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01-03-2021 | Arterial Occlusive Disease | Article

HDL particle size is increased and HDL-cholesterol efflux is enhanced in type 1 diabetes: a cross-sectional study

Authors: Mohamad O. Ahmed, Rachel E. Byrne, Agnieszka Pazderska, Ricardo Segurado, Weili Guo, Anjuli Gunness, Isolda Frizelle, Mark Sherlock, Khalid S. Ahmed, Anne McGowan, Kevin Moore, Gerard Boran, Fiona C. McGillicuddy, James Gibney

Published in: Diabetologia | Issue 3/2021

Abstract

Aims/hypothesis

The prevalence of atherosclerosis is increased in type 1 diabetes despite normal-to-high HDL-cholesterol levels. The cholesterol efflux capacity (CEC) of HDL is a better predictor of cardiovascular events than static HDL-cholesterol. This cross-sectional study addressed the hypothesis that impaired HDL function contributes to enhanced CVD risk within type 1 diabetes.

Methods

We compared HDL particle size and concentration (by NMR), total CEC, ATP-binding cassette subfamily A, member 1 (ABCA1)-dependent CEC and ABCA1-independent CEC (by determining [³H]cholesterol efflux from J774-macrophages to ApoB-depleted serum), and carotid intima–media thickness (CIMT) in 100 individuals with type 1 diabetes (37.6 ± 1.2 years; BMI 26.9 ± 0.5 kg/m²) and 100 non-diabetic participants (37.7 ± 1.1 years; 27.1 ± 0.5 kg/m²).

Results

Compared with non-diabetic participants, total HDL particle concentration was lower (mean ± SD 31.01 ± 8.66 vs 34.33 ± 8.04 μmol/l [mean difference (MD) −3.32 μmol/l]) in participants with type 1 diabetes. However, large HDL particle concentration was greater (9.36 ± 3.98 vs 6.99 ± 4.05 μmol/l [MD +2.37 μmol/l]), resulting in increased mean HDL particle size (9.82 ± 0.57 vs 9.44 ± 0.56 nm [MD +0.38 nm]) (p < 0.05 for all). Total CEC (14.57 ± 2.47%CEC/4 h vs 12.26 ± 3.81%CEC/4 h [MD +2.31%CEC/4 h]) was greater in participants with type 1 diabetes relative to non-diabetic participants. Increased HDL particle size was independently associated with increased total CEC; however, following adjustment for this in multivariable analysis, CEC remained greater in participants with type 1 diabetes. Both components of CEC, ABCA1-dependent (6.10 ± 2.41%CEC/4 h vs 5.22 ± 2.57%CEC/4 h [MD +0.88%CEC/4 h]) and ABCA1-independent (8.47 ± 1.79% CEC/4 h vs 7.05 ± 1.76% CEC/4 h [MD +1.42% CEC/4 h]) CEC, were greater in type 1 diabetes but the increase in ABCA1-dependent CEC was less marked and not statistically significant in multivariable analysis. CIMT was increased in participants with type 1 diabetes but in multivariable analysis it was only associated negatively with age and BMI.

Conclusions/interpretation

HDL particle size but not HDL-cholesterol level is independently associated with enhanced total CEC. HDL particle size is greater in individuals with type 1 diabetes but even after adjusting for this, total and ABCA1-independent CEC are enhanced in type 1 diabetes. Further studies are needed to understand the mechanisms underlying these effects, and whether they help attenuate progression of atherosclerosis in this high-risk group.

Lind M, Svensson AM, Rosengren A (2015) Glycemic control and excess mortality in type 1 diabetes. N Engl J Med 372(9):880–881. https://doi.org/10.1056/NEJMc1415677CrossRefPubMed

Livingstone SJ, Levin D, Looker HC et al (2015) Estimated life expectancy in a Scottish cohort with type 1 diabetes, 2008–2010. JAMA 313(1):37–44. https://doi.org/10.1001/jama.2014.16425

de Ferranti SD, de Boer IH, Fonseca V et al (2014) Type 1 diabetes mellitus and cardiovascular disease: a scientific statement from the American Heart Association and American Diabetes Association. Circulation 130(13):1110–1130. https://doi.org/10.1161/CIR.0000000000000034CrossRefPubMed

Miller GJ, Miller NE (1975) Plasma-high-density-lipoprotein concentration and development of ischaemic heart-disease. Lancet 1(7897):16–19. https://doi.org/10.1016/s0140-6736(75)92376-4CrossRefPubMed

Barter PJ, Caulfield M, Eriksson M et al (2007) Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 357(21):2109–2122. https://doi.org/10.1056/NEJMoa0706628CrossRefPubMed

Schwartz GG, Olsson AG, Abt M et al (2012) Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med 367(22):2089–2099. https://doi.org/10.1056/NEJMoa1206797CrossRefPubMed

Navab M, Reddy ST, Van Lenten BJ, Fogelman AM (2011) HDL and cardiovascular disease: atherogenic and atheroprotective mechanisms. Nat Rev Cardiol 8(4):222–232. https://doi.org/10.1038/nrcardio.2010.222CrossRefPubMed

Rader DJ (2003) Regulation of reverse cholesterol transport and clinical implications. Am J Cardiol 92(4A):42J–49J. https://doi.org/10.1016/s0002-9149(03)00615-5CrossRefPubMed

Back SS, Kim J, Choi D, Lee ES, Choi SY, Han K (2013) Cooperative transcriptional activation of ATP-binding cassette sterol transporters ABCG5 and ABCG8 genes by nuclear receptors including Liver-X-Receptor. BMB Rep 46(6):322–327. https://doi.org/10.5483/BMBRep.2013.46.6.246CrossRefPubMedPubMedCentral

10.

Noe J, Kullak-Ublick GA, Jochum W et al (2005) Impaired expression and function of the bile salt export pump due to three novel ABCB11 mutations in intrahepatic cholestasis. J Hepatol 43(3):536–543. https://doi.org/10.1016/j.jhep.2005.05.020CrossRefPubMed

11.

Yancey PG, Bortnick AE, Kellner-Weibel G, de la Llera-Moya M, Phillips MC, Rothblat GH (2003) Importance of different pathways of cellular cholesterol efflux. Arterioscler Thromb Vasc Biol 23(5):712–719. https://doi.org/10.1161/01.ATV.0000057572.97137.DDCrossRefPubMed

12.

Khera AV, Cuchel M, de la Llera-Moya M et al (2011) Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. N Engl J Med 364(2):127–135. https://doi.org/10.1056/NEJMoa1001689CrossRefPubMedPubMedCentral

13.

Rohatgi A, Khera A, Berry JD et al (2014) HDL cholesterol efflux capacity and incident cardiovascular events. N Engl J Med 371(25):2383–2393. https://doi.org/10.1056/NEJMoa1409065CrossRefPubMedPubMedCentral

14.

Shea S, Stein JH, Jorgensen NW et al (2019) Cholesterol mass efflux capacity, incident cardiovascular disease, and progression of carotid plaque. Arterioscler Thromb Vasc Biol 39(1):89–96. https://doi.org/10.1161/ATVBAHA.118.311366CrossRefPubMed

15.

Ganjali S, Dallinga-Thie GM, Simental-Mendía LE, Banach M, Pirro M, Sahebkar A (2017) HDL functionality in type 1 diabetes. Atherosclerosis 267:99–109. https://doi.org/10.1016/j.atherosclerosis.2017.10.018CrossRefPubMed

16.

Costacou T, Evans RW, Orchard TJ (2011) High-density lipoprotein cholesterol in diabetes: is higher always better? J Clin Lipidol 5(5):387–394. https://doi.org/10.1016/j.jacl.2011.06.011CrossRefPubMedPubMedCentral

17.

Jeyarajah EJ, Cromwell WC, Otvos JD (2006) Lipoprotein particle analysis by nuclear magnetic resonance spectroscopy. Clin Lab Med 26(4):847–870. https://doi.org/10.1016/j.cll.2006.07.006CrossRefPubMed

18.

Adrees M, Gibney J, El-Saeity N, Boran G (2009) Effects of 18 months of L-T4 replacement in women with subclinical hypothyroidism. Clin Endocrinol 71(2):298–303. https://doi.org/10.1111/j.1365-2265.2008.03509.xCrossRef

19.

Daffu G, Shen X, Senatus L et al (2015) RAGE suppresses ABCG1-mediated macrophage cholesterol efflux in diabetes. Diabetes 64(12):4046–4060. https://doi.org/10.2337/db15-0575CrossRefPubMedPubMedCentral

20.

Mauldin JP, Nagelin MH, Wojcik AJ et al (2008) Reduced expression of ATP-binding cassette transporter G1 increases cholesterol accumulation in macrophages of patients with type 2 diabetes mellitus. Circulation 117(21):2785–2792. https://doi.org/10.1161/CIRCULATIONAHA.107.741314CrossRefPubMedPubMedCentral

21.

de Vries R, Kerstens MN, Sluiter WJ, Groen AK, van Tol A, Dullaart RP (2005) Cellular cholesterol efflux to plasma from moderately hypercholesterolaemic type 1 diabetic patients is enhanced, and is unaffected by simvastatin treatment. Diabetologia 48(6):1105–1113. https://doi.org/10.1007/s00125-005-1760-0CrossRefPubMed

22.

Manjunatha S, Distelmaier K, Dasari S, Carter RE, Kudva YC, Nair KS (2016) Functional and proteomic alterations of plasma high density lipoproteins in type 1 diabetes mellitus. Metabolism 65(9):1421–1431. https://doi.org/10.1016/j.metabol.2016.06.008CrossRefPubMed

23.

Mutharasan RK, Thaxton CS, Berry J et al (2017) HDL efflux capacity, HDL particle size, and high-risk carotid atherosclerosis in a cohort of asymptomatic older adults: the Chicago Healthy Aging Study. J Lipid Res 58(3):600–606. https://doi.org/10.1194/jlr.P069039CrossRefPubMedPubMedCentral

24.

El Khoudary SR, Hutchins PM, Matthews KA et al (2016) Cholesterol efflux capacity and subclasses of HDL particles in healthy women transitioning through menopause. J Clin Endocrinol Metab 101(9):3419–3428. https://doi.org/10.1210/jc.2016-2144CrossRefPubMedPubMedCentral

25.

de la Llera-Moya M, Drazul-Schrader D, Asztalos BF, Cuchel M, Rader DJ, Rothblat GH (2010) The ability to promote efflux via ABCA1 determines the capacity of serum specimens with similar high-density lipoprotein cholesterol to remove cholesterol from macrophages. Arterioscler Thromb Vasc Biol 30(4):796–801. https://doi.org/10.1161/ATVBAHA.109.199158CrossRefPubMedPubMedCentral

26.

Rosenson RS, Brewer HB Jr, Chapman MJ et al (2011) HDL measures, particle heterogeneity, proposed nomenclature, and relation to atherosclerotic cardiovascular events. Clin Chem 57(3):392–410. https://doi.org/10.1373/clinchem.2010.155333CrossRefPubMed

27.

Favari E, Lee M, Calabresi L et al (2004) Depletion of pre-β-high density lipoprotein by human chymase impairs ATP-binding cassette transporter A1- but not scavenger receptor class B type I-mediated lipid efflux to high density lipoprotein. J Biol Chem 279(11):9930–9936. https://doi.org/10.1074/jbc.M312476200CrossRefPubMed

28.

McEneny J, Daniels JA, McGowan A et al (2015) A cross-sectional study demonstrating increased serum amyloid a related inflammation in high-density lipoproteins from subjects with type 1 diabetes mellitus and how this association was augmented by poor glycaemic control. J Diabetes Res 2015:351601. https://doi.org/10.1155/2015/351601CrossRefPubMedPubMedCentral

29.

Vaisar T, Tang C, Babenko I et al (2015) Inflammatory remodeling of the HDL proteome impairs cholesterol efflux capacity. J Lipid Res 56(8):1519–1530. https://doi.org/10.1194/jlr.M059089CrossRefPubMedPubMedCentral

30.

Banka CL, Yuan T, de Beer MC, Kindy M, Curtiss LK, de Beer FC (1995) Serum amyloid A (SAA): influence on HDL-mediated cellular cholesterol efflux. J Lipid Res 36(5):1058–1065CrossRefPubMed

31.

de la Llera Moya M, McGillicuddy FC, Hinkle CC et al (2012) Inflammation modulates human HDL composition and function in vivo. Atherosclerosis 222(2):390–394. https://doi.org/10.1016/j.atherosclerosis.2012.02.032CrossRefPubMedPubMedCentral

32.

McGillicuddy FC, de la Llera Moya M, Hinkle CC et al (2009) Inflammation impairs reverse cholesterol transport in vivo. Circulation 119(8):1135–1145. https://doi.org/10.1161/CIRCULATIONAHA.108.810721CrossRefPubMedPubMedCentral

33.

Han CY, Tang C, Guevara ME et al (2016) Serum amyloid A impairs the antiinflammatory properties of HDL. J Clin Invest 126(2):796. https://doi.org/10.1172/JCI86401CrossRefPubMedPubMedCentral

34.

Coetzee GA, Strachan AF, van der Westhuyzen DR, Hoppe HC, Jeenah MS, de Beer FC (1986) Serum amyloid A-containing human high density lipoprotein 3. Density, size, and apolipoprotein composition. J Biol Chem 261(21):9644–9651CrossRefPubMed

35.

Martel C, Li W, Fulp B et al (2013) Lymphatic vasculature mediates macrophage reverse cholesterol transport in mice. J Clin Invest 123(4):1571–1579. https://doi.org/10.1172/JCI63685CrossRefPubMedPubMedCentral

36.

Miller NE, Olszewski WL, Hattori H et al (2013) Lipoprotein remodeling generates lipid-poor apolipoprotein A-I particles in human interstitial fluid. Am J Physiol Endocrinol Metab 304(3):E321–E328. https://doi.org/10.1152/ajpendo.00324.2012CrossRefPubMed

37.

Apro J, Tietge UJ, Dikkers A, Parini P, Angelin B, Rudling M (2016) Impaired cholesterol efflux capacity of high-density lipoprotein isolated from interstitial fluid in type 2 diabetes mellitus-brief report. Arterioscler Thromb Vasc Biol 36(5):787–791. https://doi.org/10.1161/ATVBAHA.116.307385CrossRefPubMedPubMedCentral

38.

Otvos JD, Collins D, Freedman DS et al (2006) Low-density lipoprotein and high-density lipoprotein particle subclasses predict coronary events and are favorably changed by gemfibrozil therapy in the Veterans Affairs High-Density Lipoprotein Intervention Trial. Circulation 113(12):1556–1563. https://doi.org/10.1161/CIRCULATIONAHA.105.565135CrossRefPubMed

39.

Kuller LH, Grandits G, Cohen JD, Neaton JD, Prineas R, Multiple Risk Factor Intervention Trial Research Group (2007) Lipoprotein particles, insulin, adiponectin, C-reactive protein and risk of coronary heart disease among men with metabolic syndrome. Atherosclerosis 195(1):122–128. https://doi.org/10.1016/j.atherosclerosis.2006.09.001CrossRefPubMed

40.

Kontush A (2015) HDL particle number and size as predictors of cardiovascular disease. Front Pharmacol 6:218. https://doi.org/10.3389/fphar.2015.00218CrossRefPubMedPubMedCentral

41.

Khera AV, Demler OV, Adelman SJ et al (2017) Cholesterol efflux capacity, high-density lipoprotein particle number, and incident cardiovascular events: an analysis from the JUPITER trial (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin). Circulation 135(25):2494–2504. https://doi.org/10.1161/CIRCULATIONAHA.116.025678CrossRefPubMedPubMedCentral

42.

Kuller L, Arnold A, Tracy R et al (2002) Nuclear magnetic resonance spectroscopy of lipoproteins and risk of coronary heart disease in the cardiovascular health study. Arterioscler Thromb Vasc Biol 22(7):1175–1180. https://doi.org/10.1161/01.atv.0000022015.97341.3aCrossRefPubMed

43.

Asztalos BF, Schaefer EJ (2003) HDL in atherosclerosis: actor or bystander? Atheroscler Suppl 4(1):21–29. https://doi.org/10.1016/s1567-5688(03)00006-0CrossRefPubMed

44.

Asztalos BF, Schaefer EJ (2003) High-density lipoprotein subpopulations in pathologic conditions. Am J Cardiol 91(7A):12E–17E. https://doi.org/10.1016/s0002-9149(02)03383-0CrossRefPubMed

45.

Lamon-Fava S, Herrington DM, Reboussin DM et al (2008) Plasma levels of HDL subpopulations and remnant lipoproteins predict the extent of angiographically-defined coronary artery disease in postmenopausal women. Arterioscler Thromb Vasc Biol 28(3):575–579. https://doi.org/10.1161/ATVBAHA.107.157123CrossRefPubMed

46.

Soedamah-Muthu SS, Chang YF, Otvos J, Evans RW, Orchard TJ, Pittsburgh Epidemiology of Diabetes Complications Study (2003) Lipoprotein subclass measurements by nuclear magnetic resonance spectroscopy improve the prediction of coronary artery disease in Type 1 diabetes. A prospective report from the Pittsburgh Epidemiology of Diabetes Complications Study. Diabetologia 46(5):674–682. https://doi.org/10.1007/s00125-003-1094-8CrossRefPubMed

47.

Colhoun HM, Otvos JD, Rubens MB, Taskinen MR, Underwood SR, Fuller JH (2002) Lipoprotein subclasses and particle sizes and their relationship with coronary artery calcification in men and women with and without type 1 diabetes. Diabetes 51(6):1949–1956. https://doi.org/10.2337/diabetes.51.6.1949CrossRefPubMed

48.

Li X-M, Tang WHW, Mosior MK et al (2013) Paradoxical association of enhanced cholesterol efflux with increased incident cardiovascular risks. Arterioscler Thromb Vasc Biol 33(7):1696–1705. https://doi.org/10.1161/ATVBAHA.113.301373CrossRefPubMedPubMedCentral

Title: HDL particle size is increased and HDL-cholesterol efflux is enhanced in type 1 diabetes: a cross-sectional study
Authors: Mohamad O. Ahmed
Rachel E. Byrne
Agnieszka Pazderska
Ricardo Segurado
Weili Guo
Anjuli Gunness
Isolda Frizelle
Mark Sherlock
Khalid S. Ahmed
Anne McGowan
Kevin Moore
Gerard Boran
Fiona C. McGillicuddy
James Gibney
Publication date: 01-03-2021
Publisher: Springer Berlin Heidelberg
Keywords: Arterial Occlusive Disease
Type 1 Diabetes
Published in: Diabetologia / Issue 3/2021
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-020-05320-3

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