help button home button Endocrine Society JCEM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Tan, K. C. B.
Right arrow Articles by Lam, K. S. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Tan, K. C. B.
Right arrow Articles by Lam, K. S. L.
The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 9 3212-3216
Copyright © 1999 by The Endocrine Society

Original Studies

Influence of Low Density Lipoprotein (LDL) Subfraction Profile and LDL Oxidation on Endothelium-Dependent and Independent Vasodilation in Patients with Type 2 Diabetes1

K. C. B. Tan, V. H. G. Ai, W. S. Chow, M. T. Chau, L. Leong and K. S. L. Lam

Department of Medicine, University of Hong Kong, and the Department of Diagnostic Radiology, Queen Mary Hospital (V.H.G.A., M.T.C., L.L.), Hong Kong

Address all correspondence and requests for reprints to: Dr. K. Tan, Department of Medicine, Queen Mary Hospital, Pokfulam Road, Hong Kong.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Recent studies have suggested that hypercholesterolemia is associated with endothelial dysfunction. In patients with type 2 diabetes mellitus, dyslipidemia is mainly characterized by hypertriglyceridemia, low high density lipoprotein, and a preponderance of small dense low density lipoprotein (LDL) particles. We have examined the relationships among LDL subfractions, the susceptibility of LDL to oxidation in vitro, and endothelial function in type 2 diabetes mellitus. LDL subfractions were measured by density gradient ultracentrifugation. The susceptibility of LDL to oxidation was determined by measuring the kinetics of conjugated dienes formation during copper-mediated oxidation of LDL. Endothelium-dependent and independent vasodilation of the brachial artery were assessed by high resolution vascular ultrasound. Diabetic patients had a higher concentration of small dense LDL-III than matched controls (P < 0.01). The lag phase of conjugated dienes formation was shorter in the diabetic patients (P < 0.05), and the rate of LDL oxidation was faster (P < 0.05). Both endothelium-dependent (P < 0.01) and independent dilation of the brachial artery (P < 0.01) were impaired in the diabetic patients. On multivariate analysis, the rate of oxidation and LDL-III concentration accounted for 12% and 6%, respectively, of the variation in endothelium-dependent vasodilation (adjusted r2 = 0.18; P < 0.05), whereas LDL-III concentration and the maximum amount of conjugated dienes formed accounted for 27% and 5%, respectively, of the variation in endothelium-independent vasodilation (adjusted r2 = 0.32; P < 0.01) in the diabetic patients. In conclusion, endothelial and smooth muscle cell dysfunction in type 2 diabetes were related to abnormalities in LDL subfractions and in LDL oxidation.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
IT IS INCREASINGLY recognized that the endothelium has many important functions and is not just a passive semipermeable barrier between blood and the interstitium. These include the regulation of vasomotor tone, the inhibition of platelet activity, the maintenance of the balance between thrombosis and fibrinolysis, and the regulation of the recruitment of inflammatory cells into the vascular wall. There is evidence from both experimental and clinical studies that endothelial dysfunction is an early event in atherogenesis and precedes the thickening of the intima and the formation of atherosclerotic plaques (1, 2). Abnormalities in endothelial cell function have recently been demonstrated in patients with coronary heart disease, hypertension, and hypercholesterolemia (3, 4, 5) and in the majority of the studies of patients with type 1 diabetes mellitus (6, 7, 8) or type 2 diabetes mellitus (9, 10, 11, 12, 13). Several mechanisms have been suggested to cause or contribute to the endothelial dysfunction in diabetes mellitus. These include increased oxidative stress, hyperlipidemia, formation of advanced glycation end products, insulin resistance, activation of protein kinase C, and expression of certain cytokines (14).

In patients with type 2 diabetes, dyslipidemia is characterized by hypertriglyceridemia, low high density lipoprotein (HDL), and a preponderance of small dense low density lipoprotein (LDL) particles (15, 16). Watts et al. reported that endothelial dysfunction was independently related to the degree of dyslipidemia in type 2 diabetes (10), and they subsequently showed that small LDL particle size was associated with endothelial dysfunction in these patients (13). LDL heterogeneity is known to be linked to coronary risk status, and individuals with predominantly small dense LDL have an increased risk of developing coronary heart disease (17, 18). A small dense LDL particle appears to be particularly atherogenic because it is more easily oxidized than its larger counterpart (19) and binds more readily to arterial wall proteoglycans (20). The aim of the present study was to examine whether changes in endothelial function in patients with type 2 diabetes were related to LDL heterogeneity and to the susceptibility of LDL to oxidation.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Patients with type 2 diabetes were recruited from the diabetic clinics at Queen Mary Hospital. Only patients without proteinuria and history of cardiovascular disease were selected. All patients were nonsmokers and normotensive and had stable glycemic control and normal renal function. A resting electrocardiogram was normal in all of the patients, and ultrasound studies of the carotid arteries were performed to exclude patients with asymptomatic macrovascular disease. Subjects found to have atherosclerotic plaques were not recruited into the study. Forty-five patients (22 men and 23 women) fulfilled the recruitment criteria. Two patients were receiving dietary treatment, 41 patients were taking oral hypoglycemic agents (a sulfonylurea, metformin, or both), and 2 patients were taking a combination of insulin and metformin. None of the patients was taking lipid-lowering agents. Each patient was matched with a nonsmoking control subject of the same sex, similar age, and similar body mass index (BMI). Females were matched for menopausal status, and none of the postmenopausal patients or controls were taking hormone replacement therapy. The study was approved by the ethics committee of the University of Hong Kong, and informed consent was obtained from all subjects.

Fasting blood samples were taken for the measurement of lipids, glucose, and hemoglobin A1c (HbA1c) and for the isolation of LDL. Total cholesterol and triglycerides (TG) were determined enzymatically (Roche Molecular Biochemicals, Mannheim, Germany) using a Hitachi 717 analyzer (Roche Molecular Biochemicals). HDL cholesterol was measured by the same method after precipitation of apolipoprotein B-containing lipoproteins with polyethylene glycol 6000. LDL cholesterol was calculated using the Friedewald equation. HbA1c was measured in whole blood using ion exchange high performance liquid chromatography (Variant Analyzer System, Bio-Rad Laboratories, Inc., Richmond, CA).

Oxidation of unfractionated LDL

Measurement of LDL oxidation was carried out immediately after blood samples were collected. LDL was isolated by discontinuous density gradient ultracentrifugation using a Beckman Coulter, Inc. VTi-65 rotor (Palo Alto, CA; 1.5 h at 65,000 rpm at 10 C). The LDL fraction was aspirated and passed over an Econo-PacI0DG column (Bio-Rad Laboratories, Inc.) to desalt and remove the ethylenediamine tetraacetate, and the cholesterol content was measured enzymatically. LDL purity was confirmed by gel electrophoresis. LDL oxidation was measured by the method of Esterbauer et al. (21). Copper (1.66 µmol/L) was added to a spectrophotometer cuvette containing LDL (80 µg cholesterol/mL in phosphate-buffered saline), and the kinetics of conjugated dienes formation were monitored by changes in absorbance at 234 nm at 30 C recorded every 2 min for up to 8 h. Three characteristic phases (lag, propagation, and decomposition) were observed. The lag time was calculated from the time interval between initiation of oxidation and the intercept of the tangent of the slope of the absorbance curve. The rate of oxidation was derived form the slope of the curve, and the maximum amount of dienes formed before onset of decomposition was calculated by the maximum increase in absorbance.

LDL subfractions

LDL subfractionation was achieved by density gradient ultracentrifugation using a six-step discontinuous salt gradient as previously described (16). In brief, plasma was fractionated into three distinct LDL subfractions after 24-h centrifugation in a Beckman Coulter, Inc. SW40 rotor (Palo Alto, CA; 40,000 rpm, 23 C). The gradient containing the separated LDL fractions was displaced from the tube by upward displacement and identified by absorbance at 280 nm. The elution times of the first, least dense, LDL fraction and the appearance of plasma proteins were reproducible and provided references for the identification of LDL subfractions. Major LDL subfractions were identified by peak maxima that occurred between hydrated density intervals of 1.025–1.034 g/mL (LDL-I), 1.034–1.044 g/mL (LDL-II), or 1.044–1.060 g/mL (LDL-III). The individual subfraction areas beneath the LDL profiles were quantified, and the total LDL mass (all protein and lipid components) was then subdivided in proportion to the percent area. This gave rise to concentration values for each LDL subfraction in milligrams of lipoprotein per 100 mL plasma.

Vascular ultrasound study

High resolution B-mode ultrasound was used to document the presence or absence of carotid artery atherosclerosis and to measure carotid intima-media thickness (IMT). Subjects with carotid atherosclerotic lesions based on criteria similar to those used in the Atherosclerosis Risk in Communities Study (22) were excluded from the study. Ultrasonographic scanning of carotid arteries was performed with an ATL HDI 3000 ultrasound system (Advanced Technology Laboratories, Inc., Bothell, WA). The anterior, lateral, and posterolateral projections were used to image longitudinally the right and left common carotid arteries. At each longitudinal projection, three determinations of IMT were made at 2 cm proximal to the bulb and at the site of greatest thickness. The values at each site were averaged, and the greatest value of the averaged IMT was used as the representative value for each individual.

Endothelium-dependent vasodilation and endothelium-independent vasodilation of the brachial artery were assessed noninvasively using high resolution ultrasound as described by Celermajer et al. (23). Flow-mediated vasodilation caused by reactive hyperemia is related to the release of nitric oxide and is therefore an endothelium-dependent phenomenon, whereas endothelium-independent vasodilation is induced by glyceryl trinitrate (GTN), which acts on the vascular smooth muscle. Brachial artery diameter was measured from B-mode ultrasound images (10-MHz linear array transducer on an ATL HDI 3000 ultrasound system) with continuous electrocardiogram recording. After optimal transducer positioning, the arm was kept in the same position, and the skin was marked. Diameter measurements of the right brachial artery were taken at rest after the subject had been lying quietly for at least 15 min, and then during reactive hyperemia after occlusion by inflation of pneumatic tourniquet to a pressure of 300 mm Hg for 4.5 min. Twenty minutes were allowed for vessel recovery, and then a further resting scan was taken. Sublingual GTN spray (400 µg) was administered, and measurements were repeated after 5 min. Measurements were taken from the anterior to the posterior m line at end diastole, incident with the R-wave on the electrocardiogram. Three cardiac cycles were analyzed, and measurements were averaged. Flow-mediated and GTN-induced vasodilation was calculated as the percent change in diameter compared to baseline. Blood pressure was measured with a Dinamap (Critikon, Inc., Tampa, FL). All scans were performed by V.A., who was blinded with respect to the group to which the subject belonged.

Statistical analysis was performed using the SPSS, Inc. (version 4, SPSS, Inc., Chicago, IL) statistics package. Data were tested for normality, and results were expressed as the mean and SD or as the median and range if the distribution of the data were skewed. TG was logarithmically transformed before analyses were made because of the skewed distribution. Comparisons between groups were made by t test. Correlation between variables was tested using both univariate and multivariate analyses (Pearson’s correlation analysis and multiple stepwise regression analysis).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The clinical characteristics of the patients and controls are shown in Table 1Go. The two groups were well matched for age and BMI. As expected, HbA1c was significantly higher in the diabetic patients than in the controls (Table 1Go). There was no significant difference in plasma total cholesterol and LDL cholesterol, but the diabetic patients had higher fasting TG (P < 0.05) and lower HDL cholesterol than the controls (P < 0.01; Table 1Go). The LDL subfraction profile is shown in Fig. 1Go. The diabetic patients had significantly higher concentration of small dense LDL-III than the controls (P < 0.01). The results for the parameters of LDL oxidation are shown in Table 2Go. The lag time was significantly shorter in the diabetic patients than in the controls (P < 0.05), and the rate of LDL oxidation was faster (P < 0.05). The maximum amount of dienes formed (maximum increase in absorbance) was also higher in the diabetic patients (P < 0.01). The lag phase correlated inversely with LDL-III concentration (r = -0.35; P < 0.05) in the diabetic patients.


View this table:
[in this window]
[in a new window]
  		Table 1. Clinical characteristics of diabetic patients and controls

 


View larger version (24K):
[in this window]
[in a new window]
  		Figure 1. LDL subfractions in diabetic patients and controls. *, P < 0.05; **, P < 0.01 (vs. controls).

 

View this table:
[in this window]
[in a new window]
  		Table 2. Parameters of copper-induced oxidation of LDL

 
There was no significant difference in carotid IMT (diabetic patients vs. controls, 0.77 ± 0.38 vs. 0.60 ± 0.21 mm) and brachial artery diameter between the diabetic patients and the controls (3.7 ± 0.7 vs. 3.8 ± 0.6 mm). Both flow-mediated (5.1 ± 3.9% vs. 9.8 ± 4.8%; P < 0.01) and GTN-induced (13.8 ± 5.0% vs. 17.5 ± 5.7%; P < 0.01) vasodilation of the brachial artery were impaired in the diabetic patients. Univariate analyses were performed to determine the relationships between various lipid parameters and LDL oxidation with flow-mediated and GTN-induced vasodilation. In the controls, no significant correlations were seen with flow-mediated dilation, and GTN-induced dilation correlated with HDL (r = 0.28; P < 0.05). In the diabetic patients, flow-mediated dilation correlated with LDL-III concentration (r = -0.32; P < 0.05), with the lag phase (r = 0.29; P < 0.05), and with the rate of oxidation (r = -0.33; P < 0.05; Fig. 2Go, A–C, respectively). GTN-induced dilation correlated inversely with LDL-III mass (r = -0.49; P < 0.01) and with the maximum amount of dienes formed (r = -0.31; P < 0.05). Neither flow-mediated nor GTN-induced dilation correlated with the other lipid parameters or with age, BMI, duration of diabetes, HbA1c, carotid IMT, or blood pressure measurements. On multivariate analysis, the rate of oxidation and the LDL-III concentration accounted for 12% and 6%, respectively, of the variation in flow-mediated vasodilation (adjusted r2 = 0.18; P < 0.05), whereas LDL-III mass and the maximum amount of dienes formed accounted for 27% and 5% of the variation in GTN-induced dilation (adjusted r2 = 0.32; P < 0.01) in the diabetic patients. As there were previous studies suggesting that age, sex, BMI, and HbA1c might also be important determinants, multivariate analyses performed with the inclusion of these additional variables did not further improve the predictive power of the model.



View larger version (13K):
[in this window]
[in a new window]
  		Figure 2. A–C, Correlations between flow-mediated vasodilation and LDL-III concentration (A), lag time (B), and oxidation rate (C) in patients with type 2 diabetes.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In the present study, we have investigated the relationships between LDL heterogeneity and the susceptibility of LDL to oxidation in vitro with vasomotor function in patients with type 2 diabetes. Impaired endothelium-dependent vasodilation has been consistently demonstrated in patients with type 2 diabetes in previous studies using either vascular ultrasound (11) or strain gauge plethysmography (9, 10, 12, 13) to measure forearm blood flow. However, some, but not all, studies have shown abnormalities in endothelium-independent vasodilation (9, 10, 13). We have found that both endothelium-dependent and independent vasodilation are impaired in patients with type 2 diabetes and are related to small dense LDL concentration and to parameters of LDL oxidation in diabetes. Similar to our findings, Watts et al. reported that endothelium-dependent vasodilation in type 2 diabetes was related to LDL particle size, but they did not find a similar relationship between endothelium-independent vasodilation and LDL particle size (13). There were some differences in methodology, which might partly explain this discrepancy. Watts et al. measured the particle size of the dominant LDL peak by nondenaturing gradient gel electrophoresis. This would not take into account the relative proportion and absolute concentration of each LDL subfraction, whereas we have measured LDL subfractions by a density gradient ultracentrifugation method that gives a quantitative measurement of individual LDL subfraction. Other than the changes in LDL subfractions and oxidation, the small difference in systolic blood pressure between the diabetic patients and the controls, although not statistically significant, might have also contributed to some of the differences in endothelial function in our study.

Oxidatively modified LDL is an important mediator in the pathogenesis of atherosclerosis. As the plasma compartment is well buffered against oxidative stress, LDL oxidation is thought to take place at the endothelial surface, as LDL traverses the endothelial barrier, or within the subendothelial space. Hence, factors that control the extent of LDL entry and retention into the subendothelial space may have an influence on endothelial vasomotor function (24). This might partly explain the relationship between small dense LDL concentration and endothelium-dependent and independent vasodilation. Small dense LDL is less well recognized by LDL receptor clearance mechanisms and therefore has a longer half-life in the plasma compartment than other lipoprotein subfractions (18). It also penetrates the arterial intima more readily than other lipoproteins and exhibits increased residence time because of its greater affinity for subendothelial proteoglycans (18, 20). As a result, small dense LDL is more readily available to be oxidized. In addition, small dense LDL particles are themselves more susceptible to oxidation. Although we have only measured the susceptibility of total unfractionated LDL to oxidation in our study, we have shown that the lag phase was inversely proportional to the concentration of LDL-III present in the LDL fraction. Tribble et al. had also demonstrated that the oxidative susceptibility of unfractionated LDL correlated with the diameter of the predominant LDL species (19). Different LDL subfractions differ in their susceptibility to oxidation in vitro, and large buoyant LDL is more resistant, whereas small dense LDL is more susceptible to oxidation (19, 25). Upon oxidation, the formation of the lysophospholipid lysophosphatidylcholine, which is known to mediate some of the adverse effects on vasomotor function ascribed to oxidized LDL (26), is also greater in dense LDL subfractions (27).

Increased susceptibility of LDL to oxidation in vitro has been reported in type 2 diabetes (28). In addition to changes in LDL subfractions, increased glycation of LDL and the seeding of lipoproteins with lipid peroxidation products in vivo may also contribute to the increase in the susceptibility of LDL to oxidation in diabetes (29). Our findings of enhanced LDL oxidation in vitro are consistent with the observation that autoantibodies to oxidized LDL are increased in type 2 diabetic patients, implying that there might be increased LDL oxidation in these patients in vivo (29). Abnormalities in LDL oxidation were related to impaired vasomotor function in our diabetic patients. Oxidized LDL has been shown to have a marked effect on endothelium-dependent vasodilation. An association between the in vitro susceptibility of LDL to oxidation and endothelium-dependent coronary vasomotion has been described in patients with hypercholesterolemia (30). When added to arterial rings in vitro, oxidized LDL inhibits nitric oxide-stimulated (endothelium-dependent) vasodilation (31, 32). Oxidized LDL interferes with the L-arginine pathway and may affect the intracellular availability of L-arginine and hence nitric oxide production (33). It can also cause enhanced destruction of nitric oxide (34). Experimental studies have shown that oxidized LDL may also affect the viability and function of vascular smooth muscle cells and leads to changes in endothelium-independent vasodilation. Oxidized LDL has been found in the subendothelium of atherosclerotic arterial wall and in direct contact with smooth muscle cells in atherosclerotic fibrous plaques (35). When added to deendothelialized segments, oxidized LDL causes inhibition of vascular smooth muscle relaxation by causing an intense and sustained rise in intracellular calcium in smooth muscle cell (36, 37). It has therefore been suggested that the endothelium-independent contractile effect elicited by oxidized LDL in vascular smooth muscle may constitute an additional mechanism leading to abnormalities in vascular tone.

In summary, we have demonstrated that both endothelium-dependent and independent vasodilation are impaired in patients with type 2 diabetes, and these changes in vasomotor function are partly related to the abnormalities in LDL subfraction profile and to LDL oxidation in these patients.


   Acknowledgments
 
The authors are grateful to Mr. Sammy Shiu and Ms. Betty Chu for their technical assistance.


   Footnotes
 
1 This work was supported by a grant from the Hong Kong Research Grants Council (HKU 483/96M). Back

Received January 19, 1999.

Revised May 7, 1999.

Accepted May 10, 1999.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Cohen RA, Zitnay KM, Haudenschild CC, Cunningham LD. 1988 Loss of selective endothelial cell vasoactive functions caused by hypercholesterolaemia in pig coronary arteries. Circ Res. 63:903–910.[Abstract/Free Full Text]
  2. McLenachan JM, Williams JK, Fish ED, Ganz P, Selwyn AP. 1991 Loss of flow-mediated endothelium dependent dilation occurs early in the development of atherosclerosis. Circulation. 84:1273–1278.[Abstract/Free Full Text]
  3. Zeiher AM, Drexler H, Wollschlager H, Just H. 1991 Modulation of coronary vasomotor tone in humans. Progressive endothelial dysfunction with different early stages of coronary atherosclerosis. Circulation. 83:391–401.[Abstract/Free Full Text]
  4. Creager MA, Cooke JP, Mendelsohn ME, Gallagher SJ, Coleman SM, Loscalzo J, Dzau VJ. 1990 Impaired vasodilation of forearm resistance vessels in hypercholesterolaemic humans. J Clin Invest. 86:228–234.
  5. Reddy KG, Nair RN, Sheehan HM, Hodgson JMcB. 1994 Evidence that selective endothelial dysfunction may occur in the absence of angiographic or ultrasound atherosclerosis in patients with risk factors for atherosclerosis. J Am Coll Cardiol. 23:833–843.[Abstract]
  6. Johnstone MT, Creager SJ, Scales KM, Cusco JA, Lee BK, Creager MA. 1993 Impaired endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus. Circulation. 88:2510–2516.[Abstract/Free Full Text]
  7. Clarkson P, Celermajer DS, Donald AE, et al. 1996 Impaired vascular reactivity in insulin-dependent diabetes mellitus is related to disease duration and low density lipoprotein cholesterol levels. J Am Coll Cardiol. 28:573–579.[Abstract]
  8. Lambert J, Aarsen M, Donker AJM, Stehower CDA. 1996 Endothelium-dependent and independent vasodilation of large arteries in normoalbuminuric insulin-dependent diabetes mellitus. Arterioscler Thromb Vasc Biol. 16:705–710.[Abstract/Free Full Text]
  9. McVeigh GE, Brennan GM, Johnston GD, et al. 1992 Impaired endothelium-dependent and independent vasodilation in patients with type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia. 35:771–776.[Medline]
  10. Watts GF, O’Brein SF, Silvester W, Millar JA. 1996 Impaired endothelium-dependent and independent dilatation of forearm resistance arteries in men with diet-treated non-insulin-dependent diabetes mellitus: role of dyslipidaemia. Clin Sci. 91:567–573.[Medline]
  11. Goodfellow J, Ramsey M, Luddington LA, et al. 1996 Endothelium and inelastic arteries: an early marker of vascular dysfunction in non-insulin-dependent diabetes. Br Med J. 312:744–745.[Free Full Text]
  12. Willams SB, Cusco JA, Roddy MA, Johnstone MT, Creager MA. 1996 Impaired nitric oxide-mediated vasodilation in patients with non-insulin-dependent diabetes mellitus. J Am Coll Cardiol. 27:567–574.[Abstract]
  13. O’Brien SF, Watts GF, Playford DA, Burke V, O’Neal DN, Best JD. 1997 Low density lipoprotein size, high density lipoprotein concentration, and endothelial dysfunction in non-insulin-dependent diabetes. Diabetic Med. 14:974–978.[CrossRef][Medline]
  14. Feener EP, King GL. 1997 Vascular dysfunction in diabetes mellitus. Lancet. 350(Suppl 1):9–13.
  15. Betteridge DJ. 1996 Lipids and atherogenesis in diabetes mellitus. Atherosclerosis. 124:S43–S47.
  16. Tan KCB, Cooper MB, Ling KLE, et al. 1995 Fasting and postprandial determinants for the occurrence of small dense LDL species in non-insulin-dependent diabetic patients with and without hypertriglyceridaemia: the involvement of insulin, insulin precursor species and insulin resistance. Atherosclerosis. 113:273–287.[CrossRef][Medline]
  17. Austin MA, Breslow JL, Hennekens CH, Buring JE, Willett WC, Krauss RM. 1988 Low density lipoprotein subclass patterns and risk of myocardial infarction. JAMA. 260:1917–1921.[Abstract/Free Full Text]
  18. Krauss RM. 1994 Heterogeneity of low density lipoproteins and atherosclerosis risk. Curr Opin Lipidol. 5:339–349.[Medline]
  19. Tribble DL, Holl LG, Wood PD, Krauss RM. 1992 Variations in oxidative susceptibility among six low density lipoprotein subfractions of varying size and density. Atherosclerosis. 93:189–199.[CrossRef][Medline]
  20. Anber V, Griffin BA, McConnell M, Packard CJ, Shepherd J. 1996 Influence of plasma lipid and LDL subfraction profile on the interaction between low density lipoprotein with human arterial wall proteoglycans. Atherosclerosis. 124:261–271.[CrossRef][Medline]
  21. Esterbauer H, Striegel G, Puhl H, Rotheneder M. 1989 Continuous monitoring of in vitro oxidation of human LDL. Free Radic Res Commun. 6:67–75.[Medline]
  22. Li R, Duncan BB, Metcalf PA, et al. 1994 for the Atherosclerosis Risk in Communities (ARIC) Study Investigators B-mode-detected carotid artery plaque in a general population. Stroke. 25:2377–2383.[Abstract]
  23. Celermajer DS, Sorensen KE, Gooch VM, et al. 1992 Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet. 340:1111–1115.[CrossRef][Medline]
  24. Witzum JL. 1993 Susceptibility of low-density lipoprotein to oxidative modification. Am J Med. 94:348–349.
  25. Tribble DL. 1995 Lipoprotein oxidation in dyslipidaemia: insights into general mechanisms affecting lipoprotein oxidative behaviour. Curr Opin Lipidol. 6:196–208.[Medline]
  26. Murohara T, Kugiyama K, Ohgushi M, Sugiyama S, Ohta Y, Yasue H. 1994 Lysophosphatidylcholine in oxidised LDL elicits vasoconstriction and inhibits endothelium-dependent relaxation. Am J Physiol 267:H2441–H2449.
  27. Karabina SAP, Liappokos TA, Grekas G, Goudevenos J, Tselepis AD. 1994 Distribution of PAF-acetylhydrolase activity in human plasma low-density lipoprotein subfractions. Biochim Biophys Acta. 1225:34–38.
  28. Cominacini L, Garbin U, Pastorino AM, et al. 1994 Increased susceptibility of LDL to in vitro oxidation in patients with insulin-dependent and non-insulin-dependent diabetes mellitus. Diabetes Res. 26:173–184.[Medline]
  29. Bellomo G, Maggi E, Poli M, Agosta FG, Bollati P, Finardi G. 1995 Autoantibodies against oxidatively modified low density lipoproteins in NIDDM. Diabetes. 44:60–66.[Abstract]
  30. Anderson DJ, Meredith IT, Charbonneau F, Yeung AC, Frei B, Selwyn AP, Ganz P. 1996 Endothelium-dependent coronary vasomotion relates to the susceptibility of LDL to oxidation in humans. Circulation. 93:1647–1650.[Abstract/Free Full Text]
  31. Plane F, Bruckdorfer KR, Kerr P Steuer A, Jacobs M. 1992 Oxidative modification of low density lipoproteins and the inhibition of relaxations mediated by endothelium-derived nitric oxide in rabbit aorta. Br J Pharmacol. 105:216–222.[Medline]
  32. Mougenot N, Lesnik P, Ramirez-Gil JF, Nataf P, Diczfalusy U, Chapman MJ, Lechat P. 1997 Effect of the oxidation state of LDL on the modulation of arterial vasomotor response in vitro. Atherosclerosis. 133:183–192.[CrossRef][Medline]
  33. Tanner FC, Noll G, Boulanger CM, Luscher TF. 1991 Oxidised low density lipoproteins inhibit relaxations of porcine coronaries: role of scavenger receptor and endothelium-derived nitric oxide. Circulation. 83:2012–2020.[Abstract/Free Full Text]
  34. Chin JA, Azhar S, Hoffman BB. 1992 Inactivation of endothelial derived relaxing factor by oxidised lipoprotein. J Clin Invest. 89:10–12.
  35. Ross R. 1993 The pathogenesis of atherosclerosis. Nature. 362:801–809.[CrossRef][Medline]
  36. Gale J, Bauersachs J, Busse R, Bassenge E. 1992 Inhibition of cyclic AMP-and cyclic GMP-mediated dilations in isolated arteries by oxidised low density lipoproteins. Arterioscler Thromb. 12:180–186.[Abstract/Free Full Text]
  37. Auge N, Fitoussi G, Bascands JL, et al. 1996 Mildly oxidised LDL evokes a sustained Ca2+-dependent retraction of vascular smooth muscle cells. Circ Res. 79:871–880.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 Am. J. Clin. Nutr.Home page
M. Negrean, A. Stirban, B. Stratmann, T. Gawlowski, T. Horstmann, C. Gotting, K. Kleesiek, M. Mueller-Roesel, T. Koschinsky, J. Uribarri, et al.
Effects of low- and high-advanced glycation endproduct meals on macro- and microvascular endothelial function and oxidative stress in patients with type 2 diabetes mellitus
Am. J. Clinical Nutrition, May 1, 2007; 85(5): 1236 - 1243.
[Abstract] [Full Text] [PDF]

Home page
 HeartHome page
T H Schindler, A D Facta, J O Prior, J Cadenas, W A Hsueh, M J Quinones, and H R Schelbert
Improvement in coronary vascular dysfunction produced with euglycaemic control in patients with type 2 diabetes
Heart, March 1, 2007; 93(3): 345 - 349.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
H. E. Tawfik, A. B. El-Remessy, S. Matragoon, G. Ma, R. B. Caldwell, and R. W. Caldwell
Simvastatin Improves Diabetes-Induced Coronary Endothelial Dysfunction
J. Pharmacol. Exp. Ther., October 1, 2006; 319(1): 386 - 395.
[Abstract] [Full Text] [PDF]

Home page
 Diabetes CareHome page
E. D. Beishuizen, J. T. Tamsma, J. W. Jukema, M. A. van de Ree, J. C. M. van der Vijver, A. E. Meinders, and M. V. Huisman
The Effect of Statin Therapy on Endothelial Function in Type 2 Diabetes Without Manifest Cardiovascular Disease
Diabetes Care, July 1, 2005; 28(7): 1668 - 1674.
[Abstract] [Full Text] [PDF]

Home page
 FASEB J.Home page
F. R. DANESH and Y. S. KANWAR
Modulatory effects of HMG-CoA reductase inhibitors in diabetic microangiopathy
FASEB J, May 1, 2004; 18(7): 805 - 815.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
K. C. B. Tan, A. Xu, W. S. Chow, M. C. W. Lam, V. H. G. Ai, S. C. F. Tam, and K. S. L. Lam
Hypoadiponectinemia Is Associated with Impaired Endothelium-Dependent Vasodilation
J. Clin. Endocrinol. Metab., February 1, 2004; 89(2): 765 - 769.
[Abstract] [Full Text] [PDF]

Home page
 DiabetesHome page
L. Li, T. Sawamura, and G. Renier
Glucose Enhances Endothelial LOX-1 Expression: Role for LOX-1 in Glucose-Induced Human Monocyte Adhesion to Endothelium
Diabetes, July 1, 2003; 52(7): 1843 - 1850.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
D. Osgood, D. Corella, S. Demissie, L. A. Cupples, P. W. F. Wilson, J. B. Meigs, E. J. Schaefer, O. Coltell, and J. M. Ordovas
Genetic Variation at the Scavenger Receptor Class B Type I Gene Locus Determines Plasma Lipoprotein Concentrations and Particle Size and Interacts with Type 2 Diabetes: The Framingham Study
J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2869 - 2879.
[Abstract] [Full Text] [PDF]

Home page
 Diabetes CareHome page
K. C.B. Tan, W.-S. Chow, V. H.G. Ai, C. Metz, R. Bucala, and K. S.L. Lam
Advanced Glycation End Products and Endothelial Dysfunction in Type 2 Diabetes
Diabetes Care, June 1, 2002; 25(6): 1055 - 1059.
[Abstract] [Full Text] [PDF]

Home page
 Arterioscler. Thromb. Vasc. Bio.Home page
R. W. van Etten, E. J.P. de Koning, M. L. Honing, E. S. Stroes, C. A. Gaillard, and T. J. Rabelink
Intensive Lipid Lowering by Statin Therapy Does Not Improve Vasoreactivity in Patients With Type 2 Diabetes
Arterioscler Thromb Vasc Biol, May 1, 2002; 22(5): 799 - 804.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
K. C. B. Tan, W. S. Chow, S. C. F. Tam, V. H. G. Ai, C. H. L. Lam, and K. S. L. Lam
Atorvastatin Lowers C-Reactive Protein and Improves Endothelium-Dependent Vasodilation in Type 2 Diabetes Mellitus
J. Clin. Endocrinol. Metab., February 1, 2002; 87(2): 563 - 568.
[Abstract] [Full Text] [PDF]

Home page
 Cardiovasc ResHome page
J. Malik, V. Melenovsky, D. Wichterle, T. Haas, J. Simek, R. Ceska, and J. Hradec
Both fenofibrate and atorvastatin improve vascular reactivity in combined hyperlipidaemia (fenofibrate versus atorvastatin trial -- FAT)
Cardiovasc Res, November 1, 2001; 52(2): 290 - 298.
[Abstract] [Full Text] [PDF]

Home page
 HypertensionHome page
D. Perregaux, A. Chaudhuri, S. Rao, A. Airen, M. Wilson, B.-H. Sung, and P. Dandona
Brachial Vascular Reactivity in Blacks
Hypertension, November 1, 2000; 36(5): 866 - 871.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Tan, K. C. B.
Right arrow Articles by Lam, K. S. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Tan, K. C. B.
Right arrow Articles by Lam, K. S. L.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals