Diabetic dyslipidaemia: from basic research to clinical practice*

Abstract

The recognition that the increase of plasma triglyceride rich lipoproteins (TRLs) is associated with multiple alterations of other lipoproteins species that are potentially atherogenic has expanded the picture of diabetic dyslipidaemia. The discovery of heterogeneity within major lipoprotein classes VLDL, LDL and HDL opened new avenues to reveal the specific pertubations of diabetic dyslipidaemia. The increase of large VLDL 1 particles in Type 2 diabetes initiates a sequence of events that generates atherogenic remnants, small dense LDL and small dense HDL particles. Together these components comprise the atherogenic lipid triad. Notably the malignant nature of diabetic dyslipidaemia is not completely shown by the lipid measures used in clinical practice. The key question is what are the mechanisms behind the increase of VLDL 1 particles in diabetic dyslipidaemia? Despite the advances of recent years, our understanding of VLDL assembly and secretion is still surprisingly incomplete. To date it is still unclear how the liver is able to regulate the amount of triglycerides incorporated into VLDL particles to produce either VLDL 1 or VLDL 2 particles. The current evidence suggests that the machinery driving VLDL assembly in the liver includes (i) low insulin signalling via PI-3 kinase pathway that enhances lipid accumulation into "nascent" VLDL particles (ii) up-regulation of SREBP-1C that stimulates de novo lipogenesis and (iii) excess availability of "polar molecules" in hepatocytes that stabilizes apo B 100. Recent data suggest that all these steps could be fundamentally altered in Type 2 diabetes explaining the overproduction of VLDL apo B as well as the ability of insulin to suppress VLDL 1 apo B production in Type 2 diabetes.Recent discoveries have established the transcription factors including PPARs, SREBP-1 and LXRs as the key regulators of lipid assembly in the liver. These observations suggest these factors as a new target to tailor more efficient drugs to treat diabetic dyslipidaemia. [Diabetologia (2003) 46:733-749]

High-dose thiamine therapy counters dyslipidaemia in streptozotocin-induced diabetic rats

“…CHD risk determinants in the diabetic population include hyperglycaemia, hyperinsulinaemia in insulin resistance, systolic hypertension, low-grade inflammation, increased triglycerides, cholesterol and plasminogen activator inhibitor-1 [1,2]. Dyslipidaemia is a crucial feature in diabetic CHD where increased levels of VLDL-1 particles initiate the development of small dense LDL and HDL particles that pose the main atherogenic threat [3]. Increased lipoprotein secretion by the liver, preceded by a switch from lipid oxidation to lipogenesis and increased lipoprotein synthesis, appears to be central to the development of dyslipidaemia.…”

Third Annual World Congress on the Insulin Resistance Syndrome

“…Insulin resistance enhances hepatic VLDL synthesis and causes resistance to the action of insulin on lipoprotein lipase in peripheral tissues and enhanced HDL cholesterol degradation. The consequence is the well-recognized pattern of increased triglyceride, with longer residence time in plasma leading to increased exchange of triglyceride (under the influence of cholesterol ester transfer protein) between these particles and LDL and HDL, with hepatic lipase leading to low HDL cholesterol levels and an increased proportion of small dense LDL particles (33), as well as postprandial hyperlipidemia. Childhood hyperlipidemia is associated with adult CVD, with fatty streaks beginning to appear during childhood and subsequently developing into advanced plaques.…”

Clinical significance of the physicochemical properties of LDL in type 2 diabetes

“…This study also provided conclusive evidence that lowering cholesterol is beneficial to people with diabetes. Dyslipidaemia, characterised by hypertriglyceridaemia (fasting and postprandial) and a reduced HDL cholesterol level (particularly HDL2), is common in patients with the metabolic syndrome and type 2 diabetes [6,7], and is an independent predictor of cardiovascular disease. In the Skaraborg Hypertension and Diabetes Project, HbA 1 c and duration of diabetes were positively associated with plasma triglyceride concentrations [8], consistent with the finding that those with poor glucose control have higher concentrations of serum triglyceride-a phenomenon that is often attributed to insulin resistance (Fig.…”

“…Synthesis of VLDL1 by the liver is increased at fasting triglyceride concentrations exceeding 1.5 mmol/l. Paradoxically, large VLDL1 is preferentially metabolised into small, dense LDL particles [6]. Multiple genes may contribute to LDL particle size, and heritability analyses have suggested that genetic influences account for one-third to one-half of the variation in LDL peak particle diameter in humans [16].…”