The Reciprocal Relationship between LDL Metabolism and Type 2 Diabetes Mellitus

Abstract

Type 2 diabetes mellitus and insulin resistance feature substantial modifications of the lipoprotein profile, including a higher proportion of smaller and denser low-density lipoprotein (LDL) particles. In addition, qualitative changes occur in the composition and structure of LDL, including changes in electrophoretic mobility, enrichment of LDL with triglycerides and ceramides, prolonged retention of modified LDL in plasma, increased uptake by macrophages, and the formation of foam cells. These modifications affect LDL functions and favor an increased risk of cardiovascular disease in diabetic individuals. In this review, we discuss the main findings regarding the structural and functional changes in LDL particles in diabetes pathophysiology and therapeutic strategies targeting LDL in patients with diabetes.

Keywords: deleterious effects; endothelial dysfunction; glycation; low-density lipoprotein; modified LDL; oxidation; small and dense LDL; type 2 diabetes mellitus.

Figure 1

Schematic representation of the mechanism behind the generation of sdLDL in T2DM. Mechanisms leading to sdLDL in T2DM. Insulin resistance promotes triglyceride lipolysis in adipocytes and the release of free fatty acids (FFA) in circulation. Uptake and accumulation of FFA in the liver results in hepatic gluconeogenesis and affects lipid metabolism. FFAs taken up by hepatocytes are used to form new TG-rich VLDL particles. Remodeling of TG-rich VLDL through the action of CETP, HL, and LPL enzymes promotes the formation of small and dense LDL and more atherogenic particles. Consequently, these particles are electronegative, remain longer in the plasma, are more susceptible to oxidation and glycation, are more prone to bind to proteoglycans in the subendothelial space of the arterial vessel wall, and interact with beta2-glycoprotein I to form autoimmune complexes related to inflammation state. On the other hand, there is a decrease in affinity with LDLR. FFA: free fatty acid, TG: triglyceride, HL: hepatic lipase, LPL: lipoprotein lipase, CETP: cholesteryl ester transfer protein, VLDL: very low-density lipoprotein, IDL: intermediate density lipoprotein, LDL: low-density lipoprotein, sdLDL: small dense lipoprotein, LDLR: LDL receptor.

Figure 2

Representation of the main mechanisms that lead to LDL modification as a result of T2DM. The oxidation process can occur via two main pathways, by an enzymatic or non-enzymatic process, playing an important role in the development of atherosclerosis. Oxidation by the enzymatic process involves lipoxygenases, myeloperoxidases, NADPH oxidase, and nitric oxide synthase. Oxidation by a non-enzymatic process involves free transition metal ions. The Ox-LDL loses its affinity with LDLR and binds to SRs activating signaling pathways like Akt, JNK, Wnt, and NF-κB. It is also capable of forming a complex with β2GPI and CRP, promoting an inflammatory process. It serves as a potent regulator of macrophage gene expression involving PPAR-γ activation through 9-HODE and 13-HODE metabolites. Both mechanisms alter LDL, increasing macrophage uptake, promoting foam cell formation, and leading to more LDL modification. A higher level of AGEs is a consequence of diabetes, and it can be formed by three distinct pathways, both of which decrease affinity with LDLR, promoting an increase in half-life and contributing to the formation of foam cells. Lipidomic alteration of LDL being enriched with ceramides plays an important role in the development of tissue insulin resistance, involving insulin-signaling pathways such as IRS and Akt. They also promote the induction of transcription factors involving inflammation and the consequent formation of foam cells. O³: ozone, ¹ΔgO²: singlet oxygen, ROS: reactive oxygen species, SR: scavenger receptors, Ox-LDL: oxidized LDL, β2GPI: beta2-glycoprotein I, CRP: C-reactive protein, LDLR: LDL receptor, 9-HODE and 13-HODE: 9- and 13-hydroxyoctadecadienoic acid, respectively, AGEs: advanced glycation end products, SLC2A4: insulin-sensitive solute carrier family 2, member 4, TLR4: toll-like receptor 4, MCP-1: monocyte chemoattractant protein-1, TNF- α: tumor necrosis factor-α, IL-6 and IL-1β: interleukin 6 and 1β, respectively.

Figure 3

Effect of increased glucose on LDL-C metabolism and insulin secretion. In enterocytes, the increase in plasma glucose causes a decrease in cholesterol excretion consecutive to the reduction in the expression of ABCG5 and ABCG8. On the other hand, there is an increase in cholesterol absorption as a result of the high expression of NPC1L1. Both mechanisms contribute to raised plasma LDL-C levels. The increase in plasma glucose also reduces expression of LDLR in hepatocytes, another mechanistic pathway contributing to the increased plasma concentration of LDL-C. Such elevated plasma LDL-C levels together with the high expression of LDLR in pancreatic beta cells stimulate insulin secretion [2]. LDLR: LDL receptor, ABCG5/8: ATP Binding Cassette Subfamily G Member 5/ABCG8: ATP Binding Cassette Subfamily G Member 8, NPC1L1: Niemann–Pick C1-like 1 protein, LDL-C: LDL cholesterol.