ReviewNew insights into the pathophysiology of dyslipidemia in type 2 diabetes
Introduction
In recent decades, the world has seen an unprecedented rise in the prevalence of diabetes, and it is predicted that the number of people with type 2 diabetes will increase from about 350 million today to 592 million by 2035 [1], [2]. Between 2010 and 2030, the number of adults with diabetes is expected to increase by 20% in developed countries and by 69% in developing countries [3], [4]. These escalating rates of diabetes worldwide represent a heavy disease burden at the population and individual level as well as for the total health care system.
Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality for patients with type 2 diabetes, despite recent significant advances in management strategies to lessen CVD risk factors [5]. It has been estimated that diabetes will shorten the life of a 50-year-old person by on average six years, and about 58% of this effect is due to increased vascular disease [6]. The difference in CVD risk between individuals with and without diabetes has narrowed substantially in recent decades, but strong associations between diabetes and vascular outcomes remain [7], [8], [9]. Recent data indicate that diabetes per se increases CVD risk about two-fold on average but the risk varies widely depending on the population [10]. Importantly, those with diabetes and coronary heart disease are at substantially higher risk of future CVD events [6], [11], [12].
The excess CVD risk in individuals with diabetes is due to several risk factors including both unmodifiable factors (age, gender and genetics) and traditional risk factors such as hypertension, lipids, hyperglycemia and smoking. The overall cardiometabolic risk is driven by a complex interplay between these factors and the components of the metabolic syndrome commonly associated with type 2 diabetes. A major cause is the atherogenic dyslipidemia, which consists of elevated plasma concentrations of both fasting and postprandial triglyceride-rich lipoproteins (TRLs), small dense low-density lipoprotein (LDL) and low high-density lipoprotein (HDL) cholesterol. Importantly, statins fail to adequately correct these features of dyslipidemia and several recent trials have failed to show benefits from fibrates or niacin when added to statins [13], [14]. This review aims to summarize recent advances in our understanding of the pathophysiology of diabetic dyslipidemia.
Lipid abnormalities are common in people with Type 2 diabetes but the prevalence varies between different populations, the presence of the metabolic syndrome and the variable definition of the cut off levels for serum triglycerides [15], [16]. The Botnia study reported the prevalence of dyslipidemia (TG > 1.7 mmol/L and HDL chol < 0.9 mmol/L in men and <1.15 mmol/L in women) to be 54% in men and 56% in women [17]. In the FIELD study about 38% of recruited subjects had both high triglycerides (>1.7 mmol/L) and low HDL cholesterol (<1.03 mmol/L in men and <1.29 mmol/L in women) [18]. A large population based registry of 75,048 patients with type 2 diabetes in Sweden reported that about 37–38% had elevated triglycerides (>1.7 mmol/L but < 4.0 mmol/L) with or without low HDL cholesterol [19]. Recent studies have consistently reported high prevalence (about 35–50%) of dyslipidemia also in T2D subjects treated with statins leaving the subjects at high residual risk [20], [21], [22].
Section snippets
Distribution of TRL species
Plasma TRLs are a mixture of lipoprotein species characterized by different densities and apoprotein composition and are derived either from the intestine (chylomicrons) or the liver [very low-density lipoprotein (VLDL)]. TRLs consist of a core of neutral lipids (mainly triglycerides but also some cholesteryl esters) surrounded by a monolayer of phospholipids, free cholesterol and proteins. Each TRL particle contains one molecule of apolipoprotein B (apoB) [23], [24], [25]. ApoB exists in two
Regulation of TRL clearance
The clearance of TRLs from the circulation is a complex process and includes both the hydrolysis of triglycerides and removal of remnant particles by the liver. After secretion of TRLs from the intestine and liver, triglycerides are removed from the lipoproteins by LPL allowing the delivery of FFAs to muscle and adipose tissue. The key regulator of LPL activity is insulin, which stimulates the expression of LPL in endothelial cells [194]. Interestingly, insulin deficiency in mice leads to
Consequences of VLDL overproduction on LDL and HDL metabolism
In subjects with type 2 diabetes, hepatic uptake of VLDL, IDL and LDL is decreased, resulting in increased plasma residence time of these lipoproteins [217], [218], [230] and thus further contributing to the increased TRL levels in circulation. There are also reports of increased production of IDL and LDL in insulin-resistant women without diabetes [231], and in men with mild but not severe diabetes [232].
The formation of small dense LDL is closely associated with insulin resistance and
Summary
Patients with diabetes have an approximately two-fold increased risk of CVD compared with patients who do not have diabetes. The evidence that raised concentrations of remnant cholesterol, marked by raised triglycerides, is a causal risk factor for CVD and all-cause mortality is strong and supported by both genetic and epidemiological studies. However, randomized intervention trial evidence is urgently needed, that triglyceride-lowering reduces cardiovascular disease in patients with raised
Acknowledgments
This work was funded by EU-project RESOLVE (Nr. 305707), Leducq Foundation (11 CVD 03), the Helsinki University Central Hospital Research Foundation (TYH2012134), Swedish Research Council, the Sigrid Juselius Foundation, Novo Nordisk Foundation, Swedish Diabetes Foundation, Diabetes Wellness, the Swedish Heart-Lung Foundation, and the Sahlgrenska University Hospital ALF Research Grants.
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