Chronic hyperglycemia increases arterial low-density lipoprotein metabolism and atherosclerosis in cynomolgus monkeys

Abstract

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 investiated 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.