Low cholesterol efflux capacity and abnormal lipoprotein particles in youth with type 1 diabetes: a case control study

Evgenia Gourgari, Martin P Playford, Umberto Campia, Amit K Dey, Fran Cogen, Stephanie Gubb-Weiser, Mihriye Mete, Sameer Desale, Maureen Sampson, Allen Taylor, Kristina I Rother, Alan T Remaley, Nehal N Mehta, Evgenia Gourgari, Martin P Playford, Umberto Campia, Amit K Dey, Fran Cogen, Stephanie Gubb-Weiser, Mihriye Mete, Sameer Desale, Maureen Sampson, Allen Taylor, Kristina I Rother, Alan T Remaley, Nehal N Mehta

Abstract

Background: Patients with type 1 diabetes (T1DM) have increased mortality from cardiovascular disease (CVD). Risk factors for CVD include an elevation of LDL (LDLp) and small HDL (sHDLp) particles, and a decrease in reverse cholesterol transport i.e. HDL-cholesterol efflux capacity (CEC). Our objective was to compare lipoprotein particles and CEC between T1DM and healthy controls (HC) and to explore the associations between NMR lipid particles and cholesterol efflux.

Methods: 78 patients with T1DM and 59 HC underwent fasting lipoprotein profile testing by NMR and measurements of CEC by cell-based method. The associations between NMR lipid particles with CEC were analyzed using multivariable linear regression models.

Results: Youth with T1DM had higher total LDLp 724 [(563-985) vs 622 (476-794) nmol/L (P = 0.011)] (Maahs et al. in Circulation 130(17):1532-58, 2014; Shah et al. in Pediatr Diabetes 16(5):367-74, 2015), sHDLp [11.20 (5.7-15.3) vs 7.0 (3.2-13.1) μmol/L (P = 0.021)], and lower medium HDLp [11.20 (8.5-14.5) vs 12.3 (9-19.4), (P = 0.049)] and lower CEC (0.98 ± 0.11% vs 1.05 ± 0.15%, P = 0.003) compared to HC. Moreover, CEC correlated with sHDLp (β = - 0.28, P = 0.045) and large HDLp (β = 0.46, P < 0.001) independent of age, sex, ethnicity, BMIz, HbA1c, hsCRP and total HDLp in the diabetic cohort.

Conclusions: Youth with T1DM demonstrated a more atherogenic profile including higher sHDL and LDLp and lower CEC. Future efforts should focus on considering adding lipoprotein particles and CEC in CVD risk stratification of youth with T1DM. Trial registration Clinical Trials Registration Number NCT02275091.

Keywords: Adolescent; Cardiovascular risk; Cholesterol efflux; NMR; Type 1 diabetes.

Figures

Fig. 1
Fig. 1
Predicted scores for CEC based on adjusted regression models and their relationships to small and large HDL particles

References

    1. Maahs DM, Daniels SR, de Ferranti SD, Dichek HL, Flynn J, Goldstein BI, Kelly AS, Nadeau KJ, Martyn-Nemeth P, Osganian SK, et al. Cardiovascular disease risk factors in youth with diabetes mellitus: a scientific statement from the American Heart Association. Circulation. 2014;130(17):1532–1558. doi: 10.1161/CIR.0000000000000094.
    1. Shah AS, Wadwa RP, Dabelea D, Hamman RF, D’Agostino R, Jr, Marcovina S, Daniels SR, Dolan LM, Fino NF, Urbina EM. Arterial stiffness in adolescents and young adults with and without type 1 diabetes: the SEARCH CVD study. Pediatr Diabetes. 2015;16(5):367–374. doi: 10.1111/pedi.12279.
    1. Bradley TJ, Slorach C, Mahmud FH, Dunger DB, Deanfield J, Deda L, Elia Y, Har RL, Hui W, Moineddin R, et al. Early changes in cardiovascular structure and function in adolescents with type 1 diabetes. Cardiovasc Diabetol. 2016;15:31. doi: 10.1186/s12933-016-0351-3.
    1. Gourgari E, Dabelea D, Rother K. Modifiable risk factors for cardiovascular disease in children with type 1 diabetes: can early intervention prevent future cardiovascular events? Curr Diab Rep. 2017;17(12):134. doi: 10.1007/s11892-017-0968-y.
    1. Rohatgi A, Khera A, Berry JD, Givens EG, Ayers CR, Wedin KE, Neeland IJ, Yuhanna IS, Rader DR, de Lemos JA, et al. HDL cholesterol efflux capacity and incident cardiovascular events. N Engl J Med. 2014;371(25):2383–2393. doi: 10.1056/NEJMoa1409065.
    1. Zhang Y, Jenkins AJ, Basu A, Stoner JA, Lopes-Virella MF, Klein RL, Group DER, Lyons TJ. Associations between intensive diabetes therapy and NMR-determined lipoprotein subclass profiles in type 1 diabetes. J Lipid Res. 2016;57(2):310–317. doi: 10.1194/jlr.P060657.
    1. Mora S, Otvos JD, Rifai N, Rosenson RS, Buring JE, Ridker PM. Lipoprotein particle profiles by nuclear magnetic resonance compared with standard lipids and apolipoproteins in predicting incident cardiovascular disease in women. Circulation. 2009;119(7):931–939. doi: 10.1161/CIRCULATIONAHA.108.816181.
    1. Austin MA, Breslow JL, Hennekens CH, Buring JE, Willett WC, Krauss RM. Low-density lipoprotein subclass patterns and risk of myocardial infarction. JAMA. 1988;260(13):1917–1921. doi: 10.1001/jama.1988.03410130125037.
    1. Lamarche B, Tchernof A, Moorjani S, Cantin B, Dagenais GR, Lupien PJ, Despres JP. Small, dense low-density lipoprotein particles as a predictor of the risk of ischemic heart disease in men. Prospective results from the Quebec Cardiovascular Study. Circulation. 1997;95(1):69–75. doi: 10.1161/01.CIR.95.1.69.
    1. Kontush A. HDL particle number and size as predictors of cardiovascular disease. Front Pharmacol. 2015;6:218. doi: 10.3389/fphar.2015.00218.
    1. Freedman DS, Otvos JD, Jeyarajah EJ, Barboriak JJ, Anderson AJ, Walker JA. Relation of lipoprotein subclasses as measured by proton nuclear magnetic resonance spectroscopy to coronary artery disease. Arterioscler Thromb Vasc Biol. 1998;18(7):1046–1053. doi: 10.1161/01.ATV.18.7.1046.
    1. Austin MA, King MC, Vranizan KM, Krauss RM. Atherogenic lipoprotein phenotype. A proposed genetic marker for coronary heart disease risk. Circulation. 1990;82(2):495–506. doi: 10.1161/01.CIR.82.2.495.
    1. Nikkila EA. High density lipoproteins in diabetes. Diabetes. 1981;30(Suppl 2):82–87. doi: 10.2337/diab.30.2.S82.
    1. Kingwell BA, Chapman MJ, Kontush A, Miller NE. HDL-targeted therapies: progress, failures and future. Nat Rev Drug Discov. 2014;13(6):445–464. doi: 10.1038/nrd4279.
    1. Khera AV, Cuchel M, de la Llera-Moya M, Rodrigues A, Burke MF, Jafri K, French BC, Phillips JA, Mucksavage ML, Wilensky RL, et al. Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. N Engl J Med. 2011;364(2):127–135. doi: 10.1056/NEJMoa1001689.
    1. Gourgari E, Lodish M, Shamburek R, Keil M, Wesley R, Walter M, Sampson M, Bernstein S, Khurana D, Lyssikatos C, et al. Lipoprotein particles in adolescents and young women with pcos provide insights into their cardiovascular risk. J Clin Endocrinol Metab. 2015;100(11):4291–4298. doi: 10.1210/jc.2015-2566.
    1. Mehta NN, Li R, Krishnamoorthy P, Yu Y, Farver W, Rodrigues A, Raper A, Wilcox M, Baer A, DerOhannesian S, et al. Abnormal lipoprotein particles and cholesterol efflux capacity in patients with psoriasis. Atherosclerosis. 2012;224(1):218–221. doi: 10.1016/j.atherosclerosis.2012.06.068.
    1. Howard BV. Lipoprotein metabolism in diabetes mellitus. J Lipid Res. 1987;28(6):613–628.
    1. Maahs DM, Maniatis AK, Nadeau K, Wadwa RP, McFann K, Klingensmith GJ. Total cholesterol and high-density lipoprotein levels in pediatric subjects with type 1 diabetes mellitus. J Pediatr. 2005;147(4):544–546. doi: 10.1016/j.jpeds.2005.04.068.
    1. Guy J, Ogden L, Wadwa RP, Hamman RF, Mayer-Davis EJ, Liese AD, D’Agostino R, Jr, Marcovina S, Dabelea D. Lipid and lipoprotein profiles in youth with and without type 1 diabetes: the SEARCH for Diabetes in Youth case–control study. Diabetes Care. 2009;32(3):416–420. doi: 10.2337/dc08-1775.
    1. Colhoun HM, Otvos JD, Rubens MB, Taskinen MR, Underwood SR, Fuller JH. Lipoprotein subclasses and particle sizes and their relationship with coronary artery calcification in men and women with and without type 1 diabetes. Diabetes. 2002;51(6):1949–1956. doi: 10.2337/diabetes.51.6.1949.
    1. Basu A, Jenkins AJ, Zhang Y, Stoner JA, Klein RL, Lopes-Virella MF, Garvey WT, Lyons TJ. Nuclear magnetic resonance-determined lipoprotein subclasses and carotid intima-media thickness in type 1 diabetes. Atherosclerosis. 2016;244:93–100. doi: 10.1016/j.atherosclerosis.2015.10.106.
    1. Lyons TJ, Jenkins AJ, Zheng D, Klein RL, Otvos JD, Yu Y, Lackland DT, McGee D, McHenry MB, Lopes-Virella M, et al. Nuclear magnetic resonance-determined lipoprotein subclass profile in the DCCT/EDIC cohort: associations with carotid intima-media thickness. Diabetic Med. 2006;23(9):955–966. doi: 10.1111/j.1464-5491.2006.01905.x.
    1. Heier M, Borja MS, Brunborg C, Seljeflot I, Margeirsdottir HD, Hanssen KF, Dahl-Jorgensen K, Oda MN. Reduced HDL function in children and young adults with type 1 diabetes. Cardiovasc Diabetol. 2017;16(1):85. doi: 10.1186/s12933-017-0570-2.
    1. Manjunatha S, Distelmaier K, Dasari S, Carter RE, Kudva YC, Nair KS. Functional and proteomic alterations of plasma high density lipoproteins in type 1 diabetes mellitus. Metabolism. 2016;65(9):1421–1431. doi: 10.1016/j.metabol.2016.06.008.
    1. Farbstein D, Levy AP. HDL dysfunction in diabetes: causes and possible treatments. Expert Rev Cardiovasc Ther. 2012;10(3):353–361. doi: 10.1586/erc.11.182.
    1. Duell PB, Oram JF, Bierman EL. Nonenzymatic glycosylation of HDL and impaired HDL-receptor-mediated cholesterol efflux. Diabetes. 1991;40(3):377–384. doi: 10.2337/diab.40.3.377.
    1. Passarelli M, Tang C, McDonald TO, O’Brien KD, Gerrity RG, Heinecke JW, Oram JF. Advanced glycation end product precursors impair ABCA1-dependent cholesterol removal from cells. Diabetes. 2005;54(7):2198–2205. doi: 10.2337/diabetes.54.7.2198.
    1. de Vries R, Kerstens MN, Sluiter WJ, Groen AK, van Tol A, Dullaart RP. Cellular cholesterol efflux to plasma from moderately hypercholesterolaemic type 1 diabetic patients is enhanced, and is unaffected by simvastatin treatment. Diabetologia. 2005;48(6):1105–1113. doi: 10.1007/s00125-005-1760-0.
    1. Apro J, Tietge UJ, Dikkers A, Parini P, Angelin B, Rudling M. Impaired cholesterol efflux capacity of high-density lipoprotein isolated from interstitial fluid in type 2 diabetes mellitus-brief report. Arterioscler Thromb Vasc Biol. 2016;36(5):787–791. doi: 10.1161/ATVBAHA.116.307385.
    1. Yassine HN, Belopolskaya A, Schall C, Stump CS, Lau SS, Reaven PD. Enhanced cholesterol efflux to HDL through the ABCA1 transporter in hypertriglyceridemia of type 2 diabetes. Metabolism. 2014;63(5):727–734. doi: 10.1016/j.metabol.2014.03.001.
    1. Bjornstad P, Eckel RH, Pyle L, Rewers M, Maahs DM, Snell-Bergeon JK. Relation of combined non-high-density lipoprotein cholesterol and apolipoprotein b with atherosclerosis in adults with type 1 diabetes mellitus. Am J Cardiol. 2015;116(7):1057–1062. doi: 10.1016/j.amjcard.2015.07.020.
    1. Rawshani A, Rawshani A, Franzen S, Eliasson B, Svensson AM, Miftaraj M, McGuire DK, Sattar N, Rosengren A, Gudbjornsdottir S. Range of risk factor levels: control, mortality, and cardiovascular outcomes in type 1 diabetes mellitus. Circulation. 2017;135(16):1522–1531. doi: 10.1161/CIRCULATIONAHA.116.025961.
    1. Tan HC, Tai ES, Sviridov D, Nestel PJ, Ng C, Chan E, Teo Y, Wai DC. Relationships between cholesterol efflux and high-density lipoprotein particles in patients with type 2 diabetes mellitus. J Clin Lipidol. 2011;5(6):467–473. doi: 10.1016/j.jacl.2011.06.016.
    1. Du XM, Kim MJ, Hou L, Le Goff W, Chapman MJ, Van Eck M, Curtiss LK, Burnett JR, Cartland SP, Quinn CM, et al. HDL particle size is a critical determinant of ABCA1-mediated macrophage cellular cholesterol export. Circ Res. 2015;116(7):1133–1142. doi: 10.1161/CIRCRESAHA.116.305485.
    1. Cree-Green M, Maahs DM, Ferland A, Hokanson JE, Wang H, Pyle L, Kinney GL, King M, Eckel RH, Nadeau KJ. Lipoprotein subfraction cholesterol distribution is more atherogenic in insulin resistant adolescents with type 1 diabetes. Pediatric Diabetes. 2016;17(4):257–265. doi: 10.1111/pedi.12277.
    1. Maahs DM, Hokanson JE, Wang H, Kinney GL, Snell-Bergeon JK, East A, Bergman BC, Schauer IE, Rewers M, Eckel RH. Lipoprotein subfraction cholesterol distribution is proatherogenic in women with type 1 diabetes and insulin resistance. Diabetes. 2010;59(7):1771–1779. doi: 10.2337/db09-1626.
    1. Urbina EM, Dabelea D, D’Agostino RB, Jr, Shah AS, Dolan LM, Hamman RF, Daniels SR, Marcovina S, Wadwa RP. Effect of type 1 diabetes on carotid structure and function in adolescents and young adults: the SEARCH CVD study. Diabetes Care. 2013;36(9):2597–2599. doi: 10.2337/dc12-2024.

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