吳熒宸,丁 淼,李揚(yáng)志,陳冬梅,謝梅青
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糖負(fù)荷后1h血糖值與絕經(jīng)后女性代謝綜合征相關(guān)研究
吳熒宸,丁 淼,李揚(yáng)志,陳冬梅,謝梅青*
(中山大學(xué)孫逸仙紀(jì)念醫(yī)院婦產(chǎn)科,廣州 510120)
探討絕經(jīng)前后非糖尿病人群代謝綜合征(MS)及動脈粥樣硬化因素與糖負(fù)荷后1h血糖(1h-PG)的關(guān)系,及1h-PG在絕經(jīng)后MS人群的可能切點(diǎn)值。以2013年8月~10月在中山大學(xué)孫逸仙紀(jì)念醫(yī)院進(jìn)行健康體檢年齡30~70歲女性為研究對象,收集身高、體質(zhì)量、腰圍、血壓、血脂及葡萄糖耐量試驗(yàn)(OGTT)0,1,2h相對應(yīng)的血糖、胰島素水平。根據(jù)OGTT結(jié)果剔除糖尿病患者,按照不同絕經(jīng)階段分為兩組:絕經(jīng)前組143例,絕經(jīng)后組145例,根據(jù)國際糖尿病聯(lián)盟(IDF)MS定義標(biāo)準(zhǔn),分析1h-PG與MS的相關(guān)性及在絕經(jīng)后女性MS的切點(diǎn)值。(1)絕經(jīng)后組年齡、甘油三酯、總膽固醇、低密度脂蛋白膽固醇、收縮壓、舒張壓均高于絕經(jīng)前組,差異均有統(tǒng)計(jì)學(xué)意義(<0.05)。(2)各組受檢者行OGTT測試后,相比于絕經(jīng)前組,絕經(jīng)后組各時點(diǎn)葡萄糖、胰島素及恒穩(wěn)態(tài)模型評價-胰島素抵抗(HOMA-IR)水平均顯著增高,差異均有統(tǒng)計(jì)學(xué)意義(<0.05)。(3)絕經(jīng)前組中,檢出MS患者22例(13.39%),絕經(jīng)后組中,檢出MS患者47例(32.40%),兩組MS發(fā)生率比較,差異有統(tǒng)計(jì)學(xué)意義(2=11.46,=0.01)。(4)MS相關(guān)影響因素的logistic回歸分析結(jié)果顯示,1h-PG與MS顯著相關(guān)(OR=1.849,95%CI=1.557?2.195,<0.001)。(5)當(dāng)1h-PG以8.70mmol/L為臨界值時,1h-PG對絕經(jīng)后組MS預(yù)測的敏感度為87.50%,特異度為81.44%,Youden指數(shù)為0.689,受試者工作特征(ROC)曲線下面積(AUC)為0.907。絕經(jīng)前后非糖尿病人群MS與1h-PG均密切相關(guān),推測1h-PG預(yù)測絕經(jīng)后女性MS的可能切點(diǎn)值為8.70mmol/L,可以作為預(yù)測絕經(jīng)后女性MS的一個可選指標(biāo),對早期臨床干預(yù)或治療有指導(dǎo)意義。
糖負(fù)荷后1h血糖;絕經(jīng);代謝綜合征;心血管疾病
絕經(jīng)后女性體內(nèi)雌激素水平下降,并常伴隨一系列代謝相關(guān)疾病的發(fā)生。眾多臨床資料顯示,絕經(jīng)后女性心血管疾病,代謝綜合征(metabolic syndrome,MS)以及2型糖尿病發(fā)病率較絕經(jīng)前顯著上升[1]。中國的1項(xiàng)大型研究發(fā)現(xiàn),在女性死因排序中,心血管疾病已成為首位死亡原因[2]。在糖代謝方面,絕經(jīng)前,女性糖尿病的發(fā)生率低于同齡男性;但是,絕經(jīng)>10年的女性,糖尿病的發(fā)生率超過同齡男性[3]。女性空腹血糖和口服葡萄糖耐量試驗(yàn)(oral glucose tolerance test,OGTT)負(fù)荷后2h血糖(2 hour postload plasma glucose,2h-PG)隨年齡增長速度大于同齡男性[4]。這提示卵巢功能衰退參與絕經(jīng)后代謝相關(guān)疾病,可能通過雌激素水平下降伴隨胰島素抵抗(insulin resistance,IR)產(chǎn)生作用。
目前,OGTT中負(fù)荷后1h血糖(1 hour postload plasma glucose,1h-PG)的臨床價值正越來越受到關(guān)注,在正常糖耐量人群中,1h-PG與代謝指標(biāo)如IR和β細(xì)胞功能紊亂有很強(qiáng)的相關(guān)性[5]。眾多研究等都證實(shí)了1h-PG較OGTT中2h-PG更早發(fā)生改變,是代謝相關(guān)疾病如糖尿病、心腦血管疾病的獨(dú)立危險(xiǎn)因素[6,7],在非糖尿病老年人群中,lh-PG甚至可以預(yù)測全因死亡率[6]。對于絕經(jīng)期女性,本身受雌激素缺乏影響,處于IR易感狀態(tài)下,若能及早發(fā)現(xiàn)這部分人群潛在的代謝紊亂并給予臨床干預(yù)可使患者遠(yuǎn)期獲益。特別是近年絕經(jīng)領(lǐng)域提出的圍絕經(jīng)期激素治療心血管疾病的時間窗假說,即支持在近絕經(jīng)期即開始使用激素治療,能降低心血管疾病風(fēng)險(xiǎn)[8],更為圍絕經(jīng)期女性心血管疾病早期干預(yù)提供了選擇。目前國內(nèi)尚無關(guān)于1h-PG在絕經(jīng)前后女性中變化及與代謝指標(biāo)相關(guān)性的研究,MS是心血管疾病的多種代謝危險(xiǎn)因素在個體內(nèi)集結(jié)的狀態(tài)。是評價心血管疾病高風(fēng)險(xiǎn)的重要指標(biāo),因此,我們的研究側(cè)重于在絕經(jīng)后非糖尿病女性中,探討1h-PG與MS的關(guān)系。
選取2013年8月~10月在中山大學(xué)孫逸仙紀(jì)念醫(yī)院接受健康體檢,年齡30~70歲的女性為研究對象。我們共招募374名女性,排除嚴(yán)重肝腎疾病、甲狀腺疾病、子宮或卵巢切除者、多囊卵巢綜合征、卵巢早衰、長期使用影響糖代謝藥物者26例;排除資料信息不全者39例;月經(jīng)紊亂、周期不詳者13例。排除糖尿病患者8例,最終288例納入研究。既往月經(jīng)規(guī)律,停經(jīng)>1年以上絕經(jīng)狀態(tài)。
由統(tǒng)一訓(xùn)練的??漆t(yī)師詢問病史,受檢者測量身高、體質(zhì)量、腰圍、血壓,檢測方法均由經(jīng)過訓(xùn)練的醫(yī)師按照標(biāo)準(zhǔn)的方法進(jìn)行受檢者晨起后空腹脫鞋、帽、外衣;身高、體質(zhì)量測量使用經(jīng)過校正的電子身高體質(zhì)量稱進(jìn)行測量;腰圍:被檢者直立,兩腳分開30~40cm,用一根無彈性、最小刻度為1mm的軟尺放在右側(cè)腋中線髂骨上緣與第12肋骨下緣連線的中點(diǎn),沿著水平方向圍繞腹部一周,將軟尺緊貼而不壓迫皮膚,在正常呼氣末測量,讀數(shù)準(zhǔn)確至1mm;臀圍:被檢者直立,腳跟并緊,在恥骨聯(lián)合水平測量臀部最大周徑;血壓:使用經(jīng)過校準(zhǔn)的臺式水銀血壓計(jì)測量血壓,測量3次,每次間隔30min。計(jì)算體質(zhì)量指數(shù)(body mass index,BMI)=體質(zhì)量(kg)/身高(m)2。
受檢者嚴(yán)格空腹10~12h,于次日上午7∶00~8∶00采取肘靜脈血行檢測,檢測包括:甘油三酯(triglycerides,TG)、總膽固醇(total cholesterol,TC)、高密度脂蛋白膽固醇(high density lipoprotein cholesterol,HDL-C)、低密度脂蛋白膽固醇(low density lipoprotein cholesterol,LDL-C);所有參與者均口服75g無水葡萄糖行OGTT,分別于空腹、口服75g葡萄糖水后1、2h抽血行相應(yīng)時點(diǎn)血糖、胰島素檢測。胰島素采用化學(xué)發(fā)光法測定(Immulite 2000 Analyser);血糖采用葡萄糖氧化酶法測定(Hitachi 7600);血脂檢測使用全自動生化分析儀(Hitachi 7600)。計(jì)算恒穩(wěn)態(tài)模型評價(HOMA-IR)=空腹血糖(mmol/L)×空腹胰島素(mU/ L)/22.5。
MS采用國際糖尿病聯(lián)盟(International Diabetes Federation,IDF)定義標(biāo)準(zhǔn):以中心性肥胖(女性腰圍≥80cm)作為診斷指標(biāo);同時合并以下4項(xiàng)指標(biāo)中的任何2項(xiàng):(1)TG≥1.7mmol/L,或已接受相應(yīng)治療;(2)HDL-C<1.29mmol/L,或已接受相應(yīng)治療;(3)血壓升高:收縮壓(systolic blood pressure,SBP)≥130mmHg(1mmHg=0.133kPa)或舒張壓(diastolic blood pressure,DBP)≥85mmHg,或已接受相應(yīng)治療或此前已診斷為高血壓;(4)空腹血糖≥5.6mmol/L,或已接受相應(yīng)治療或此前已診斷為2型糖尿病。
采用SPSS13.0軟件進(jìn)行統(tǒng)計(jì)學(xué)分析。正態(tài)分布的計(jì)量資料應(yīng)用均數(shù)±標(biāo)準(zhǔn)差描述,非正態(tài)分布的計(jì)量資料采用中位數(shù)(四分位間距)表示;兩組間均數(shù)采用Student檢驗(yàn),非正態(tài)分布組間比較采用Kruskal?Wallis秩和檢驗(yàn);計(jì)數(shù)資料比較用卡方檢驗(yàn);危險(xiǎn)因素分析用非條件logistic回歸分析;采用靈敏度、特異度、Youden指數(shù)(正確指數(shù))及繪制受試者工作特征(receiver operating characteristic,ROC)曲線,計(jì)算曲線下面積(area under curve,AUC)等指標(biāo),計(jì)算Youden指數(shù)(靈敏度+特異度-1),來確定最佳靈敏度和特異度,值越接近1,診斷效力越高,取Youden指數(shù)最大值的點(diǎn)作為預(yù)測切點(diǎn)。評價診斷的準(zhǔn)確性。<0.05為差異有統(tǒng)計(jì)學(xué)意義。
按照不同絕經(jīng)階段分為兩組:絕經(jīng)前組143例,絕經(jīng)后組145例;兩組受檢者一般臨床及生化指標(biāo)情況見表1。兩組受檢者之間腰圍、BMI、HDL-C差異無統(tǒng)計(jì)學(xué)意義(>0.05);絕經(jīng)后組年齡、TG、TC、LDL-C、SBP、DBP均高于絕經(jīng)前組,差異均有統(tǒng)計(jì)學(xué)意義(<0.05)。
各組受檢者行OGTT后,血糖和胰島素的變化見表2。相比于絕經(jīng)前組,絕經(jīng)后組各時段葡萄糖及胰島素水平均增高,差異均有統(tǒng)計(jì)學(xué)意義(<0.05)。HOMA-IR水平絕經(jīng)后組高于絕經(jīng)前組,且差異有統(tǒng)計(jì)學(xué)意義(<0.05)。
絕經(jīng)前組中,檢出MS患者22例(13.39%),絕經(jīng)后組中,檢出MS患者47例(32.40%),兩組MS發(fā)生率比較,差異有統(tǒng)計(jì)學(xué)意義(2=11.46,=0.01)。
表1 兩組受檢者一般臨床及生化指標(biāo)情況
BMI: body mass index;WC: waist circumference; SBP: systolic blood pressure; DBP: diastolic blood pressure; TG: triglycerides; HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol; TC: total cholesterol.1mmHg=0.133kPa. Compared with pre-menopausal group,*<0.05
表2 兩組受檢者OGTT測試中血糖及胰島素水平
Data are presented as mean±SD for normal distribution, medians (Q75-Q25) for skewed distribution. Thevalues were derived from independent-sampletest (for normal distribution) or Kruskal- Wallis test (for skewed distribution). OGTT: oral glucose tolerance test; FPG: fasting plasma glucose; 1h-PG: 1 hour postload plasma glucose; 2h-PG: 2 hour postload plasma glucose; FIN: fasting plasma insulin; 1h-IN: 1h plasma insulin; 2h-IN: 2h plasma insulin; HOMA-IR: Homeostasis Model Assessment-Insulin Resistance. Compared with pre-menopausal group,*<0.05
以MS作為自變量,選取年齡、是否絕經(jīng)、BMI、空腹血糖、1h-PG、2h-PG、HOMA-IR水平進(jìn)行多變量logistic回歸分析來篩選MS的影響因素,其中年齡、BMI、空腹血糖、1h-PG、2h-PG為連續(xù)型定量變量;采用逐步前進(jìn)法篩選變量,設(shè)定<0.01為差異有統(tǒng)計(jì)學(xué)意義。最終回歸方程僅納入1h-PG和BMI水平,提示1h-PG每增加1mmol/L,發(fā)生MS的風(fēng)險(xiǎn)增加1.849倍(表3)。
以是否為MS為狀態(tài)變量,以1h-PG為測定變量,繪制ROC曲線,選取Youden指數(shù)值最大的點(diǎn)作為診斷分界點(diǎn),在絕經(jīng)前組,當(dāng)1h-PG以7.75mmol/L為臨界值時,1h-PG對女性MS預(yù)測的敏感度為81.82%,特異度為72.73%,Youden指數(shù)為0.545,ROC的AUC為0.839;在絕經(jīng)后組,當(dāng)1h-PG以8.70mmol/L為臨界值時,1h-PG對女性MS預(yù)測的敏感度為87.50%,特異度為81.44%,Youden指數(shù)為0.689,ROC的AUC為0.907(表4,圖1)。
表3 MS風(fēng)險(xiǎn)預(yù)測的多變量logistic回歸分析
MS: metabolic syndrome; BMI: body mass index
圖1 1h-PG絕經(jīng)后組預(yù)測MS的ROC曲線
Figure 1 ROC curves giving the diagnostic value of 1h-PG for predicting MS in post-menopausal women1h-PG: 1 hour postload plasma glucose; MS: metabolic syndrome; ROC: receiver operating characteristic curve
以是否為MS為狀態(tài)變量,分別以空腹血糖、1h-PG、2h-PG為測定變量,繪制ROC曲線,ROC的AUC分別為0.758,0.907,0.760,可見僅1h-PG為測定變量時,ROC的AUC最大(表5)。
卵巢分泌的雌激素在維持正常β細(xì)胞功能上起重要作用[9],雌激素水平的降低會減少胰島素分泌并促進(jìn)IR的發(fā)生[10]。通常認(rèn)為,不論絕經(jīng)與否,IR是所有心血管疾病相關(guān)代謝異常的中心病因[11]。女性絕經(jīng)后,會經(jīng)歷卵巢功能衰竭繼而雌激素水平下降,這部分人群更易受IR作用的影響,伴隨代謝相關(guān)疾病。我們的研究同樣支持這一觀點(diǎn),在一般資料及生化指標(biāo)的比較中,雖然其中有些指標(biāo)末達(dá)到統(tǒng)計(jì)學(xué)差異。但總體上,絕經(jīng)后女性腰圍、BMI、TG、TC、LDL-C、SBP、DBP水平均較絕經(jīng)前高,HDL-C低于絕經(jīng)前女性,同樣,在OGTT測試后,絕經(jīng)后組,各時段葡萄糖及胰島素水平均高于絕經(jīng)前。在這部分人群中,絕經(jīng)后組MS的發(fā)病率也較絕經(jīng)前組高,表明隨著體內(nèi)雌激素水平的降低,女性體內(nèi)已經(jīng)出現(xiàn)潛在的代謝紊亂。
雌激素缺乏以及雄激素活性的相對增加,破壞了絕經(jīng)后女性體內(nèi)的血糖穩(wěn)態(tài)[12,13]。因此絕經(jīng)后女性更易發(fā)生血糖異常。OGTT為目前作為篩查糖尿病和糖調(diào)節(jié)受損的標(biāo)準(zhǔn)方法,可較敏感地識別血糖異常的患者。近年有研究表明OGTT中1h-PG比2h-PG更早發(fā)生改變,可以更好地預(yù)測糖尿病的轉(zhuǎn)歸,在正常人群中1h-PG>10.0mmol/L者比<10.0mmol/L者更易轉(zhuǎn)化為糖尿病,且此風(fēng)險(xiǎn)獨(dú)立于空腹血糖和2h-PG[14]。1h-PG不僅被報(bào)道與糖代謝疾病具有強(qiáng)關(guān)聯(lián),與其他代謝異常的關(guān)系也受到越來越多的關(guān)注。對30~59歲的1 059名男性進(jìn)行5年的隨訪證實(shí),冠心病死亡率和非致死性心肌梗死的發(fā)病率與高lh-PG有明確的相關(guān)性,而與空腹血糖和2h-PG無相關(guān)性[15]。因此,研究OGTT中l(wèi)h血糖切點(diǎn)值的臨床意義就顯得尤為重要。Abdul-Ghani等[16]發(fā)現(xiàn)在墨西哥裔美國人群中的OGTT、1h-PG與IR指數(shù)和胰島素分泌指數(shù)有很好的相關(guān)性。Bardini等[17]的研究中發(fā)現(xiàn)高水平的1h-PG與亞臨床炎癥高血脂比率以及IR相關(guān),并認(rèn)為1h-PG可作為是心血管疾病風(fēng)險(xiǎn)的新指標(biāo)。另一項(xiàng)研究也支持以上的觀點(diǎn),Succurro等[18]發(fā)現(xiàn)正常糖耐量伴高1h-PG水平的患者與糖耐量異?;颊叩膭用}粥樣硬化指標(biāo)水平并無差異,這項(xiàng)研究認(rèn)為1h-PG可幫助識別在正常糖耐量人群中高心血管疾病風(fēng)險(xiǎn)患者。在本研究中,通過logistic回歸分析,我們也證實(shí)了1h-PG為MS的獨(dú)立危險(xiǎn)因素,肥胖可以增加MS的風(fēng)險(xiǎn),而單純的空腹血糖或2h-PG并沒有顯著增加MS的風(fēng)險(xiǎn),在本人群中l(wèi)h-PG也可一定程度上反映代謝異常的情況。對空腹血糖、1h-PG、2h-PG在絕經(jīng)后組預(yù)測MS的ROC分析中,以1h血糖作為測定變量,可獲得最大ROC曲線下面積,本結(jié)果也同樣支持1h-PG在預(yù)測代謝相關(guān)疾病中的優(yōu)越性。
表4 1h-PG在兩組間預(yù)測MS的ROC分析
MS: metabolic syndrome; 1h-PG: 1 hour postload plasma glucose; ROC: receiver operating characteristic; AUC: area under ROC curve
表5 絕經(jīng)后組空腹血糖、1h-PG、2h-PG預(yù)測MS的ROC分析
MS: metabolic syndrome; 1h-PG: 1 hour postload plasma glucose; 2h-PG: 2 hour postload plasma glucose; FPG: fasting plasma glucose; ROC: receiver operating characteristic; AUC: area under ROC curve
MS是肥胖、高血壓、血脂紊亂、糖尿病多種代謝危險(xiǎn)因素在個體內(nèi)集結(jié)的狀態(tài),IR和高血糖是MS的核心要素,研究認(rèn)為在女性人群中,MS預(yù)測了心血管疾病的危險(xiǎn)性[19]。那么在絕經(jīng)后這部分易伴隨糖脂代謝異常的人群中,早期識別MS具有重要意義。本研究通過ROC曲線分析得出,在絕經(jīng)后非糖尿病人群中,lh-PG篩查MS最佳切點(diǎn)值為8.70mmol/L,敏感度為87.50%,特異度為81.44%。這一結(jié)果與Bardini等的研究中認(rèn)為1h-PG>8.6mmol/L可以預(yù)測心血管疾病風(fēng)險(xiǎn)的截?cái)嘀到咏?。這提示,lh-PG對于識別絕經(jīng)后MS有一定意義,近年絕經(jīng)領(lǐng)域提出的圍絕經(jīng)期激素治療心血管疾病的時間窗假說,認(rèn)為明顯的心血管保護(hù)作用,早期激素干預(yù)應(yīng)在女性約65歲之前,因此早期發(fā)現(xiàn)潛在代謝異常的圍絕經(jīng)期女性并給予早期生活方式干預(yù)或者藥物治療可得到遠(yuǎn)期獲益。1h-PG對MS的預(yù)測及其預(yù)后的相關(guān)作用還需要更多大規(guī)模的前瞻性研究來證實(shí)。
綜上所述,本研究發(fā)現(xiàn)MS與lh-PG水平密切相關(guān),以8.70mmol/L為lh-PG切點(diǎn)值,預(yù)測絕經(jīng)后非糖尿病女性MS具有較好的敏感度和特異度。可以作為預(yù)測絕經(jīng)后女性MS的一個可選指標(biāo)。絕經(jīng)后女性隨著體內(nèi)雌激素水平的降低,體內(nèi)已經(jīng)出現(xiàn)潛在的代謝紊亂。如果在此階段對相關(guān)的代謝危險(xiǎn)因素進(jìn)行防治,能獲得更好的收益。
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(編輯: 周宇紅)
Correlation of one-hour postload plasma glucose levels with metabolic syndrome in postmenopausal women
WU Ying-Chen, DING Miao, LI Yang-Zhi, CHEN Dong-Mei, XIE Mei-Qing*
(Department of Obstetrics and Gynecology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China)
To investigate the relationship of one-hour postload plasma glucose (1h-PG) levels with atherosclerotic risk factors and metabolic syndrome (MS) between pre-menopause and post-menopause in a group of nondiabetic population, and to determine the possible cut point of 1h-PG for MS in postmenopausal women.A cross-sectional study was performed in our hospital during August to October 2013, and the women (aged from 30 to 70 years) who were in hospital for routine check-up at the Medical Examination Center were enrolled. All subjects underwent laboratory examinations of oral glucose tolerance test (OGTT), lipid, and anthropometric measurements (height, body mass and waistline). Diabetes were excluded according to the results of OGTT. According to their menstrual status, the subjects were divided into 2 groups: premenopausal group (=143) and postmenopausal group (=145). MS was defined according to the International Diabetes Federation (IDF) criteria. The relationship of 1h-PG and MS of women in different stage of menopause was analyzed, and the cut point of 1h-PG for MS in postmenopausal women was determined.(1) Triglycerides, total cholesterol, low density lipoprotein cholesterol, systolic and diastolic blood pressure were significantly higher in postmenopausal group than in premenopausal group (<0.05).(2) Subjects in postmenopausal group had higher plasma glucose and insulin levels in each time point of OGTT accordingly when compared with premenopausal group (<0.05). Homeostasis Model Assessment-Insulin Resistance (HOMA-IR) was also significantly higher in the former group (<0.05). (3) The incidence of MS was 13.39% (22/143) in premenopausal group and 32.40% (47/145) in postmenopausal group, with significant difference between the 2 groups (Chi-square=11.46,=0.01). (4) The logistic regression analysis for MS showed that MS was significantly associated with 1h-PG (OR=1.849, 95% CI=1.557?2.195,<0.001). (5) When the cut-off value of 1h-PG was defined at 8.70mmol/L, the sensitivity of 1h-PG for predicting MS was 87.50%, the specificity was 81.44%, the area under the receiver operating characteristic curve (ROC) was 0.907, and Youden index was 0.689 in post-menopausal group.MS is closely related to 1h-PG in both pre-menopausal and post-menopausal nondiabetic women. When the cut point of 1h-PG is 8.70mmol/L, it is a selectable marker to predict MS in postmenopausal woman, and represents useful in clinical practice for early intervention or treatment.
one-hour postload plasma glucose; menopause; metabolic syndrome; cardiovascular disease
(2009B060300019).
R589
A
10.3724/SP.J.1264.2014.000157
2014?06?20;
2014?07?30
廣東省科技計(jì)劃基金(2009B060300019)
謝梅青, E-mail: mqxie123@163.com