皮肤胶原蛋白晚期糖基化终产物（AGEs）与1型糖尿病亚临床心血管疾病的长期进展
Skin collagen advanced glycation endproducts (AGEs) and the long-term progression of sub-clinical cardiovascular disease in type 1 diabetes.
作者信息
Monnier Vincent M, Sun Wanjie, Gao Xiaoyu, Sell David R, Cleary Patricia A, Lachin John M, Genuth Saul
机构信息
Departments of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
Departments of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
出版信息
Cardiovasc Diabetol. 2015 Sep 5;14:118. doi: 10.1186/s12933-015-0266-4.
BACKGROUND
We recently reported strong associations between eight skin collagen AGEs and two solubility markers from skin biopsies obtained at DCCT study closeout and the long-term progression of microvascular disease in EDIC, despite adjustment for mean glycemia. Herein we investigated the hypothesis that some of these AGEs (fluorescence to be reported elsewhere) correlate with long-term subclinical cardiovascular disease (CVD) measurements, i.e. coronary artery calcium score (CAC) at EDIC year 7-9 (n = 187), change of carotid intima-media thickness (IMT) from EDIC year 1 to year 6 and 12 (n = 127), and cardiac MRI outcomes at EDIC year 15-16 (n = 142).
METHODS
Skin collagen AGE measurements obtained from stored specimens were related to clinical data from the DCCT/EDIC using Spearman correlations and multivariable logistic regression analyses.
RESULTS
Spearman correlations showed furosine (early glycation) was associated with future mean CAC (p < 0.05) and CAC >0 (p = 0.039), [corrected] but not with CAC score <100 vs. >100. Glucosepane and pentosidine crosslinks, methylglyoxal hydroimidazolones (MG-H1) and pepsin solubility (inversely) correlated with IMT change from year 1 to 6(all P < 0.05). Left ventricular (LV) mass (cMRI) correlated with MG-H1, and inversely with pepsin solubility (both p < 0.05), while the ratio LV mass/end diastolic volume correlated with furosine and MG-H1 (both p < 0.05), and highly with CML (p < 0.01). In multivariate analysis only furosine (p = 0.01) was associated with CAC. In contrast IMT was inversely associated with lower collagen pepsin solubility and positively with glucosepane,
CONCLUSIONS
In type 1 diabetes, multiple AGEs are associated with IMT progression in spite of adjustment for A1c implying a likely participatory role of glycation and AGE mediated crosslinking on matrix accumulation in coronary arteries. This may also apply to functional cardiac MRI outcomes, especially left ventricular mass. In contrast, early glycation measured by furosine, but not AGEs, was associated with CAC score, implying hyperglycemia as a risk factor in calcium deposition perhaps via processes independent of glycation.
TRIAL REGISTRATION
Registered at Clinical trial reg. nos. NCT00360815 and NCT00360893, http://www.clinicaltrials.gov.
背景
我们最近报道，在糖尿病控制与并发症试验（DCCT）研究结束时获取的皮肤活检样本中，8种皮肤胶原蛋白晚期糖基化终末产物（AGEs）与两种溶解性标志物之间存在强关联，且在糖化血红蛋白均值校正后，这些关联与糖尿病干预和并发症流行病学研究（EDIC）中微血管疾病的长期进展相关。在此，我们探讨了这样一个假设，即其中一些AGEs（荧光情况将在其他地方报告）与长期亚临床心血管疾病（CVD）测量指标相关，即EDIC第7 - 9年的冠状动脉钙化评分（CAC）（n = 187）、EDIC第1年至第6年和第12年颈动脉内膜中层厚度（IMT）的变化（n = 127），以及EDIC第15 - 16年的心脏磁共振成像结果（n = 142）。
方法
使用Spearman相关性分析和多变量逻辑回归分析，将从储存样本中获得的皮肤胶原蛋白AGE测量值与DCCT/EDIC的临床数据相关联。
结果
Spearman相关性分析显示，呋喃果糖（早期糖基化）与未来平均CAC相关（p < 0.05）以及CAC > 0相关（p = 0.039），[校正后]但与CAC评分<100对比>100无关。葡糖胺聚糖和戊糖苷交联物、甲基乙二醛氢咪唑酮（MG - H1）以及胃蛋白酶溶解性（呈负相关）与第1年至第6年的IMT变化相关（所有P < 0.05）。左心室（LV）质量（心脏磁共振成像）与MG - H1相关，与胃蛋白酶溶解性呈负相关（两者p < 0.05），而LV质量/舒张末期容积比值与呋喃果糖和MG - H1相关（两者p < 0.05），与羧甲基赖氨酸（CML）高度相关（p < 0.01）。在多变量分析中，只有呋喃果糖（p = 0.01）与CAC相关。相比之下，IMT与较低的胶原蛋白胃蛋白酶溶解性呈负相关，与葡糖胺聚糖呈正相关。
结论
在1型糖尿病中，尽管对糖化血红蛋白进行了校正，但多种AGEs与IMT进展相关，这意味着糖基化和AGE介导的交联在冠状动脉基质积累中可能起到参与作用。这也可能适用于功能性心脏磁共振成像结果，尤其是左心室质量。相比之下，由呋喃果糖测量的早期糖基化而非AGEs与CAC评分相关，这意味着高血糖可能是钙沉积的一个风险因素，可能是通过独立于糖基化的过程。
试验注册
在临床试验注册编号为NCT00360815和NCT00360893注册，网址为http://www.clinicaltrials.gov。
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