【摘要】：背景及目的：糖尿病的患病率逐年上升,成為當(dāng)今威脅人類健康的重要慢性疾病之一。據(jù)IDF統(tǒng)計,2011年全球糖尿病患病總?cè)藬?shù)達(dá)3.66億,預(yù)期至2030年將增加至5.52億(患病率達(dá)7.7%),而這其中又以亞洲地區(qū)的增長速度最為突出。最新流行病學(xué)調(diào)查研究顯示,我國成人糖尿病患病率已達(dá)11.6%,總患病人數(shù)達(dá)1.14億,躍居世界第一位。2型糖尿病占糖尿病患病總數(shù)的90%,主要表現(xiàn)為胰島p細(xì)胞功能受損以及胰島素抵抗。傳統(tǒng)的口服降糖藥以及胰島素注射等方式雖然能夠有效地改善糖尿病患者高血糖狀態(tài),卻不能修復(fù)或補充受損的胰島μ細(xì)胞,從根本上延緩疾病的進展。修復(fù)受損的胰島μ細(xì)胞、增加胰島p細(xì)胞的數(shù)量、改善機體胰島素抵抗?fàn)顟B(tài),成為治療糖尿病的理想途徑。在糖尿病發(fā)病初期針對病理生理學(xué)發(fā)病機制進行防治,可以在有效改善患者血糖譜的同時改善機體胰島素抵抗?fàn)顟B(tài),延緩疾病的進展及相關(guān)并發(fā)癥的發(fā)生。Betatrophin是一種由193個氨基酸組成的內(nèi)分泌蛋白,高表達(dá)于胰島素受體拮抗劑S961誘導(dǎo)的嚴(yán)重胰島素抵抗小鼠模型肝臟組織內(nèi),并能以劑量依賴的方式促進小鼠胰島p細(xì)胞大量增殖。因其能促進胰島p細(xì)胞增殖并參與機體血脂調(diào)節(jié)等不同作用,分別被命名為：betatrophin、ANGPTL8、RIFL以及Lipasin等。目前研究結(jié)果表明,人體血清betatrophin濃度與糖尿病、肥胖以及血脂譜之間的關(guān)系仍然存在諸多分歧。部分臨床研究發(fā)現(xiàn)糖尿病、胰島素抵抗以及血脂異�；颊哐h(huán)血清betatrophin濃度發(fā)生改變,并隨著種族以及人群差異其變化趨勢不盡相同；與此同時,一些基礎(chǔ)研究卻發(fā)現(xiàn)betatrophin并不能刺激體外培養(yǎng)的人類胰島p細(xì)胞增殖,不參與人體血糖穩(wěn)態(tài)的調(diào)節(jié)。作為一種新發(fā)現(xiàn)的促代謝因子,betatrophin在新診斷的中國2型糖尿病患者體內(nèi)的表達(dá)情況仍未被闡明,循環(huán)血清betatrophin濃度與血糖、血脂、胰島素抵抗以及各代謝指標(biāo)的關(guān)系也不明確,betatrophin可否作為預(yù)測2型糖尿病的一個生化指標(biāo),這些問題都亟待解決。有鑒于此,本研究通過探討了新診斷的2型糖尿病患者與非糖尿病人群循環(huán)血清betatrophin濃度及其與各代謝指標(biāo)的相關(guān)關(guān)系,旨在尋求betatrophin與2型糖尿病、胰島素抵抗以及其他代謝參數(shù)之間的關(guān)系,并探索betatrophin濃度對中國人群2型糖尿病的可能預(yù)測作用,以期為臨床以及基礎(chǔ)研究提供依據(jù)。方法：本研究共納入131例研究對象,其中新診斷2型糖尿病患者73例,男性38例,女性35例,均來自于廣東省廣州市南方醫(yī)科大學(xué)珠江醫(yī)院內(nèi)分泌科2014年8月至2014年12月的門診及住院病人；另外按照年齡、性別、體質(zhì)指數(shù)(BMI)匹配,入選了58例非糖尿病受試者作為對照,其中男性31例,女性27例,均來源于同時期南方醫(yī)科大學(xué)北(?)醫(yī)院體檢中心。糖尿病組和對照組分別按照BMI各分為正常體重(BMI24kg/m2)、超重(24kg/m2≤BMI28kg/m2)以及肥胖(BMI≥28kg/m2)三個亞組。排除：1)正在接受口服降糖藥治療以及合并大血管病變的2型糖尿病(T2DM)患者；2)近1個月內(nèi)服用過可能影響血糖和血脂藥物的患者；3)其他類型糖尿病患者；4)病毒性肝炎、肝衰竭、腫瘤、嚴(yán)重精神障礙、接受血液透析的慢性腎功能不全、充血性心力衰竭及其他嚴(yán)重疾病的患者。該項目符合赫爾辛基宣言倫理準(zhǔn)則標(biāo)準(zhǔn)并獲得珠江醫(yī)院倫理委員會同意,所有患者均簽署知情同意書。采用體格檢查以及問卷調(diào)查表格的形式,由經(jīng)過統(tǒng)一培訓(xùn)的醫(yī)務(wù)人員收集受試者的一般人口學(xué)資料,包括現(xiàn)病史、既往史、家族史以及用藥史等。詳細(xì)詢問每位受試者近半年來有無穩(wěn)定或不穩(wěn)定型心絞痛病史、心肌梗塞病史、腦卒中或其他腦血管意外病史,以排除不合格的患者；詢問患者吸煙史(每日吸煙量、持續(xù)時間)、飲酒史(每日飲酒量、持續(xù)時間)、高血壓病史、血脂異常病史；詢問患者既往用藥史。由經(jīng)過統(tǒng)一培訓(xùn)的醫(yī)務(wù)人員對每位受試者行體格檢查,記錄受試者體重、身高、血壓、腰圍、臀圍以及心率等。采集所有受試者清晨空腹(禁食12小時)肘前靜脈血液標(biāo)本3.0ml,常溫靜置2小時,離心機分離血清(2000-3000轉(zhuǎn)/分,20min),自然凝固10-20min后,提取血清于EP管內(nèi),編號、封口后置于-80℃低溫冰箱保存,以待檢測指標(biāo)時使用。檢測每位受試者空腹血糖(FPG)、胰島素(FINs)、C-肽、總膽固醇(TC)、甘油三酯(TG)、低密度脂蛋白膽固醇(LDL-C)、高密度脂蛋白膽固醇(HDL-C)、尿素氮(BUN)、肌酐(Cr)、谷丙轉(zhuǎn)氨酶(ALT)、谷草轉(zhuǎn)氨酶(AST)以及尿酸(UA)水平。采用穩(wěn)態(tài)模型胰島素抵抗指數(shù)(HOMA-IR)、穩(wěn)態(tài)模型胰島素分泌指數(shù)(HOMA-%p)以及定量胰島素敏感性檢測指數(shù)(QUICKI)評價β細(xì)胞功能。HOMA-IR的計算公式為：胰島素(mIU/1)*血糖(mmol/1)/22.5(胰島素和血糖采用的單位下同)；HOMA-%β的計算公式為：20*胰島素/(血糖-3.5)；QUICKI指數(shù)=1/[log(FINs) l+log(FPG)] (FINs單位采用μU/ml, FPG單位采用mg/dl)。血清Betatrophin濃度采用中國武漢伊艾博科技有限公司生產(chǎn)的ELISA試劑盒測定(中國武漢,產(chǎn)品批號No.E11644h),嚴(yán)格按照說明書的指示對每份血樣重復(fù)測量兩次,變異指數(shù)大于15%的樣本棄除。在450nm波長下采用酶聯(lián)儀檢測各樣本分光光度值(OD),每份標(biāo)本檢測兩次,取平均值計算最終OD值。以標(biāo)準(zhǔn)物的濃度為橫坐標(biāo),平均OD值為縱坐標(biāo),繪制標(biāo)準(zhǔn)曲線。依據(jù)標(biāo)準(zhǔn)曲線計算出每份血樣betatrophin的濃度。統(tǒng)計學(xué)運用SPSS 20.0軟件進行統(tǒng)計分析。K-S檢驗用于檢測資料的正態(tài)性與否。正態(tài)分布的定量資料采用x±s表示,組間比較采用兩獨立樣本t檢驗或者ANOVA方差分析；非正態(tài)分布的資料采用中位數(shù)及四分位間距表示,組間比較采用Mann-Whitney U檢驗。計數(shù)資料以百分?jǐn)?shù)表示,組間比較采用x2檢驗及趨勢分析。采用Pearson相關(guān)分析分析betatrophin與各代謝指標(biāo)的相關(guān)性。以P0.05為差異有統(tǒng)計學(xué)意義。采用人工受試者曲線分析血清betatrophin濃度對2型糖尿病的預(yù)測作用。采用Youden指數(shù)評估最佳切點,Youden指數(shù)的計算公式為：特異性+敏感性-1結(jié)果：第一節(jié)兩組患者的一般臨床資料對比本研究共納入131例研究對象,2型糖尿病患者73例以及年齡、性別、BMI匹配的非糖尿病對照組58例。兩組患者在年齡、性別、BMI、WHR、TG、LDL-C、 ALT.AST水平上均沒有顯著差異(P0.05)。2型糖尿病組患者血清betatrophin濃度是對照組患者的1.8倍(中位數(shù)：747.12pg/ml vs.407.41pg/ml,P0.001).第二節(jié)各亞組血清betatrophin濃度的表達(dá)情況2.1按照BMI指數(shù)將T2DM組、對照組各分為正常體重、超重和肥胖三個亞組：結(jié)果顯示對照組中超重和肥胖患者血清betatrophin濃度顯著高于正常體重者(中位數(shù)：肥胖的對照組vs.超重的對照組vs.正常體重的對照組：592.02pg/ml vs.501.57pg/ml vs.155.39 pg/ml, P0.05),而T2DM組患者中僅肥胖患者betatrophin濃度升高(1003.28pg/ml)。肥胖的T2DM組患者血清betarophin濃度是對照組中正常體重者的6.5倍(中位數(shù)：肥胖的糖尿病患者vs.正常體重的非糖尿病患者：1003.28 pg/ml vs.155.29 pg/ml, P0.001)。2.2按照腰圍水平將T2DM組、對照組各分為腹型肥胖和非腹型肥胖兩個亞組：結(jié)果顯示腹型肥胖組患者血清betatrophin濃度顯著高于非腹型肥胖組(中位數(shù)：腹型肥胖的糖尿病組vs.非腹型肥胖的糖尿病組vs.腹型肥胖的對照組vs.非腹型肥胖的對照組：1014.89pg/ml vs.551.17pg/ml vs.658.30 pg/ml vs.321.31pg/ml, P0.05)。腹型肥胖的糖尿病患者血清betarophin濃度是非腹型肥胖對照組患者的3.2倍(中位數(shù)：腹型肥胖的糖尿病組vs.非腹型肥胖的對照組：1014.89pg/ml vs.321.31pg/ml, P0.001)。第三節(jié)血清betatrophin濃度與各代謝指標(biāo)的相關(guān)性3.1血清betatrophin濃度與血糖水平的相關(guān)性：對兩組患者血清betatrophin濃度與各代謝指標(biāo)行雙變量相關(guān)分析,結(jié)果提示對照組患者血清betatrophin濃度與FPG水平正相關(guān)(P0.05)；而在T2DM組中,betatrophin濃度與FPG沒有相關(guān)性(P0.05)。3.2血清betatrophin濃度與血脂水平的相關(guān)性：雙變量相關(guān)分析顯示,血清betatrophin濃度與TG、TC以及LDL-C水平無顯著相關(guān)性(P0.05),與HDL-C水平呈負(fù)相關(guān)(P0.05),按照BMI水平分為6個亞組后,血清betatrophin濃度均與HDL-C水平呈負(fù)相關(guān)(P0.05)。3.3血清betatrophin濃度與其他各代謝指標(biāo)的相關(guān)性：雙變量相關(guān)分析顯示,對照組患者血清betatrophin濃度與WHR、FINs、C肽、HOMA-IR以及UA水平正相關(guān),與QUICKI負(fù)相關(guān)(P0.05)；而在T2DM組中,betatrophin濃度僅與年齡呈現(xiàn)出相關(guān)性(P0.05)。第四節(jié)血清betatrophin濃度對2型糖尿病的預(yù)測作用采用ROC曲線評估血清betatrophin濃度對T2DM的預(yù)測作用。結(jié)果顯示預(yù)測T2DM的血清betatrophin濃度最佳切點是501.23pg/ml,曲線下面積為0.82(95%CI,0.748-0.885,P0.001),敏感性為83.56%,特異性為72.41%。結(jié)論：我們的橫斷面調(diào)查顯示,相較于年齡、性別以及BMI匹配的對照組,2型糖尿病和肥胖患者體內(nèi)血清betatrophin濃度顯著上升。相比對照組,新診斷的2型糖尿病患者血清betatrophin濃度上升1.8倍,而肥胖的2型糖尿病患者其濃度是正常體重的對照組的6.5倍,腹型肥胖的2型糖尿病患者血清betarophin濃度是非腹型肥胖對照組患者的3.2倍。與此同時我們的研究首次發(fā)現(xiàn)健康人群以及2型糖尿病患者體內(nèi)HDL-C水平與betatrophin呈負(fù)相關(guān)。通過ROC曲線分析,我們進一步發(fā)現(xiàn)betatrophin或可作為預(yù)測2型糖尿病的一個生化指標(biāo),其最佳切點為501.23pg/ml。鑒于目前已有的關(guān)于betatrophin在人體及動物實驗的研究結(jié)果,結(jié)合本研究結(jié)果,認(rèn)為中國新診斷的2型糖尿病患者血清betatrophin濃度升高；同時在新診斷的2型糖尿病以及健康人群中血清betatrophin與HDL-C水平呈負(fù)相關(guān)；另外,在中國人群中betatrophin或可作為預(yù)測2型糖尿病的一個生化指標(biāo)。
[Abstract]:BACKGROUND & OBJECTIVE: The prevalence of diabetes mellitus is increasing year by year, and it has become one of the most important chronic diseases threatening human health. According to IDF statistics, the total number of diabetes mellitus cases worldwide in 2011 will reach 366 million, and it is expected to increase to 552 million by 2030 (the prevalence rate is 7.7%). Among them, the latest epidemic is in Asia. Investigation shows that the prevalence of adult diabetes mellitus in China has reached 11.6%, and the total number of diabetic patients has reached 114 million, ranking the first in the world. Type 2 diabetes accounts for 90% of the total number of diabetes mellitus, mainly manifested by impaired pancreatic P-cell function and insulin resistance. Diabetes mellitus patients with hyperglycemia can not repair or replenish damaged islet mu cells, fundamentally delaying the progress of the disease. Repairing damaged islet mu cells, increasing the number of islet P cells, improving insulin resistance, become an ideal way to treat diabetes mellitus. Betatrophin, an endocrine protein consisting of 193 amino acids, is highly expressed in the liver of a mouse model of severe insulin resistance induced by insulin receptor antagonist S961. In vivo and in a dose-dependent manner, it can promote the proliferation of mouse pancreatic islet P cells. Because it can promote the proliferation of pancreatic islet P cells and participate in the regulation of blood lipids and other different roles, they were named as: betatrophin, ANGPTL8, RIFL and Lipasin. Some clinical studies have found that the circulating serum betatrophin levels in patients with diabetes, insulin resistance, and dyslipidemia vary with race and population; at the same time, some basic studies have found that betatrophin does not stimulate in vitro culture. As a newly discovered pro-metabolic factor, betatrophin expression in newly diagnosed Chinese type 2 diabetes mellitus has not been elucidated. The relationship between betatrophin concentration in circulating serum and blood glucose, blood lipids, insulin resistance and metabolic parameters is not clear. Whether etatrophin can be used as a biochemical marker for predicting type 2 diabetes mellitus is an urgent problem. In view of this, this study explored the relationship between betatrophin concentration in circulating serum and metabolic markers in newly diagnosed type 2 diabetes mellitus and non-diabetic people, in order to seek betatrophin and type 2 diabetes mellitus, insulin. Methods: A total of 131 subjects were included in this study, including 73 newly diagnosed type 2 diabetes mellitus patients, 38 males and 35 females, all from Guangdong Province. In addition, 58 non-diabetic subjects (31 males and 27 females) were selected as controls according to age, sex and body mass index (BMI) matching. They all came from the physical examination center of the North (?) Hospital of Southern Medical University at the same time. Urinary disease group and control group were divided into normal body weight (BMI 24kg/m2), overweight (24kg/m2 < BMI 28kg/m2) and obesity (BMI < 28kg/m2). Exclusion: 1) Type 2 diabetes mellitus (T2DM) patients who were receiving oral hypoglycemic therapy and complicated with macrovascular disease were taking drugs that may affect blood glucose and blood lipids within 1 month; Patients with viral hepatitis, liver failure, tumors, severe mental disorders, chronic renal insufficiency undergoing hemodialysis, congestive heart failure, and other serious diseases. The project met the ethical standards of the Helsinki Declaration and was approved by the Pearl River Hospital Ethics Committee. Physical examination and questionnaires were used to collect general demographic data, including current, past, family and medication history. Each subject was asked whether he had a history of stable or unstable angina and myocardial infarction in the past six months. History of seizure, stroke, or other cerebrovascular accident to exclude unqualified patients; history of smoking (daily smoking, duration), drinking (daily drinking, duration), hypertension, and history of dyslipidemia; history of past medication; body movements of each subject by uniformly trained medical staff The body weight, height, blood pressure, waist circumference, hip circumference and heart rate were recorded. Blood samples of anterior cubital vein were collected from all subjects on an empty stomach (fasting for 12 hours) in the morning. Serum was separated by centrifuge (2000-3000 rpm, 20 min). After natural coagulation for 10-20 min, the serum was extracted into EP tube and numbered. The fasting blood glucose (FPG), insulin (FINs), C-peptide, total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), urea nitrogen (BUN), creatinine (Cr), alanine aminotransferase (ALT), glutamic oxaloacetyltransferase (AST) and uric acid (UA) levels were measured in each subject. The homeostasis model insulin resistance index (HOMA-IR), homeostasis model insulin secretion index (HOMA-% p) and quantitative insulin sensitivity index (QUICKI) were used to evaluate the function of beta cells. 20 * Insulin / (blood glucose - 3.5); QUICKI index = 1 /[log (FINs) L + log (FPG)] (FINs unit using mu U / ml, FPG unit using mg / dl). Serum Betatrophin concentration was determined by ELISA kit produced by Wuhan Yiebo Technology Co., Ltd. (Wuhan, China, product batch No. E11644h), and repeated strictly according to the instructions of the manual for each blood sample. Samples with a variation index greater than 15% were measured twice and discarded. At 450 nm wavelength, the spectrophotometric value (OD) of each sample was detected by ELISA, and the final OD value was calculated by averaging the OD value of each sample twice. Statistical analysis was carried out by SPSS 20.0 software. K-S test was used to test the normality of data. Quantitative data of normal distribution were expressed by X + s. Intergroup comparisons were performed by two independent samples t-test or ANOVA analysis of variance. Data of non-normal distribution were expressed by median and quartile spacing. Intergroup comparisons were performed by Ma. Nn-Whitney U test. Counting data were expressed as percentage. Comparison between groups was performed by x2 test and trend analysis. Pearson correlation analysis was used to analyze the correlation between betatrophin and metabolic indices. The difference was statistically significant (P 0.05). The best cut-off point of en index was evaluated by Youden index. The formula of Youden index was: specificity + sensitivity - 1 Results: Section 1 Comparison of general clinical data between the two groups. This study included 131 subjects, 73 patients with type 2 diabetes mellitus and 58 non-diabetic controls matched by age, sex, and BMI. There was no significant difference in the levels of DL-C and ALT-AST (P 0.05). The serum betatrophin levels in type 2 diabetes mellitus patients were 1.8 times higher than those in control group (median: 747.12 pg/ml vs. 407.41 pg/ml, P 0.001). The expression of betatrophin serum in each subgroup in Section 2.1 was divided into normal weight, overweight and fat groups according to BMI index. The results showed that the serum betatrophin levels in overweight and obese patients in the control group were significantly higher than those in the normal weight group (median: obese vs. overweight vs. normal weight vs. 592.02 pg/ml vs. 501.57 pg/ml vs. 155.39 pg/ml, P 0.05), whereas in the T2DM group, only obese patients had betatrophin concentrations. The serum betarophin level in obese T2DM group was 6.5 times higher than that in normal weight control group (median: obese diabetes vs. normal weight non-diabetic: 1003.28 pg / ml vs. 155.29 pg / ml, P 0.001). 2.2 According to waist circumference level, T2DM group was divided into abdominal obesity and non-abdominal obesity groups. Two subgroups: the results showed that the serum betatrophin concentration in abdominal obesity group was significantly higher than that in non-abdominal obesity group (median: abdominal obesity group vs. non-abdominal obesity group vs. abdominal obesity control group vs. non-abdominal obesity control group vs. 1014.89pg/ml vs. 551.17pg/ml vs. 658.30 pg/ml vs. 321.31pg/ml, P 0.05). (Median: abdominal obesity vs. abdominal obesity vs. non-abdominal obesity vs. 321.31pg/ml, P 0.001). Section 3. Correlation between serum betatrophin concentration and metabolic parameters Correlation between serum betatrophin level and serum FPG level: Bivariate correlation analysis between betatrophin concentration and metabolic parameters in two groups showed that there was a positive correlation between betatrophin concentration and serum FPG level in control group (P 0.05), while there was no correlation between betatrophin concentration and FPG level in T2DM group (P 0.05). Correlation: Bivariate correlation analysis showed that serum betatrophin levels were not significantly correlated with TG, TC and LDL-C levels (P 0.05), but negatively correlated with HDL-C levels (P 0.05). After divided into six subgroups according to BMI levels, serum betatrophin levels were negatively correlated with HDL-C levels (P 0.05). 3.3 Serum betatrophin levels were negatively correlated with other metabolic parameters. Sex: Bivariate correlation analysis showed that the serum betatrophin concentration in the control group was positively correlated with WHR, FINs, C peptide, HOMA-IR and UA levels, and negatively correlated with QUICKI (P 0.05); in the T2DM group, betatrophin concentration was only correlated with age (P 0.05). The best cut-off point for predicting serum betatrophin concentration was 501.23 pg/ml, the area under the curve was 0.82 (95% CI, 0.748-0.885, P 0.001), the sensitivity was 83.56%, and the specificity was 72.41%. Conclusion: Our cross-sectional study showed that the betatrophin concentration was more sensitive than that of age, sex and BMI matched pairs. Serum betatrophin levels in newly diagnosed type 2 diabetes mellitus were 1.8 times higher than those in the control group, while those in obese type 2 diabetes mellitus were 6.5 times higher than those in normal weight, and those in abdominal obese type 2 diabetes mellitus were not. At the same time, our study found for the first time that there was a negative correlation between HDL-C levels and betatrophin in healthy people and type 2 diabetes mellitus. Through ROC curve analysis, we further found that betatrophin may be a biochemical marker for predicting type 2 diabetes mellitus. The best cut-off point was 501.23 pg/ml. Based on the results of the existing studies on betatrophin in human and animal, it is concluded that the serum betatrophin levels in newly diagnosed type 2 diabetes mellitus patients in China are elevated, and the serum betatrophin levels in newly diagnosed type 2 diabetes mellitus patients and healthy people are negatively correlated with HDL-C levels. Etatrophin can be used as a biochemical marker for predicting type 2 diabetes mellitus.
【學(xué)位授予單位】：南方醫(yī)科大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2016
【分類號】：R587.1

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