, which should contain bacterial populations resembling the bacterial persisters in lesions that are responsible for the long duration of treatment. The next stage is the mouse model of the chemotherapy of established tuberculosis, which has proved remarkably useful in assessing the value of the different drugs. The main problem in clinical assessment arises from the use of relapse after treatment as the main end-point, and the consequent need for very large numbers of patients required to provide measurable relapse rates in final phase III licensing studies. For this reason, surrogate studies are necessary in phase II which require much smaller numbers of patients. The first such investigations are phase IIA studies of early bactericidal activity which establish whether the drug given alone has bactericidal activity on cavitary bacilli and which can estimate the minimal effective dose of the drug, useful for decisions of dose size. The next step should be phase IIB studies which measure the rate of elimination of viable bacilli in sputum during the initial 8-weeks of treatment with various combinations of the new drug with established drugs. Measurement can be as (1) the proportion of patients with positive sputum at the end of the 8-weeks period, the easiest method but the least sensitive, or (2) as the speed with which sputum cultures become negative in a survival analysis, or (3) as the mean regression in modeling of serial sputum collections colony counts (SSCC). The relation between these surrogate estimates and the amoun of treatment shortening that can be obtained has still to be worked out.

Classical and model-based estimates of beta-cell function during a mixed meal vs. an OGTT in a population-based cohort

This study compared classical and model-based beta-cell responses during an oral glucose tolerance test (OGTT) and a meal tolerance test (MTT) in a population-based cohort. Individuals with normal glucose metabolism (NGM, n = 161), impaired glucose metabolism (IGM, n = 19) and type 2 diabetes mellitus (DM, n = 20) underwent a 75g-OGTT and an MTT (75 g carbohydrates, 50 g fat, 24 g proteins). Classical estimates of beta-cell function (insulinogenic index and the ratio of areas under insulin and glucose curves) were calculated. Mathematical modelling was used to determine beta-cell glucose sensitivity, rate sensitivity and potentiation. Insulin sensitivity was characterized by three surrogate estimates. Both classical and model-based estimates of beta-cell function were higher during MTT than during OGTT ( P < 0.05). Regarding the model-based parameters, especially beta-cell sensitivity was increased following MTT as compared with OGTT ( P < 0.05). Both during OGTT and MTT, across most parameters describing beta-cell function, the largest reduction in beta-cell response occurred between IGM and DM, while the largest reduction in insulin sensitivity occurred between NGM and IGM. We conclude that beta-cell response is stronger after a mixed meal than after an OGTT with equal carbohydrate quantity, both for classical and model-based parameters. The higher response was mostly explained by higher beta-cell sensitivity during the meal.