Pharmacogenetic study of the effects of NK2R G231E G>A and TBX21 H33Q C>G polymorphisms on asthma control with inhaled corticosteroid treatment

Background and Objective: Inhaled corticosteroids (ICS) are widely used as maintenance regimens for asthma patients. However, response to ICS shows marked inter‐individual variability. Genetic factors have been shown to be potential predictors of responsiveness to ICS. We aimed to evaluate those pharmacogenetic effects on asthma control in further detail. Methods: Fifty‐three mild‐to‐moderate asthmatics were genotyped for four genetic polymorphisms of four genes: β2‐adrenergic receptor (ADRB2), adenylate cyclase 9 (ADCY9), neurokinin receptor 2 (NK2R) and T‐box 21 (TBX21). The principal clinical outcome was the achievement of asthma control, as assessed using the Global Initiative for Asthma (GINA) guidelines. During treatment with ICS, the forced expiratory volume in 1 second (FEV₁), maximal mid‐expiratory flow (MMEF) and peak expiratory flow rate (PEFR) were monitored every 4 weeks and twice daily. Results: Forty‐eight of the 53 patients with asthma were in a controlled or partly controlled state after 12 weeks of treatment with ICS, whereas five asthmatics were in an uncontrolled state even after active treatment. Of the four genetic polymorphisms examined, NK2R G231E G>A and TBX21 H33Q C>G were significantly associated with asthma control status (P = 0·041 and P = 0·006). The subjects with wild‐type alleles at each polymorphism showed a significant association with the well‐controlled or partly controlled state, as compared to those with mutant alleles. At 5–12 weeks after ICS treatment, the NK2R G231E G>A was associated with therapeutic response to ICS, as reflected by improvement in predicted FEV₁%. Conclusion: Our results suggest that NK2R G231E G>A and TBX21 H33Q C>G are genetic predictors of response to ICS, at least with respect to asthma control status and changes in FEV₁%, in Korean patients with asthma. Further prospective validation of those associations is necessary.     

糖负荷后血尿酸与胰岛素分泌及胰岛素敏感性/抵抗的相关性分析

目的研究不同糖负荷人群血尿酸(SUA)水平与胰岛素分泌及胰岛素抵抗的关系。方法 389例符合要求的研究对象行口服糖耐量试验(OGTT),测量空腹SUA,OGTT 0、30、60、120min血糖(GLU)和胰岛素(INS)水平,按照OGTT结果将研究对象分为糖耐量正常组(NGT组,n=88)、糖尿病前期组(preDM,n=119)、糖尿病组(DM,n=182),计算研究对象的胰岛素分泌指数(IGI)、120min胰岛素分泌指数(AUC INS_(120)/AUC GLU_(120))、胰岛素抵抗指数(HOMA-IR)、及Matsuda指数;将SUA按四分位水平分组,比较各糖负荷组不同SUA水平胰岛素分泌及胰岛素抵抗差异;计算SUA与胰岛素分泌及HOMA-IR的直线回归方程。结果 DM组SUA水平低于PreDM组[(346.66±90.60)mmol/Lvs.(367.36±92.34)mmol/L],但是略高于NGT组(339.34±89.51)mmol/L,差异有统计学意义(P0.01);DM组IGI指数、AUC INS_(120)/AUC GLU_(120)指数随着SUA升高有降低趋势(P0.01),Matsuda指数随着SUA水平升高有降低趋势(P0.05)。SUA与IGI、AUC INS_(120)/AUC GLU_(120)、HOMAIR、Matsuda指数的二元一次方程分别是Y=4.050+0.144 X,Y=2.343+0.206 X,Y=1.288+0.176 X,Y=129.373-0.202 X。结论 SUA与胰岛素分泌及胰岛素敏感性显著相关,DM组胰岛素分泌随着SUA水平升高而升高,胰岛素敏感性随着SUA水平升高而降低。SUA与胰岛素分泌及胰岛素敏感性的二元一次方程可大概评估胰岛素功能。     

Plasma protein thiols: an early marker of oxidative stress in asthma and chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) and asthma are both characterized by heterogeneous chronic airway inflammation and obstruction as well as oxidative stress (OS). However, it is unknown whether OS occurs in early disease and how to best assess its presence. Plasma OS markers (TBARS, PSH, taurine, GSH, ergothioneine and paraoxonase 1 activity) and lung function tests were measured in patients with mild stable asthma (n = 24) and mild stable COPD (n = 29) and in age‐ and sex‐matched controls. Forced expiratory volume in 1 s (FEV₁) was associated with age both in patients and control groups. By contrast, FEV₁ was positively correlated with PSH only in COPD (ρ = 0·49, P = 0·007). In multiple logistic regression analysis, lower PSH was the only OS marker independently associated with increased odds of both asthma (OR = 0·32, 95% CI 0·13–0·78, P = 0·01) and COPD (OR = 0·50, 95% CI 0·26–0·95, P = 0·03). These findings suggest that proteins ‐SH are a sensitive OS marker in early COPD and asthma.     

Prehospital Use of Inhaled Corticosteroids and Point Prevalence of Pneumonia at the Time of Hospital Admission: Secondary Analysis of a Multicenter Cohort Study

ObjectiveTo address clinical concern regarding the use of inhaled corticosteroids (ICSs) and the risk for pneumonia, particularly among patients with chronic obstructive pulmonary disease (COPD) and asthma.Patients and MethodsA multicentered prospective cohort of patients admitted to the hospital from March 1, 2009, through August 31, 2009, with pneumonia or another risk factor for acute respiratory distress syndrome was analyzed to determine the risk for pneumonia requiring hospitalization among patients taking ICSs. The adjusted risk (odds ratio [OR]) for developing pneumonia because of ICSs was determined in a multiple logistic regression model.ResultsOf the 5584 patients in the cohort, 495 (9%) were taking ICSs and 1234 (22%) had pneumonia requiring hospitalization. In univariate analyses, pneumonia occurred in 222 (45%) of the patients on ICSs vs 1012 (20%) in those who were not (OR, 3.28; 95% CI, 2.71-3.96; P<.001). After adjusting in the logistic regression model, prehospital ICS use was not significantly associated with pneumonia in the whole cohort (OR, 1.20; 95% CI, 0.93-1.53; P=.162), among the subset of 589 patients with COPD (OR, 1.40; 95% CI, 0.95-2.09; P=.093), among the 440 patients with asthma (OR, 1.07; 95% CI, 0.61-1.87; P=.81), nor among the remaining 4629 patients without COPD or asthma (OR, 1.32; 95% CI, 0.88-1.97; P=.179).ConclusionWhen adjusted for multiple confounding variables, ICS use was not substantially associated with an increased risk for pneumonia requiring admission in our cohort.     

Risk of progression to type 2 diabetes based on relationship between postload plasma glucose and fasting plasma glucose

OBJECTIVE: We sought to assess the risk of progression to type 2 diabetes in normal glucose tolerance (NGT) subjects based on the relationship between the plasma glucose concentration during oral glucose tolerance tests (OGTTs) and the fasting plasma glucose (FPG) concentration. RESEARCH DESIGN AND METHODS: Subjects with NGT (n = 1,282) from the San Antonio Heart Study received an OGTT with measurement of the plasma glucose concentration at 0, 30, 60, and 120 min at baseline and after 7-8 years of follow-up. Subjects were divided into four groups based on the relationship between the plasma glucose concentration during the OGTT and the FPG concentration on the same day as the OGTT. Insulin resistance was calculated by the homeostasis model assessment of insulin resistance (HOMA-IR) and Matsuda index. Early-phase insulin secretion was calculated as the ratio between the incremental plasma insulin and glucose concentrations during the first 30 min of the OGTT (DeltaI(0-30)/DeltaG(0-30)). Total insulin secretion was calculated as the ratio between the incremental areas under the insulin and glucose curves during the OGTT [DeltaG(AUC)/DeltaI(AUC)]. RESULTS: In 23 subjects (group I), the plasma glucose concentration during the OGTT returned to levels below the FPG concentration at 30 min; in 111 subjects (group II) and in 313 subjects (group III), the plasma glucose concentration during the OGTT returned to levels below the FPG concentration at 60 and 120 min, respectively. In the remaining 835 subjects (group IV), the plasma glucose concentration during the OGTT never fell below the FPG concentration. Insulin resistance, measured by HOMA-IR and the Matsuda index, increased progressively from group I through group IV, while insulin secretion measured by DeltaI(0-30)/DeltaG(0-30) and DeltaG(AUC)/DeltaI(AUC) decreased progressively from group I through group IV. The incidence of type 2 diabetes was 0% in group I and progressively increased to 0.9% in group II, 3.2% in group III, and 6.4% in group IV. CONCLUSIONS: Subjects whose postload plasma glucose concentration returned to baseline (i.e., FPG level) more quickly had greater insulin sensitivity, a higher insulinogenic index, and a lower risk of developing type 2 diabetes after 8 years of follow-up compared with subjects whose postload glucose concentration returned to baseline more slowly.     

Insulin secretion and its determinants in the progression of impaired glucose tolerance to type 2 diabetes in impaired glucose-tolerant individuals: the Finnish Diabetes Prevention Study

OBJECTIVE

We investigated the effect of early-phase insulin secretion on the incidence of type 2 diabetes in individuals with impaired glucose tolerance (IGT) participating in the Finnish Diabetes Prevention Study (DPS). We examined how a lifestyle intervention affected early-phase insulin secretion (ratio of total insulin area under the curve [AUC] and total glucose AUC [AIGR] from 0 to 30 min) during a 4-year follow-up intervention trial and whether AIGR_0–30 response was modified by insulin sensitivity (IS) and obesity.

RESEARCH DESIGN AND METHODS

A total of 443 participants with IGT originally randomized to a lifestyle intervention or control group were studied. IS and AIGR_0–30 were estimated from an oral tolerance glucose test administered annually during the 4-year follow-up trial and were related to the risk of diabetes onset over a 6-year follow-up.

RESULTS

Lifestyle intervention resulted in higher IS (P = 0.02) and lower unadjusted AIGR_0–30 (P = 0.08) during the 4-year follow-up. A higher IS and a lower BMI during the follow-up were associated with a lower unadjusted AIGR_0–30 during the follow-up, independently of study group (P < 0.001). A greater increase in IS on the median cutoff point of a 0.69 increase was associated with higher IS-adjusted AIGR_0–30 during the follow-up (P = 0.002). In multivariate models, IS and IS-adjusted AIGR_0–30 were both inversely associated with diabetes incidence (P < 0.001). Participants who progressed to type 2 diabetes were more obese and had lower IS and Matsuda IS index-AIGR_0–30 than nonprogressors.

CONCLUSIONS

Our results indicate that the reduction in the risk of developing type 2 diabetes after lifestyle intervention is related to the improvement of IS along with weight loss. Improved IS may also have beneficial effects on preservation of β-cell function.Genetic and environmental factors both contribute to the development of type 2 diabetes (1). Current evidence indicates that an underlying defect in insulin secretion in the presence of insulin resistance leads to the development of diabetes. Impaired glucose tolerance (IGT) is already characterized by impaired first-phase insulin secretion, a determinant for further progression to diabetes (2–5).Lifestyle changes involving healthy diet, moderate weight loss, and increased physical activity reduce the risk of diabetes (6–8). The extent to which this is due to reduced insulin resistance or improved insulin secretion is not known. Improvements in insulin secretion and insulin sensitivity after 1 year of lifestyle intervention were associated with lower diabetes risk in the Diabetes Prevention Program (DPP) study during a follow-up of 3.2 years (6). In a substudy of the Finnish Diabetes Prevention Study (DPS) in persons with IGT who did not progress to diabetes, insulin secretion measured during a frequently sampled intravenous glucose tolerance test (IVGTT) remained stable for years (9). However, data from long-term intervention trials on the mechanisms that may result in improvement of glucose metabolism and prevention of diabetes associated with healthy lifestyle changes are scarce.Therefore, we investigated the effect of surrogate indices of early-phase insulin secretion and insulin sensitivity from an oral glucose tolerance test (OGTT) on diabetes incidence in individuals participating in the Finnish DPS. We also evaluated whether insulin secretion response in the OGTT was modified by insulin sensitivity and obesity, and how lifestyle intervention may affect the β-cell function.     

Evaluation of genetic predisposition to insulin resistance by nutrient-induced insulin output ratio (NIOR).

BACKGROUND: New tools to identify genotype-phenotype interactions need to be described and implemented. The aim of this study was to identify correlation between the risk originating from gene variation and diet-dependent development of insulin resistance. METHODS: Insulin output in terms of area under the curve after an oral glucose tolerance test (AUC Ins OGTT) and lipid tolerance tests (AUC Ins OLTT) were measured in 167 overweight/obese patients. Estimation of the 18 common gene polymorphisms for obesity risk and standard phenotyping were performed. RESULTS: Insulin output (AUC Ins OGTT) correlated strongly between both insulin treatments across the whole group. However, within the genotype sub-groups, correlation was lower or did not exist. Using a nutrient-induced insulin output ratio (NIOR), calculated as AUC Ins OLTT/AUC Ins OGTT, values ranged from 0.42 to 5.83 and correlated significantly with body mass index (BMI) and leptin, but not with age, gender, waist-to-hip ratio (WHR) and homeostasis model assessment of insulin resistance (HOMA-IR) or plasma adiponectin. High NIOR was found in a subgroup of carriers of rare allelic variants of genes characteristic for poorer tolerance to lipids in the diet. Low NIOR values were found within a sub-group with rare genetic variants regulating carbohydrate metabolism. Thus, the new insulin index NIOR may distinguish gene variant carriers into groups of glucose- or lipid-sensitive phenotypes. CONCLUSIONS: We suggest that the OLTT/OGTT insulin output ratio (NIOR) may be predictive for identifying individuals who are phenotypically susceptible to insulin resistance in response to high fat or carbohydrate in their habitual diet.     

Respiratory muscle strength and muscle endurance are not affected by acute metabolic acidemia

Respiratory muscle fatigue in asthma and chronic obstructive lung disease (COPD) contributes to respiratory failure with hypercapnia, and subsequent respiratory acidosis. Therapeutic induction of acute metabolic acidosis further increases the respiratory drive and, therefore, may diminish ventilatory failure and hypercapnia. On the other hand, it is known that acute metabolic acidosis can also negatively affect (respiratory) muscle function and, therefore, could lead to a deterioration of respiratory failure. Moreover, we reasoned that the impact of metabolic acidosis on respiratory muscle strength and respiratory muscle endurance could be more pronounced in COPD patients as compared to asthma patients and healthy subjects, due to already impaired respiratory muscle function. In this study, the effect of metabolic acidosis was studied on peripheral muscle strength, peripheral muscle endurance, airway resistance, and on arterial carbon dioxide tension (PaCO₂). Acute metabolic acidosis was induced by administration of ammonium chloride (NH₄Cl). The effect of metabolic acidosis was studied on inspiratory and expiratory muscle strength and on respiratory muscle endurance. Effects were studied in a randomized, placebo‐controlled cross‐over design in 15 healthy subjects (4 male; age 33·2 ± 11·5 years; FEV₁ 108·3 ± 16·2% predicted), 14 asthma patients (5 male; age 48·1 ± 16·1 years; FEV₁ 101·6 ± 15·3% predicted), and 15 moderate to severe COPD patients (9 male; age 62·8 ± 6·8 years; FEV₁ 50·0 ± 11·8% predicted). An acute metabolic acidemia of BE –3·1 mmol.L^?1 was induced. Acute metabolic acidemia did not significantly affect strength or endurance of respiratory and peripheral muscles, respectively. In all subjects airway resistance was significantly decreased after induction of metabolic acidemia (mean difference –0·1 kPa.sec.L^?1 [95%‐CI: ?0·1 –?0·02]. In COPD patients PaCO₂ was significantly lowered during metabolic acidemia (mean difference –1·73 mmHg [?3·0 –?0·08]. In healthy subjects and in asthma patients no such effect was found. Acute metabolic acidemia did not significantly decrease respiratory or peripheral muscle strength, respectively muscle endurance in nomal subjects, asthma, or COPD patients. Metabolic acidemia significantly decreased airway resistance in asthma and COPD patients, as well as in healthy subjects. Moreover, acute metabolic acidemia slightly improved blood gas values in COPD patients. The results suggest that stimulation of ventilation in respiratory failure, by induction of metabolic acidemia will not lead to deterioration of the respiratory failure.     

Short-term glucose dysregulation following acute poisoning with organophosphorus insecticides but not herbicides,carbamate or pyrethroid insecticides in South Asia

Background: Ingestion of organophosphorus (OP) insecticides is associated with acute hyperglycaemia. We conducted a prospective study to determine whether glucose dysregulation on admission associated with ingestion of OP insecticides or other pesticides is sustained to hospital discharge or to 3–12 months later.

Methods: We recruited participants to two similar studies performed in parallel in Anuradhapura, Sri Lanka, and Chittagong, Bangladesh, following hospitalisation for OP insecticide, herbicide or other pesticide self-poisoning. Two-hour 75?g oral glucose tolerance testing (OGTT) was performed after recovery from the acute poisoning, at around the time of discharge. In Sri Lanka, a four time-point OGTT for area-under-the-curve (AUC), C-peptide and homeostatic modelling of insulin resistance (HOMA-IR) was undertaken, repeated after 1 year. In Bangladesh, a 2-h OGTT for glucose was undertaken and repeated after 3 months in participants with initial elevated 2-h glucose. We compared glucose homeostasis by poison group and adjusted findings for age, BMI and sex.

Findings: Seventy-three Sri Lankan and 151 Bangladeshi participants were recruited. We observed higher mean [SD] fasting (4.91 [0.74] vs. 4.66 [0.46] mmol/L, p?=?.003) and 2-h glucose (7.94 [2.54] vs. 6.71 [1.90] mmol/L, p?p?=?.352; 2-h glucose 6.96 [2.31] mmol/L vs. 6.27 [1.86] mmol/L, p?=?.225).

Conclusion: We found in this small prospective study that acute OP insecticide poisoning caused acute glucose dysregulation that was sustained to hospital discharge but had recovered by 3–12 months. Acute glucose dysregulation was related to defects in insulin action and secretion. This study did not address long-term risk of diabetes following acute OP insecticide poisoning, but could provide the data for a power calculation for such a study     

Accuracy and repeatability of a pocket turbine spirometer: comparison with a rolling seal flow-volume spirometer

Summary. The accuracy and repeatability of a recently introduced pocket spirometer (Micro Spirometer©; Micro Medical Instruments Ltd, Rochester, UK) was evaluated. FEV] and FVC values obtained with this instrument were compared with those measured with a rolling-seal flow-volume spirometer (CPI220 with microcomputer) in 31 patients and 11 healthy volunteers. In the whole material, expressed as mean ± SD, the pocket spirometer recorded 0.44 ±0.23 1 (13 ±7%) smaller values for FEV₁ (P<0.001) and 0.64 + 0.48 1 (15 ± 11%) smaller values for FVC (P<0.001) than the rolling-seal spirometer. The short-term repeatability of the measurements expressed as the coefficient of variation of repeated measurements using the pocket spirometer was 2.2% for FEV₁ and 2.3% for FVC in a series of 10 healthy subjects and 10 patients with COPD. It is concluded that the underestimation of FEV₁ and FVC of the pocket spirometer was too large and inconsistent for the device to be used interchangeably with conventional spirometers. However, the repeatability of the measurements with the pocket spirometer is close to that reported previously for flow-volume spirometry. Thus the pocket spirometer may be suitable in assessing acute changes of spirometric indices e.g. during provocation tests or during patient follow-up in asthma.     

Clinically useful estimates of insulin sensitivity during pregnancy: validation studies in women with normal glucose tolerance and gestational diabetes mellitus

OBJECTIVE: We examined whether selected indexes of insulin sensitivity derived from an oral glucose tolerance test (IS(OGTT)) or fasting glucose/insulin levels (IS(QUICKI) and IS(HOMA)) can be used to predict insulin sensitivity in women before and during pregnancy. RESEARCH DESIGN AND METHODS: A 2-h euglycemic-hyperinsulinemic clamp (5 mmol/l glucose, 40 mU. m(-2). min(-1) insulin) and a 120-min oral glucose tolerance test (75 g load pregravid, 100 g pregnant) were repeated on 15 women (10 with normal glucose tolerance [NGT] and 5 with gestational diabetes mellitus [GDM]) pregravid and during both early (12-14 weeks) and late (34-36 weeks) pregnancy. An index of insulin sensitivity derived from the clamp (IS(CLAMP)) was obtained from glucose infusion rates adjusted for change in fat-free mass and endogenous glucose production measured using [6,6(-2)H(2)]glucose. RESULTS: Univariate analysis using combined groups and periods of pregnancy resulted in significant correlations between IS(CLAMP) and IS(OGTT) (r(2) = 0.74, P < 0.0001), IS(QUICKI) (r(2) = 0.64, P < 0.0001), and IS(HOMA) (r(2) = 0.53, P < 0.0001). The IS(OGTT) provided a significantly better correlation (P < 0.0001) than either IS(QUICKI) or IS(HOMA.) Multivariate analysis showed a significant group effect (P < 0.0003) on the prediction model, and separate equations were developed for the NGT (r(2) = 0.64, P < 0.0001) and GDM (r(2) = 0.85, P < 0.0001) groups. When subdivided by period of pregnancy, the correlation between IS(CLAMP) and IS(OGTT) pregravid was r(2) = 0.63 (P = 0.0002), during early pregnancy was r(2) = 0.80 (P < 0.0001), and during late pregnancy was r(2) = 0.64 (P = 0.0002). CONCLUSIONS: Estimates of insulin sensitivity from the IS(OGTT) during pregnancy were significantly better than from fasting glucose and insulin values. However, separate prediction equations are necessary for pregnant women with NGT and women with GDM.     

胸部CT评估慢性阻塞性肺疾病患者竖脊肌萎缩及脂肪浸润程度北大核心CSCD

目的观察胸部CT评估慢性阻塞性肺疾病(COPD)患者竖脊肌(ESM)萎缩及脂肪浸润程度的价值。方法纳入113例接受胸部CT平扫及肺功能检查的稳定期COPD男性患者(COPD组)及40名健康男性(对照组);比较组间及COPD组内不同慢性阻塞性肺疾病全球倡议(GOLD)分级患者一般资料、肺功能检查结果及ESM CT参数,并行相关性分析,观察COPD患者ESM萎缩及脂肪浸润特征。结果组间肺活量(VC)、用力VC(FVC)、第1秒用力呼气容积(FEV_(1))、FEV_(1)/FVC、残气量(RV)、RV/肺总量(TLC)、一氧化碳弥散量(DLco)、ESM总横截面积(CSA)、肌肉密度、放射性密度比(RDR)、CSA指数、ESM局部体积、面积密度乘积及肺气肿区域占总肺容积百分比(LAA%)差异均有统计学意义(P均<0.05)。COPD组内各GOLD分级COPD患者体质量、体质量指数(BMI)、深吸气量(IC)、VC、FVC、FEV_(1)、FEV_(1)/FVC、TLC、RV/TLC、DLco、ESM总CSA、CSA指数、ESM局部体积、面积密度乘积及LAA%差异均有统计学意义(P均<0.05)。COPD患者ESM局部体积与FEV_(1)呈中度相关(r=0.52,P<0.001)。结论胸部CT可定量评估COPD患者ESM萎缩及脂肪浸润程度;ESM局部体积为最佳评估指标。     

Limitations in the Use of Indices Using Glucose and Insulin Levels to Predict Insulin Sensitivity: Impact of race and gender and superiority of the indices derived from oral glucose tolerance test in African Americans

OBJECTIVE

To examine the utility of commonly used insulin sensitivity indices in nondiabetic European Americans (EAs) and African Americans (AAs).

RESEARCH DESIGN AND METHODS

Two-hundred forty nondiabetic participants were studied. Euglycemic-hyperinsulinemic clamp was the gold standard approach to assess glucose disposal rates (GDR) normalized by lean body mass. The homeostatic model assessment for insulin resistance (HOMA-IR) and the quantitative insulin sensitivity check index (QUICKI) were calculated from fasting plasma glucose and insulin (FIL). Oral glucose tolerance test (OGTT) was performed to determine Matsuda index, the simple index assessing insulin sensitivity (SI_isOGTT), Avignon index, and Stomvoll index. Relationships among these indices with GDR were analyzed by multiple regression.

RESULTS

GDR values were similar in EA and AA subgroups; even so, AA exhibited higher FIL and were insulin-resistant compared with EA, as assessed by HOMA-IR, QUICKI, Matsuda index, SI_isOGTT, Avignon index, and Stumvoll index. In the overall study population, GDR was significantly correlated with all studied insulin sensitivity indices (/r/ = 0.381–0.513); however, these indices were not superior to FIL in predicting GDR. Race and gender affected the strength of this relationship. In AA males, FIL and HOMA-IR were not correlated with GDR. In contrast, Matsuda index and SI_isOGTT were significantly correlated with GDR in AA males, and Matsuda index was superior to HOMA-IR and QUICKI in AAs overall.

CONCLUSIONS

Insulin sensitivity indices based on glucose and insulin levels should be used cautiously as measures of peripheral insulin sensitivity when comparing mixed gender and mixed race populations. Matsuda index and SI_isOGTT are reliable in studies that include AA males.Insulin resistance is central to pathogenesis of cardiometabolic disease and confers increased risk of type 2 diabetes and cardiovascular disease (1). The gold standard approach for measuring insulin resistance is euglycemic-hyperinsulinemic clamp (2); however, it is rarely used in clinical practice and in epidemiological studies because it is laborious and requires intravenous infusions. Several surrogate indices using glucose and insulin levels have been devised as alternative measures of insulin sensitivity and are commonly used in cohort studies, including fasting insulin level (FIL), homeostasis model assessment of insulin resistance (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), Matsuda index, Avignon index, Stumvoll index, and the new simple index assessing insulin sensitivity using oral glucose tolerance test (SI_isOGTT). FIL is a simple and practical surrogate marker for insulin resistance (3) when elevated in the presence of normoglycemia or hyperglycemia; however, insulin assay has not been standardized for more universal applications. HOMA-IR (4) and QUICKI (5) are models that incorporate both fasting insulin and glucose levels, although QUICKI uses a log-transformation that is reported to provide a stronger linear correlation with the clamp (5). Matsuda index (6) and SI_isOGTT (7) are models that use dynamic glucose and insulin values obtained during oral glucose tolerance tests (OGTT). Avignon index (8) and Stumvoll index (9) also are derived from OGTT with incorporation of glucose’s volume of distribution or BMI in their equations. These indices are potentially of high value because they are facile and inexpensive in comparison with euglycemic-hyperinsulinemic clamp. Furthermore, it is difficult to clinically identify insulin resistance because individual variability in insulin sensitivity exists largely independent of obesity in populations (10). Clinical constructs such as metabolic syndrome and prediabetes are used to assess risk for future diabetes and cardiometabolic disease; however, insulin sensitivity indices potentially could be used to more optimally identify insulin resistance in individuals as a central pathophysiological process responsible for cardiometabolic disease.Given the widespread use of insulin sensitivity indices in epidemiology and clinical trials, it is important to assess their predictive value for insulin resistance. Several studies have assessed correlations between various indices and clamp measures of insulin resistance (11–17); however, these studies are often lacking in three aspects. First, the correlations often include nondiabetic subjects together with type 2 diabetic patients. Type 2 diabetes is a disease state with distortions in the relationship between circulating glucose and insulin values in a manner that does not reflect systemic insulin sensitivity. Hyperglycemia is the hallmark of type 2 diabetes and is accompanied by “glucose toxicity” with respect to insulin secretion. Consequently, studies assessing the relationship between indices based on fasting glucose and insulin levels and clamp measures could reflect falsely inflated slopes and correlation coefficients in regression equations when data from nondiabetic and diabetic subjects are included in the same regression analyses. Hence, rigorous analyses confined to nondiabetic subjects are needed to evaluate true value of insulin sensitivity indices. Second, even among nondiabetic subjects, there are factors influencing insulin secretion and circulating insulin concentrations independent of insulin sensitivity. Studies have shown that insulin secretory responses primarily can be impaired, independent of insulin resistance, and this trait is an independent risk factor for future diabetes (18). African Americans (AAs) are known to have hypersecretion of insulin independent of systemic insulin sensitivity (19–25), and this could alter glucose-to-insulin ratios in a manner that distorts ability to use insulin sensitivity indices in studies involving multiple racial groups. Thus, careful analyses across racial and ethnic groups are warranted. Finally, few studies have addressed the relative values of multiple insulin sensitivity indices in the same population, with attention to the potential impact of race.Our study attempted to address these shortcomings in the literature. We performed euglycemic-hyperinsulinemic glucose clamp in a substantial number of nondiabetic European American (EA) and AA subjects and compared the predictive value of FIL, HOMA-IR, log HOMA-IR, QUICKI, Matsuda index, SI_isOGTT, Avignon index, and Stumvoll index as indices of peripheral insulin resistance.     

Randomization to Treadmill Training Improves Physical and Metabolic Health in Association With Declines in Oxidative Stress in Stroke

ObjectiveTo investigate the effect of aerobic exercise vs control (stretching/balance) on inflammatory and oxidative stress biomarkers in stroke survivors and whether these changes are associated with improvements in physical and metabolic health.DesignRandomized controlled trial.SettingThe general communities of Baltimore, Maryland, and Atlanta, Georgia.ParticipantsTwo hundred forty-six older (>50 years), chronic (>6 months) survivors of stroke (N=246) with hemiparetic gait were recruited, with 51 completing pre-intervention testing and 39 completing postintervention testing. Participants were required to have completed all conventional physical therapy and be capable of walking 3 minutes on a treadmill (N=246).InterventionParticipants completed 6 months of 2 times/wk stretching or balance (ST; n=19) or 3 times/wk aerobic treadmill rehabilitation (TM; n=20;).Main Outcome Measure(s)Peak oxygen uptake rate (V?o₂peak), 6-minute walking distance (6MWD), fasting plasma glucose, insulin, oxidative stress, and inflammatory biomarkers were assessed pre- and postintervention. Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) was calculated.ResultsPhysical function and metabolic health parameters tended to improve after TM but not ST (ST vs TM: V?o₂peak: ?9% vs 24%, P<.01; 6MWD: 1% vs 15%, P=.05; insulin: ?1% vs ?31%, P=.05; HOMA-IR: ?3% vs ?29%, P=.06). Plasma concentrations of nitrotyrosine, protein carbonyls, and oxidized low-density lipoprotein (oxLDL) tended to decrease from pre-intervention concentrations in response to TM compared to ST (ST vs TM: nitrotyrosine: 2% vs ?28%, P=.01; protein carbonyls: ?4% vs ?34%, P=.08; oxLDL: ?3% vs ?32%, P<.01). Changes in circulating concentrations of C-reactive protein, protein carbonyls, and oxLDL were negatively associated with changes in V?o₂peak and 6MWD (r's=?0.40 to ?0.76) and positively associated with fasting plasma insulin and HOMA-IR (r's=0.52-0.81, Ps<.01).ConclusionsSix months of TM tends to be associated with increased functional capacity and reduced oxidative stress in chronic stroke survivors. Our findings identify potentially modifiable systemic markers of inflammation and oxidative stress important to stroke rehabilitation and provide potential targets for novel therapeutics in future studies.     

空腹血糖、空腹胰岛素、胰岛素抵抗指数和同型半胱氨酸水平对2型糖尿病合并缺血性脑卒中发生的影响

目的:分析空腹胰岛素(FINS)、空腹血糖(FBG)、同型半胱氨酸(Hcy)及胰岛素抵抗指数(HOMA-IR)对2型糖尿病(T2DM)合并缺血性脑卒中(IS)发生的影响。方法:选取T2DM患者85例,根据患者是否伴有IS分为T2DM+IS组(44例)和T2DM组(41例),另选取同期于本院健康体检的志愿者30例为对照组。比较3组体质量指数(BMI)、血压、血糖及血脂4项指标的差异,并计算HOMA-IR。采用多因素Logistic回归分析T2DM患者合并IS的影响因素,并用Pearson相关性分析FBG与其它指标的关系。结果:T2DM组与T2DM+IS组BMI、收缩压(SBP)、舒张压(DBP)、甘油三酯(TG)、总胆固醇(TC)、低密度脂蛋白-胆固醇(LDL-C)、糖化血红蛋白(HbA1c)、FINS、FBG、Hcy及HOMA-IR的水平较对照组均明显升高,高密度脂蛋白-胆固醇(HDL-C)的水平较对照组明显下降(P<0.05)。T2DM+IS组SBP、DBP、LDL-C、HbA1c、FINS、FBG、Hcy及HOMA-IR的水平较T2DM组均明显升高(P<0.05)。多因素Logistic回归分析显示,FINS、FBG、Hcy及HOMA-IR是T2DM患者发生IS的影响因素(P<0.05)。经Pearson相关性分析显示,FBG与HbA1c、FINS、Hcy及HOMA-IR均具有正相关关系(P<0.01)。结论:T2DM患者FBG水平与IS的发生存在显著关系。     

Effect of once-daily fluticasone furoate/vilanterol on 24-hour pulmonary function in patients with chronic obstructive pulmonary disease: a randomized, three-way, incomplete block, crossover study

BackgroundAvailable inhaled corticosteroid/long-acting β₂-agonist combinations for chronic obstructive pulmonary disease (COPD) require twice-daily administration. The combination of fluticasone furoate (FF) and vilanterol (VI) FF/VI is being developed in a novel dry powder inhaler for the treatment of COPD and asthma with the potential for once-daily dosing. Results from Phase II studies have shown clinically and statistically significant improvements over placebo in trough (24-hour postdose) forced expiratory volume in 1 second (FEV₁) after once-daily dosing with FF or VI (VI concurrently with an inhaled corticosteroid) in asthma and VI in COPD.ObjectivesThis Phase III, multicenter, randomized, double-blind, placebo-controlled study was designed based on guidance from drug regulators with the goal of evaluating the 24-hour spirometric effect of once-daily FF/VI in patients with COPD.MethodsPatients (aged ≥40 years) who completed a 2-week placebo run-in period were randomized to 1 of 18 three-course sequences of placebo and 2 of 3 dose combinations of FF/VI (50/25 μg, 100/25 μg, and 200/25 μg), dosed once daily in the morning. Each 28-day treatment period was separated by a 2-week, single-blind, placebo washout period. The primary end point was time-adjusted (weighted mean) 0 to 24-hour FEV₁ (AUC) at the end of each 28-day treatment period (period days 28–29). Safety profile assessments included incidence of adverse events (AEs) (defined according to the Medical Dictionary for Regulatory Activities), 12-lead ECG outputs, vital signs (pulse rate, diastolic and systolic blood pressure) and clinical laboratory assessments (including fasting serum glucose and potassium) and 24-hour serum cortisol. The pharmacokinetics of FF and VI were assessed at the end of each 28-day treatment period with FF/VI.ResultsEighty-seven patients were screened; 54 completed run-in and were randomized to double-blind treatment. The mean patient age was 57.9 years, and 46% were male. The majority of patients were current smokers (83%) and were receiving short-acting β₂-agonists within the 3 months before screening (63%). All 3 strengths of once-daily FF/VI demonstrated significantly higher 0 to 24-hour (period days 28–29) change from period baseline weighted mean FEV₁ than placebo: adjusted mean improvements from placebo in FEV₁ for FF/VI were 220 to 236 mL (all, P < 0.001). Improvements versus placebo in change from period baseline serial FEV₁ measures were observed at each time-point and with each strength of FF/VI over the 0 to 25-hour period (period days 28–29), indicating sustained bronchodilation. The overall incidence of on-treatment AEs was low (10%–12% with FF/VI; 4% with placebo); 2 serious AEs were reported during washout periods (1 AE after FF/VI 50/25 μg and 1 AE after placebo) but neither was considered treatment related. No serious AEs were reported during the treatment periods or during the follow-up period. No clinically or statistically significant differences from placebo were reported for serum glucose or potassium. No significant effects on vital signs, ECG, or 24-hour serial serum cortisol were reported. The extent of systemic exposure to FF and VI at steady state was low for all strengths of FF/VI.ConclusionsFF/VI inhaled once daily in the morning for 28 days produced significant improvements in pulmonary function with a prolonged (>24 hours') duration of action in this population of patients with COPD. The combination was well tolerated. ClinicalTrials.gov identifier: NCT01072149.     

Amplitude variation in static-charge-sensitive bed signal increased in obstructive airways disease

The relationship between oesophageal pressure variation and amplitude variation in the static-charge-sensitive bed (SCSB) ballistocardiogram suggests that changes in intrathoracic pressure can be detected using the SCSB method. We investigated whether amplitude variation in the static-charge-sensitive bed ballistocardiogram (SAV) is related to severity of airway obstruction in patients with asthma and chronic obstructive pulmonary disease. The ability of SAV to detect an increase in airway obstruction induced by histamine challenge was also tested. Twenty-six patients suffering from asthma and 12 patients with chronic obstructive pulmonary disease (COPD) were enrolled in the study. SAV, amplitude from the SCSB ballistocardiogram, respiratory amplitude from the SCSB respiratory wave form and heart rate from the electrocardiogram (ECG) were computed using analysing software (Biorec, Helsinki, Finland) during a 7-min supine rest. SAV was related to forced expiratory volume in one second (FEV₁) immediately after signal recording. Asthma patients participated in a standardized histamine challenge test to reveal the effect of acute bronchoconstriction on SAV. An inverse relationship existed between baseline FEV₁ and SAV in asthma and COPD. In the histamine inhalation test, FEV₁ fell by 0·7 ± 0·3 l or 26% ± 11% (P<0·0001) and SAV increased by 12% ± 5% (P<0·0001) in 12 asthma patients. The fall in FEV₁ induced by histamine followed regularly and correlated significantly with the rise in SAV (n = 24, r = ?0·58, P = 0·002). Changes in respiratory amplitude or heart rate did not explain changes in SAV. SAV may not separate the upper airway obstruction from the bronchial obstruction but it is related to severity of airway obstruction. The clinically significant increase in airway obstruction induced by histamine inhalation increases amplitude variation in SCSB.     

Muscle and liver insulin resistance indexes derived from the oral glucose tolerance test

OBJECTIVE: To derive indexes for muscle and hepatic insulin sensitivity from the measurement of plasma glucose and insulin concentrations during an oral glucose tolerance test (OGTT). RESEARCH DESIGN AND METHODS: A total of 155 subjects of Mexican-American origin (58 male and 97 female, aged 18-70 years, BMI 20-65 kg/m(2)) with normal glucose tolerance (n = 100) or impaired glucose tolerance (n = 55) were studied. Each subject received a 75-g OGTT and a euglycemic insulin clamp in combination with tritiated glucose. The OGTT-derived indexes of muscle and hepatic insulin sensitivity were compared with hepatic and muscle insulin sensitivity, which was directly measured with the insulin clamp, by correlation analysis. RESULTS: The product of total area under curve (AUC) for glucose and insulin during the first 30 min of the OGTT (glucose(0-30)[AUC] x insulin(0-30)[AUC]) strongly correlated with the hepatic insulin resistance index (fasting plasma insulin x basal endogenous glucose production) (r = 0.64, P < 0.0001). The rate of decay of plasma glucose concentration from its peak value to its nadir during the OGTT divided by the mean plasma insulin concentration (dG/dt / I) strongly correlated with muscle insulin sensitivity measured with the insulin clamp (P = 0.78, P < 0.0001). CONCLUSIONS: Novel estimates for hepatic and muscle insulin resistance from OGTT data are presented for quantitation of insulin sensitivity in nondiabetic subjects.     

老年人不同糖耐量状态胰岛素抵抗和胰岛β细胞功能的研究

目的观察老年人群中空腹血糖受损(IFG)、糖耐量受损(IGT)和糖调节受损(IFG/IGT)三种不同糖耐量状态下的胰岛素抵抗(IR)和胰岛β细胞功能的变化,了解其发病机制。方法筛选60~75岁的IFG40例,IGT60例,IGT/IFG40例,正常糖耐量(NGT)70例。HOMA-IR评价胰岛素抵抗,HBC I和I30/G30分别评价基础及糖负荷后早期胰岛β细胞功能。结果(1)HOMA-IR:IFG、IFG/IGT和IGT组明显高于NGT组,P<0.01,IFG/IGT组高于IFG和IGT组,P<0.01;(2)HBC I:IFG组和IFG/IGT组明显低于NGT和IGT组,P<0.01;(3)I30/G30:IGT组和IFG/IGT组明显低于NGT组及IFG组,P<0.01。结论老年人群IFG主要表现基础状态下β细胞功能受损伴有胰岛素抵抗,IGT主要表现为早期胰岛素分泌缺陷,IFG/IGT胰岛β细胞早期胰岛素分泌功能受损更明显,胰岛素抵抗更严重。     

The Effect of an Inhaled Corticosteroid on Glucose Control in Type 2 Diabetes

Objective: To determine the effect of inhaled corticosteroid (ICS) therapy on glucose control in adults with type 2 diabetes mellitus and coexisting asthma or chronic obstructive pulmonary disease (COPD).