Elsevier

Atherosclerosis

Volume 239, Issue 2, April 2015, Pages 483-495
Atherosclerosis

Review
New insights into the pathophysiology of dyslipidemia in type 2 diabetes

https://doi.org/10.1016/j.atherosclerosis.2015.01.039Get rights and content

Highlights

  • The different components of diabetic dyslipidemia are not isolated abnormalities but closely linked metabolically to each other.

  • The underlying disturbances are hepatic overproduction and delayed clearance of TRLs.

  • Recent results show unequivocally that triglyceride-rich lipoproteins and their remnants are atherogenic.

Abstract

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. 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. The different components of diabetic dyslipidemia are not isolated abnormalities but closely linked to each other metabolically. The underlying disturbances are hepatic overproduction and delayed clearance of TRLs. Recent results have unequivocally shown that triglyceride-rich lipoproteins and their remnants are atherogenic. To develop novel strategies for the prevention and treatment of dyslipidaemia, it is essential to understand the pathophysiology of dyslipoproteinaemia in humans. Here, we review recent advances in our understanding of the pathophysiology of diabetic dyslipidemia.

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.

References (250)

  • M. Adiels et al.

    Postprandial accumulation of chylomicrons and chylomicron remnants is determined by the clearance capacity

    Atherosclerosis

    (2012)
  • C. Xiao et al.

    Regulation of chylomicron production in humans

    Biochim. Biophys. Acta

    (2012)
  • C. Xiao et al.

    New and emerging regulators of intestinal lipoprotein secretion

    Atherosclerosis

    (2014)
  • J.S. Cohn et al.

    Contribution of apoB-48 and apoB-100 triglyceride-rich lipoproteins (TRL) to postprandial increases in the plasma concentration of TRL triglycerides and retinyl esters

    J. Lipid Res.

    (1993)
  • A.J. Tremblay et al.

    Effects of ezetimibe and simvastatin on apolipoprotein B metabolism in males with mixed hyperlipidemia

    J. Lipid Res.

    (2009)
  • B. Verges

    Abnormal hepatic apolipoprotein B metabolism in type 2 diabetes

    Atherosclerosis

    (2010)
  • Z. Sun et al.

    Dissociating fatty liver and diabetes

    Trends Endocrinol. Metab.

    (2013)
  • M.E. Haas et al.

    The regulation of ApoB metabolism by insulin

    Trends Endocrinol. Metab.

    (2013)
  • Y.F. Otero et al.

    Pathway-selective insulin resistance and metabolic disease: the importance of nutrient flux

    J. Biol. Chem.

    (2014)
  • C. Koutsari et al.

    Thematic review series: patient-oriented research. Free fatty acid metabolism in human obesity

    J. Lipid Res.

    (2006)
  • S.W. Koppe

    Obesity and the liver: nonalcoholic fatty liver disease

    Transl. Res.

    (2014)
  • R.G. Victor et al.

    The Dallas Heart Study: a population-based probability sample for the multidisciplinary study of ethnic differences in cardiovascular health

    Am. J. Cardiol.

    (2004)
  • M. Kumari et al.

    Adiponutrin functions as a nutritionally regulated lysophosphatidic acid acyltransferase

    Cell. Metab.

    (2012)
  • M.K. Basantani et al.

    Pnpla3/Adiponutrin deficiency in mice does not contribute to fatty liver disease or metabolic syndrome

    J. Lipid Res.

    (2011)
  • C. Pirazzi et al.

    Patatin-like phospholipase domain-containing 3 (PNPLA3) I148M (rs738409) affects hepatic VLDL secretion in humans and in vitro

    J. Hepatol.

    (2012)
  • L. Valenti et al.

    The APOC3 T-455C and C-482T promoter region polymorphisms are not associated with the severity of liver damage independently of PNPLA3 I148M genotype in patients with nonalcoholic fatty liver

    J. Hepatol.

    (2011)
  • A. Vedala et al.

    Delayed secretory pathway contributions to VLDL-triglycerides from plasma NEFA, diet, and de novo lipogenesis in humans

    J. Lipid Res.

    (2006)
  • F. Diraison et al.

    Contribution of hepatic de novo lipogenesis and reesterification of plasma non esterified fatty acids to plasma triglyceride synthesis during non-alcoholic fatty liver disease

    Diabetes Metab.

    (2003)
  • J.M. Schwarz et al.

    Hepatic de novo lipogenesis in normoinsulinemic and hyperinsulinemic subjects consuming high-fat, low-carbohydrate and low-fat, high-carbohydrate isoenergetic diets

    Am. J. Clin. Nutr.

    (2003)
  • I. Marques-Lopes et al.

    Postprandial de novo lipogenesis and metabolic changes induced by a high-carbohydrate, low-fat meal in lean and overweight men

    Am. J. Clin. Nutr.

    (2001)
  • P. Karagianni et al.

    Transcription factor networks regulating hepatic fatty acid metabolism

    Biochim. Biophys. Acta

    (2015)
  • I.J. Lodhi et al.

    Lipoexpediency: de novo lipogenesis as a metabolic signal transmitter

    Trends Endocrinol. Metab.

    (2011)
  • J.J. Joseph et al.

    Type 2 diabetes and cardiovascular disease: what next?

    Curr. Opin. Endocrinol. Diabetes Obes.

    (2014)
  • Emerging Risk Factors Collaboration et al.

    Diabetes mellitus, fasting glucose, and risk of cause-specific death

    N Engl J Med.

    (2011)
  • E.W. Gregg et al.

    Changes in diabetes-related complications in the United States, 1990–2010

    N. Engl. J. Med.

    (2014)
  • K. Faerch et al.

    Improved survival among patients with complicated type 2 diabetes in Denmark: a prospective study (2002–2010)

    J. Clin. Endocrinol. Metab.

    (2014)
  • Emerging Risk Factors Collaboration et al.

    Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies

    Lancet

    (2010)
  • N. Sattar

    Revisiting the links between glycaemia, diabetes and cardiovascular disease

    Diabetologia

    (2013)
  • S. Vilbergsson et al.

    Coronary heart disease mortality amongst non-insulin-dependent diabetic subjects in Iceland: the independent effect of diabetes. The Reykjavik Study 17-year follow up

    J. Intern. Med.

    (1998)
  • S.M. Haffner et al.

    Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabettic subjects with and without prior myocardial infarction

    N. Engl. J. Med.

    (1998)
  • W.E. Boden et al.

    Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy

    N. Engl. J. Med.

    (2011)
  • H.T.C. Group et al.

    Effects of extended-release niacin with laropiprant in high-risk patients

    N. Engl. J. Med.

    (2014)
  • M.R. Taskinen

    Type 2 diabetes as a lipid disorder

    Curr. Mol. Med.

    (2005)
  • M.J. Chapman et al.

    Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management

    Eur. Heart J.

    (2011)
  • B. Isomaa et al.

    Cardiovascular morbidity and mortality associated with the metabolic syndrome

    Diabetes Care

    (2001)
  • R. Scott et al.

    Impact of metabolic syndrome and its components on cardiovascular disease event rates in 4900 patients with type 2 diabetes assigned to placebo in the FIELD randomised trial

    Cardiovasc. Diabetol.

    (2011)
  • M. Eriksson et al.

    Blood lipids in 75,048 type 2 diabetic patients: a population-based survey from the Swedish National Diabetes Register

    Eur. J. Cardiovasc. Prev. Rehabil. Off. J. Eur. Soc. Cardiol.

    (2011)
  • M. Feher et al.

    Persistent hypertriglyceridemia in statin-treated patients with type 2 diabetes mellitus

    Diabetes Metab. Syndr. Obes.

    (2013)
  • L.A. Leiter et al.

    Persistent lipid abnormalities in statin-treated patients with diabetes mellitus in Europe and Canada: results of the Dyslipidaemia International Study

    Diabet. Med.

    (2011)
  • S.O. Olofsson et al.

    Apolipoprotein B: a clinically important apolipoprotein which assembles atherogenic lipoproteins and promotes the development of atherosclerosis

    J. Intern. Med.

    (2005)
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