【摘要】：成人遲發(fā)型自身免疫性糖尿病(latent autoimmune diabetes in adults,LADA)是成人自身免疫性糖尿病的一個亞型,起病初期其臨床特點與2型糖尿病極其相似,很難與2型糖尿病鑒別。但隨著病程進(jìn)展,胰島β細(xì)胞功能衰竭速度較2型糖尿病快,表現(xiàn)與2型糖尿病不同的臨床特點。同時,LADA臨床特點又不同于青少年起病的經(jīng)典1型糖尿病。目前,國內(nèi)對LADA慢性并發(fā)癥的患病特點及其危險因素的研究報道較少。尚缺乏對LADA慢性并發(fā)癥發(fā)生的有效預(yù)測模型。盡管目前關(guān)于LADA病生理機制研究較多,但關(guān)于LADA胰腺形態(tài)的變化特點及其與臨床特點之間的關(guān)系,特別是胰腺體積對LADA胰島β細(xì)胞功能的評估作用目前尚缺乏相關(guān)研究報道。第一部分LADA與2型糖尿病臨床特點與慢性并發(fā)癥關(guān)系的研究目的比較LADA和2型糖尿病兩組患者臨床特點、慢性并發(fā)癥異同點。并進(jìn)一步分析兩組患者慢性并發(fā)癥的危險因素,構(gòu)建慢性并發(fā)癥發(fā)生的預(yù)測模型。研究對象和方法本研究為橫斷面研究,收集了近10年來我科住院的成人起病的(糖尿病診斷年齡:30~75歲)并進(jìn)行了胰島相關(guān)抗體檢測的表型為2型糖尿病的6,975例住院患者資料。我們根據(jù)相同年齡、同性別、相同病程將LADA患者與2型糖尿病患者進(jìn)行1:2匹配,并比較LADA和2型糖尿病患者臨床特點和慢性并發(fā)癥特點的異同點。并進(jìn)一步采用臨床指標(biāo),包括包括性別、年齡、糖尿病病程、血糖控制水平(Hb A1c≥9.0%)、高血壓病、高甘油三脂血癥、低高密度脂蛋白膽固醇血脂以及BMI為自變量,各慢性并發(fā)癥為因變量,擬合logistic回歸方程,構(gòu)建糖尿病慢性并發(fā)癥發(fā)生的預(yù)測模型,并繪制ROC曲線。結(jié)果384例(5.5%)患者被確診為LADA。與2型糖尿病患者比較,LADA患者有較低的空腹C肽水平(1.77 ng/ml vs.1.18 ng/ml,P0.001),較低水平的收縮壓、舒張壓、BMI、TG和較高水平的HDL-C(P0.05)。此外,LADA患者代謝綜合征及其組分的患病率顯著低于2型糖尿病患者。當(dāng)糖尿病病程5年時,LADA患者較2型糖尿病者有更低的糖尿病白蛋白尿(12.2%vs.21.8%,P=0.018)和糖尿病視網(wǎng)膜病變患病率(8.1%vs.15.9%,P=0.011);當(dāng)病程≥5年時,兩組患者上述慢性微血管并發(fā)癥的患病率無顯著差異。同時,觀察到LADA患者中這兩種微血管并發(fā)癥患病率隨病程延長呈快速增長趨勢。LADA和2型糖尿病患者的大血管并發(fā)癥(頸動脈斑塊)患病率無顯著差異。在糖尿病白蛋白尿和糖尿病視網(wǎng)膜病變預(yù)測模型中,LADA的ROC曲線下面積顯著大于2型糖尿病(糖尿病白蛋白尿模型:0.75 vs.0.67,P=0.080;糖尿病視網(wǎng)膜病變模型:0.80 vs.0.69,P=0.018)。但在糖尿病大血管預(yù)測模型中,LADA和2型糖尿病ROC曲線下面積相似(P0.05)。結(jié)論與2型糖尿病患者比較,LADA患者代謝綜合征及其相關(guān)組分的患病率均較低,但胰島功能較差。當(dāng)病程5年,LADA患者較2型糖尿病患者有較低的白蛋白尿和糖尿病視網(wǎng)膜病變的患病率,相似的大血管病變患病率;當(dāng)病程≥5年,兩組患者微血管和大血管并發(fā)癥患病率均相似。此外,臨床特點對LADA白蛋白尿和視網(wǎng)膜病變的預(yù)測效能優(yōu)于2型糖尿病。第二部分BMI與LADA和2型糖尿病視網(wǎng)膜病變之間的關(guān)系目的探討我國LADA和2型糖尿病患者中體質(zhì)指數(shù)(body mass index,BMI)與糖尿病視網(wǎng)膜病變之間的關(guān)系及其可能機制。研究對象和方法共計有316例LADA患者和2,533例2型糖尿病患者納入研究。所有的患者均進(jìn)行了雙側(cè)眼底免散瞳攝片并由專業(yè)眼科醫(yī)師讀片。糖尿病視網(wǎng)膜病變根據(jù)其嚴(yán)重程度分為以下3個等級:無眼底病變(non-DR),輕中度視網(wǎng)膜病變(DRI~II期),和影響視力的視網(wǎng)膜病變(DR III~IV期);任何程度糖尿病視網(wǎng)膜病變包括DR I~IV期。體質(zhì)指數(shù)(kg/m2)分為3類:正常體重(18.5≤BMI25),超重(25≤BMI30),和肥胖(BMI≥30)。BMI18.5 kg/m2患者未納入本研究。結(jié)果共計有69例LADA患者(21.8%)和701例(27.7%)2型糖尿病患者伴發(fā)糖尿病視網(wǎng)膜病變。LADA患者中,與無視網(wǎng)膜病變的患者比較,合并糖尿病視網(wǎng)膜病變者其BMI無顯著性差異(23.0 kg/m2 vs.22.8 kg/m2,P=0.211),但腰圍水平略高(85 cm vs.84 cm,P=0.024)。多因素logistic回歸分析提示超重/肥胖及腹型肥胖與糖尿病視網(wǎng)膜病變之間無顯著相關(guān)性(P0.05)。在2型糖尿病患者中,伴有糖尿病視網(wǎng)膜病變的患者較無視網(wǎng)膜病變者有較低的BMI(24.3 kg/m2vs.24.9 kg/m2,P=0.001)和空腹C肽水平(1.46 ng/ml vs.1.86 ng/ml,P0.001)。將BMI按2 kg/m2進(jìn)行分組,計算各組糖尿病視網(wǎng)膜病變的比值比(odds ratio,OR),數(shù)據(jù)顯示BMI和糖尿病視網(wǎng)膜病變之間呈U型關(guān)系;當(dāng)BMI在28-29.9 kg/m2區(qū)間時,患者有最低的糖尿病視網(wǎng)膜病變患病風(fēng)險。而將BMI按正常、超重和肥胖進(jìn)行分組,數(shù)據(jù)顯示:校正性別、糖尿病診斷年齡和病程,超重患者較正常體重者有更低的任何程度的糖尿病視網(wǎng)膜病變(OR=0.73)、DR I-II(OR=0.76)、DR III-IV(OR=0.64)患病風(fēng)險(模型1)。但進(jìn)一步校正其它混雜因素如吸煙、飲酒、平均血壓、TC、HDL-C、胰島素治療(模型2)以及進(jìn)一步校正空腹C肽(模型3)后,兩者的關(guān)聯(lián)強度減弱甚至消失。此外,按照空腹C肽三分位數(shù)進(jìn)行分層后分析發(fā)現(xiàn),不同BMI類別的患者糖尿病視網(wǎng)膜病變患病風(fēng)險相似。結(jié)論在LADA患者中,BMI與糖尿病視網(wǎng)膜病變之間無顯著關(guān)系。在2型糖尿病患者中,超重患者較正常體重者有較低的糖尿病視網(wǎng)膜病變患病風(fēng)險;但肥胖患者糖尿病視網(wǎng)膜病變發(fā)生風(fēng)險與正常體重者相似。較好的胰島功能可能是超重患者有較低糖尿病視網(wǎng)膜病變患病風(fēng)險的主要原因。第三部分:LADA和2型糖尿病患者胰腺體積的比較及其臨床意義目的比較不同類型糖尿病患者胰腺體積的變化特點,考察胰腺體積大小對不同類型糖尿病患者胰島β細(xì)胞功能的預(yù)測價值。研究對象和方法2013年5月~2013年7月對門診70例LADA患者和66例1型糖尿病患者完成隨訪。同時,選取89例我院內(nèi)分泌科住院2型糖尿病患者和106例其它科室住院的血糖正常的患者作為正常對照組。上述患者均進(jìn)行了上腹部CT檢查,并排除惡性腫瘤和急慢性胰腺炎等疾病。使用西門子Virtuoso工作平臺繪制胰腺輪廓,并計算每個層面面積(cm2)。胰腺體積即為每個層面面積之和乘以層距(5cm)。本研究采用空腹C肽(FCP)評估胰島功能,FCP≤0.9ng/ml被定義為絕對胰島素不足。在LADA患者中,以絕對胰島素不足為因變量,胰腺體積為自變量擬合回歸方程,繪制ROC曲線并計算ROC曲線下面積(AUC),構(gòu)建絕對胰島素不足的預(yù)測模型。結(jié)果不同類型糖尿病患者的胰腺體積均顯著小于正常對照組(P0.05)。胰腺體積從大到小依次為正常對照組(64.8 cm3)、LADA(56.2 cm3)和2型糖尿病患者(54.3 cm3)、以及1型糖尿病(44.1 cm3)。LADA和2型糖尿病患者胰腺體積大小相似,但均顯著大于1型糖尿病(P0.05)。在三個糖尿病亞組中,胰腺體積與性別、BMI、腰圍和體表面積顯著相關(guān)(P0.05)。在LADA和2型糖尿病患者中胰腺體積和空腹C肽水平呈中度相關(guān),其偏相關(guān)系數(shù)分別為0.624(P0.001)和0.449(P0.001)。ROC曲線下面積為多變量回歸分析顯示,胰腺體積與LADA患者絕對胰島素不足呈獨立顯著相關(guān)。ROC曲線下面積為0.82(0.72-0.92,P0.001)。根據(jù)最大約登指數(shù)(Maximum Youden index)原則,胰腺體積的最佳切點為51cm3,其相應(yīng)的靈敏度和特異度分別為81%和70%。結(jié)論與正常對照組比較,不同類型糖尿病的胰腺體積均顯著降低:LADA和2型糖尿病患者胰腺體積無顯著性差異,但均大于1型糖尿病患者。在LADA和2型糖尿病中,胰腺體積與性別、BMI、體表面積、腰圍和空腹C肽等臨床指標(biāo)呈中度相關(guān)。胰腺體積能較好地評估LADA患者胰島β細(xì)胞功能。
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圖片說明：患者納入流程圖
[Abstract]:Adult delayed-type autoimmune diabetes (LADA) is a subtype of autoimmune diabetes, and its clinical characteristics are very similar to type 2 diabetes, and it is difficult to identify with type 2 diabetes. However, with the progress of the course of the disease, the rate of pancreatic islet cell failure is faster than that of type 2 diabetes, and it is different from type 2 diabetes. At the same time, the clinical characteristic of LADA is different from that of the classic type 1 diabetes. At present, there are few studies on the characteristics and risk factors of the chronic complications of LADA in China. An effective prediction model for the occurrence of chronic complications of LADA is still lacking. Although there are many studies on the physiological mechanism of the LADA, the relationship between the changes of the form of the LADA pancreas and its relationship with the clinical features, in particular the pancreatic volume, has not yet been reported on the evaluation of the function of the LADA pancreatic islet cell. The study of the relationship between the clinical characteristics of the first part of the LADA and the type 2 diabetes and the chronic complication is to compare the clinical characteristics of the two groups of patients with type 2 diabetes and the similarities and differences of the chronic complications. The risk factors of chronic complications of the two groups were further analyzed, and the prediction model of the occurrence of chronic complications was constructed. The subject and method of the study were cross-sectional study, and the data of the 6 and 975 hospitalized patients with type 2 diabetes were collected from the adult onset (diabetes diagnosis age:30-75 years) in the family in the last 10 years and the detection of the islet-related antibodies was performed. We matched 1:2 of LADA patients with type 2 diabetic patients according to the same age, gender and the same course of course, and compared the clinical features and the characteristics of chronic complications between the patients with LADA and type 2 diabetes. and further adopts the clinical indexes, including the sex, the age, the course of diabetes, the blood sugar control level (Hb, the rate of 9.0%), the hypertension, the hypertriglyceridemia, the low-density lipoprotein cholesterol blood fat and the BMI as the independent variable, and each chronic complication is the dependent variable, A logistic regression equation was fitted to construct a predictive model for the occurrence of chronic complications of diabetes, and the ROC curve was drawn. Results 384 (5.5%) patients were diagnosed as LADA. Compared with type 2 diabetes, LADA patients had lower fasting C-peptide levels (1.77 ng/ ml vs. 1.18 ng/ ml, P0.001), lower levels of systolic blood pressure, diastolic blood pressure, BMI, TG and higher levels of HDL-C (P0.05). In addition, the prevalence of metabolic syndrome and its components in patients with LADA is significantly lower than that of type 2 diabetes. The prevalence of diabetic retinopathy (12.2% vs. 21.8%, P = 0.018) and the prevalence of diabetic retinopathy (8.1% vs. 15.9%, P = 0.011) and the prevalence of diabetic retinopathy (8.1% vs. 15.9%, P = 0.011) were found in patients with type 2 diabetes in the course of diabetes. At the same time, the prevalence of these two microvascular complications in patients with LADA increased rapidly with the course of the course of the disease. There was no significant difference in the prevalence of major vascular complications (carotid plaque) in patients with type 2 diabetes. In the model of diabetic albuminuria and diabetic retinopathy, the area of the ROC curve of LADA was significantly greater than type 2 diabetes (diabetic albuminuria model: 0.75 vs. 0.67, P = 0.080; diabetic retinopathy model: 0.80 vs. 0.69, P = 0.018). However, in the diabetic large-vessel prediction model, the area of the LADA and the 2-type diabetic ROC curve was similar (P0.05). Conclusion Compared with type 2 diabetes, the prevalence of metabolic syndrome and its related components in LADA is lower, but the function of pancreatic islet is poor. In the course of the course of the course of the course of the course of the course of the course of the course of the course of the course of the course of the course of the course of the course of the course of the course of the course of the course of the course of the course of the course of the course of the course of the course of the course of the course of the course of the course of the course of the course of the course of the course of the course of the course In addition, the clinical features are superior to type 2 diabetes in the prediction of LADA albuminuria and retinopathy. The relationship between body mass index (BMI) and diabetic retinopathy and the possible mechanism of body mass index (BMI) in patients with LADA and type 2 diabetes mellitus were discussed in this paper. A total of 316 LADA patients and 2,533 patients with type 2 diabetes were included in the study. All patients were subject to a bilateral eye-free mydriasis and read by a professional ophthalmologist. Diabetic retinopathy is divided into the following three levels according to their severity: non-fundus lesions (non-DR), mild-to-moderate retinopathy (DRI-II), and retinal lesions that affect vision (DR III-IV); and any degree of diabetic retinopathy including DR I to IV. The body mass index (kg/ m2) was divided into three groups: normal weight (18.5% BMI25), overweight (25% BMI30), and obesity (BMI-30). The BMI18.5 kg/ m2 patient was not included in this study. Results A total of 69 patients with LADA (21.8%) and 701 (27.7%) patients with type 2 diabetes were associated with diabetic retinopathy. In LADA patients, there was no significant difference in BMI between patients with diabetic retinopathy (23.0 kg/ m2 vs. 22.8 kg/ m2, P = 0.211) compared with those without retinopathy (P = 0.211), but the waist level was slightly higher (85 cm vs.84 cm, P = 0.024). Multivariate logistic regression analysis showed no significant correlation between overweight/ obesity and abdominal obesity and diabetic retinopathy (P0.05). In patients with type 2 diabetes, patients with diabetic retinopathy had lower BMI (24.3 kg/ m2vs. 24.9 kg/ m2, P = 0.001) and fasting C-peptide levels (1.46 ng/ ml vs. 1.86 ng/ ml, P0.001) in patients with diabetic retinopathy. The ratio of BMI was 2 kg/ m2 to calculate the ratio of the ratio of the diabetic retinopathy (OR), and the data showed a U-shaped relationship between the BMI and the diabetic retinopathy. When the BMI was in the range of 28-29.9 kg/ m2, the patient had the lowest risk of diabetic retinopathy. The BMI was grouped according to normal, overweight and obesity data showing that the risk of diabetic retinopathy (OR = 0.73), DR I-II (OR = 0.76), and DR III-IV (OR = 0.64) was associated with the risk of diabetic retinopathy (OR = 0.73), DR I-II (OR = 0.76), and DR III-IV (OR = 0.64) for overweight patients with a lower level of diabetic retinopathy (OR = 0.73), DR I-II (OR = 0.76), and DR III-IV (OR = 0.64). However, further correction of other confounding factors such as smoking, alcohol consumption, average blood pressure, TC, HDL-C, insulin therapy (model 2), and further correction of fasting C-peptide (model 3), the associated strength of both decreased or even disappeared. In addition, post-stratification analysis according to the three-digit number of fasting C-peptide found that the risk of diabetic retinopathy in patients with different BMI categories was similar. Conclusion There is no significant relationship between BMI and diabetic retinopathy in patients with LADA. In patients with type 2 diabetes, patients with overweight have a lower risk of diabetic retinopathy than those of normal body weight; however, the risk of diabetic retinopathy in obese patients is similar to those of normal body weight. The better islet function may be the main cause of the risk of low diabetic retinopathy in overweight patients. The third part: The comparison of the pancreatic volume of the patients with type 2 diabetes and the clinical significance of the changes in the volume of the pancreas in different types of diabetic patients, and the prediction value of the pancreatic volume size on the function of the pancreatic islet cells in different types of diabetes. The subjects and methods were followed up in 70 LADA patients and 66 patients with type 1 diabetes from May 2013 to July 2013. In the meantime,89 patients with type 2 diabetes in our hospital and 106 other patients with normal blood glucose were selected as the normal control group. The above-mentioned patients underwent upper abdominal CT examination and ruled out the diseases such as malignant tumor and acute and chronic pancreatitis. The pancreas profile was plotted using the Siemens Outoso working platform and the area of each layer (cm2) was calculated. The volume of the pancreas is the sum of the area of each layer multiplied by the layer distance (5 cm). The study used fasting C-peptide (FCP) to assess the islet function, and FCP-0.9 ng/ ml was defined as absolute insulin deficiency. In the LADA patients, the regression equation was fitted with the absolute insulin deficiency as the dependent variable and the volume of the pancreas as the independent variable, the ROC curve was drawn and the area under the ROC curve (AUC) was calculated, and the prediction model of absolute insulin deficiency was constructed. Results The volume of pancreas in patients with different type of diabetes was significantly lower than that of normal control group (P0.05). The volume of pancreas was from large to small in the normal control group (64.8 cm3), LADA (56.2 cm3) and type 2 diabetes (54.3 cm3), and type 1 diabetes (44.1 cm3). The size of the pancreas in the patients with type 2 diabetes was similar, but was significantly higher than that of type 1 diabetes (P0.05). In the three diabetic subgroups, the volume of pancreas was significantly related to sex, BMI, waist circumference and body surface area (P0.05). In the patients with type 2 diabetes, the volume of the pancreas and the level of fasting C-peptide were moderately correlated, the partial correlation coefficient was 0.624 (P0.001) and 0.449 (P0.001), and the area under the ROC curve was a multi-variable regression analysis, and the volume of the pancreas was significantly related to the absolute insulin deficiency in the patients with LADA. The area under the ROC curve was 0.82 (0.72-0.92, P0.001). The best point of tangency of the pancreatic volume is 51 cm3, and the corresponding sensitivity and specificity are 81% and 70%, respectively. Conclusion Compared with the normal control group, the volume of pancreas of different type of diabetes is significantly lower: there is no significant difference in the volume of pancreas in the patients with type 2 diabetes, but it is greater than that of type 1 diabetes. In LADA and type 2 diabetes, the volume of pancreas was moderately correlated with clinical indicators such as sex, BMI, body surface area, waist circumference, and fasting C-peptide. The pancreatic volume can be used to evaluate the function of pancreatic islet cell in LADA patients.
【學(xué)位授予單位】：上海交通大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2015
【分類號】：R587.2

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