Clinical significance of small dense low‐density lipoprotein cholesterol measurement in type 2 diabetes

Figures

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  Figure 1. Mechanisms of potent atherogenicity of sdLDL particles. sdLDL is an ideal substrate for the formation of highly toxic oxidized LDL for following reasons. ① Longer Circulation Time: sdLDL has a prolonged residence time in the bloodstream due to its low affinity for LDL receptors, which decreases its clearance. ② Higher Affinity for Proteoglycans: sdLDL has an increased affinity for arterial proteoglycans, likely due to changes in its surface composition, which promotes retention in the arterial wall. ③ Easier to Penetrate the Arterial Wall: small particle size allows it to penetrate the arterial wall more easily, though this is not necessarily the primary determining factor. ④ Higher Oxidation Susceptibility: sdLDL is more prone to oxidation due to its low content of antioxidants. Endothelial damage generates reactive oxygen species (ROS) which readily oxidize sdLDL particles. The immune system reacts to oxidized LDL by activating macrophages and become foam cells. These foam cells accumulate beneath the endothelial layer, forming atheromatous plaque. lbLDL, large buoyant LDL.

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  Figure 2. Mechanisms of enhanced sdLDL generation in hypertriglyceridemia. In hypertriglyceridemia, via the action of transferrin protein (CETP), excess TG in TG‐rich lipoproteins (TRLs) (chylomicrons and VLDLs) is transferred to LDL, and conversely, cholesteryl ester (CE) is transferred from LDL to TRLs. This process raises the TG content in LDL while reducing its CE. Subsequently, hepatic lipase (HL) removes TG from LDL, resulting in the formation of CE‐poor LDL, or sdLDL.

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  Figure 3. Mechanisms of enhanced sdLDL generation by insulin resistance. Hepatic TG production is regulated by free fatty acid (FFA) flux from adipose tissue (particularly visceral fat), hepatic de novo lipogenesis (DNL), and hepatic uptake of TG‐rich lipoproteins (TRLs). VLDL particles are assembled in the liver using TG and apoB. In insulin resistance, apoB degradation by insulin is impaired, leading to increased availability of apoB for VLDL assembly. Elevated FFA flux also inhibits apoB degradation, further promoting VLDL production. Hyperinsulinemia, a compensatory response to insulin resistance, stimulates de novo lipogenesis (DNL), thereby increasing TG production. Microsomal TG transfer protein (MTP) plays a critical role in VLDL assembly, and MTP activity is enhanced by insulin resistance. VLDL1 production is pronounced when hepatic TG production is active, and overproduction of VLDL1 leads to an increase in the sdLDL‐C level.