Georgopoulos A, Kafonek S D, Raikhel I
Department of Veterans Affairs Medical Center, Minneapolis, MN.
Metabolism. 1994 Sep;43(9):1063-72. doi: 10.1016/0026-0495(94)90046-9.
The risk of cardiovascular disease is increased in subjects with insulin-dependent diabetes mellitus (IDDM), although the mechanism remains unclear. To assess whether diabetic postprandial triglyceride (TG)-rich lipoprotein (TGRLP) subfractions (Sf > 400, 100-400, and 20-100) isolated from non-obese, normolipidemic IDDM subjects (n = 14) are potentially more atherogenic than lipoproteins from normal controls (n = 13), we measured cholesteryl ester (CE) synthesis and esterified cholesterol (EC) mass accumulation in THP-1 macrophages incubated with postprandial TGRLP. Diabetic Sf > 400 and Sf 100-400 but not Sf 20-100 significantly increased the mean (+/- SE) rate (pmol/mg cell protein/24 h) of CE synthesis in THP-1 macrophages compared with normal controls (Sf > 400, 673 +/- 26 v 301 +/- 64, P < .025; Sf 100-400, 560 +/- 27 v 298 +/- 39, P < .0005; Sf 20-100, 743 +/- 51 v 831 +/- 45). As well, all three diabetic TGRLP increased the mass of EC (microgram EC/mg cell protein/48 h) as compared with normal controls (Sf > 400, 4.9 +/- 0.61 v 2.9 +/- 0.50, P < .025; Sf 100-400, 5.7 +/- 0.91 v 3.4 +/- 0.34, P < .05; Sf 20-100, 5.4 +/- 0.7 v 3.2 +/- 0.52, P < .05). This effect is sustained for at least 7 hours postprandially and is greater than that of fasting Sf 100-400 (P < .03) and Sf 20-100 (P < .05) and similar to malondealdehyde low-density lipoprotein (MDA-LDL). To assess the mechanisms involved, the chemical composition and cellular degradation of diabetic and control lipoproteins were compared. Postprandial diabetic Sf 100-400 had abnormal composition (phospholipid to protein ratio, 1.86 +/- 0.14 v 1.5 +/- 0.13, P < .05) and in preliminary experiments demonstrated increased cell association (mean +/- SD at 6 hours, 126 +/- 34.3 v 57 +/- 4.2) and degradation (584 +/- 141 v 254 +/- 13) compared with that of normal controls, and may account for the observed increase in EC accumulation. In summary, postprandial diabetic Sf > 400 and Sf 100-400 TGRLP increase CE synthesis and Sf > 400, Sf 100-400, and Sf 20-100 lipoproteins increase EC accumulation in human macrophages compared with normal control lipoproteins. Diabetic Sf 100-400 lipoproteins have abnormal composition and seem to have increased cellular association and degradation compared with normal lipoproteins. Our findings suggest a role for postprandial TGRLP in the increased risk of cardiovascular disease among subjects with IDDM.
胰岛素依赖型糖尿病（IDDM）患者患心血管疾病的风险增加，但其机制尚不清楚。为了评估从非肥胖、血脂正常的IDDM患者（n = 14）中分离出的糖尿病餐后富含甘油三酯（TG）的脂蛋白（TGRLP）亚组分（Sf > 400、100 - 400和20 - 100）是否比正常对照组（n = 13）的脂蛋白更具致动脉粥样硬化性，我们测量了与餐后TGRLP孵育的THP - 1巨噬细胞中胆固醇酯（CE）合成和酯化胆固醇（EC）质量积累。与正常对照组相比，糖尿病患者Sf > 400和Sf 100 - 400但不是Sf 20 - 100显著增加了THP - 1巨噬细胞中CE合成的平均（+/- SE）速率（pmol/mg细胞蛋白/24小时）（Sf > 400，673 +/- 26对301 +/- 64，P <.025；Sf 100 - 400，560 +/- 27对298 +/- 39，P <.0005；Sf 20 - 100，743 +/- 51对831 +/- 45）。同样，与正常对照组相比，所有三种糖尿病TGRLP均增加了EC的质量（微克EC/mg细胞蛋白/48小时）（Sf > 400，4.9 +/- 0.61对2.9 +/- 0.50，P <.025；Sf 100 - 400，5.7 +/- 0.91对3.4 +/- 0.34，P <.05；Sf 20 - 100，5.4 +/- 0.7对3.2 +/- 0.52，P <.05）。这种作用在餐后至少持续7小时，且大于空腹Sf 100 - 400（P <.03）和Sf 20 - 100（P <.05），与丙二醛低密度脂蛋白（MDA - LDL）相似。为了评估其中涉及 的机制，比较了糖尿病和对照脂蛋白的化学组成和细胞降解情况。餐后糖尿病患者Sf 100 - 400的组成异常（磷脂与蛋白质比率为1.86 +/- 0.14对1.5 +/- 0.13，P <.05），并且在初步实验中显示与正常对照组相比细胞结合增加（6小时时平均+/- SD，126 +/- 34.3对57 +/- 4.2）和降解增加（584 +/- l41对254 +/- 13），这可能解释了观察到的EC积累增加。总之，与正常对照脂蛋白相比，糖尿病餐后Sf > 400和Sf 100 - 400 TGRLP增加CE合成，Sf > 400、Sf 100 - 400和Sf 20 - 100脂蛋白增加人巨噬细胞中EC积累。糖尿病患者Sf 100 - 400脂蛋白组成异常，与正常脂蛋白相比似乎细胞结合和降解增加。我们的研究结果表明餐后TGRLP在IDDM患者心血管疾病风险增加中起作用。
