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.

Fig. 1

An overview of human lipoprotein metabolism and the effects of insulin on lipoprotein metabolism. (1) Insulin inhibits hormone-sensitive lipase. (2) Insulin inhibits hepatic VLDL production. (3) Insulin activates LPL. (4) Insulin increases LRP expression on the plasma membrane. (5) Insulin increases LDL receptor (LDL-R) expression. CE, cholesterol ester; CETP, cholesteryl ester transfer protein; HDL_n, nascent HDL HL, hepatic lipase; HSL, hormone-sensitive lipase; LPL, lipoprotein lipase; SR-B1, scavenger receptor B1; TAG, triacylglycerol

Fig. 2

An overview of VLDL assembly and secretion. Step 1: In the rough ER, ApoB is lipidated by MTP, leading to the formation of pre-VLDL, then VLDL₂ by further lipidation. VLDL₂ exits the ER compartment via Sar1/COPII vesicles, which are directed to the Golgi apparatus. ARF-1 is involved in VLDL₂ trafficking between the ER and the Golgi apparatus. Step 2: In the Golgi apparatus, VLDL₂ is converted into larger VLDL₁ by the addition of lipids. This step is promoted by phospholipase D1 and extracellular signal-regulated kinase 2 (ERK2). At this stage degradation by PERPP may occur. COPII, coat protein II; FA, fatty acid; MTP, microsomal triglyceride transfer protein; TAG, triacylglycerol

Fig. 3

Main lipid abnormalities in type 2 diabetes. Triacylglycerols (hypertriglyceridaemia, qualitative and kinetic abnormalities): (1) increased VLDL production (mostly VLDL₁), (2) increased chylomicron production, (3) reduced catabolism of both chylomicrons and VLDLs (diminished LPL activity), (4) increased production of large VLDL (VLDL₁), preferentially taken up by macrophages; LDL (qualitative and kinetic abnormalities): (5) reduced LDL turnover (decreased LDL B/E receptor), (6) increased number of glycated LDLs, small, dense LDLs (TAG-rich) and oxidised LDLs, which are preferentially taken up by macrophages; HDL (low HDL-cholesterol, qualitative and kinetic abnormalities): (7) increased CETP activity (increased transfer of triacylglycerols from TAG-rich lipoproteins to LDLs and HDLs), (8) increased TAG content of HDLs, promoting HL activity and HDL catabolism, (9) low plasma adiponectin favouring the increase in HDL catabolism. CE, cholesterol esters; CETP, cholesteryl ester transfer protein; dLDL, small, dense LDL; HDL_n, nascent HDL; HL, hepatic lipase; HSL, hormone-sensitive lipase; LPL, lipoprotein lipase; sLDL-R, LDL receptor; SR-B1, scavenger receptor B1; TAG, triacylglycerol

Fig. 4

Pathophysiology of increased hepatic VLDL production in type 2 diabetes. 1. Insulin resistance is responsible for: (a) a reduction in ApoB degradation, leading to an increased ApoB level in hepatocytes (including ApoB degradation by PERPP); (b) increased MTP expression; and (c) increased activity of two factors involved in the formation of VLDL₁, phospholipase D1 and ARF-1. Moreover, peripheral insulin resistance is responsible for increased levels of NEFA, which activate VLDL production (see a′′). 2. Increased de novo lipogenesis secondary to: (a′) increased activation of SREBP-1c (by ER stress); and (b′) increased activation ChREBP (by hyperglycaemia). 3. Reduced plasma adiponectin level responsible for: (a′′) increased plasma NEFA levels as a consequence of reduced muscle NEFA oxidation; and (b′′) a reduction in AMP-kinase activation in the liver, which promotes de novo lipogenesis. COPII, coat protein II; ERK2, extracellular signal-regulated kinase 2; FA, fatty acid; TAG, triacylglycerol;