Lipid modification in type 2 diabetes: the role of LDL and HDL

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1 REVIEW ARTICLE doi: /j x Lipid modification in type 2 diabetes: the role of LDL and HDL Bruno Vergès* Service d Endocrinologie, Diabétologie et Maladies Métaboliques, Hôpital du Bocage, C.H.U. Dijon, France Keywords diabetes, HDL, LDL, lipids, lipoprotein Received 20 September 2008; revised 27 March 2009; accepted 23 April 2009 *Correspondence and reprints: bruno.verges@chu-dijon.fr ABSTRACT Patients with type 2 diabetes feature important modification of both low density lipoprotein (LDL) and high density lipoprotein particles which are likely to play an important role in the development of atherosclerosis. Although plasma LDL cholesterol level is usually normal in type 2 diabetic patients, LDLs show a significant increase in their plasma residence time which may promote cholesterol deposition in the arterial wall. Moreover, important qualitative abnormalities of LDLs, potentially atherogenic, are observed in type 2 diabetic patients: small dense, triglyceride-rich, LDL particles (known as subclass B), oxidized LDL and glycated LDL. All these qualitative modification of LDLs amplify the atherosclerotic process. Plasma high density lipoprotein (HDL) cholesterol is decreased in type 2 diabetes related to increased catabolism of HDL particles. One of the mechanism responsible for increased catabolism of HDLs is hypertriglyceridemia, promoting through cholesteryl ester transfer protein (CETP) the transfer of triglycerides (TG) to HDL leading to the formation of TG-rich HDLs which are very good substrates for hepatic lipase, enzyme in charge of HDLs catabolism. The reduction in plasma adiponectin level, observed in type 2 diabetes may be another mechanism involved in the diminution of HDL cholesterol. Furthermore, qualitative abnormalities of HDLs are described in type 2 diabetes: enrichment in triglycerides and glycation, which may impair HDL-mediated cholesterol efflux and reverse cholesterol transport. In addition to their role in reverse cholesterol transport, HDLs usually show antioxidative, anti-inflammatory, antithrombotic and endothelium-dependent vasorelaxant effects. It has been shown that HDLs from patients with type 2 diabetes have a significant reduction in their antioxidative and endothelium-dependent vasorelaxant properties. Cardiovascular disease (CVD) is the major cause of morbidity and mortality in patients with type 2 diabetes and CVD risk is two to fourfold increased over non-diabetic subjects [1,2]. Abnormalities of lipid metabolism, observed in type 2 diabetes, are one of the major factors contributing to vascular risk [1,3]. Patients with type 2 diabetes feature important modification of both low density lipoprotein (LDL) and HDL particles which are likely to play an important role in the development of atherosclerosis. This article will present LDL and HDL abnormalities observed in type 2 diabetes and discuss their pathophysiological mechanisms as their consequences on the arterial wall. LDL IN TYPE 2 DIABETES Although plasma LDL cholesterol level is usually normal in type 2 diabetic patients, metabolism of LDL is significantly modified [4]. Indeed, it has been shown in vivo in type 2 diabetic patients featuring similar LDL cholesterol values than normolipidemic non-diabetic controls, a significant 28% reduction of LDL catabolism associated with a reduced LDL production (secondary to decreased intermediate density lipoprotein (IDL) catabolism) [5]. Thus, although having normal plasma LDL cholesterol levels, patients with type 2 diabetes show reduced turn-over of their LDL particles with a reduction 681

2 682 B. Vergès of catabolism, leading automatically to increased LDL plasma residence time. Augmented LDL residence time in plasma is likely to promote cholesterol deposition in the arterial wall. Indeed, animal studies have shown that augmented LDL plasma residence time was associated with lipid deposition in the arterial wall and atherosclerosis lesions [6]. Our group has shown that insulin treatment in type 2 diabetic patients completely normalize LDL catabolism [7]. The impaired LDL catabolism in type 2 diabetes could be due to a reduction in the number of LDL B/E receptors (LDL receptor which can bind apolipoprotein B and apolipoprotein E). Indeed, type 2 diabetic patients show a significant reduction of LDL B/E receptors on cell surface [8]. Moreover, insulin treatment restores a normal number of LDL B/E receptors on cell surface in type 2 diabetic patients [8]. It has also been suggested that reduced LDL catabolism could be partly attributed to a decreased affinity of LDLs for their receptors secondary to apob glycation [9]. The decreased LDL catabolism associated with reduced expression of LDL B/E receptors in patients with type 2 diabetes is normalized by statin treatment [10]. Indeed, statins inhibit cholesterol synthesis, which in turn stimulates an increase in the number of surface LDL-C receptors leading to an increase in the rate of clearance of LDL-C from the plasma. Moreover, this faster turnover may also reduce LDL-C qualitative abnormalities such as LDL-C oxidation [11]. This significant acceleration of LDL catabolism with statin therapy is associated with a dramatic decrease of cardio-vascular risk as demonstrated by several trials. Simvastatin has been shown to reduce cardiovascular outcomes, in patients with diabetes, by 55% in the 4S study [12] and by about a quarter in the MRC/BHF Heart Protection Study (HPS) [13]. In the Cholesterol and Recurrent Events (CARE) trial, a significant reduction of coronary events by 25% was obtained with pravastatin therapy in patients with type 2 diabetes [14]. The Collaborative Atorvastatin Diabetes Study (CARDS), looking at primary prevention of coronary heart disease (CHD), provides further evidence in support of statin use in patients with diabetes. In this study, treatment with atorvastatin 10 mg/day reduced significantly CHD events by 36% and stroke by 48% [15]. Important qualitative abnormalities of LDLs, potentially atherogenic, are observed in type 2 diabetic patients. Small dense, triglyceride-rich, LDL particles (known as subclass B) are more prevalent in type 2 diabetes [16]. The presence of small dense LDLs appears to be mainly related to hypertriglyceridaemia [17]. It seems likely that the increase in triglyceride-rich lipoprotein level, observed in type 2 diabetes, stimulates CETP activity, promoting the transfer of triglycerides to LDLs leading to the formation of small dense triglyceriderich LDL particles. It has been shown that the presence of small dense LDL particles is associated with increased cardiovascular risk [18]. Many data indicate that small dense LDL particles have atherogenic properties. Indeed, small dense LDL particles have reduced affinity for the LDL B/E receptor and are preferentially taken up by macrophages, through the scavenger receptor, leading to the formation of foam cells. Small dense LDL particles have higher affinity for intimal proteoglycans than large LDL particles which may favor the penetration of LDL particles into the arterial wall [19]. It has been shown that subjects with small dense LDL particles show an impaired response to endothelium dependent vasodilator acetylcholine [20]. Moreover, small dense LDL particles showed an increased susceptibility to oxidation [21]. Another lipoprotein modification with marked atherogenic potential observed in type 2 diabetes is increased LDL oxidation [4]. In vitro studies have shown an increased oxidability of LDL particles from type 2 diabetic patients [22]. Moreover, an increased number of plasma oxidized LDL particles is observed in patients with type 2 diabetes [23]. Several factors are likely to promote LDL oxidation in patients with type 2 diabetes, such as glycation, increased triglyceride content and decreased anti-oxidative properties of HDL [24 26]. Oxidative modification of LDL results in rapid uptake by macrophages, leading to foam cell formation. Oxidized LDLs produce chemotactic effects on monocytes by increasing the formation of adhesion molecules, such as intercellular adhesion molecule 1 (ICAM-1) by endothelial cells. Oxidized LDLs stimulate the formation by macrophages of cytokines, such as tumor necrosis factor a or interleukin 1, which amplify the inflammatory atherosclerotic process. Glycation of LDL (glycation of apob within LDL particles), an additional qualitative lipoprotein abnormality noted in diabetic patients, may significantly modify LDL metabolism [24]. Indeed, glycated LDL have reduced affinity for LDL B/E receptor [24] and are preferentially taken up by macrophages leading to the formation of foam cells [27]. Furthermore, glycated LDL are easily oxidized. HDL IN TYPE 2 DIABETES Type 2 diabetes is associated with decreased plasma HDL cholesterol levels related to reduction of the HDL 2

3 LDL and HDL in diabetes 683 subfraction [28]. Reduced HDL 2 level, in type 2 diabetes, has been shown to be correlated with both hypertriglyceridaemia and obesity [29]. The decrease in HDL cholesterol, noted in patients with type 2 diabetes, is due to increased catabolism of HDL particles, which has been demonstrated by in vivo kinetic studies using radioisotopes [30] and more recently using stable isotopes [31]. An increased activity of hepatic lipase, which is in charge of HDL catabolism, was observed in type 2 diabetes [32]. The increased HDL catabolism was related to the insulin-resistant state. Indeed, a similar increase of HDL catabolism is observed in obese insulin-resistant non-diabetic patients [33]. One of the mechanisms responsible for increased catabolism of HDL particles in insulin-resistant states and type 2 diabetes is the increased pool of triglyceride-rich lipoproteins (mainly very low density lipoproteins). The augmented level of plasma triglyceride-rich lipoproteins drives through CETP the transfer of triglycerides from triglyceride-rich lipoproteins to HDL leading to the formation of triglyceride-rich HDL particles [34]. HDL enriched in triglycerides become very good substrate for hepatic lipase, whose activity is augmented in insulin-resistant states and type 2 diabetes, leading to increased catabolism of HDL particles. The reduction in plasma adiponectin level, observed in individuals with insulin resistance and type 2 diabetes may be another mechanism involved in the diminution of HDL cholesterol levels. Indeed, a significant negative correlation between HDL-apoA-I catabolism and plasma adiponectin, independently of abdominal obesity, insulin sensitivity, age, sex and plasma lipids has been reported [35]. According to this study, 43% of the reduction of plasma HDL cholesterol could be explained by the diminution of plasma adiponectin and 19% by HDL triglyceride enrichment [35]. These data suggest a direct effect of adiponectin on HDL metabolism. However, the exact role of adiponectin on HDL metabolism is not yet known. Several qualitative abnormalities of HDL particles are described in type 2 diabetes. HDLs of patients with type 2 diabetes are enriched in triglycerides which is responsible for increased catabolism of HDL particles (see above). Furthermore, HDL particles are glycated in type 2 diabetes and a direct correlation has been observed between plasma glucose level and glycation of apoa-i [36]. It has been demonstrated that glycation of apo A-I induces a decrease in the stability of the lipid apoprotein interaction and in that of the apoprotein self-association, facilitating dissociation of apoa-i from HDL and affecting the structural cohesion of HDL particles [36]. These structural modification of HDL particles induced by apoa-i glycation has been shown to reduce HDL binding to its receptor [37]. The qualitative abnormalities of HDL particles may impair HDL-mediated cholesterol efflux and reverse cholesterol transport as suggested by in vitro studies [38]. The cardiovascular protective role of HDLs is thought to be mainly due to their role in reverse cholesterol transport and potentially to the antioxidative, antiinflammatory, anti-thrombotic and endothelium-dependent vasorelaxant effects of HDL particles [39]. Some studies have shown that HDL particles from patients with type 2 diabetes have a significant reduction of their antioxidative and endothelium-dependent vasorelaxant properties. Indeed, a reduction of the antioxidative effect of HDL particles has been described in patients with type 2 diabetes [40]. This reduction of the anti-oxidative effect of HDL lipoproteins has been shown to be promoted by hyperglycemia and triglyceride enrichment of lipoproteins likely to be through structural modification of the lipoprotein [40]. Furthermore, in a study, using rabbit aorta rings, it has been shown that the ability of HDL to counteract the inhibition of endothelium-dependent vasorelaxation induced by oxidized LDL is impaired, in comparison with HDL from controls [41]. This reduction of HDL vasorelaxant effect is inversely correlated with HDL triglyceride content [41]. In conclusion, patients with type 2 diabetes show important modification of both LDL and HDL lipoproteins. Although plasma LDL cholesterol level is usually normal in type 2 diabetes, significant qualitative and kinetic abnormalities of LDL particles are present. HDL particles from patients with type 2 diabetes show important quantitative but also qualitative and kinetic abnormalities. All these abnormalities of both LDL and HDL lipoproteins are likely to promote the development of atherosclerosis and should be considered as therapeutic targets in patients with type 2 diabetes. REFERENCES 1 Pyörälä K., Laakso M., Uusitupa M. 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