Endocrinol Metab.  2015 Jun;30(2):208-215. 10.3803/EnM.2015.30.2.208.

Apolipoprotein B Is Related to Metabolic Syndrome Independently of Low Density Lipoprotein Cholesterol in Patients with Type 2 Diabetes

• Lim Y
• Yoo S
• Lee SA
• Chin SO
• Heo D
• Moon JC
• Moon S
• Boo K
• Kim ST
• Seo HM
• Jwa H
• Koh G

• KMID: 2282012
• DOI: http://doi.org/10.3803/EnM.2015.30.2.208

Abstract

BACKGROUND
Increased low density lipoprotein cholesterol (LDL-C) level and the presence of metabolic syndrome (MetS) are important risk factors for cardiovascular disease (CVD) in type 2 diabetes mellitus (T2DM). Recent studies demonstrated apolipoprotein B (apoB), a protein mainly located in LDL-C, was an independent predictor of the development of CVD especially in patients with T2DM. The aim of this study was to investigate the relationship between apoB and MetS in T2DM patients.
METHODS
We analyzed 912 patients with T2DM. Fasting blood samples were taken for glycated hemoglobin, high-sensitivity C-reactive protein, total cholesterol, triglyceride (TG), high density lipoprotein cholesterol, LDL-C, and apoB. MetS was defined by the modified National Cholesterol Education Program Adult Treatment Panel III criteria. We performed a hierarchical regression analysis with apoB as the dependent variable. Age, sex, the number of components of MetS and LDL-C were entered at model 1, the use of lipid-lowering medications at model 2, and the individual components of MetS were added at model 3.
RESULTS
Seventy percent of total subjects had MetS. ApoB level was higher in subjects with than those without MetS (104.5+/-53.3 mg/dL vs. 87.7+/-33.7 mg/dL, P<0.01) even after adjusting for LDL-C. ApoB and LDL-C were positively correlated to the number of MetS components. The hierarchical regression analysis showed that the increasing number of MetS components was associated with higher level of apoB at step 1 and step 2 (beta=0.120, P<0.001 and beta=0.110, P<0.001, respectively). At step 3, TG (beta=0.116, P<0.001) and systolic blood pressure (beta=0.099, P<0.05) were found to significantly contribute to apoB.
CONCLUSION
In patients with T2DM, apoB is significantly related to MetS independently of LDL-C level. Of the components of MetS, TG, and systolic blood pressure appeared to be determinants of apoB.

Keyword

Diabetes mellitus, type 2; Apolipoproetin B; Metabolic syndrome; Cardiovascular diseases

MeSH Terms

Adult
Apolipoproteins B
Apolipoproteins*
Blood Pressure
C-Reactive Protein
Cardiovascular Diseases
Cholesterol
Cholesterol, HDL
Cholesterol, LDL*
Diabetes Mellitus, Type 2
Education
Fasting
Hemoglobin A, Glycosylated
Humans
Risk Factors
Triglycerides
Apolipoproteins
Apolipoproteins B
C-Reactive Protein
Cholesterol
Cholesterol, HDL
Cholesterol, LDL

Figure

• 

  Fig. 1 (A) Differences in low density lipoprotein cholesterol (LDL-C) and (B) apolipoprotein B (apoB) according to the presence of metabolic syndrome. Values are expressed as mean±SE. aAdjusted for LDL-C by analysis of covariance.

• 

  Fig. 2 (A) Differences in low density lipoprotein cholesterol (LDL-C) and (B) apolipoprotein B (apoB) according to the number of components of metabolic syndrome. Values are expressed as mean±SE. ANOVA, analysis of variance; P for trend, P value by the test for linear trend.

Reference

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; 260:1917–1921.

2. Koba S, Hirano T, Kondo T, Shibata M, Suzuki H, Murakami M, Geshi E, Katagiri T. Significance of small dense low-density lipoproteins and other risk factors in patients with various types of coronary heart disease. Am Heart J. 2002; 144:1026–1035.

3. Nakamura H, Arakawa K, Itakura H, Kitabatake A, Goto Y, Toyota T, Nakaya N, Nishimoto S, Muranaka M, Yamamoto A, Mizuno K, Ohashi Y;. Primary prevention of cardiovascular disease with pravastatin in Japan (MEGA Study): a prospective randomised controlled trial. Lancet. 2006; 368:1155–1163.

4. Taylor F, Huffman MD, Macedo AF, Moore TH, Burke M, Davey Smith G, Ward K, Ebrahim S. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2013; 1:CD004816.

5. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM J, Kastelein JJ, Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ. JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008; 359:2195–2207.

6. LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC, Gotto AM, Greten H, Kastelein JJ, Shepherd J, Wenger NK. Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005; 352:1425–1435.

7. Walldius G, Jungner I. The apoB/apoA-I ratio: a strong, new risk factor for cardiovascular disease and a target for lipid-lowering therapy: a review of the evidence. J Intern Med. 2006; 259:493–519.

8. Lamarche B, Moorjani S, Lupien PJ, Cantin B, Bernard PM, Dagenais GR, Despres JP. Apolipoprotein A-I and B levels and the risk of ischemic heart disease during a five-year follow-up of men in the Quebec cardiovascular study. Circulation. 1996; 94:273–278.

9. Packard CJ, Shepherd J. Lipoprotein heterogeneity and apolipoprotein B metabolism. Arterioscler Thromb Vasc Biol. 1997; 17:3542–3556.

10. Anber V, Millar JS, McConnell M, Shepherd J, Packard CJ. Interaction of very-low-density, intermediate-density, and low-density lipoproteins with human arterial wall proteoglycans. Arterioscler Thromb Vasc Biol. 1997; 17:2507–2514.

11. Nielsen LB. Transfer of low density lipoprotein into the arterial wall and risk of atherosclerosis. Atherosclerosis. 1996; 123:1–15.

12. Krauss RM. Atherogenic lipoprotein phenotype and diet-gene interactions. J Nutr. 2001; 131:340S–343S.

13. Watson KE, Horowitz BN, Matson G. Lipid abnormalities in insulin resistant states. Rev Cardiovasc Med. 2003; 4:228–236.

14. Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med. 1998; 15:539–553.

15. Bonora E, Targher G, Formentini G, Calcaterra F, Lombardi S, Marini F, Zenari L, Saggiani F, Poli M, Perbellini S, Raffaelli A, Gemma L, Santi L, Bonadonna RC, Muggeo M. The metabolic syndrome is an independent predictor of cardiovascular disease in type 2 diabetic subjects. Prospective data from the Verona Diabetes Complications Study. Diabet Med. 2004; 21:52–58.

16. Ginsberg HN, Zhang YL, Hernandez-Ono A. Regulation of plasma triglycerides in insulin resistance and diabetes. Arch Med Res. 2005; 36:232–240.

17. Ryoo JH, Park SK. Association of apolipoprotein B and incidence of metabolic syndrome in Korean men: a 5-years' follow-up study. Atherosclerosis. 2013; 226:496–501.

18. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA. 2001; 285:2486–2497.

19. Lee SY, Park HS, Kim DJ, Han JH, Kim SM, Cho GJ, Kim DY, Kwon HS, Kim SR, Lee CB, Oh SJ, Park CY, Yoo HJ. Appropriate waist circumference cutoff points for central obesity in Korean adults. Diabetes Res Clin Pract. 2007; 75:72–80.

20. Sniderman AD, Marcovina SM. Apolipoprotein A1 and B. Clin Lab Med. 2006; 26:733–750.

21. Walldius G, Jungner I, Holme I, Aastveit AH, Kolar W, Steiner E. High apolipoprotein B, low apolipoprotein A-I, and improvement in the prediction of fatal myocardial infarction (AMORIS study): a prospective study. Lancet. 2001; 358:2026–2033.

22. Bruno G, Merletti F, Biggeri A, Bargero G, Prina-Cerai S, Pagano G, Cavallo-Perin P. Effect of age on the association of non-high-density-lipoprotein cholesterol and apolipoprotein B with cardiovascular mortality in a Mediterranean population with type 2 diabetes: the Casale Monferrato study. Diabetologia. 2006; 49:937–944.

23. Martin SS, Qasim AN, Mehta NN, Wolfe M, Terembula K, Schwartz S, Iqbal N, Schutta M, Bagheri R, Reilly MP. Apolipoprotein B but not LDL cholesterol is associated with coronary artery calcification in type 2 diabetic whites. Diabetes. 2009; 58:1887–1892.

24. Jeppesen J, Hein HO, Suadicani P, Gyntelberg F. Triglyceride concentration and ischemic heart disease: an eight-year follow-up in the Copenhagen Male Study. Circulation. 1998; 97:1029–1036.

25. Castelli WP. The triglyceride issue: a view from Framingham. Am Heart J. 1986; 112:432–437.

26. Assmann G, Cullen P, Schulte H. The Munster Heart Study (PROCAM). Results of follow-up at 8 years. Eur Heart J. 1998; 19:Suppl A. A2–11.

27. Manninen V, Tenkanen L, Koskinen P, Huttunen JK, Manttari M, Heinonen OP, Frick MH. Joint effects of serum triglyceride and LDL cholesterol and HDL cholesterol concentrations on coronary heart disease risk in the Helsinki Heart Study. Implications for treatment. Circulation. 1992; 85:37–45.

28. AIM-HIGH Investigators. Boden WE, Probstfield JL, Anderson T, Chaitman BR, Desvignes-Nickens P, Koprowicz K, McBride R, Teo K, Weintraub W. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011; 365:2255–2267.

29. Nielsen S, Karpe F. Determinants of VLDL-triglycerides production. Curr Opin Lipidol. 2012; 23:321–326.

30. Meyers CD, Tremblay K, Amer A, Chen J, Jiang L, Gaudet D. Effect of the DGAT1 inhibitor pradigastat on triglyceride and apoB48 levels in patients with familial chylomicronemia syndrome. Lipids Health Dis. 2015; 14:8.

31. Kolovou GD, Mikhailidis DP, Kovar J, Lairon D, Nordestgaard BG, Ooi TC, Perez-Martinez P, Bilianou H, Anagnostopoulou K, Panotopoulos G. Assessment and clinical relevance of non-fasting and postprandial triglycerides: an expert panel statement. Curr Vasc Pharmacol. 2011; 9:258–270.

32. Yuan G, Al-Shali KZ, Hegele RA. Hypertriglyceridemia: its etiology, effects and treatment. CMAJ. 2007; 176:1113–1120.

33. Sparks JD, Sparks CE, Adeli K. Selective hepatic insulin resistance, VLDL overproduction, and hypertriglyceridemia. Arterioscler Thromb Vasc Biol. 2012; 32:2104–2112.

34. Ryomoto KI, Suzuki M, Kanazawa A, Hasegawa M, Kimura Y, Yamamura T, Harano Y. Hyperapobetalipoproteinemia with compositional abnormality of LDL and IDL, a characteristic lipoprotein alteration in essential hypertension. Am J Hypertens. 2000; 13(6 Pt 1):617–624.

35. Okosun IS, Choi S, Hash R, Dever GE. Apolipoprotein B, ratio of total cholesterol to HDL-C, and blood pressure in abdominally obese white and black American women. J Hum Hypertens. 2001; 15:299–305.

36. Suzuki M, Hirose J, Asakura Y, Sato A, Kageyama A, Harano Y, Omae T. Insulin insensitivity in nonobese, nondiabetic essential hypertension and its improvement by an alpha 1-blocker (bunazosin). Am J Hypertens. 1992; 5(12 Pt 1):869–874.

37. Yokota C, Ikebuchi M, Suzuki M, Norioka M, Ikeda K, Shinozaki K, Harano Y. Insulin resistance rather than hyperinsulinemia more closely associated with essential hypertension. Clin Exp Hypertens. 1995; 17:523–536.