第2型糖尿病患者血漿中YKL-40濃度與血管併發症之關聯性研究

Abstract

[研究背景] 糖尿病的大、小血管併發症，包括視網膜病變、腎病變、腦中風、週邊動脈阻塞疾病、神經病變及冠狀動脈心臟病等，均會對糖尿病患者造成重大影響。而就目前所知，第2型糖尿病本身，及其血管併發症的發生，可能都與人體內之慢性發炎狀態有關。YKL-40 為一40kD的凝集素(lectin)分子，會在各種急性或慢性發炎情況下上升。各個研究顯示：在第2型糖尿病患者血液中，YKL-40濃度較非糖尿病之對照組為高；並且，在第1型及第2型糖尿病患者的身上，血液中的YKL-40濃度與患者白蛋白尿的嚴重度亦呈現一正相關性。 本研究的目的，在於檢視第2型糖尿病患者血液內YKL-40濃度，與各項併發症，以及死亡率間之關係；並進一步評估其作為預後指標之潛力。 [方法] 本試驗的研究世代來自於先前對代謝疾病功能基因體及蛋白體學研究的參加者，收案期間自1996年7月至2003年6月，共包括232名男性及241名女性。參加者的平均年齡為61.71 9.67歲。臨床測量數據及生化檢驗結果來自收案時測量的數據。血漿中的YKL-40濃度則利用市售之ELISA套件進行測量。於測量前，血漿樣本均儲存於-80℃的環境中。整個研究世代追蹤至2008年12月31日為止，並記錄其生存狀態。參加者並根據YKL-40濃度的四分位數，分為四組（Q1: 11.29-52.92 ng/dl; Q2: 53.40-87.02 ng/dl; Q3: 87.20-150.71 ng/dl, and Q4: 151.69-417.35 ng/dl）。 [結果] 於四分組中，蛋白尿的盛行率分別為10.62%、16.24%、16.38%及32.48%（p<0.01）。在調整可能的混淆變項後，Q4組發生蛋白尿的勝算比為Q1組的2.63倍（95% CI: 1.00-6.28, p<0.05）。四分組的死亡率分別為12.61%、13.56%、29.66%及40.68%（p<0.01）。在調整可能的混淆變項後，Q4組的總死亡風險為Q1組之2.03倍（95% CI: 1.07-3.84, p<0.05）。而在先前沒有心血管疾病病史的受試者中，其血漿中YKL-40濃度高於中位數者(86.49 ng/dl)，其因心血管疾病死亡的風險，為血漿中YKL-40濃度低於中位數者之3.45 (95% CI: 1.28-9.30, p<0.05)倍。 [結論] 與此一研究中，我們發現到了，當第2型糖尿病患者血漿內的YKL-40濃度越高，其蛋白尿、因所有原因或心血管疾病死亡的風險就越高。因此，後續的研究，應專注於YKL-40在糖尿病內皮功能失調的致病機轉角色上。

Background Various micro- and macro-vascular diabetic complications cause major impacts on patients with diabetes. Plasma YKL-40 concentration had been found to correlate with severity of albuminuria in type 1 and type 2 diabetic patients. In this study, we evaluated the association among plasma concentration of YKL-40, PAOD, proteinuria and mortality in type 2 diabetic patients. Methods The study cohort consisted of 232 male and 241 female type 2 diabetic patients who participated in previous study of functional genomic and proteomics in metabolic disorders from July, 1996 to June, 2003. The mean age was 61.71 9.67 years old Presence of proteinuria was determined by semi-quantitative Multistix test. Presence of peripheral arterial occlusive disease (PAOD) was determined by Ankle-brachial index (ABI). The plasma YKL-40 level was measured by a commercial ELISA assay with samples stored at -80℃. The cohort was followed subsequently till December 31st, 2008 with the vital status recorded. The participants were divided into 4 subgroups according to plasma YKL-40 quartile (Q1: 11.29-52.92 ng/dl; Q2: 53.40-87.02 ng/dl; Q3: 87.20-150.71 ng/dl, and Q4: 151.69-417.35 ng/dl). Results The prevalence of proteinuria in Q1 to Q4 were 10.62%, 16.24%, 16.38% and 32.48%, respectively (p<0.01). After adjusting possible confounding variables, the odds ratio of proteinuria for Q4 group was 2.63 (95% CI: 1.10-6.28, p<0.05) compared with Q1 group. The mortality rate of quartile groups were 12.61%, 13.56%, 29.66% and 40.68%, respectively (p<0.01). After adjusting possible confounding variables, the hazard ratio (HR) of all-cause mortality in Q4 group was 2.03 fold (95% CI: 1.07-3.84, p<0.05) higher compared with Q1 group. In subgroup analysis without history of previous admission due to cardiovascular diseases (CVDs), the HR for CVD-specific mortality in those YKL-40 above median (86.49 ng/dl) was 3.45 fold (95% CI 1.28-9.30, p<0.05) higher compared with those YKL-40 below median. Conclusion In our study, we demonstrated that elevation of plasma YKL-40 level in type 2 diabetic patients was correlated with increased risk of proteinuria, all-cause and CVD-specific mortality. Further study should focus on the pathological role of YKL-40 in diabetic endothelial dysfunction.