Hypertriglyceridemia in type 2 diabetes results from high fasting and postprandial triglyceride-rich lipoproteins, especially VLDL (24), which is the consequence of both overproduction and impaired catabolism of VLDL (25). Increased VLDL production is almost uniformly present in patients with type 2
diabetes and hypertriglyceridemia, owing to an increase in free fatty acids (FFA) flux to the liver (25). Because maintenance of stored fat in adipose tissue depends on the suppression of hormone-sensitive lipase by insulin, insulin deficiency, or resistance results in increased hormone-sensitive lipase activity and excessive release of FFA from adipocytes. Because FFA availability is a major determinant of VLDL production by the liver, VLDL overproduction and hypertriglyceridemia ensues (25,26) (Fig. 4.1).

In type 2 patients with more severe hypertriglyceridemia, VLDL clearance by lipoprotein lipase (LPL), the rate-limiting enzyme responsible for the removal of plasma triglyceride-rich lipoproteins, is also impaired (24). LPL requires insulin for maintenance of normal tissue levels, and its activity is low in patients with poorly controlled type 2 diabetes (24). The result is enzymatic activity insufficient to match the overproduction rate, with further accumulation of VLDL triglyceride.

Increased fatty acid flux to the liver also results in the production of large triglyceride-rich VLDL particles because the size of VLDL is also mainly determined by the amount of triglyceride available. VLDL size is an important determinant of its metabolic fate (see below).

Decreased HDL levels in diabetes are closely related to the abnormal metabolism of triglyceride-rich lipoproteins (24,25,26) (Fig. 4.2). During lipolysis of chylomicrons and VLDL, surface components (free cholesterol, redundant phospholipids, and apolipoproteins) are transferred into the HDL fraction. These components may enter nascent discoid HDL particles secreted by the liver. The free cholesterol is esterified by lecithin cholesterol acyl transferase to generate mature spherical HDL. Alternatively, these surface components may be incorporated into preexisting HDL particles. The latter process results in an increase in size and decrease in density of HDL particles, leading to the conversion of preexisting HDL₃ (triglyceride depleted) to HDL₂.

In diabetes, decreased HDL synthesis is related to the decreased LPL activity because the rate of HDL₂ formation depends on the rate of flux of surface components from lipolysis of triglyceride-rich lipoprotein (see Figure 4.2). When LPL-mediated VLDL catabolism is inefficient, less surface material is transferred to HDL, impairing HDL formation.

Increased catabolism of HDL in diabetes also occurs because increased secretion of VLDL into plasma promotes the transfer of triglycerides from these lipoproteins to HDL in exchange for cholesteryl ester. This exchange occurs in plasma, and is facilitated by cholesteryl ester transfer protein (CETP), generating a triglyceride-enriched (and cholesteryl ester–depleted) HDL₂. This particle is highly susceptible to catabolism by hepatic triglyceride lipase (HTGL), an enzyme found primarily on endothelial cells of hepatic sinusoids (25). HTGL has both triglyceride hydrolase and phospholipase activity, and generates smaller HDL₃ particle, which are depleted in triglycerides and phospholipids (see Fig. 4.2).

In diabetes, although the absolute number of LDL particles is normal, alterations in LDL clearance and susceptibility to oxidative modification result in an increase in LDL atherogenic potential. The composition of LDL particles is altered, resulting in a preponderance of small, triglyceride-enriched and cholesterol depleted particles (22,23). These particles are more susceptible to oxidative modification, are particularly prone to induce endothelial dysfunction, and easily penetrate the arterial wall.

The formation of small, dense LDL in diabetes occurs in a similar fashion to the increased formation of small and dense HDL₃, as described. CETP mediates the exchange of triglyceride from VLDL for cholesteryl ester in LDL. If sufficient LDL cholesteryl ester is replaced by triglyceride from VLDL then when the particle comes into contact with hepatic lipase, hydrolysis of newly acquired triglyceride in LDL and HDL by HTGL in turn decreases the size of LDL particles (27). The symmetry of the mechanisms for the formation of small, dense species of LDL and HDL (see Figure 4.2) helps to explain why low HDL levels and a preponderance of small, dense LDL are associated with diabetes and the metabolic syndrome and why HDL cholesterol level is strongly correlated with LDL size (27).

The glycosylation process (see Advanced Glycosylation End Products) occurs both on the apoprotein B (Apo B) (28) and phospholipid (29) components of LDL. Glycosylation of LDL Apo B occurs within the putative LDL receptor–binding domain, and impairs LDL-receptor–mediated LDL clearance.

Advanced glycosylation of an amine-containing phospholipids component of LDL is accompanied by progressive oxidative modification of unsaturated fatty acid residues and confers increased susceptibility of LDL to oxidative modification (29).