Section of Diabetes, Endocrinology, and Metabolism, Dartmouth-Hitchcock Medical Center, 1 Medical Center Drive, Lebanon, NH, 03756, USA,
Amino Acids. 2014 Feb;46(2):311-9. doi: 10.1007/s00726-013-1533-x. Epub 2013 Sep 14.
Increased advanced glycation endproducts (AGEs) and oxidation products (OPs) have been proposed as pathogenic for diabetic nephropathy (DN). We investigated the relationship between AGEs and OPs measured in different plasma and urine preparations, and progression of DN in 103 young, normoalbuminuric, normotensive participants with type 1 diabetes in the Natural History of Diabetic Nephropathy Study. The primary endpoint was electron microscopy-measured change in glomerular basement membrane (GBM) width from baseline to 5 years; change in mesangial fractional volume was a secondary endpoint. Fast progressors (FP) were defined as the upper quartile (n = 24) of rate of GBM thickening; slow progressors (SP) were the remainder (n = 79). Four AGEs [3-deoxyglucosone and methylglyoxal hydroimidazolones (DG3H1, MGH1) and carboxymethyl and ethyl lysine (CML, CEL)], and two oxidation products methionine sulfoxide and aminoadipic acid were measured by liquid chromatography, triple quadrupole mass spectrometry. Measurements were done on 10 K plasma filtrates and plasma proteolytic digests (PPD) at year 5, and at four time points over 5 years for urinary 10 K filtrates. Urinary filtrate CEL levels were significantly higher in FP, but not after adjustment for HbA1c, sex, and duration of diabetes. MGHI, CEL, and CML plasma filtrate levels were significantly higher in FP relative to SP (p < 0.05). In PPD, only MGHI showed borderline significantly higher levels in FP relative to SP (p = 0.067), while no other product showed correlation. AGE and OP measurements were not correlated with mesangial expansion. In plasma filtrates, HbA1c at year 5 accounted for 4.7 % of the variation in GBM width. The proportion of variation in GBM width was increased to 11.6 % when MGHI, CEL, and CML were added to the model (6.9 % increase).
已有研究提出，晚期糖基化终产物（AGEs）和氧化产物（OPs）可能是糖尿病肾病（DN）发病的原因。我们研究了在 103 名患有 1 型糖尿病的年轻、微量白蛋白尿、血压正常的参与者中，不同血浆和尿液标本中AGEs 和 OPs 的测量值与 DN 进展之间的关系，这些参与者来自糖尿病肾病自然史研究。主要终点是电子显微镜测量的肾小球基底膜（GBM）宽度从基线到 5 年的变化；肾小球系膜容积分数的变化是次要终点。快速进展者（FP）定义为 GBM 增厚率的上四分位数（n = 24）；缓慢进展者（SP）为其余部分（n = 79）。通过液相色谱、三重四极杆质谱法测定了 4 种 AGEs[3-脱氧葡萄糖酮和甲基乙二醛的氢咪唑酮（DG3H1、MGH1）以及羧甲基赖氨酸和乙基赖氨酸（CML、CEL）]和 2 种氧化产物蛋氨酸亚砜和氨基己二酸。在第 5 年时对 10 K 血浆滤液和血浆蛋白水解物（PPD）进行了测量，并在 5 年内的 4 个时间点对 10 K 尿液滤液进行了测量。FP 组的尿液滤液 CEL 水平显著升高，但在校正 HbA1c、性别和糖尿病病程后，差异无统计学意义。FP 组的 MGH1、CEL 和 CML 血浆滤液水平明显高于 SP 组（p < 0.05）。在 PPD 中，只有 MGH1 显示 FP 组相对于 SP 组的水平有统计学意义的升高（p = 0.067），而其他产物均无相关性。AGE 和 OP 测量值与系膜扩张无相关性。在血浆滤液中，第 5 年的 HbA1c 占 GBM 宽度变化的 4.7%。当将 MGH1、CEL 和 CML 添加到模型中时，GBM 宽度变化的比例增加到 11.6%（增加 6.9%）。
