Pathophysiology of diabetic dyslipidaemia: where are we?

Abstract

Cardiovascular disease is a major cause of morbidity and mortality in patients with type 2 diabetes mellitus, with a two- to fourfold increase in cardiovascular disease risk compared with non-diabetic individuals. Abnormalities in lipid metabolism that are observed in the context of type 2 diabetes are among the major factors contributing to an increased cardiovascular risk. Diabetic dyslipidaemia includes not only quantitative lipoprotein abnormalities, but also qualitative and kinetic abnormalities that, together, result in a shift towards a more atherogenic lipid profile. The primary quantitative lipoprotein abnormalities are increased triacylglycerol (triglyceride) levels and decreased HDL-cholesterol levels. Qualitative lipoprotein abnormalities include an increase in large, very low-density lipoprotein subfraction 1 (VLDL1) and small, dense LDLs, as well as increased triacylglycerol content of LDL and HDL, glycation of apolipoproteins and increased susceptibility of LDL to oxidation. The main kinetic abnormalities are increased VLDL1 production, decreased VLDL catabolism and increased HDL catabolism. In addition, even though LDL-cholesterol levels are typically normal in patients with type 2 diabetes, LDL particles show reduced turnover, which is potentially atherogenic. Although the pathophysiology of diabetic dyslipidaemia is not fully understood, the insulin resistance and relative insulin deficiency observed in patients with type 2 diabetes are likely to contribute to these lipid changes, as insulin plays an important role in regulating lipid metabolism. In addition, some adipocytokines, such as adiponectin or retinol-binding protein 4, may also contribute to the development of dyslipidaemia in patients with type 2 diabetes.

Impact of bariatric surgery on apolipoprotein C-III levels and lipoprotein distribution in obese human subjects

“…47,48 This reduction in lipolytic activity seems also to be related to insulin resistance, insulin being a potent activator of LPL. 49 In the present study, the marked improvement in insulin sensitivity after bariatric surgery and its effects on TRL production and LPL activity could explain the decrease in plasma TG concentrations. Hypertriglyceridemia is a major factor contributing to HDL catabolism and to the increased formation of atherogenic small and dense LDL particles.…”

“…A significant negative correlation has already been reported between HDL-apoA-I catabolism and plasma adiponectin, independent of insulin resistance and plasma lipids, suggesting as in our study a direct effect of adiponectin on HDL metabolism. 49 We found a marked, significant reduction of total plasma apoC-III and non-HDL-apoC-III concentrations after GBP and SG and strong positive associations between plasma apoC-III or non-HDL-apoC-III and plasma TG in M0, M12, and DM12-M0 univariate analyses.…”

“…Hypertriglyceridemia is a major factor contributing to HDL catabolism and to the increased formation of atherogenic small and dense LDL particles. 49 The decrease in plasma TG could partly explain the increase in HDL-C after surgery. Our univariate analyses showed a significant negative association between TG and HDL-C at M0 and M12.…”

PCSK9 Inhibitors in Lipid Management of Patients With Diabetes Mellitus and High Cardiovascular Risk: A Review

“…This has important implications for individuals with type 2 diabetes mellitus (T2D), and for those with type 1 diabetes mellitus (T1D) with poor glycemic control, who typically have a pattern of lipid abnormalities related to insulin resistance that is characterized by reduced hepatic clearance of triglyceride‐rich lipoproteins, increased hepatic production of very‐low‐density lipoproteins, and enhanced intestinal production of chylomicrons 32. These lipid abnormalities, termed diabetic (or mixed) dyslipidemia (Figure), account for their elevated levels of non‐high‐density lipoprotein cholesterol, triglycerides, and small dense LDLs 32, 33. Remnants of triglyceride‐rich lipoproteins, which include chylomicrons and very‐low‐density lipoproteins, have enhanced atherogenic potential since they contain more cholesterol per particle than LDL,34 and have been shown to have a substantial and independent causal association with cardiovascular risk 35.…”

“…Overview of lipid abnormalities in T2 DM 32. Triacylglycerols (hypertriglyceridemia, qualitative and kinetic abnormalities): (1) increased VLDL production (mostly VLDL 1); (2) increased chylomicron production; (3) reduced catabolism of both chylomicrons and VLDL s (diminished LPL activity); (4) increased production of large VLDL ( VLDL 1), preferentially taken up by macrophages; LDL (qualitative and kinetic abnormalities); (5) reduced LDL turnover (decreased LDL B/E receptors); (6) increased number of glycated LDL s, small, dense LDL s ( TAG ‐rich) and oxidized LDL s, which are preferentially taken up by macrophages; HDL (low HDL ‐C, qualitative and kinetic abnormalities); (7) increased CETP activity (increased transfer of triacylglycerols from TAG ‐rich lipoproteins to LDL s and HDL s); (8) increased TAG content of HDL s, promoting HL activity and HDL catabolism; (9) low plasma adiponectin favoring the increase in HDL catabolism.…”