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Small-dense LDL and LDL glycation in metabolic syndrome and in statin-treated and non-statin-treated type 2 diabetes
Nahla N Younis, Handrean Soran, Reena Sharma, Valentine Charlton-Menys, Adam Greenstein, Mohamed M Elseweidy and Paul N Durrington Diabetes and Vascular Disease Research 2010 7: 289 originally published online 27 September 2010 DOI: 10.1177/1479164110383063 The online version of this article can be found at: http://dvr.sagepub.com/content/7/4/289

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Original article

Small-dense LDL and LDL glycation in metabolic syndrome and in statin-treated and non-statin-treated type 2 diabetes
Nahla N Younis1,2, Handrean Soran1, Reena Sharma1, Valentine Charlton-Menys1, Adam Greenstein1, Mohamed M Elseweidy2 and Paul N Durrington1

Diabetes & Vascular Disease Research 7(4) 289295 The Author(s) 2010 Reprints and permission: sagepub. co.uk/journalsPermissions.nav DOI: 10.1177/1479164110383063 dvr.sagepub.com

Abstract Small-dense LDL (SD-LDL) has been particularly implicated in atherosclerosis. It has previously been reported that in non-diabetic people SD-LDL is preferentially glycated. The distribution of glycated apolipoprotein B (glyc-apoB) in lipoproteins in metabolic syndrome (MS) and in type 2 diabetes has not previously been studied. Plasma apoB and glyc-apoB were determined in different apoB-containing lipoproteins including buoyant and SD-LDL in MS (n=18) and type 2 diabetes (DM) [n=48; 12 statin-untreated (DMS) and 36 statin-treated (DM+S)]. Plasma glyc-apoB was 5.6 0.9, 3.5 0.5 and 4.0 0.2 mg/dl in DMS, DM+S and MS, respectively. The glycated proportion of SD-LDL-apoB was greater than buoyant LDL in all groups. SD-LDL contributed most to plasma glyc-apoB in DMS, because SD-LDL-apoB was higher in DMS than in MS and DM+S (p < 0.001). Plasma glyc-apoB correlated with SD-LDL-apoB (r=0.74, p < 0.0001 in diabetes and r=0.53, p < 0.001 in MS), but not with HbA1c. SD-LDL is preferentially glycated in type 2 diabetes and MS. Its concentration is a stronger determinant of plasma glycapoB than glycaemia. Statin-induced changes in its level may be important in decreasing apoB glycation in diabetes. These findings may explain the small effect of improving glycaemia relative to statin treatment in reducing atherosclerosis risk in type 2 diabetes and the increased risk in MS even before the onset of type 2 diabetes. Key words Glycaemic control, glycation, metabolic syndrome, small-dense LDL, statin, type 2 diabetes

Introduction
It has been known for many years that foam cells essential for atherogenesis are derived from the receptor-mediated uptake of apolipoprotein B (apoB)-containing lipoproteins by monocyte-macrophages in the arterial wall.1 However, in tissue culture monocyte-macrophage uptake of low density lipoproteins (LDL), the most abundant of the apoBcontaining lipoproteins, occurs too slowly for foam cell formation. It has thus become a central tenet of current hypotheses to explain atherogenesis that the apoB of LDL must first undergo chemical modification so that it becomes a ligand for macrophage scavenger receptors before its rapid uptake.2 Oxidative modification has been most widely studied,3 but, although it may be part of the explanation for the participation of LDL in atherogenesis, it is unsatisfactory as the sole explanation. Trials of antioxidant therapy have, for example, generally been unsuccessful in the prevention of atherosclerosis.4,5 Glycation of apoB, in a process similar to that of haemoglobin and other proteins,6 also leads to rapid scavenger uptake of LDL7 and, even in non-diabetic people, the serum concentration of glyc-apoB is typically substantially higher than that of oxidatively modified LDL.8 The level of glyc-apoB is higher still when LDL levels are raised and in diabetes.9 If, however, glycation of LDL is to be considered as an important atherogenic modification of LDL, some explanation must be found for the generally disappointing outcome of clinical trials seeking to demonstrate a decrease in cardiovascular disease risk

Cardiovascular Research Group, School of Clinical & Laboratory Sciences, University of Manchester, UK 2 Department of Biochemistry, Faculty of Pharmacy, Zagazig University, Egypt
1

Corresponding author: Paul N Durrington, Cardiovascular Research Group, School of Clinical & Laboratory Sciences, Core Technology Facility (3rd Floor), University of Manchester, 46 Grafton Street, Manchester M13 9NT, UK. Email: pdurrington@manchester.ac.uk

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290 with improved glycaemic control1012 compared, say, with trials of LDL lowering with statin treatment.13 We have recently reported that in non-diabetic people glyc-apoB is predominantly present in small-dense LDL (SD-LDL; LDL3; D=1.0441.063 g/ml), which we also found to be more susceptible to glycation than more buoyant LDL.8 This gives rise to the hypothesis that in diabetes factors that regulate the concentration of SD-LDL may be more important than glycaemia in determining circulating levels of glyc-apoB. This might explain the relative lack of effect of glycaemic control in decreasing cardiovascular disease (CVD) risk, as opposed to statin treatment, which is effective in lowering apoB-containing lipoproteins generally, including SD-LDL. Furthermore, it is known that in metabolic syndrome (MS), even before the onset of diabetes, CVD risk is increased.14 SD-LDL is often increased in MS1517 and thus might lead to an increase in glyc-apoB even before glycaemia reaches diabetic proportions. In this investigation we test the hypothesis that in type 2 diabetes and MS glyc-apoB predominates in SD-LDL and that the concentration of SD-LDL may be a more important determinant of the total plasma gly-apoB concentration than glycaemic control.

Diabetes and Vascular Disease Research 7(4)

Isolation of lipoproteins
Blood samples were collected between 9 and 11 a.m. after participants had fasted from 10 p.m. the previous day. Serum and EDTA-plasma were isolated by centrifugation at 2000 g for 15 min at 4C within 2 h of collection and were maintained at that temperature until further use. Serum was used for cholesterol, triglyceride and HDL-cholesterol assays and EDTA-plasma for apoB and glyc-apoB assay. EDTA-plasma was also subjected to ultracentrifugation to obtain different density lipoprotein fractions [very low density lipoprotein (VLDL; D < 1.006 g/ml), intermediate density lipoprotein (IDL; D=1.0061.019 g/ml), whole LDL (D=1.0191.063 g/ml), LDL1 and 2 (D=1.0191.044 g/ml) and SD-LDL, also known as LDL3 (D=1.0441.063 g/ml)] using methods described previously.8,20 Ultracentrifugation procedures were performed in 11 34 mm2 polycarbonate tubes (Beckman Coulter, Palo Alto, CA) in a Beckman TLA fixed angle rotor (100,000 rpm; 435,680 g for 5 h) using a Beckman Optima TLX ultracentrifuge.

Other laboratory analyses


Cholesterol and triglycerides were determined using Cholesterol oxidase phenol 4-aminoantipyrine peroxidase (CHODPAP) and Glycerol phosphate oxidase phenol 4-aminoantipyrine peroxidase (GPO-PAP) methods respectively, using reagents from ABX Horiba-UK, Northampton, UK. HDL-cholesterol was measured by a direct second generation homogeneous method (Roche Diagnostics, Burgess Hill, UK). ApoB was measured immunoturbidimetrically. A Cobas Mira autoanalyser (ABX Horiba-UK, Northampton, UK) was employed for all these assays. Glyc-apoB was determined in plasma and lipoprotein fractions by ELISA21 using Glycacor kits (Exocell Inc., PA, USA) obtained from Biognosis Ltd, Hailsham, UK. Glycated haemoglobin (HbA1c) was measured by HPLC using an automated system [Bio-Rad Variant II dual kit, Bio-Rad Laboratories (UK) Ltd, UK] aligned to the DCCT method and plasma glucose by an automated glucose oxidase method in the routine clinical biochemistry laboratory, which participates in the United Kingdom National External Quality Assessment Service (UK NEQAS).

Methods Subjects
Forty-eight type 2 diabetic patients, as defined by the WHO criteria,18 were recruited from the Lipid Clinic and the Manchester Diabetes Centre at Manchester Royal Infirmary. Of these, 36 had received statin treatment for 24 3 (mean SD) months (simvastatin 40 mg daily or atorvastatin 1040 mg daily) (DM+S) and 12 were not on statins or other lipid-lowering medication (DMS). The duration of type 2 diabetes was 42 4 months in DM+S and 23 8 months in DMS (p < 0.025). Eighteen people with MS defined according to the 2001 National Cholesterol Education Program Adult Treatment Panel guidelines19 who were non-diabetic were recruited from the Manchester Wellcome Trust Clinical Research Facility. None of the patients with MS received lipid-lowering medication or oral hypoglycaemic agents. All the diabetic participants had MS and 28% of them were on no hypoglycaemic agents, 17% were receiving metformin monotherapy, 3% sulfonylurea alone, 15% a combination of metformin and sulfonylurea, 15% a thiazolidinedione with either metformin or sulfonylurea or a combination of metformin and sulfonylurea, and 23% received insulin alone or combined with oral hypoglycaemic therapy. None of the patients studied were on supplements of omega-3 fatty acids or fish oil. All participants gave informed consent to the study, which was approved by the Local Research Ethics Committee.

Statistical analyses
Statistical analyses of data were done by the Statistical Package for Social Sciences software (SPSS, IL, USA). Results were expressed as mean SEM except for triglyceride, which had a non-Gaussian distribution, for which median and range were used. Statistical differences were sought using Students t-test or one way ANOVA (if more than two sets of data were being compared), taking p < 0.05 as statistically significant. Triglyceride data were logarithmically transformed before these analyses. The study had more than 90% statistical power to detect a difference in plasma glyc-apoB concentration of 0.5 mg/dl in a two-tailed test p < 0.05.

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291 substantially higher levels in the SD-LDL of DMS (4.05 0.78 mg/dl) than in DM+S (1.4 0.06 mg/dl) and MS (0.65 0.17 mg/dl) respectively (both p < 0.001). In IDL there was an increase in glyc-apoB in DMS (1.01 0.33 mg/dl) compared with DM+S (0.42 0.10 mg/ dl; p < 0.01), but it was not significantly different from that in MS (0.72 0.09 mg/dl; p=0.221). In MS more glyc-apoB was present in VLDL (1.28 0.28 mg/dl) than in DMS (0.35 0.10 mg/dl; p < 0.01), whereas the apparently higher level in DM+S compared with MS just failed to achieve significance (0.80 0.10 mg/dl; p=0.056). The proportion of glycated apoB in SD-LDL compared with whole LDL

Results
Clinical details of the patients who participated in the study are shown in Table 1. The total plasma glyc-apoB was 5.6 0.9 mg/dl (mean SEM) in DMS. This was significantly higher than the level in DM+S (3.5 0.5 mg/dl; p < 0.05), but the concentration in MS (4.0 0.2 mg/dl) was not significantly different from that in DMS (Figure 1). The concentration of plasma glyc-apoB previously reported in non-diabetic, healthy, normolipidaemic controls8 (2.9 0.4 mg/dl) was significantly lower than that in MS (p < 0.02) and in DMS (p < 0.01). The distribution of glycapoB among the apoB-containing lipoproteins revealed
Table 1. Characteristics of study population. Metabolic syndrome

Type 2 diabetes Not statin-treated (DMS) Statin-treated (DM+S) 36 (22/14) 60 2 34 2 8.1 0.5** 7.73 0.33** 4.43 0.24 1.78 (0.664.41) 1.0 0.1 2.47 0.24 91 5

N (M/F) Age (years) BMI (kg/m2) Fasting glucose (mmol/l) HbA1c (%) Total cholesterol (mmol/l) Triglycerides (mmol/l) HDL-cholesterol (mmol/l) LDL-cholesterol (mmol/l) ApoB (mg/dl)

18 (11/7) 56 2 33 1 6.2 0.2 6.42 0.13 4.61 0.21 1.81 (0.864.38) 1.2 0.1 2.70 0.24 91 6

12 (8/4) 53 4 30 3 10.8 2.9** 8.59 0.84* 5.36 0.73 1.95 (1.087.38) 1.3 0.1 2.60 0.39 106 11

Results are presented either as mean SEM or median (range). To convert values for glucose to mg/dl divide by 0.0555. To convert values for cholesterol to mg/dl divide by 0.02586. To convert values for triglyceride to mg/dl divide by 0.01129. Significantly different from metabolic syndrome group: * p<0.05, **p<0.01. ApoB: apolipoprotein B, BMI: body mass index, HbA1c: glycated haemoglobin, HDL: high density lipoprotein, LDL: low density lipoprotein.

Figure 1. The concentration of glycated apolipoprotein B (glyc-apoB) in whole plasma, very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), whole low density lipoprotein (whole LDL), LDL1 and 2 (combined) and SD-LDL isolated from individuals with metabolic syndrome (MS) (n=18), diabetic patients receiving statin treatment (DM+S) (n=36) and diabetic patients not receiving statin (DMS) (n=12).
Results are mean SEM. Significantly different from statin-untreated diabetes: ap < 0.05, bp < 0.01 and cp < 0.001.

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Figure 2. The percentage of apolipoprotein B (apoB) glycated in whole plasma, very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), whole low density lipoprotein (whole LDL), LDL1 and 2 (combined) and SD-LDL isolated from individuals with metabolic syndrome (MS: n=18), diabetic patients receiving statin treatment (DM+S: n=36) and diabetic patients not receiving statin (DMS: n=12). Results are mean SEM. Significantly different from whole LDL: ap < 0.01. Significantly different from LDL1 and 2 (combined): *p < 0.01. Significantly different from statin-untreated diabetes: p < 0.05, p < 0.01.

Figure 3. The percentage distribution of apolipoprotein B (apoB) in the different apoB-containing lipoproteins isolated from individuals with metabolic syndrome (MS: n=18) and type 2 diabetic patients either receiving (DM+S: n=36) or not receiving statins (DMS: n=12). Results are mean SEM. Significantly different from LDL1 and 2 (combined): ap < 0.001. Significantly different from statin-untreated diabetes: *p < 0.001.

was increased in MS, in DMS (both p < 0.01) and in DM+S (p < 0.01) (Figure 2). DM+S patients had a lower proportion of glycated apoB in both plasma and whole LDL than those with DMS (both p < 0.05). On the other hand, people with MS had a significantly higher proportion of glycated apoB in VLDL, but a lower proportion in LDL, than those with diabetes (both p < 0.01).

The proportion of apoB distributed among the plasma lipoproteins (Figure 3) revealed that a much higher proportion was present in SD-LDL in DMS patients (p < 0.001), which was reflected in their high SD-LDL gly-Sc-apoB levels. The plasma concentration of glyc-apoB correlated positively with SD-LDL in both MS and diabetes (DMS and DM+S combined) [r=0.74; p < 0.001 in diabetes and

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Figure 4. The plasma concentration of glycated apolipoprotein B (apoB) in (A) metabolic syndrome (r=0.53; p < 0.05; n=18), (B) statin-treated and non-statin-treated type 2 diabetes mellitus combined [DMS and DM+S combined (r=0.74; p < 0.01; n=33); DMS represented by open circles and DMS represented by black circles (r=0.85; p < 0.005; n=9)] plotted as a function of plasma SD-LDL-apoB.

r=0.53; p < 0.05 in MS (Figure 4)], but there were no significant correlations with HbA1c. Among the three groups, the correlation between plasma glyc-apoB and SD-LDL was the strongest in the DMS group (r=0.85; p < 0.005). Their plasma glycated apoB also came closest to correlating significantly with HbA1c (r=0.5; p=0.17).

Discussion
Foam cells are central to atherogenesis in diabetes, as in other conditions predisposing to atherosclerotic cardiovascular disease.22 They are largely derived from monocytemacrophages, and the cytoplasmic cholesterol droplets causing the foam-like appearance are the result of LDL uptake. However, macrophage LDL receptor expression is inadequate for sufficiently rapid uptake of LDL to permit foam cell formation.2 Many chemical modifications of LDL that do allow macrophage foam cell formation by increasing its uptake through scavenger receptor pathways have been reported.2,2325 Only a few are possible in vivo. Of these, lipid peroxidation has been the most extensively studied. However, randomised clinical trials of chain-breaking antioxidants have failed to prevent CVD.4,5 It is possible to argue that such agents may not have been ideal antioxidants; perhaps, for example, they may themselves yield free radicals once they have undergone oxidation.26 Whatever the explanation, however, the trial evidence certainly does not support the hypothesis that oxidative modification is the only modification of LDL that can lead to atherosclerosis. Furthermore, LDL oxidised to the extent that is required for macrophage uptake is present in the circulation only at low concentration.27 It has been suggested that conditions in the arterial wall may provide a more intensively oxidative environment and that LDL may be sequestered there.2 However, the

possibility must be entertained that other naturally occurring modifications of LDL that permit it to participate in foam cell formation are worthy of further attention. Glycation is one such modification, and glycated LDL is present in the circulation of both non-diabetic and diabetic people at relatively high concentration.9,28 We have also previously shown that its concentration is increased in primary conditions in which LDL is raised, such as heterozygous familial hypercholesterolaemia.9 Furthermore, we have recently reported that in non-diabetic people SD-LDL is more heavily glycated than other apoB-containing lipoproteins, probably because of the greater surface exposure of the lysine residues of apoB in smaller LDL particles and the longer circulating half-life of SD-LDL.8 In the present study we extend this observation to MS and type 2 diabetes. The overall plasma concentration of glyc-apoB is strongly determined by the concentration of SD-LDL. This is likely to be the major reason for the higher level of glyc-apoB observed here in type 2 diabetic patients not receiving statin treatment. They had a higher proportion of their plasma apoB in SD-LDL than either MS or DM+S patients. The proportion of apoB glycated in SD-LDL was, nonetheless, higher in MS and DM+S than in more buoyant LDL, which may explain at least some of the increased CVD risk in MS and persisting risk in statintreated patients. In terms of both plasma glyc-apoB concentration and CVD risk,29 MS appears to be an intermediate phenotype between non-diabetic, healthy, normolipidaemic people and those with frank diabetes. Although the present study was small and should be viewed in some respects as hypothesis-generating rather than definitive, the relationship between plasma glyc-apoB and SD-LDL was clearly stronger than that with HbA1c in both diabetes and MS. In other studies, too,30,31 glyc-apoB did not show any correlation with glycaemic indices. We9

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294 and others32,28 have, however, previously reported a positive association between plasma glyc-apoB and HbA1c, glucose or fructosamine. In none of these studies was SD-LDL measured. The implication of our present findings is that the earlier reported associations with indices of glycaemia were likely to be due to correlations between these and the concentration of SD-LDL in non-statin-treated type 2 diabetes.33 If glycation of apoB is relevant to atherogenesis, our observations are potentially of fundamental importance in explaining the relative ineffectiveness of improvements in glycaemic control in decreasing CVD risk in diabetes,10 as opposed to statin treatment, which has proved highly effective in this regard.13 The effect of glycaemia might have been underestimated in our study if the glycaemic control in patients on statin treatment had been better or the duration of their diabetes shorter than in those not receiving statins. However, the opposite was the case, providing a more rigorous test of the hypothesis that glyc-apoB is decreased by statin treatment independently of glycaemic control or the severity of diabetes. This conclusion is capable of being tested in randomised trials of glycaemic control, in which we would predict little decrease in glyc-apoB, whereas a much greater decrease would be expected in randomised placebo-controlled statin trials. We cannot rule out the possibility that oral hypoglycaemic therapy may have had some influence on our findings independently of its effect on hypoglycaemia. Metformin, by decreasing methylglyoxal, might have such an effect.34 MS differed from diabetes in terms of the distribution of glyc-apoB among the lipoproteins in that the predominance of glyc-apoB in SD-LDL was less clearly established in MS and, perhaps related to this, the concentration of glyc-apoB in VLDL was higher than in SD-LDL. If MS is viewed as a pre-diabetic state,35 our observation suggests that the transition of MS to diabetes involves the more rapid transfer of apoB to SD-LDL from VLDL. This gains some credence because the proportion of VLDL consisting of large VLDL is known to increase as insulin resistance and hyperglycaemia progress to frank diabetes.36,37 Large VLDL is more rapidly converted to SD-LDL.36,37 It is likely, therefore, that this leads to the increase in SD-LDL in diabetes relative to MS and to the greater accumulation of glyc-apoB in SD-LDL as opposed to VLDL and more buoyant LDL. We conclude that substantial amounts of glyc-apoB circulate in type 2 diabetes and that SD-LDL is the major determinant of its overall concentration in plasma. Plasma levels of glyc-apoB are already increased in MS. Both glyc-apoB and SD-LDL are lower in diabetic patients treated with statins than in patients not receiving such treatment. Further research to elucidate the factors governing LDL glycation may improve our understanding of atherogenesis and suggest novel means of preventing it.

Diabetes and Vascular Disease Research 7(4) Acknowledgements We are grateful to the British Heart Foundation for a grant to carry out this work and for the support provided by the Manchester Academic Health Sciences Centre (MAHSC). Funding This work was supported by the British Heart Foundation. References
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