Sugar turns LDL cholesterol "ultra-bad"

That serving of french toast may be doing more to contribute to cardiovascular disease than promoting insulin resistance and dyslipidemia. A paper just published in the journal Diabetes details how excess blood sugar causes LDL cholesterol to stick more readily to arterial plaque. Inflamed vulnerable plaque on arterial walls is the main precipitating factor for heart attacks and strokes. The authors set out to...

"...study whether modification of LDL by methylglyoxal (MG), a potent arginine-directed glycating agent that is increased in diabetes, is associated with increased atherogenicity."

Glycation is the damaging process by which sugar binds to substances in the body that it shouldn't do normally. As the practitioners reading this know, hemoglobin A1c (HbgA1c, produced by glycation of hemoglobin) is an important laboratory metric for determining how high a person's blood sugar has been on average over the previous few months. People with pre-diabetes (metabolic syndrome) and type 2 diabetes have higher levels. By modifying human LDL by methylglyoxal to reproduce what happens in vivo, the authors were able to measure the effect on LDL particle characteristics and its tendency to deposit in the arterial wall. What did they find?

"MGmin-LDL [glycated LDL] had decreased particle size, increased binding to proteoglycans, and increased aggregation in vitro. Cell culture studies showed that MGmin-LDL was bound by the LDL receptor but not by the scavenger receptor and had increased binding affinity for cell surface heparan sulfate–containing proteoglycan. Radiotracer studies in rats showed that MGmin-LDL had a similar fractional clearance rate in plasma to unmodified LDL but increased partitioning onto the aortal wall...A computed structural model predicted that MG modification of apoB100 induces distortion, increasing exposure of the N-terminal proteoglycan–binding domain on the surface of LDL. This likely mediates particle remodeling and increases proteoglycan binding."

In other words, glycated LDL is a nasty compound that is less likely to be scavenged from the bloodstream; and it is smaller, denser and stickier than normal LDL so that it has a higher tendency to adhere to the blood vessel well. Glycated LDL has been called the "ultra-bad cholesterol". It also shows part of the reason why blood sugar lowering therapies reduce cardiovascular disease. The authors conclude:

"MG modification of LDL forms small, dense LDL with increased atherogenicity that provides a new route to atherogenic LDL and may explain the escalation of cardiovascular risk in diabetes and the cardioprotective effect of metformin."