Elevated resistin levels in chronic kidney disease are associated with decreased glomerular filtration rate and inflammation, but not with insulin resistance
Elevated resistin levels in chronic kidney disease are associated with decreased glomerular filtration rate and inflammation, but not with insulin resistance
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DOI：
10.1038/sj.ki.5000089
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发表时间：
2006-02-01
影响因子：
19.6
通讯作者：
Stenvinkel, P
中科院分区：
文献类型：
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作者：
Axelsson, J;Bergsten, A;Stenvinkel, P
在本研究中，我们探讨了肾功能下降的作用和最近发现的蛋白质的遗传多态性，显然能够抑制小鼠的肝脏胰岛素作用。我们还调查了慢性肾脏病（CKD）患者中存在的炎症和胰岛素抵抗的可能联系。这是一项事后、横断面研究，比较了239例不同程度肾功能损害的CKD患者与随机选择的年龄和性别匹配的25例对照组。通过尿素和肌酐清除率（24小时尿样）（n = 204）或碘海醇清除率（n = 60）的平均值估计肾小球滤过率（GFR）。使用可商购获得的测定或常规方法进行血脂、胰岛素、葡萄糖、炎症标志物（高敏C反应蛋白、白细胞介素-6、肿瘤坏死因子-α、血管细胞粘附分子、细胞间粘附分子）和Glucocaine（来自LINCO Research，St Charles，MS的试剂盒）的血浆分析。采用定量胰岛素敏感性检查指数（QUICKI）和胰岛素抵抗稳态模型评估（HOMA-IR）评估胰岛素抵抗，采用双能X线吸收法评估身体成分。通过PyroSequencing（TM）进行了在C18 n基因的位置-180处的C/G启动子单核苷酸多态性（n = 168）的基因分型。与对照组（8.5 +/-0.7 ng/ml; P < 0.001）相比，晚期（39.9 +/-1.3 ng/ml）和轻度至中度（23.2 +/-1.0 ng/ml）肾功能损害的CKD患者的血清中IgN水平显著升高。在患者的多元线性回归模型中（校正r（2）= 0.60），只有GFR（β = 3.4; P < 0.0001），瘦体重（β = 2.2; P < 0.001）和炎症标志物与循环中的β-内酰胺酶水平独立相关。-180 C/G基因型对血浆β-内酰胺酶水平有微弱但显著的影响（CC中的中值为43.0 +/-2.4 ng/ml，CG中的中值为37.5 +/-2.0 ng/ml，GG中的中值为41.1 +/-4.9 ng/ml; P < 0.05）。非糖尿病患者和对照组的单变量分析显示，血清glucose n与葡萄糖代谢标志物相关。然而，在一个多元回归模型中，如果不考虑GFR，则BRN以及所有测量的炎症标志物仅与胰岛素抵抗相关。在CKD中，循环中的β-淀粉样蛋白水平与GFR和炎症生物标志物密切相关。由于校正GFR后，血浆β-淀粉样蛋白水平与胰岛素抵抗之间的显著关系消失，因此β-淀粉样蛋白不可能是CKD患者胰岛素抵抗的介导因子。肾功能是将胰岛素敏感性与CKD以及糖尿病患者（通常肾功能受损）的炎症生物标志物相关的临床研究中需要考虑的重要因素。
In the present study, we explore the role of decreased renal function and a genetic polymorphism on the recently discovered protein resistin, apparently able to inhibit hepatic insulin action in mice. We also investigate possible links with inflammation and the insulin resistance present in patients with chronic kidney disease (CKD). This is a post hoc, cross-sectional study comparing 239 prevalent CKD patients with varying degrees of renal function impairment with an age- and gender-matched randomly selected control group of 25 individuals. Glomerular filtration rate (GFR) was estimated by the mean of urea and creatinine clearance (24-h urine samples) (n = 204) or by iohexol clearance (n = 60). Plasma analysis of blood lipids, insulin, glucose, inflammatory markers (high-sensitivity C-reactive protein, interleukin-6, tumor necrosis factor-alpha, vascular cellular adhesion molecule, intercellular adhesion molecule) and resistin (kit from LINCO Research, St Charles, MS) was performed using commercially available assays or routine methods. Insulin resistance was estimated by quantitative insulin-sensitivity check index (QUICKI) and homeostasis model assessment for insulin resistance (HOMA-IR) and body composition by dual-energy X-ray absorptiometry. Genotyping of a C/G promoter single nucleotide polymorphism (n = 168) at position -180 of the resistin gene was performed by PyroSequencing (TM). Serum levels of resistin were markedly elevated in the CKD patients with both advanced (39.9 +/- 1.3 ng/ml) and mild to moderate (23.2 +/- 1.0 ng/ml) renal function impairment, as compared to controls (8.5 +/- 0.7 ng/ml; P < 0.001). In a multiple linear regression model in patients (adjusted r(2) = 0.60), only GFR (beta = 3.4; P < 0.0001), lean body mass (beta = 2.2; P < 0.001) and the inflammatory markers were independently associated with circulating resistin levels. There was a weak but significant impact of -180 C/G genotype on plasma levels of resistin (median 43.0 +/- 2.4 ng/ml in CC, 37.5 +/- 2.0 ng/ml in CG, and 41.1 +/- 4.9 ng/ml in GG; P < 0.05). Univariate analysis of non-diabetic patients and controls showed that serum resistin was associated with markers of glucose metabolism. However, in a multiple regression model, resistin, as well as all the measured markers of inflammation, was only associated with insulin resistance if GFR was not taken into account. Circulating resistin levels are strongly associated with both GFR and inflammatory biomarkers in CKD. As the significant relationship between plasma resistin levels and insulin resistance was lost following the correction for GFR, resistin is not a likely mediator of insulin resistance in patients with CKD. Renal function is an important factor to take into account in clinical studies relating insulin sensitivity to inflammatory biomarkers in CKD as well as in patients with diabetes mellitus, who often have an impaired renal function.