Litwak K N, Cefalu W T, Wagner J D
Department of Comparative Medicine, Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, NC 27157-1040, USA.
Metabolism. 1998 Aug;47(8):947-54. doi: 10.1016/s0026-0495(98)90349-3.
Diabetes mellitus confers a threefold to fivefold increased risk of mortality from vascular disease. The primary cause of this increased incidence of vascular disease is atherosclerosis, but the mechanisms accounting for the increase are unclear. Chronic hyperglycemia is a common feature of all forms of diabetes mellitus and may contribute greatly to the increased incidence of atherosclerosis, via promotion of both lipoprotein and tissue glycation, which may have atherogenic effects. The present study investigated the effect of chronic hyperglycemia on measures of low-density lipoprotein (LDL) metabolism and atherosclerosis in streptozotocin-induced diabetic (STZ-DM) and control cynomolgus monkeys after 6 months of study. Consistent with a chronic hyperglycemic state, diabetic monkeys had significant increases in glycated hemoglobin (GHb) and glycated plasma LDL concentrations, but had minimal changes in total plasma cholesterol (TPC) or triglyceride (TG) concentrations during the study. Forty-eight hours before necropsy, control and in vitro-glycated LDL were differentially radiolabeled and coinjected into diabetic and control monkeys. There was a significant increase in arterial LDL accumulation in femoral arteries from diabetic monkeys compared with controls, with similar trends in other arterial sites. The effect of LDL glycation on arterial LDL accumulation was minimal in both groups. Arterial segments from diabetic monkeys also had greater amounts of arterial cholesterol content compared with controls. Histomorphometric analyses showed that diabetic monkeys had significantly greater intimal areas in the femoral artery and abdominal aorta compared with controls. Diabetic monkeys also had reduced arterial remodeling, or compensation, in the femoral artery and abdominal aorta. However, there was no difference in advanced glycation end products (AGE) in arterial collagen between groups. In conclusion, experimentally induced diabetes mellitus increases arterial LDL accumulation and atherosclerosis extent in cynomolgus monkeys before changes in AGE formation. The increased atherogenesis may be due to changes in lipoproteins or direct effects of hyperglycemia on the artery wall.
糖尿病使血管疾病导致的死亡风险增加两到四倍。血管疾病发病率增加的主要原因是动脉粥样硬化，但其增加的机制尚不清楚。慢性高血糖是所有类型糖尿病的共同特征，可能通过促进脂蛋白和组织糖化作用，极大地导致动脉粥样硬化发病率增加，而糖化作用可能具有致动脉粥样硬化的效应。本研究在6个月的研究期后，调查了慢性高血糖对链脲佐菌素诱导的糖尿病（STZ-DM）食蟹猴和对照食蟹猴低密度脂蛋白（LDL）代谢指标及动脉粥样硬化的影响。与慢性高血糖状态一致，糖尿病猴糖化血红蛋白（GHb）和糖化血浆LDL浓度显著升高，但在研究期间总血浆胆固醇（TPC）或甘油三酯（TG）浓度变化极小。在尸检前48小时，对对照LDL和体外糖化LDL进行不同放射性标记，并共同注射到糖尿病猴和对照猴体内。与对照组相比，糖尿病猴股动脉中动脉LDL蓄积显著增加，其他动脉部位也有类似趋势。两组中LDL糖化对动脉LDL蓄积的影响均极小。与对照组相比，糖尿病猴的动脉段动脉胆固醇含量也更高。组织形态计量学分析表明，与对照组相比，糖尿病猴股动脉和腹主动脉内膜面积显著更大。糖尿病猴股动脉和腹主动脉的动脉重塑或代偿也减少。然而，两组动脉胶原中晚期糖基化终产物（AGE）并无差异。总之，实验性诱导的糖尿病在AGE形成变化之前，会增加食蟹猴动脉LDL蓄积和动脉粥样硬化程度。动脉粥样硬化增加可能是由于脂蛋白变化或高血糖对动脉壁的直接作用。
