Hirano T, Naito H, Kurokawa M, Ebara T, Nagano S, Adachi M, Yoshino G
First Department of Internal Medicine, Showa University School of Medicine, Tokyo, Japan.
Atherosclerosis. 1996 Jun;123(1-2):57-72. doi: 10.1016/0021-9150(95)05772-2.
To determine whether small-sized low density lipoprotein (LDL) is associated with a high incidence of coronary heart disease in diabetic nephropathy, we measured the LDL particle size in non-insulin-dependent diabetes mellitus (NIDDM) patients with various degrees of albuminuria (n = 95) and age-, weight-matched non-diabetic control subjects (n = 31). The diabetic subjects were divided into three groups, normoalbuminuric, microalbuminuric and macroalbuminuric NIDDM, based on the amount of albuminuria. The average diameter of LDL particles was determined by non-denaturing polyacrylamide gradient (2-16%) gel electrophoresis. The plasma lipid and lipoprotein concentrations were comparable between the non-diabetic controls and normoalbuminuric NIDDM, whereas the plasma triglyceride, very-low-density lipoprotein (VLDL) or LDL concentration was significantly increased in diabetic nephropathy. The mean LDL particle size was significantly smaller in microalbuminuric NIDDM compared with the controls or normoalbuminuric NIDDM, and the LDL size was further decreased in macroalbuminuric NIDDM. The incidence of small LDL (diameter < 255 A) was remarkably increased in microalbuminuric (58%) and macroalbuminuric NIDDM (67%) compared to the control (13%) and normoalbuminuric NIDDM (27%). Corresponding to the decreased LDL size, the cholesterol content of the LDL was significantly depleted in NIDDM with nephropathy. The high prevalence of small LDL in diabetic nephropathy was also observed even when hypertriglyceridemic or hypertensive subjects were excluded from each group. The increment in triglyceride-rich lipoprotein (d < 1.006) after oral fat-loading was increased, and postheparin lipoprotein lipase activity was decreased significantly in diabetic nephropathy. These abnormalities were significantly associated with LDL particle size. Multivariate regression analysis revealed that the amount of albuminuria was closely associated with the average LDL particle size, and this association was independent of the plasma triglyceride level. Neither insulin resistance nor glycemic control was directly associated with LDL particle diameter. The present study indicates that LDL particles become smaller in diabetic nephropathy, and this may be associated primarily with abnormal triglyceride metabolism. However, in addition to hypertriglyceridemia, other metabolic abnormalities caused by diabetic nephropathy may also be involved in the pathogenesis of small LDL particles.
为了确定小颗粒低密度脂蛋白（LDL）是否与糖尿病肾病患者冠心病的高发病率相关，我们测定了不同程度白蛋白尿的非胰岛素依赖型糖尿病（NIDDM）患者（n = 95）以及年龄、体重匹配的非糖尿病对照者（n = 31）的LDL颗粒大小。根据白蛋白尿的量，将糖尿病患者分为三组，即正常白蛋白尿NIDDM、微量白蛋白尿NIDDM和大量白蛋白尿NIDDM。LDL颗粒的平均直径通过非变性聚丙烯酰胺梯度（2 - 16%）凝胶电泳测定。非糖尿病对照组和正常白蛋白尿NIDDM之间的血浆脂质和脂蛋白浓度相当，而糖尿病肾病患者的血浆甘油三酯、极低密度脂蛋白（VLDL）或LDL浓度显著升高。与对照组或正常白蛋白尿NIDDM相比，微量白蛋白尿NIDDM的平均LDL颗粒大小显著更小，而大量白蛋白尿NIDDM的LDL大小进一步减小。与对照组（13%）和正常白蛋白尿NIDDM（27%）相比，微量白蛋白尿（58%）和大量白蛋白尿NIDDM（67%）中小LDL（直径< 255 Å）的发生率显著增加。与LDL大小减小相对应，肾病NIDDM患者LDL的胆固醇含量显著降低。即使从每组中排除高甘油三酯血症或高血压患者，糖尿病肾病中小LDL的高患病率仍然存在。糖尿病肾病患者口服脂肪负荷后富含甘油三酯脂蛋白（d < 1.006）的增加以及肝素后脂蛋白脂肪酶活性显著降低。这些异常与LDL颗粒大小显著相关。多变量回归分析显示，白蛋白尿的量与平均LDL颗粒大小密切相关，且这种关联独立于血浆甘油三酯水平。胰岛素抵抗和血糖控制均与LDL颗粒直径无直接关联。本研究表明，糖尿病肾病患者的LDL颗粒变小，这可能主要与甘油三酯代谢异常有关。然而，除了高甘油三酯血症外，糖尿病肾病引起的其他代谢异常也可能参与小LDL颗粒的发病机制。
