European Journal of Clinical Investigation

Original Article

Increased large VLDL particles confer elevated cholesteryl ester transfer in diabetes

Corresponding Author

Robin P. F. Dullaart

Department of Endocrinology, University of Groningen and University Medical Center Groningen, Groningen, the Netherlands

Correspondence to: Robin P. F. Dullaart, MD, PhD, Department of Endocrinology, University Medical Center Groningen, PO Box 30001, 9700 RB Groningen, the Netherlands. Tel.: +31 50 361 3731; fax: +31 50 361 9392; e-mail:[email protected]Search for more papers by this author

Rindert de Vries,

Rindert de Vries

Department of Endocrinology, University of Groningen and University Medical Center Groningen, Groningen, the Netherlands

Search for more papers by this author

Arjan J. Kwakernaak,

Arjan J. Kwakernaak

Department of Endocrinology, University of Groningen and University Medical Center Groningen, Groningen, the Netherlands

Search for more papers by this author

Frank Perton,

Frank Perton

Department of Endocrinology, University of Groningen and University Medical Center Groningen, Groningen, the Netherlands

Search for more papers by this author

Geesje M. Dallinga-Thie,

Geesje M. Dallinga-Thie

Department of Experimental Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands

Search for more papers by this author

Robin P. F. Dullaart,

Corresponding Author

Robin P. F. Dullaart

Department of Endocrinology, University of Groningen and University Medical Center Groningen, Groningen, the Netherlands

Rindert de Vries,

Rindert de Vries

Department of Endocrinology, University of Groningen and University Medical Center Groningen, Groningen, the Netherlands

Search for more papers by this author

Arjan J. Kwakernaak,

Arjan J. Kwakernaak

Department of Endocrinology, University of Groningen and University Medical Center Groningen, Groningen, the Netherlands

Search for more papers by this author

Frank Perton,

Frank Perton

Department of Endocrinology, University of Groningen and University Medical Center Groningen, Groningen, the Netherlands

Search for more papers by this author

Geesje M. Dallinga-Thie,

Geesje M. Dallinga-Thie

Department of Experimental Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands

Search for more papers by this author

First published: 17 November 2014

https://doi.org/10.1111/eci.12377

Citations: 15

Share a link

Email
Wechat
Bluesky

Abstract

Background

Plasma cholesteryl ester transfer (CET), reflecting transfer of cholesteryl esters from high density lipoproteins (HDL) towards apolipoprotein B-containing lipoproteins, may promote atherosclerosis development, and is elevated in Type 2 diabetes mellitus (T2DM). We determined the extent to which the relationship of plasma CET with very low density lipoprotein (VLDL) and low density lipoprotein (LDL) subfractions is modified in T2DM.

Materials and methods

Plasma CET, cholesteryl ester transfer protein (CETP) mass, as well as VLDL and LDL subfractions (nuclear magnetic resonance spectroscopy) were determined in 62 patients with T2DM and 53 nondiabetic subjects.

Results

Plasma CET and CETP mass were increased in T2DM, coinciding higher triglycerides and large VLDL particles (all P < 0·02). Plasma CET was positively related to the VLDL and the LDL particle concentration in age-, sex- and diabetes status-adjusted analysis (both P < 0·001). Multivariable linear regression analysis demonstrated an independent positive interaction between the presence of T2DM and the VLDL concentration on plasma CET (β = 0·238, P = 0·033). The relationship of plasma CET with the VLDL concentration was also positively modified by plasma glucose (β = 0·211, P = 0·004) and glycated haemoglobin (β = 0·190, P = 0·012). Of the individual VLDL subfractions, a positive interaction of diabetes status with large VLDL on plasma CET was observed (β = 0·280, P = 0·003). Neither the relationship of the LDL particle concentration nor of CETP mass with plasma CET was modified by the presence of T2DM (P > 0·15).

Conclusion

Abnormalities in the concentration and composition of large VLDL particles are likely to contribute to elevated plasma CET in T2DM.

Supporting Information

References

1Dallinga-Thie GM, Dullaart RPF, van Tol A. Concerted actions of cholesteryl ester transfer protein and phospholipid transfer protein in type 2 diabetes: effects of apolipoproteins. Curr Opin Lipidol 2007; 18: 251–7.
10.1097/MOL.0b013e3280e12685
CAS PubMed Web of Science® Google Scholar
2Kappelle PJ, van Tol A, Wolffenbuttel BH, Dullaart RPF. Cholesteryl ester transfer protein inhibition in cardiovascular risk management: ongoing trials will end the confusion. Cardiovasc Ther 2011; 29: e89–99.
10.1111/j.1755-5922.2010.00201.x
PubMed Web of Science® Google Scholar
3Borggreve SE, de Vries R, Dullaart RPF. Alterations in high-density lipoprotein metabolism and reverse cholesterol transport in insulin resistance and type 2 diabetes mellitus: role of lipolytic enzymes, lecithin:cholesterol acyltransferase and lipid transfer proteins. Eur J Clin Invest 2003; 33: 1051–69.
10.1111/j.1365-2362.2003.01263.x
CAS PubMed Web of Science® Google Scholar
4de Vries R, Perton FG, Dallinga-Thie GM, van Roon AM, Wolffenbuttel BH, van Tol A et al. Plasma cholesteryl ester transfer is a determinant of intima-media thickness in type 2 diabetic and nondiabetic subjects: role of CETP and triglycerides. Diabetes 2005; 54: 3554–9.
10.2337/diabetes.54.12.3554
PubMed Web of Science® Google Scholar
5Zeller M, Masson D, Farnier M, Lorgis L, Deckert V, Pais de Barros JP et al. High serum cholesteryl ester transfer rates and small high-density lipoproteins are associated with young age in patients with acute myocardial infarction. J Am Coll Cardiol 2007; 50: 1948–55.
10.1016/j.jacc.2007.06.052
CAS PubMed Web of Science® Google Scholar
6Kappelle PJ, Perton F, Hillege HL, Dallinga-Thie GM, Dullaart RPF. High plasma cholesteryl ester transfer but not CETP mass predicts incident cardiovascular disease: a nested case-control study. Atherosclerosis 2011; 217: 249–52.
10.1016/j.atherosclerosis.2011.03.020
CAS PubMed Web of Science® Google Scholar
7Mann CJ, Yen FT, Grant AM, Bihain BE. Mechanism of plasma cholesteryl ester transfer in hypertriglyceridemia. J Clin Invest 1991; 88: 2059–66.
10.1172/JCI115535
CAS PubMed Web of Science® Google Scholar
8Riemens S, van Tol A, Sluiter W, Dullaart RPF. Elevated plasma cholesteryl ester transfer in NIDDM: relationships with apolipoprotein B-containing lipoproteins and phospholipid transfer protein. Atherosclerosis 1998; 140: 71–9.
10.1016/S0021-9150(98)00111-7
CAS PubMed Web of Science® Google Scholar
9de Vries R, Dikkeschei BD, Sluiter WJ, Dallinga-Thie GM, van Tol A, Dullaart RPF. Statin and fibrate combination does not additionally lower plasma cholesteryl ester transfer in type 2 diabetes mellitus. Clin Lab 2012; 58: 1231–9.
PubMed Web of Science® Google Scholar
10Dullaart RPF, Groener JEM, Erkelens DW. Effect of the composition of very low and low density lipoproteins on the rate of cholesterylester transfer from high density lipoproteins in man, studied in vitro. Eur J Clin Invest 1987; 17: 241–8.
10.1111/j.1365-2362.1987.tb01243.x
CAS PubMed Web of Science® Google Scholar
11Eisenberg S. Preferential enrichment of large-sized very low density lipoprotein populations with transferred cholesteryl esters. J Lipid Res 1985; 26: 487–94.
CAS PubMed Web of Science® Google Scholar
12Bagdade JDD, Lane JT, Subbaiah PV, Otto ME, Ritter MC. Accelerated cholesteryl ester transfer in noninsulin-dependent diabetes mellitus. Atherosclerosis 1993; 104: 69–77.
10.1016/0021-9150(93)90177-V
CAS PubMed Web of Science® Google Scholar
13Bahanagar D, Durrington PN, Kumar S, Mackness MI, Boulton AJ. Plasma lipoprotein composition and cholesteryl ester transfer from high density lipoproteins to very low density and low density lipoproteins in patients with non-insulin-dependent diabetes mellitus. Diabet Med 1996; 13: 139–44.
10.1002/(SICI)1096-9136(199602)13:2<139::AID-DIA15>3.0.CO;2-C
PubMed Web of Science® Google Scholar
14Sutherland WH, Walker RJ, Lewis-Barned NJ, Pratt H, Tillman HC. Plasma cholesteryl ester transfer in patients with non-insulin dependent diabetes mellitus. Clin Chim Acta 1994; 231: 29–38.
10.1016/0009-8981(94)90251-8
CAS PubMed Web of Science® Google Scholar
15Lottenberg SA, Lottenberg AM, Nunes VS, McPherson R, Quintão EC. Plasma cholesteryl ester transfer protein concentration, high-density lipoprotein cholesterol esterification and transfer rates to lighter density lipoproteins in the fasting state and after a test meal are similar in Type II diabetics and normal controls. Atherosclerosis 1996; 127: 81–90.
10.1016/S0021-9150(96)05938-2
CAS PubMed Web of Science® Google Scholar
16Simera I, Moher D, Hoey J, Schulz KF, Altman DGA. A catalogue of reporting guidelines for health research. Eur J Clin Invest 2010; 40: 14–22.
10.1111/j.1365-2362.2009.02234.x
Web of Science® Google Scholar
17Jeyarajah EJ, Cromwell WC, Otvos JD. Lipoprotein particle analysis by nuclear magnetic resonance spectroscopy. Clin Lab Med 2006; 26: 847–70.
10.1016/j.cll.2006.07.006
PubMed Web of Science® Google Scholar
18Channon KM, Clegg RJ, Bhatnagar D, Ishola M, Arrol S, Durrington PN. Investigation of lipid transfer in human serum leading to the development of an isotopic method for the determination of endogenous cholesterol esterification and transfer. Atherosclerosis 1990; 80: 217–26.
10.1016/0021-9150(90)90029-I
CAS PubMed Web of Science® Google Scholar
19Selvin S. Statistical Analysis of Epidemiological Data. New York, NY: Oxford University Press; 1996.
Google Scholar
20Lu M, Lyden PD, Brott TG, Hamilton S, Broderick JP, Grotta JC. Beyond subgroup analysis: improving the clinical interpretation of treatment effects in stroke research. J Neurosci Methods 2005; 143: 209–16.
10.1016/j.jneumeth.2004.10.002
PubMed Web of Science® Google Scholar
21Taskinen MR. Diabetic dyslipidaemia: from basic research to clinical practice. Diabetologia 2003; 46: 733–49.
10.1007/s00125-003-1111-y
PubMed Web of Science® Google Scholar
22Garvey WT, Kwon S, Zheng D, Shaughnessy S, Wallace P, Hutto A et al. Effects of insulin resistance and type 2 diabetes on lipoprotein subclass particle size and concentration determined by nuclear magnetic resonance. Diabetes 2003; 52: 453–62.
10.2337/diabetes.52.2.453
CAS PubMed Web of Science® Google Scholar
23Mora S, Otvos JD, Rosenson RS, Pradhan A, Buring JE, Ridker PM. Lipoprotein particle size and concentration by nuclear magnetic resonance and incident type 2 diabetes in women. Diabetes 2010; 59: 1153–60.
10.2337/db09-1114
CAS PubMed Web of Science® Google Scholar
24Dullaart RPF, Constantinides A, Perton FG, van Leeuwen JJ, van Pelt JL, de Vries R et al. Plasma cholesteryl ester transfer, but not cholesterol esterification, is related to lipoprotein-associated phospholipase A2: possible contribution to an atherogenic lipoprotein profile. J Clin Endocrinol Metab 2011; 96: 1077–84.
10.1210/jc.2010-2139
CAS PubMed Web of Science® Google Scholar
25Dullaart RPF, De Vries R, Scheek L, Borggreve SE, Van Gent T, Dallinga-Thie GM et al. Type 2 diabetes mellitus is associated with differential effects on plasma cholesteryl ester transfer protein and phospholipid transfer protein activities and concentrations. Scand J Clin Lab Invest 2004; 64: 205–15.
10.1080/00365510410005721
CAS PubMed Web of Science® Google Scholar
26Bouillet B, Gautier T, Blache D, Pais de Barros JP, Duvillard L, Petit JM et al. Glycation of apolipoprotein C1 impairs Its CETP inhibitory property: pathophysiological relevance in patients with type 1 and type 2 diabetes. Diabetes Care 2014; 37: 1148–56.
10.2337/dc13-1467
CAS PubMed Web of Science® Google Scholar
27Adiels M, Borén J, Caslake MJ, Stewart P, Soro A, Westerbacka J et al. Overproduction of VLDL1 driven by hyperglycemia is a dominant feature of diabetic dyslipidemia. Arterioscler Thromb Vasc Biol 2005; 25: 1697–703.
10.1161/01.ATV.0000172689.53992.25
CAS PubMed Web of Science® Google Scholar
28Adiels M, Taskinen MR, Packard C, Caslake MJ, Soro-Paavonen A, Westerbacka J et al. Overproduction of large VLDL particles is driven by increased liver fat content in man. Diabetologia 2006; 49: 755–65.
10.1007/s00125-005-0125-z
CAS PubMed Web of Science® Google Scholar
29Barter PJ, Brewer HB Jr, Chapman MJ, Hennekens CH, Rader DJ, Tall AR. Cholesteryl ester transfer protein: a novel target for raising HDL and inhibiting atherosclerosis. Arterioscler Thromb Vasc Biol 2003; 23: 160–7.
10.1161/01.ATV.0000054658.91146.64
CAS PubMed Web of Science® Google Scholar
30Boekholdt SM, Kuivenhoven JA, Wareham NJ, Peters RJ, Jukema JW, Luben R et al. Plasma levels of cholesteryl ester transfer protein and the risk of future coronary artery disease in apparently healthy men and women: the prospective EPIC (European Prospective Investigation into Cancer and nutrition)-Norfolk population study. Circulation 2004; 110: 1418–23.
10.1161/01.CIR.0000141730.65972.95
CAS PubMed Web of Science® Google Scholar
31Borggreve SE, Hillege HL, Dallinga-Thie GM, de Jong PE, Wolffenbuttel BH, Grobbee DE et al. High plasma cholesteryl ester transfer protein levels may favour reduced incidence of cardiovascular events in men with low triglycerides. Eur Heart J 2007; 28: 1012–8.
10.1093/eurheartj/ehm062
CAS PubMed Web of Science® Google Scholar
32Ritsch A, Scharnagl H, Eller P, Tancevski I, Duwensee K, Demetz E et al. Cholesteryl ester transfer protein and mortality in patients undergoing coronary angiography: the Ludwigshafen Risk and Cardiovascular Health study. Circulation 2010; 121: 366–74.
10.1161/CIRCULATIONAHA.109.875013
CAS PubMed Web of Science® Google Scholar
33Vasan RS, Pencina MJ, Robins SJ, Zachariah JP, Kaur G, D'Agostino RB et al. Association of circulating cholesteryl ester transfer protein activity with incidence of cardiovascular disease in the community. Circulation 2009; 120: 2414–20.
10.1161/CIRCULATIONAHA.109.872705
CAS PubMed Web of Science® Google Scholar
34Robins SJ, Lyass A, Brocia RW, Massaro JM, Vasan RS. Plasma lipid transfer proteins and cardiovascular disease. The Framingham Heart Study. Atherosclerosis 2013; 228: 230–6.
10.1016/j.atherosclerosis.2013.01.046
CAS PubMed Web of Science® Google Scholar
35Parish S, Offer A, Clarke R, Hopewell JC, Hill MR, Otvos JD et al. Lipids and lipoproteins and risk of different vascular events in the MRC/BHF Heart Protection Study. Circulation 2012; 125: 2469–78.
10.1161/CIRCULATIONAHA.111.073684
CAS PubMed Web of Science® Google Scholar
36Arsenault BJ, Lemieux I, Després JP, Wareham NJ, Stroes ES, Kastelein JJ et al. Comparison between gradient gel electrophoresis and nuclear magnetic resonance spectroscopy in estimating coronary heart disease risk associated with LDL and HDL particle size. Clin Chem 2010; 56: 789–98.
10.1373/clinchem.2009.140939
CAS PubMed Web of Science® Google Scholar

Citing Literature

Volume45, Issue1

January 2015

Pages 36-44

Increased large VLDL particles confer elevated cholesteryl ester transfer in diabetes

Abstract

Background

Materials and methods

Results

Conclusion

Supporting Information

References

Citing Literature

References

Information

About Wiley Online Library

Help & Support

Opportunities

Connect with Wiley

Increased large VLDL particles confer elevated cholesteryl ester transfer in diabetes

Abstract

Background

Materials and methods

Results

Conclusion

Supporting Information

References

Citing Literature

References

Related

Information