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Metabonomic variations in the drug-treated type 2 diabetes mellitus patients and healthy volunteer

Metabonomic variations in the drug-treated type 2 diabetes mellitus patients and healthy volunteer
Metabonomic variations in the drug-treated type 2 diabetes mellitus patients and healthy volunteer

Metabonomic Variations in the Drug-Treated Type 2Diabetes

Mellitus Patients and Healthy Volunteers

Yuqian Bao,?,#Tie Zhao,?,#Xiaoyan Wang,?,#Yunping Qiu,?Mingming Su,?Weiping Jia,*,?and

Wei Jia*,?,§

Department of Endocrinology and Metabolism,Shanghai Jiao Tong University Af?liated Sixth People’s Hospital,Shanghai Diabetes Institute,Shanghai Clinical Center of Diabetes,Shanghai,China,School of Pharmacy,and Shanghai Center for Systems Biomedicine,Shanghai Jiao Tong University,Shanghai,China,and Department of Nutrition,University of North Carolina at Greensboro,North Carolina Research Center,

Kannapolis,North Carolina 28081

Received August 15,2008

The pathological development and the drug intervention of type 2diabetes mellitus (T2DM)involve altered expression of downstream low molecular weight metabolites including lipids and amino acids,and carbohydrates such as glucose.Currently,a small number of markers used for clinical assessment of T2DM treatment may be insuf?cient to re?ect global variations in pathophysiology.In this study,a metabonomic study was performed to determine metabolic variations associated with T2DM and the drug treatments on 74patients who were newly diagnosed with T2DM and received a 48week treatment of a single drug,repaglinide,metformin or rosiglitazone.Fasting overnight and 2h postprandial blood serum of patients were collected at 24and 48weeks to monitor the biochemical indices (FPG,2hPG,HbA 1c ,etc.).Gas chromatography/mass spectrometer coupled with multivariate statistical analysis was used to identify the alteration of global serum metabolites associated with T2DM as compared to healthy controls and responses to drug treatment.Signi?cantly altered serum metabolites in diabetic subjects include increased valine,maltose,glutamate,urate,butanoate and long-chain fatty acid (C16:0,C18:1,C18:0,octadecanoate and arachidonate),and decreased glucuronolactone,lysine and lactate.All of the three treatments were able to down-regulate the high level of glutamate to a lower level in serum of T2DM patients,but rosiglitazone treatment was able to reverse more abnormal levels of metabolites,such as valine,lysine,glucuronolactone,C16:0,C18:1,urate,and octadecanoate,suggesting that it is more ef?cient to alter the metabolism of T2DM patients than the other two drugs.

Keywords:metabonomics ?Type 2diabetes mellitus ?repaglinide ?metformin ?rosiglitazone ?gas chromatography/mass spectrometry

Introduction

Chronic perturbations of metabolic regulatory system are the basis for many metabolic disorders such as obesity and type 2diabetes mellitus (T2DM).Successful treatment of these condi-tions with drugs requires restoring the perturbed metabolism without generating defects in other metabolic pathways.In most cases,however,such medication is not able to normalize the dysregulated metabolic system,but is likely to maintain its functions at certain levels for the basic physiological needs.1Therefore,accurate assessments of therapeutic effectiveness and its impact on physiology must involve a comprehensive measurement of the global metabolism,a goal that is not to be accomplished by the analysis of a single biomarker.Quan-titative and comprehensive analyses of the metabonome can

assess metabolic response to a therapy with much more information and power than biomarker approaches,and readily reveal distinct differences in metabolism between diseased individuals and healthy ones.2,3Furthermore,identi?cation of the differential metabolites accountable for the intergroup variation will help us obtain valuable insights into molecular mechanisms of certain pathophysiological variations under treatment.In this study,a GC/MS-based metabonomic analysis was applied to identify signi?cant changes in global metabolite pro?les in serum associated with T2DM and to evaluate the impact of the long-term medication on metabolism and physiology of T2DM patients.

Currently,a number of therapeutic drugs are used for the treatment of T2DM patients.4As a ?rst-line treatment,met-formin,whose mechanisms are still not entirely clear,exerts its hypoglycemic effects by lowering hepatic glucose output with decreased gluconeogenesis and,to a lesser extent,in-creased glucose uptake by skeletal muscles.5Repaglinide,another commonly used medicine,stimulates insulin secretion primarily via closure of ATP-dependent potassium channels

*To whom correspondence may be addressed.E-mail:w_jia@https://www.doczj.com/doc/064110459.html, for Wei Jia and wpjia@https://www.doczj.com/doc/064110459.html, for Weiping Jia.?

Shanghai Jiao Tong University Af?liated Sixth People’s Hospital.?

Shanghai Jiao Tong University.#

These authors contributed equally to this work.§

University of North Carolina at

Greensboro.10.1021/pr800643w CCC:$40.75

2009American Chemical Society

Journal of Proteome Research 2009,8,1623–16301623

Published on Web 01/22/2009

D o w n l o a d e d b y S H A N G H A I J I A O T O N G U N I V o n J u l y 7, 2009P u b l i s h e d o n J a n u a r y 22, 2009 o n h t t p ://p u b s .a c s .o r g | d o i : 10.1021/p r 800643w

(KATP channels)of the outer membrane of -cells.6Rosiglita-zone,a representative of the emerging thiazolidinediones family,functions as a ligand for the peroxisome proliferator-activated receptor gamma (PPAR γ)most highly expressed in adipocytes.These nuclear receptors,which are ligand-activated transcription factors,play an integral part in the regulation of the expression of a variety of genes involved in carbohydrate and lipid metabolism,resulting in improved insulin sensitivity,particularly in the peripheral tissues.7Side effects of the medication with thiazolidinediones were observed concomi-tantly,for instance,weight gain,edema,anemia,pulmonary edema and congestive heart failure and an unacceptable risk of fulminant hepatic failure.7,8Long-term pharmacological effects of the above-mentioned three antidiabetic drugs appear to be diverse,owing to their different therapeutic mechanisms.These drugs have been used clinically for several years to decades with reasonably good knowledge of therapeutic ef-fectiveness.However,the pharmacological impacts on the global metabolism and physiology upon the long-term admin-istration are yet to be understood.

The common method used to assess the clinical effects of drug treatments is based on the measurement of a single or several biochemical marker(s),which do not suf?ciently re?ect the overall physiological status of the patients.On the basis of our recent studies,7,9-12the combined global metabolic analysis and multivariate statistical technique has become a robust metabonomics strategy,providing comprehensive metabolic information for classi?cation of different physiological states and understanding of important molecular mechanisms as-sociated with pathological variations.To date,metabonomics has been applied in disease diagnosis,therapy monitoring and R&D of new drugs.13,14In this study,we performed a gas chromatography/mass spectrometry (GC/MS)metabolic pro?l-ing coupled with the analysis of clinical biochemical indices for a comprehensive evaluation of the three antidiabetic drugs,repaglinide,metformin and rosiglitazone,on newly diagnosed T2DM patients over 48weeks.

Materials and Methods

Human Sample Collection.A total of 82patients with newly diagnosed type 2diabetes mellitus and no treatment with hypoglycaemic agents or lipid drugs received the drug treat-ment:35received repaglinide,22received metformin and 25received rosiglitazone.There were no signi?cant differences in clinical parameters among the three groups upon recruitment as indicated in Table 1and Supplemental Data Table S1(Supporting Information).All these subjects experienced a 2-week observation (wash-out)period during which they were treated with diet and exercise alone before the ?rst sample was taken.The glycated hemoglobin value (HbA 1c )of patients selected for the metabolic pro?ling was no less than 6.5%at the end of this 2-week observation period.Serum samples for metabolic pro?ling were taken from these patients,and also from 36healthy volunteers (as determined by medical history,physical examination and routine laboratory tests)as controls of GC/MS metabolic pro?les.

At the end of the observation period (baseline,0week),patients were randomly assigned to one of three treatment groups for a 48-week study comprising 8visits:repaglinide (1.5-6mg/d),metformin (0.75-1.5g/d)or rosiglitazone (4-8mg/d)groups.Fasting overnight and 2h postprandial blood serum samples of patients were collected to monitor the biochemical indices (FPG,2hPG,HbA 1c ,etc.)at patients’visit T a b l e 1.C o m p a r i s o n o f C l i n i c a l a n d B i o c h e m i c a l P a r a m e t e r s a n d T -P r e d i c t e d S c o r e V a l u e s o f P r e d i c t i o n M o d e l a t B a s e l i n e ,24a n d 48W e e k s a f t e r T r e a t m e n t a m o n g R e p a g l i n i d e ,M e t f o r m i n a n d R o s i g l i t a z o n e a

r e p a g l i n i d e

m e t f o r m i n

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m a r k e r s

b a s e l i n e

24w e e k

48w e e k

b a s e l i n e

24w e e k

48w e e k

b a s e l i n e

24w e e k

48w e e k W e i g h t (k g )68.94(8.4769.79(8.9970.08(9.7474.2(1171.57(11.5671.07(12.1371.25(9.0370.87(8.7973.4(8.14W a i s t (c m )89.29(7.1688.73(7.0288.94(7.5494.23(6.289.19(5.5189.64(6.2586.17(6.286.73(6.3788.62(6.33B M I (k g /m 2)24.64(1.9724.95(2.1324.96(2.3726.96(2.0725.95(2.3924.51(3.6825.09(2.3324.94(2.4525.79(2.29H b A 1c (%)8.61(1.296.26(0.53**6.46(0.67**8.21(1.116.19(0.38**6.29(0.55**8.8(1.346.31(0.52**6.33(0.39**F P G (m m o l /L )9.74(1.466.45(0.77**7.25(1.15**8.82(1.516.09(0.71**6.37(0.76**9.16(1.436.35(0.81**6.46(0.99**2h F G (m m o l /L )14.09(2.288.59(1.75**9.51(2.11**12.81(3.198.37(1.82**7.51(1.44**14.14(2.419.16(1.81**8.78(1.56**S y s t o l i c b l o o d p r e s s u r e (m m H g )123.17(9.75120.23(7.53121.15(11.57125.64(11.75125.91(10.45120.47(10.08124.4(8.93122.43(9.31119.24(10.65D i a s t o l i c b l o o d p r e s s u r e (m m H g )78.57(5.2777.54(6.7575.67(5.4981.86(6.9381.41(7.4179.89(6.4580.68(5.479.83(6.3376.62(6.02H e a r t r a t e (t i m e s /m i n )75(7.0974.26(5.0575.42(4.6275.27(6.8274.27(6.6974.26(5.1575.56(7.3774.91(5.974.05(5.01T o t a l c h o l e s t e r o l (m m o l /L )5.23(0.635.03(0.745.04(0.665.43(0.755.1(0.595.02(0.785.21(0.845.2(0.835.39(1.05T G (m m o l /L )2.27(0.932.77(1.582.71(1.512.44(1.062.08(0.762.07(0.741.84(0.681.95(0.742.10(1.13H D L c h o l e s t e r o l (m m o l /L )1.19(0.171.17(0.181.16(0.211.29(0.261.29(0.241.32(0.351.19(0.181.22(0.221.22(0.23L D L c h o l e s t e r o l (m m o l /L )3.25(0.522.82(0.752.83(0.593.31(0.772.93(0.452.82(0.523.31(0.753.09(0.613.07(0.68T -p r e d i c t e d s c o r e

-

0.42(1.15

0.59(1.23

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0.9(1.150.52(0.89

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*P <0.05,c o m p a r e d w i t h b a s e l i n e ,**P <0.01,c o m p a r e d w i t h b a s e l i n e .?P <0.05,c o m p a r e d w i t h t h e o t h e r t w o g r o u p s ,??

P <0.01,c o m p a r e d w i t h t h e o t h e r t w o g r o u p s .T -p r e d i c t e d s c o r e w a s a l s o i l l u s t r a t e d i n S u p p l e m e n t a l D a t a F i g u r e 1i n S u p p o r t i n g I n f o r m a t i o n .

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of 2(visit 1),4(visit 2),6(visit 3),...,24(visit 6),36(visit 7),48(visit 8)weeks of treatment.Metabolic analysis was performed using GC/MS at 24weeks and 48weeks.Antihypertensive drugs or other concurrent treatments,including dietary regimens,remained unchanged throughout the study.The number of patients taking antihypertensive medications were 16(42%)for the repaglinide group,10(45%)for the metformin group,and 11(44%)for the rosiglitazone group,respectively.None of the participants was on lipid-lowering therapy.Of all the patients recruited,80patients completed the 24week treatment and 74patients completed the 48weeks treatment,whereas the rest participants failed to follow up the protocol (two subjects from rosiglitazone group at 24week failed to return for follow up,and two subjects in each group were lost to follow-up at 48week).The protocol for this study was in accordance with the Helsinki Declaration and was approved by the ethical com-mittee of the hospital,and all subjects recruited provided written informed consent.

Biochemical Measurement.Plasma glucose levels [fasting plasma glucose (FPG)and 2-h postprandial plasma glucose 2hPG)],Serum lipid pro?les,including total cholesterol (TC),triacylglycerol (TG),high-density lipoprotein-cholesterol (HDL-cholesterol),and low-density lipoprotein-cholesterol (LDL-cholesterol),HbA 1c ,heart rate,blood pressure,weight and body mass index (BMI)were determined as previously described.7

Sample Preparation and GC/MS Analysis.Serum samples collected from fasting subjects were stored frozen at -80°C until use,at which point the samples were thawed on ice.Each 200-μL aliquot of serum sample was added into a 1.5mL of tube followed by the addition of 400μL of acetone for protein precipitation.The mixture was stirred by vortex for 30s and centrifuged at 10000rpm for 10min.A 400-μL supernatant was transferred to a 500μL of glass tube and dried under vacuum.The dried analytes were dissolved in 80μL of meth-oxylamine hydrochloride (15mg/mL,dissolved in pyridine)for 90min at 30°C and then silylated with 80μL N ,O -bis-trimethylsilyl-tri?uoroacetamide (BSTFA)and Trimethylchlo-rosilane (at a ratio of 99:1)(Supelco)for 2h at 70°C.Each 70-μL aliquot of hexane was added to the derivatization bottles.After the sample was stirred for 1min and kept at room temperature for an hour,1-μL aliquot of the solution was injected into a PerkinElmer gas chromatography coupled with a TurboMass-Autosystem XL mass spectrometer (PerkinElmer,Inc.)in the splitless mode.A DB-5MS capillary column coated with 5%Diphenyl cross-linked 95%dimethylpolysiloxane (30m ×250μm i.d.,0.25-μm ?lm thickness;Agilent J&W Scienti?c,Folsom,CA)was used for separation.Both the injection temperature and the interface temperature were set to 260°C,and the ion source temperature was adjusted to 200°C.Initial GC oven temperature was set at 80°C for 2min after injection,and was raised up to 285°C with 5°C/min and maintained at 285°C for 7min.Helium at a ?ow rate of 1mL/min was used as the carrier gas.The measurements were made with electron impact ionization (70eV)in the full scan mode (m /z 30-550).Data Analysis.GC/MS data ?les were converted into the NetCDF format via DataBridge (Perkin-Elmer,Inc.)and a pretreatment was conducted as previously described.9The mean-centered and autoscaled data were then introduced into the SIMCA-P 11.5Software (Umetrics,Ume?,Sweden)for multivariate statistical analysis.Principal component analysis (PCA)was used to obtain an overview of variations among the different groups.Orthogonal projections to latent structures discriminant analysis (OPLS-DA),a supervised pattern recogni-

tion approach,was utilized to construct a predictive model to evaluate the effect of individual drug and identify the dif-ferential metabolites accountable for the disease or the phar-macological effects.To avoid the over?tting of the models,the OPLS-DA model was carefully validated by the following three steps:?rst,an iterative 7-round cross-validation 15with one-seventh of the samples being excluded from the model in each round;second,1000random permutations test;16?nally,blind prediction test in which the data set was randomly divided into training set (70%)and test set (30%),and the model built on the training set was applied to build the classi?cation model to predict the class membership of the test set.17T-Score value which is the predictive result of the treatment by the established model was used as an index of metabonomic assessment to calculate and compare with other indices among the three treatment groups.

Univariate statistical analysis,one-way analysis of variance (ANOVA),was used to ?nd the differentially expressed me-tabolites after treatment with repaglinide and metformin whose OPLSDA models of 24and 48weeks treatment were hard to be constructed.One-way ANOVA was also employed to com-pare the biochemical indices and T-predicted score between the pretreatment (baseline)and post-treatment (24and 48weeks),and among the treatment groups.Differences are considered signi?cant at P <0.05.SPSS version 15.0(SPSS,Chicago,IL)was used for univariate statistical analyses.

Results

A total of 212individual metabolites were consistently detected in at least 90%of the serum samples using our optimized GC/MS analysis https://www.doczj.com/doc/064110459.html,pound identi?cation was carried out either by comparing mass spectra and retention time with those obtained with commercially available reference compounds or based on commercial libraries of NIST,NBS and Wiley.We were able to identify 67(31.6%)of the 212metabo-lites,most of which were organic acids/alcohol,amines,amino acids,free fatty acids and sugars.Because the statistical contribution of glucose to the division of diabetic and healthy individuals is too strong,four peaks corresponding to the glucose were removed from the original GC/MS data matrix prior to PCA so that the contributions from other differential metabolites,with good statistical signi?cance,can be identi?ed between the diabetic group and healthy control/treatment group.Orthogonal projections to latent structures discriminant analysis (OPLSDA),a newly developed supervised pattern recognition method,was used to capture the subtle intergroup variations (Figure 1A)and establish a prediction model to assess the physiological impact by drug treatment.The cumulative Q2Y of the model was 0.50(see also Supplemental Data Table S2in Supporting Information),the permutation test result was shown in Supplemental Data Figure (Supporting Information),and the sensitivity and the speci?city of the model are 95.85%and 81.36%,respectively.

The OPLSDA model calculated from the GC/MS data of diabetic versus healthy subjects was employed to evaluate the effectiveness of each drug treatment by predicting the class membership in the data set of treatment groups.To test the predose metabolic status for the three treatment groups,the OPLSDA models were used to compare one treatment group with another one at predose stage.Such OPLSDA models to compare the intergroup variations were not successfully con-structed,suggesting that the initial metabolic status of the three groups prior to the drug treatment was of no statistical

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difference.The T-predicted scatter plot (see Figure 2)from the OPLSDA model assigned the samples to either the healthy group or the diabetic group using an a priori cutoff of 0,providing a visible view of the effect of each treatment on the metabolic pro?le of diabetic patients.Such scatter plot suggests that rosiglitazone treatment yields more effective results at 24and 48weeks than the repaglinide and metformin groups,as more serum metabolites were normalized and more individuals in the rosiglitazone group were localized below the baseline.The differentially expressed metabolites in T2DM individuals and the three treatment groups deduced from the retention time and m /z of variant were summarized in Table 2,which mainly involve free fatty acids (FFAs),amino acids and organic acids in serum.

The OPLSDA was also applied to analyze the serum samples of patients before and after treatment in the study.From the scores plot,only the rosiglitazone group at 24-week and 48-week was able to separate from their predose pro?le (Figure 1B,C;cumulative Q2Y )0.39and 0.30,respectively;see Supplemental Data Table S2in Supporting Information),indicating that the rosiglitazone treatment was able to signi?-cantly alter the metabolism of T2DM patients whereas the other two drugs were not.There were more differentially expressed metabolites identi?ed in diabetic patients normalized toward healthy levels in the rosiglitazone group than the other two (Tables 2and 3),such as valine,lysine,glucuronolactone,C16:0,C18:1,urate,and octadecanoate.The differential metabolites in repaglinide and metformin groups in the table were only identi?ed by one-way ANOVA since the multivariate model can not be constructed successfully,indicating that these two treat-ments were not able to signi?cantly improve the perturbed metabolic pro?les.

Clinical and biochemical parameters of the three treatment groups at 24weeks and 48weeks were shown in Table https://www.doczj.com/doc/064110459.html,mon clinical indices for diabetes,such as HbA 1C ,FPG,and 2hFG,were found to be normalized by the drug treatment.The three treatment groups showed no signi?cant differences in the above parameters at 24and 48weeks,except for 2hFG,which is relatively lower in metformin treatment group.

Therapeutic effects and physiological improvement were also assessed using four important parameters,HbA 1c ,FPG,2hPG and T-predicted score (Figure 3).At 24and 48weeks,the percentile of patients in each treatment group meeting with the following standard,HbA 1c <6.5%,FPG <7.0mmol/L,2hPG <11.1mmol/L and T-predicted Score <0,was calculated,respectively.While the improvement in three common bio-chemical indices appears to be similar in three treatment groups,T-predicted score,re?ecting the comprehensive meta-bolic alterations,indicates different impacts on global meta-bolic network by three treatments,respectively.Treatment with rosiglitazone appears to yield more signi?cant improvement at 24and 48weeks than the repaglinide and metformin groups.

Discussion

Since T2DM is a metabolic disorder that unbalances the metabolism of carbohydrates,lipids and amino acids,

the

Figure 1.Scores plot of the OPLSDA model of metabolic pro?le of 82newly diagnosed T2DM group vs 36healthy volunteers (A),rosiglitazone treatment 24week postdose vs predose group (B)and 48week postdose vs predose group (C).

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pathological process and the drug intervention must involve altered expressions of downstream low molecular weight metabolites including glucose.The present study is designed to visualize the alteration of global serum metabolites associ-ated with the pathophysiology of T2DM and three drug treatments in comparison with the conventional biochemical indices.As compared to healthy controls,the altered serum metabolites in diabetic subjects (in Table 3),include the signi?cantly increased valine,maltose,glutamate,urate,bu-tanoate and long-chain fatty acid (C16:0,C18:1,C18:0,octa-decanoate and arachidonate),and decreased glucuronolactone,lysine and lactate.These ?ndings suggest a hypercatabolic state in T2DM patients which is consistent with previously reported results.18However,these differentially expressed metabolites observed in our study were not in good agreement with recently reported metabolite pro?les of T2DM patients.19

The mean value and the HbA 1c ,FPG and 2hPG of the three treatment groups were improved to a similar level,as seen in Figure 3and Table 1.However,the variations of the global metabolic pro?les were signi?cantly different among the groups.Multivariate statistics indicated the rosiglitazone-mediated normalization of 8-10key metabolites at 24and 48weeks,which were differentially expressed in diabetic subjects,involving glutamate,maltose,butanoate,glucuronolactone,C16:0,C18:1.In repaglinide and metformin groups,only glutamate and lysine (in repaglinide group at 48week only)were brought to the normal level.All of the three treatments were able to down-regulate the high level of glutamate to a lower level in serum,suggesting a possible effect on prevention and amelioration of diabetic complications in T2DM patients,since it has been reported that a high level of serum glutamate is involved in immunode?ciency,amyotrophic lateral sclerosis,and neurological complications.20The results also indicate that concentrations of several carbohydrates including fructose,R -galactose,mannose and maltose were signi?cantly altered,in addition to glucose levels,by rosiglitazone and repaglinide

treatments.

Figure 2.T-predicted scatter plot of the three treatment groups at the 24th week and 48th week.

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The results of quantitative assessment of the serum metabo-lome demonstrated that a number of metabolites in glutamate pathways as seen in Figure 4were down-regulated following 24and 48-week treatment of rosiglitazone,whereas those in aspartate pathways were up-regulated.As an important hydro-transfer shuttle reaction crossing mitochondrial matrix within cells,malate and aspartate were mutually biosynthesized by glutamate and 2-oxo-glutarate.Interestingly,R -glycerophos-phorate,an important participant of R -glycerophosphoric acid shuttle system,was increased by rosiglitazone,too.Among these altered metabolites,aspartate and R -glycerophosphorate were only discovered in the 48-week treatment group,suggest-ing that such alteration may be the outcome of long-term rosiglitazone administration.

Accordingly,with regard to the effect of rosiglitazone on glycol-lipid metabolisms,6,21we speculate that this impact on the two shuttle reactions may be due to the augmented glucose utility and glycolysis.On the other hand,as a product of glycometabolism and a substrate of triglyceride synthesis,R -glycerophosphorate was increased,indicating an up-regu-lated stearo-generation that is also a potential adverse reaction of adiposis hepatica and another reason for lipid metabolism dysfunction.22,23Additionally,it was reported that rosiglitazone decreased the rate of loss of -cell function and improved insulin sensitivity to a greater extent than metformin,main-taining a longer glycemic control.24

The rosiglitazone induced depletion of GABA,an important neurotransmitter in vasodilatation and neurotransmission,25,26suggesting that rosiglitazone treatment may involve the inter-ferences of lipometabolism and GABA-mediated vasodilatation.Although biochemical markers such as HbA 1c ,FPG and 2hPG were normalized in the treatment groups of repaglinide and metformin,the metabolic pro?les did not alter signi?cantly between pre-and post-treatment states,especially in met-

Table 2.The Statistical Analysis Result of the Differentially Expressed Endogenous Metabolites Correlated with T2DM (DM

Patients vs Healthy Controls),Rosiglitazone Treatment at 24Weeks (24Week Postdose vs Predose)and Rosiglitazone Treatment at 48Weeks (48Week Postdose vs Predose)a

DM patients vs healthy controls

24th week postdose vs predose 48th week postdose vs predose rt/min

metabolites

correlation coef?cient

fold change

correlation coef?cient

fold change

correlation coef?cient

fold change

6.00Lactate -0.16-1.2----8.17Butanoate 0.18 2.6-0.37-2.6-0.33-2.29.38valine

0.32 1.7----9.76unidenti?ed 0.25 1.8-0.19-1.4-0.34-1.611.4Isoleucine -----0.25-1.513.05serine --0.29 1.40.22 1.313.67theronine

--0.35 1.50.24 1.314.083-Amine-alanine ---0.26-1.4--14.52lysine -0.17-1.70.22 1.8--14.72GABA ---0.25-1.3-0.19-1.215.76aspartate ----0.19 1.516.24Malate ---0.3-1.4-0.26-1.317.00proline --0.3 1.40.31 1.417.36glutamate 0.19 1.3-0.35-1.4-0.45-1.520.61fructose

--0.22 1.30.39 1.922.49R -Glycerophosphorate ----0.22 1.322.52Glucuronolactone -0.29-1.60.20 1.2--27.84R -galactose ---0.26-1.8-0.21-1.528.23C16:00.38 1.6-0.30-1.2-0.25-1.229.21Urate

0.14 1.7----30.80unidenti?ed -0.14-2.7-0.34-2.0-0.21-1.531.32C18:10.32 1.7-0.19-1.2-0.18-1.131.78C18:0

0.26 1.3-0.29-1.2--33.48unidenti?ed ---0.32-1.9-0.33-2.133.82Arachidonate 0.19 1.3----36.82C22:6---0.33-2.0--39.37Maltose 0.21 1.8-0.32-1.6-0.39-1.839.79unidenti?ed 0.19 1.4----40.19

Octadecanoate -0.14-1.7----

a

The correlation coef?cients shown are based on O-PLS-DA analysis of the two-group model (group 1vs group 2),positive value indicate an increase of the metabolite in group 1.The “-”represents statistically nonsigni?cant values (VIP <1).

Table 3.The One-Way ANOVA Result of the Differentially Expressed Endogenous Metabolites Correlated with

Repaglinide and Metformin Treatment at 24Weeks (24Week Postdose vs Predose)and 48Weeks (48Week Post-dose vs Predose)

24week postdose

vs predose

48week postdose

vs predose rt/min

metabolites

P

fold change

P

fold change

Repaglinide Treatment

14.52lysine --0.038 2.0

14.72mannose 0.013-1.9--15.28unidenti?ed --0.035 1.416.5valine --0.035 2.017.36glutamate 0.013-1.6--17.68unidenti?ed --0.008 1.519.36GABA 0.033-1.50.042-1.520.61fructose --0.018 1.923.66unidenti?ed 0.049-1.3--27.84R -galactose 0.008-1.3--Metformin Treatment

17.36

glutamate

0.008-1.4

0.037

-1.3

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formin group.Such results suggest that the long-term admin-istration of the two antidiabetic drugs is to moderate the metabolic activity of patients to sustain their physiological functions at certain levels,rather than completely reverse the dysregulation of the metabolic network.

In conclusion,the current study demonstrates that the metabonomic analysis can reveal different treatment effects on physiology and can yield a novel,nonglucose based evaluation strategy for the systemic treatment effect in T2DM patients,which distinguished from conventional clinical indices.Sig-ni?cantly altered serum metabolites in diabetic subjects were detected including increased valine,maltose,glutamate,urate,

butanoate and long-chain fatty acid (C16:0,C18:1,C18:0,octadecanoate and arachidonate),and decreased glucurono-lactone,lysine and lactate.Rosiglitazone treatment was able to reverse more abnormally expressed metabolites,such as valine,lysine,glucuronolactone,C16:0,C18:1,urate,and oc-tadecanoate,than the other two drugs.

Abbreviations:T2DM,Type 2diabetes mellitus;HbA 1c ,glycated hemoglobin;BMI,body mass index;TC,total choles-terol;TG,triacylglycerol;HDL-cholesterol,high-density lipo-protein-cholesterol;LDL-cholesterol,low-density lipoprotein-cholesterol;BMI,body mass index;OPLSDA,orthogonal projections to latent structures discriminant analysis.

Acknowledgment.This work was ?nancially supp-orted by the National Basic Research Program of China (2007CB914700),the International Collaborative Project of Chinese Ministry of Science and Technology (2006DF-A02700)and the project of Chinese Ministry of Science and Technology (2006BAI08B04-01).

Supporting Information Available:Baseline demo-graphics of study populations;parameters of OPLSDA model;validation model of 1000random permutations.This material is available free of charge via the Internet at https://www.doczj.com/doc/064110459.html,.

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古代晋灵公不君、齐晋鞌之战原文及译文

晋灵公不君(宣公二年) 原文: 晋灵公不君。厚敛以雕墙。从台上弹人,而观其辟丸也。宰夫胹熊蹯不熟,杀之,寘诸畚,使妇人载以过朝。赵盾、士季见其手,问其故而患之。将谏,士季曰:“谏而不入,则莫之继也。会请先,不入,则子继之。”三进及溜,而后视之,曰:“吾知所过矣,将改之。”稽首而对曰:“人谁无过?过而能改,善莫大焉。诗曰:‘靡不有初,鲜克有终。’夫如是,则能补过者鲜矣。君能有终,则社稷之固也,岂惟群臣赖之。又曰:‘衮职有阙,惟仲山甫补之。’能补过也。君能补过,衮不废矣。” 犹不改。宣子骤谏,公患之,使鉏麑贼之。晨往,寝门辟矣,盛服将朝。尚早,坐而假寐。麑退,叹而言曰:“不忘恭敬,民之主也。贼民之主,不忠;弃君之命,不信。有一于此,不如死也!”触槐而死。 秋九月,晋侯饮赵盾酒,伏甲将攻之。其右提弥明知之,趋登曰:“臣侍君宴,过三爵,非礼也。”遂扶以下。公嗾夫獒焉。明搏而杀之。盾曰:“弃人用犬,虽猛何为!”斗且出。提弥明死之。 初,宣子田于首山,舍于翳桑。见灵辄饿,问其病。曰:“不食三日矣!”食之,舍其半。问之,曰:“宦三年矣,未知母之存否。今近焉,请以遗之。”使尽之,而为之箪食与肉,寘诸橐以与之。既而与为公介,倒戟以御公徒,而免之。问何故,对曰:“翳桑之饿人也。”问其名居,不告而退。——遂自亡也。 乙丑,赵穿①攻灵公于桃园。宣子未出山而复。大史书曰:“赵盾弑其君。”以示于朝。宣子曰:“不然。”对曰:“子为正卿,亡不越竟,反不讨贼,非子而谁?”宣子曰:“呜呼!‘我之怀矣,自诒伊戚。’其我之谓矣。” 孔子曰:“董狐,古之良史也,书法不隐。赵宣子,古之良大夫也,为法受恶。惜也,越竞乃免。” 译文: 晋灵公不行君王之道。他向人民收取沉重的税赋以雕饰宫墙。他从高台上用弹弓弹人,然后观赏他们躲避弹丸的样子。他的厨子做熊掌,没有炖熟,晋灵公就把他杀了,把他的尸体装在草筐中,让宫女用车载着经过朝廷。赵盾和士季看到露出来的手臂,询问原由后感到很忧虑。他们准备向晋灵公进谏,士季说:“如果您去进谏而君王不听,那就没有人能够再接着进谏了。还请让我先来吧,不行的话,您再接着来。”士季往前走了三回,行了三回礼,一直到屋檐下,晋灵公才抬头看他。晋灵公说:“我知道我的过错了,我会改过的。”士季叩头回答道:“谁能没有过错呢?有过错而能改掉,这就是最大的善事了。《诗经》说:‘没有人向善没有一个开始的,但却很少有坚持到底的。’如果是这样,那么能弥补过失的人是很少的。您如能坚持向善,那么江山就稳固了,不只是大臣们有所依靠啊。

药学英语第五版第三单元

Biochemistry Seeks to Explain Life in Chemical Terms The molecules of which living organisms are composed conform to all the familiar laws of chemistry, but they also interact with each other in accordance with another set of principles, which we shall refer to collectively as the molecular logic of life. These principles do not involve new or yet undiscovered physical laws or forces. Instead, they are a set of relationships characterizing the nature, function, and interactions of biomolecules. If living organisms are composed of molecules that are intrinsically inanimate, how do these molecules confer the remarkable combination of characteristics we call life? How is it that a living organism appears to be more than the sum of its inanimate parts? Philosophers once answered that living organisms are endowed with a mysterious and divine life force, but this doctrine (vitalism) has been firmly rejected by modern science. The basic goal of the science of biochemistry is to determine how the collections of inanimate molecules that constitute living organisms interact with each other to maintain and perpetuate life. Although biochemistry yields important insights and practical applications in medicine, agriculture, nutrition, and industry, it is ultimately concerned with the wonder of life itself. All Macromolecules Are Constructed from a Few Simple Compounds Most of the molecular constituents of living systems are composed of carbon atoms covalently joined with other carbon atoms and with hydrogen, oxygen, or nitrogen. The special bonding properties of carbon permit the formation of a great variety of molecules. Organic compounds of molecular weight less than about 500, such as amino acids, nucleotidase, and monosaccharide, serve as monomeric subunits of proteins, nucleic acids, and polysaccharides,

药学专业英语药学词汇

6-磷酸葡萄糖脱氢酶 glucose-6-phosphate dehydrogenase Janbon综合症 Janbon's syndrome PPB浓度 parts per billion concentration pphm浓度 parts per hundred million concentration PPH浓度 parts per hundred concentration ppm浓度 parts per million concentration 安全范围 safety range 安全试验法 innocuity test method 安全系统 safety coefficient 安慰剂 placebo 螯合剂 chelating agent 靶细胞 target cell 白蛋白微球制剂 albumin microballoons 百分浓度 percentage concentration 半合成抗生素 semisynthetic antibiotics 半抗原 haptene 半数致死剂量 half lethal dose ; median lethal dose; LD50 半衰期 half-life period; half life time 包衣片 coated tablet 薄膜衣 film-coating 饱和溶液 saturated solution 贝克勒尔 Becquerel 被动免疫 passive immunity 被动转运 passive transport

崩解度 disintegration 崩解剂 disintegrants 必需氨基酸 essential aminoacid 必需脂肪酸 essential fatty acid 变态反应 allergy; allergic reaction 表面活性 surface activity 表面张力 surface tension 丙种射线 gamma rays 补体 complement 补体系统 complement system 不良反应 adverse reaction 不完全抗原 incomplete antigen 搽剂 liniments 长期毒性实验 long term toxicity test 长效制剂 prolonged action preparation 肠肝循环 enterohepatic circulation 肠溶控释片 enteric controlled release tablets 肠溶衣 enteric coating 处方 prescription;recipe 穿透促进剂 penetration enhancers 磁性控释制剂 magnetic controlled release dosage form 磁性药物制剂 magnetic medicinal preparations 大分子 macromolecule 单克隆抗体 monoclonal antibody

如何翻译古文

如何翻译古文 学习古代汉语,需要经常把古文译成现代汉语。因为古文今译的过程是加深理解和全面运用古汉语知识解决实际问题的过程,也是综合考察古代汉语水平的过程。学习古代汉语,应该重视古文翻译的训练。 古文翻译的要求一般归纳为信、达、雅三项。“信”是指译文要准确地反映原作的含义,避免曲解原文内容。“达”是指译文应该通顺、晓畅,符合现代汉语语法规范。“信”和“达”是紧密相关的。脱离了“信”而求“达”,不能称为翻译;只求“信”而不顾“达”,也不是好的译文。因此“信”和“达”是文言文翻译的基本要求。“雅”是指译文不仅准确、通顺,而且生动、优美,能再现原作的风格神韵。这是很高的要求,在目前学习阶段,我们只要能做到“信”和“达”就可以了。 做好古文翻译,重要的问题是准确地理解古文,这是翻译的基础。但翻译方法也很重要。这里主要谈谈翻译方法方面的问题。 一、直译和意译 直译和意译是古文今译的两大类型,也是两种不同的今译方法。 1.关于直译。所谓直译,是指紧扣原文,按原文的字词和句子进行对等翻译的今译方法。它要求忠实于原文,一丝不苟,确切表达原意,保持原文的本来面貌。例如: 原文:樊迟请学稼,子曰:“吾不如老农。”请学为圃。子曰:“吾不如老圃。”(《论语?子路》) 译文:樊迟请求学种庄稼。孔子道:“我不如老农民。”又请求学种菜蔬。孔子道:“我不如老菜农。”(杨伯峻《论语译注》) 原文:齐宣王问曰:“汤放桀,武王伐纣,有诸?”(《孟子?梁惠王下》) 译文:齐宣王问道:“商汤流放夏桀,武王讨伐殷纣,真有这回事吗?(杨伯峻《孟子译注》) 上面两段译文紧扣原文,字词落实,句法结构基本上与原文对等,属于直译。 但对直译又不能作简单化理解。由于古今汉语在文字、词汇、语法等方面的差异,今译时对原文作一些适当的调整,是必要的,并不破坏直译。例如: 原文:逐之,三周华不注。(《齐晋鞌之战》) 译文:〔晋军〕追赶齐军,围着华不注山绕了三圈。

药学英语第五版原文翻译 (2)(2020年7月整理).pdf

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《鞌之战》阅读答案(附翻译)原文及翻 译 鞌之战[1] 选自《左传成公二年(即公元前589年)》 【原文】 癸酉,师陈于鞌[2]。邴夏御齐侯[3],逢丑父为右[4]。晋解张御郤克,郑丘缓为右[5]。齐侯曰:余姑翦灭此而朝食[6]。不介马而驰之[7]。郤克伤于矢,流血及屦,未绝鼓音[8],曰:余病[9]矣!张侯[10]曰:自始合,而矢贯余手及肘[11],余折以御,左轮朱殷[12],岂敢言病。吾子[13]忍之!缓曰:自始合,苟有险[14],余必下推车,子岂识之[15]?然子病矣!张侯曰:师之耳目,在吾旗鼓,进退从之[16]。此车一人殿之[17],可以集事[18],若之何其以病败君之大事也[19]?擐甲执兵,固即死也[20]。病未及死,吾子勉之[21]!左并辔[22],右援枹而鼓[23],马逸不能止[24],师从之。齐师败绩[25]。逐之,三周华不注[26]。 【注释】 [1]鞌之战:春秋时期的著名战役之一。战争的实质是齐、晋争霸。由于齐侯骄傲轻敌,而晋军同仇敌忾、士气旺盛,战役以齐败晋胜而告终。鞌:通鞍,齐国地名,在今山东济南西北。 [2]癸酉:成公二年的六月十七日。师,指齐晋两国军队。陈,

列阵,摆开阵势。 [3]邴夏:齐国大夫。御,动词,驾车。御齐侯,给齐侯驾车。齐侯,齐国国君,指齐顷公。 [4]逢丑父:齐国大夫。右:车右。 [5]解张、郑丘缓:都是晋臣,郑丘是复姓。郤(x )克,晋国大夫,是这次战争中晋军的主帅。又称郤献子、郤子等。 [6]姑:副词,姑且。翦灭:消灭,灭掉。朝食:早饭。这里是吃早饭的意思。这句话是成语灭此朝食的出处。 [7]不介马:不给马披甲。介:甲。这里用作动词,披甲。驰之:驱马追击敌人。之:代词,指晋军。 [8] 未绝鼓音:鼓声不断。古代车战,主帅居中,亲掌旗鼓,指挥军队。兵以鼓进,击鼓是进军的号令。 [9] 病:负伤。 [10]张侯,即解张。张是字,侯是名,人名、字连用,先字后名。 [11]合:交战。贯:穿。肘:胳膊。 [12]朱:大红色。殷:深红色、黑红色。 [13]吾子:您,尊敬。比说子更亲切。 [14]苟:连词,表示假设。险:险阻,指难走的路。 [15]识:知道。之,代词,代苟有险,余必下推车这件事,可不译。 [16]师之耳目:军队的耳、目(指注意力)。在吾旗鼓:在我们

《鞌之战》阅读答案附翻译

《鞌之战》阅读答案(附翻译) 《鞌之战》阅读答案(附翻译) 鞌之战[1] 选自《左传·成公二年(即公元前589年)》 【原文】 癸酉,师陈于鞌[2]。邴夏御齐侯[3],逢丑父为右[4]。晋解张御郤克,郑丘缓为右[5]。齐侯曰:“余姑 翦灭此而朝食[6]。”不介马而驰之[7]。郤克伤于矢, 流血及屦,未绝鼓音[8],曰:“余病[9]矣!”张侯[10]曰:“自始合,而矢贯余手及肘[11],余折以御,左轮 朱殷[12],岂敢言病。吾子[13]忍之!”缓曰:“自始合,苟有险[14],余必下推车,子岂识之[15]?——然 子病矣!”张侯曰:“师之耳目,在吾旗鼓,进退从之[16]。此车一人殿之[17],可以集事[18],若之何其以 病败君之大事也[19]?擐甲执兵,固即死也[20]。病未 及死,吾子勉之[21]!”左并辔[22],右援枹而鼓[23],马逸不能止[24],师从之。齐师败绩[25]。逐之,三周 华不注[26]。 【注释】 [1]鞌之战:春秋时期的著名战役之一。战争的实质是齐、晋争霸。由于齐侯骄傲轻敌,而晋军同仇敌忾、 士气旺盛,战役以齐败晋胜而告终。鞌:通“鞍”,齐

国地名,在今山东济南西北。 [2]癸酉:成公二年的六月十七日。师,指齐晋两国军队。陈,列阵,摆开阵势。 [3]邴夏:齐国大夫。御,动词,驾车。御齐侯,给齐侯驾车。齐侯,齐国国君,指齐顷公。 [4]逢丑父:齐国大夫。右:车右。 [5]解张、郑丘缓:都是晋臣,“郑丘”是复姓。郤(xì)克,晋国大夫,是这次战争中晋军的主帅。又称郤献子、郤子等。 [6]姑:副词,姑且。翦灭:消灭,灭掉。朝食:早饭。这里是“吃早饭”的意思。这句话是成语“灭此朝食”的出处。 [7]不介马:不给马披甲。介:甲。这里用作动词,披甲。驰之:驱马追击敌人。之:代词,指晋军。 [8]未绝鼓音:鼓声不断。古代车战,主帅居中,亲掌旗鼓,指挥军队。“兵以鼓进”,击鼓是进军的号令。 [9]病:负伤。 [10]张侯,即解张。“张”是字,“侯”是名,人名、字连用,先字后名。 [11]合:交战。贯:穿。肘:胳膊。 [12]朱:大红色。殷:深红色、黑红色。 [13]吾子:您,尊敬。比说“子”更亲切。

药学英语专业词汇

药学名词(中-英) 6-磷酸葡萄糖脱氢酶glucose-6-phosphate dehydrogenase Janbon综合症Janbon's syndrome PPB浓度parts per billion concentration pphm浓度parts per hundred million concentration PPH浓度parts per hundred concentration ppm浓度parts per million concentration 安全范围safety range 安全试验法innocuity test method 安全系统safety coefficient 安慰剂placebo 螯合剂chelating agent 靶细胞target cell 白蛋白微球制剂albumin microballoons 百分浓度percentage concentration 半合成抗生素semisynthetic antibiotics 半抗原haptene 半数致死剂量half lethal dose ; median lethal dose; LD50 半衰期half-life period; half life time 包衣片coated tablet 薄膜衣film-coating 饱和溶液saturated solution 贝克勒尔Becquerel 被动免疫passive immunity 被动转运passive transport 崩解度disintegration 崩解剂disintegrants 必需氨基酸essential aminoacid

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