- 學位論文
第2型糖尿病病人尿酸與retinol binding protein 4和high sensitivity c-reactive protein的相關性
The association of uric acid with retinol binding protein 4 and high sensitivity c-reactive protein in type 2 diabetic patients
摘要
研究背景:近來有一種由脂肪細胞分泌的激素稱作retinol binding protein 4 (RBP4)被指出與胰島素抗性有關，而在糖尿病病人白蛋白尿的出現以及尿酸指數的上升也被指出與胰島素抗性相關。因此我們就針對出現不同程度白蛋白尿的糖尿病病人來探討RBP4、尿酸與白蛋白尿的嚴重程度之間的相關係。另外high sensitivity c-reactive protein (hs-CRP)和尿酸也和不同的血管疾病有相關性，但是在糖尿病病人其尿酸與hs-CRP的相關性仍不清楚，特別是糖尿病病人大多使用可能會干擾hs-CRP的數值的多種藥物。因此我們也針對了也服用多種藥物治療糖尿病病病人探討尿酸與hs-CRP的關係。 研究方法:共有95位糖尿病病人與16位正常受試者加入了與RBP4的相關研究。糖尿病病人依據白蛋白尿嚴重程度分成正常白蛋白尿、微量白蛋白尿及巨量白蛋白尿三組，觀察RBP4在不同的白蛋白尿期是否不同。我們同時也針對RBP4做了多變數分析，以決定會影響RBP4的決定因子。我們也在846位糖尿病病人測量其hs-CRP與相關其它的危險因子。在這846位糖尿病病人也依據尿酸濃度的高低分成三組來評估在不同的尿酸濃度下其hs-CRP的數值高低。我們也針對hs-CRP做了多變數分析，來決定那一個變數是hs-CRP的重要決定因子。 結果:不管是正常白蛋白尿的糖尿病病人(43.4 ± 14.9 μg/mL)、微量白蛋白尿的糖尿病病人(57.3 ± 24.2 μg/mL)或是巨量白蛋白尿的糖尿病病人(64.7 ± 27.6 μg/mL)，其血中的RBP4濃度都比正常人(32.6 ± 10.0 μg/mL)來的高。而且在微量白蛋白尿的糖尿病病人或是巨量白蛋白尿的糖尿病病人其血中的RBP4濃度也比正常白蛋白尿的糖尿病病人來得高。在單變數分析中，血中的RBP4與三酸甘油脂、尿酸與白蛋白尿有正相關；低密度脂蛋白膽固醇及腎絲球過濾率則與RBP4有負相關。在多變數分析之後僅留下尿酸與腎絲球過濾率有獨立相關性。而在第二個研究中，我們將846位糖尿病病人依尿酸濃度分成三組。其三組平均尿酸濃度分別為4.17 mg/dL; 5.46mg/dL和6.97 mg/dL。而且我們發現在第二組及第三組其hs-CRP濃度比第一組要來得高。多變數分析後指出尿酸是hs-CRP的獨立因子，其它的包括了女性、身體質量指數、三酸甘油脂、糖化血色素、胰島素抗性和抽煙都和hs-CRP正向獨立相關。而藥物(如: ACEI/ARB、pioglitazone和statins)呈現負性相關。 討論: 我們發現尿酸是決定RBP4與hs-CRP血中濃度的重要因子。這支持高尿酸會與高胰島素抗性相關疾病和高的身體發炎狀況相關。而我們的研究也指出腎功能清除率會影響血中RBP4的濃度。至於下降血中尿酸濃度是否可以改善第2 型糖尿病胰島素抗性或發炎狀況可能就需要更進一歩的研究才能證實。
並列摘要
BACKGROUND: While some studies reported that retinol-binding protein 4 (RBP4) might induce insulin resistance, other studies demonstrated that the presence of albuminuria and increased uric acid are related to insulin resistance in diabetic patients. Therefore, in first study, we attempted to investigate the relationship between serum RBP4, serum uric acid, and the severity of nephropathy in diabetic patients. In addition, both high-sensitivity c-reactive protein (hs-CRP) and serum uric acid are linked with vascular and metabolic diseases, but the correlation between serum uric acid and hs-CRP in type 2 diabetic patients is unclear. Therefore, we also attempted to further investigate the relationship between hs-CRP, serum uric acid, and other potential risk factors in diabetic patients under multifactorial management regimes METHODS: A total of ninety-five type 2 diabetic patients and sixteen healthy subjects participated in the first study. Diabetic patients were classified into normoalbuminuria, microalbuminuria and macroalbuminuria, according to their urine albumin-to-creatinine ratio (ACR). Serum RBP4 was measured by an enzyme-linked immunosorbent assay. In the second study, we also measured hs-CRP, serum uric acid and other potential risk factors in 846 type 2 diabetic patients. These patients were trisected into groups according to their serum uric acid level. We performed multivariate stepwise analysis to evaluate the associations of hs-CRP with uric acid and other factors. RESULTS: Serum RBP4 was significantly elevated in type 2 diabetic patients with normoalbuminuria (43.4 ± 14.9 μg/mL), microalbuminuria (57.3 ± 24.2 μg/mL) and macroalbuminuria (64.7 ± 27.6 μg/mL) as compared with control patients (32.6 ± 10.0 μg/mL). Serum RBP4 was also significantly elevated in type 2 diabetic patients with microalbuminuria or macroalbuminuria as compared with the normoalbuminuric group. Serum RBP4 in diabetic subjects was positively correlated with triglycerides, uric acid and ACR, and negatively correlated with low-density lipoprotein cholesterol and estimated glomerular filtration rate (eGFR; with age and gender adjustment in each parameter). Multiple stepwise linear regression analysis showed that uric acid and eGFR remained significantly associated with serum RBP4. In the second study, these 846 participants were trisected into groups with mean serum uric acid levels of 4.17 mg/dL, 5.46 mg/dL, and 6.97 mg/dL. And an increasing trend of higher hs-CRP levels in the second and third groups was identified, as compared with the first group. Multivariate stepwise regression analysis indicated that serum uric acid was independently associated with hs-CRP. Additionally, female gender, body mass index, triglycerides, HbA1C, HOMA-IR and smoking were identified to be positively associated with hs-CRP, whereas medication use (i.e., angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, pioglitazone and statins) showed a negative association with hs-CRP. CONCLUSIONS: Uric acid is a significant determinant of serum RBP4 and hs-CRP. This result supports the link between increased serum uric acid with high insulin resistances diseases and a higher inflammatory status. We also find renal dysfunction is a significant factor to serum RBP4 concentration. Further study is necessary to evaluate if it is beneficial of lowering serum uric acid level in improving insulin resistance and inflammatory status in type 2 diabetic patients.