Hyperglycemia, Lipoprotein Glycation, and Vascular Disease

Abstract

Hyperlipidemia and its treatment are currently recognized as important modulators of cardiovascular mortality in the presence of disordered glucose control. On the other hand, the effects of hyperglycemia and its treatment on hyperlipidemia are not widely appreciated. Hyperglycemia is commonly associated with an increase in intestinal lipoproteins and a reduction in high-density lipoprotein (HDL). This could be a consequence of hyperglycemia-induced glycation of lipoproteins, which reduces the uptake and catabolism of the lipoproteins via the classical low-density lipoprotein (LDL) receptor. A high dietary carbohydrate load increases the glycation of intestinal lipoproteins, prolongs their circulation, and increases their plasma concentration. Hyperglycemia also leads to inhibition of lipoprotein lipase, further aggravating hyperlipidemia. Circulating advanced glycation end-products (AGEs) also bind lipoproteins and delay their clearance, a mechanism that has particularly been implicated in the dyslipidemia of diabetic nephropathy. As uptake via scavenger receptors is not inhibited, glycation increases the proportion of lipoproteins that are taken up via inflammatory cells and decreases the proportion taken up by hepatocytes via classical LDL receptors. This promotes the formation of atheromatous plaques and stimulates inflammation. Hyperglycemia increases the formation of oxidized LDL and glycated LDL, which are important modulators of atherosclerosis and cardiovascular death. The risk of cardiovascular death is increased by even short-term derangement of blood sugar control, owing perhaps to the glycation of lipoproteins and other critical proteins. Glycated LDL could prove very useful in measuring the effect of hyperglycemia on cardiovascular disease, its risk factors, and its complications. Comparing different glucose-lowering and lipid-lowering drugs in respect to their influence on glycated LDL could increase knowledge of the mechanism by which they alter cardiovascular risk.