Nutr Res Pract.  2017 Aug;11(4):327-333. 10.4162/nrp.2017.11.4.327.

Effects of folic acid supplementation on serum homocysteine levels, lipid profiles, and vascular parameters in post-menopausal Korean women with type 2 diabetes mellitus

• Vijayakumar A
• Kim EK
• Kim H
• Choi YJ
• Huh KB
• Chang N

• KMID: 2385471
• DOI: http://doi.org/10.4162/nrp.2017.11.4.327

Abstract

BACKGROUND/OBJECTIVES
Complications of diabetes, such as cardiovascular disease, are associated with increased mortality among type 2 diabetes mellitus patients. Homocysteine has been recently identified as a predictor of cardiovascular disease-related complications in diabetes. We investigated whether or not supplementation with folic acid tablets can lower homocysteine levels and improve parameters related with vascular complications.
SUBJECTS/METHODS
We conducted a non-randomized 8-week trial involving postmenopausal diabetic women (n = 25) supplemented with 800 µg of folic acid (400 µg twice a day) daily. Subjects' serum levels of folate, homocysteine, and vitamin B₁₂ were measured, along with vascular function and brachial-ankle pulse wave velocity.
RESULTS
Folic acid supplementation significantly increased serum folate levels (P < 0.0001), reduced homocysteine levels (P < 0.0001), and increased vitamin B₁₂ levels (P = 0.0063). There were significant decreases in low-density lipoprotein cholesterol levels as well as the ratios of low-density lipoprotein cholesterol to high-density lipoprotein cholesterol and total cholesterol to high-density lipoprotein cholesterol. Brachial-ankle pulse wave velocities were not altered by supplementation. Changes in serum vitamin B₁₂ after folic acid supplementation were negatively correlated with changes in brachial-ankle pulse wave velocity.
CONCLUSIONS
In this study on postmenopausal Korean women with type 2 diabetes mellitus, folic acid supplementation reduced serum homocysteine levels, increased serum folate and vitamin B₁₂ levels, and lowered lipid parameters.

Keyword

Folic acid; vitamin B₁₂; LDL cholesterol; pulse wave velocity

MeSH Terms

Cardiovascular Diseases
Cholesterol
Cholesterol, LDL
Diabetes Mellitus, Type 2*
Female
Folic Acid*
Homocysteine*
Humans
Lipoproteins
Mortality
Pulse Wave Analysis
Tablets
Vitamin B 12
Vitamins
Cholesterol
Cholesterol, LDL
Folic Acid
Homocysteine
Lipoproteins
Tablets
Vitamin B 12
Vitamins

Figure

• 

  Fig. 1 Correlations between changes in serum Hcys and folate in post-menopausal diabetic women before and after folic acid supplementation (r = -0.4876, P-value = 0.0134). Hcys: homocysteine

• 

  Fig. 2 Correlations between changes in serum vitamin B12 and baPWV levels (r = -0.4153, P-value = 0.0390) in post-menopausal diabetic women before and after folic acid supplementation. baPWV: brachial-ankle pulse wave velocity

Reference

1. Wei M, Gaskill SP, Haffner SM, Stern MP. Effects of diabetes and level of glycemia on all-cause and cardiovascular mortality. The San Antonio Heart Study. Diabetes Care. 1998; 21:1167–1172.

2. de Oliveira Alvim R, Santos PC, Musso MM, de Sá Cunha R, Krieger JE, Mill JG, Pereira AC. Impact of diabetes mellitus on arterial stiffness in a representative sample of an urban Brazilian population. Diabetol Metab Syndr. 2013; 5:45.

3. van de Ree MA, Huisman MV, de Man FH, van der Vijver JC, Meinders AE, Blauw GJ. Impaired endothelium-dependent vasodilation in type 2 diabetes mellitus and the lack of effect of simvastatin. Cardiovasc Res. 2001; 52:299–305.

4. Levitzky YS, Pencina MJ, D'Agostino RB, Meigs JB, Murabito JM, Vasan RS, Fox CS. Impact of impaired fasting glucose on cardiovascular disease: the Framingham Heart Study. J Am Coll Cardiol. 2008; 51:264–270.

5. Elley CR, Kenealy T, Robinson E, Drury PL. Glycated haemoglobin and cardiovascular outcomes in people with Type 2 diabetes: a large prospective cohort study. Diabet Med. 2008; 25:1295–1301.

6. Turner RC, Millns H, Neil HA, Stratton IM, Manley SE, Matthews DR, Holman RR. Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS: 23). BMJ. 1998; 316:823–828.

7. Audelin MC, Genest J Jr. Homocysteine and cardiovascular disease in diabetes mellitus. Atherosclerosis. 2001; 159:497–511.

8. Pfanzagl B, Tribl F, Koller E, Möslinger T. Homocysteine strongly enhances metal-catalyzed LDL oxidation in the presence of cystine and cysteine. Atherosclerosis. 2003; 168:39–48.

9. Jin L, Caldwell RB, Li-Masters T, Caldwell RW. Homocysteine induces endothelial dysfunction via inhibition of arginine transport. J Physiol Pharmacol. 2007; 58:191–206.

10. Patterson S, Scullion SM, McCluskey JT, Flatt PR, McClenaghan NH. Prolonged exposure to homocysteine results in diminished but reversible pancreatic β-cell responsiveness to insulinotropic agents. Diabetes Metab Res Rev. 2007; 23:324–334.

11. Patterson S, Flatt PR, McClenaghan NH. Major metabolic homocysteine-derivative, homocysteine thiolactone, exerts changes in pancreatic beta-cell glucose-sensing, cellular signal transduction and integrity. Arch Biochem Biophys. 2007; 461:287–293.

12. Wouters MG, Moorrees MT, van der Mooren MJ, Blom HJ, Boers GH, Schellekens LA, Thomas CM, Eskes TK. Plasma homocysteine and menopausal status. Eur J Clin Invest. 1995; 25:801–805.

13. El-Kadi MA, Farag AF. The effect of folic acid supplementation on serum homocysteine of egyptian post menopausal women: a randomized controlled trial. Middle East Fertil Soc J. 2014; 19:192–196.

14. Qin X, Xu M, Zhang Y, Li J, Xu X, Wang X, Xu X, Huo Y. Effect of folic acid supplementation on the progression of carotid intima-media thickness: a meta-analysis of randomized controlled trials. Atherosclerosis. 2012; 222:307–313.

15. Chambers JC, Ueland PM, Obeid OA, Wrigley J, Refsum H, Kooner JS. Improved vascular endothelial function after oral B vitamins: an effect mediated through reduced concentrations of free plasma homocysteine. Circulation. 2000; 102:2479–2483.

16. Paradisi G, Cucinelli F, Mele MC, Barini A, Lanzone A, Caruso A. Endothelial function in post-menopausal women: effect of folic acid supplementation. Hum Reprod. 2004; 19:1031–1035.

17. Villa P, Perri C, Suriano R, Cucinelli F, Panunzi S, Ranieri M, Mele C, Lanzone A. L-folic acid supplementation in healthy postmenopausal women: effect on homocysteine and glycolipid metabolism. J Clin Endocrinol Metab. 2005; 90:4622–4629.

18. Sultan N, Khan MA, Malik S. Effect of folic acid supplementation on homocysteine level in postmenopausal women. J Ayub Med Coll Abbottabad. 2007; 19:78–81.

19. Mangoni AA, Sherwood RA, Asonganyi B, Swift CG, Thomas S, Jackson SH. Short-term oral folic acid supplementation enhances endothelial function in patients with type 2 diabetes. Am J Hypertens. 2005; 18:220–226.

20. Albert CM, Cook NR, Gaziano JM, Zaharris E, MacFadyen J, Danielson E, Buring JE, Manson JE. Effect of folic acid and B vitamins on risk of cardiovascular events and total mortality among women at high risk for cardiovascular disease: a randomized trial. JAMA. 2008; 299:2027–2036.

21. Kim H, Park S, Yang H, Choi YJ, Huh KB, Chang N. Association between fish and shellfish, and omega-3 PUFAs intake and CVD risk factors in middle-aged female patients with type 2 diabetes. Nutr Res Pract. 2015; 9:496–502.

22. Organisation for Economic Co-operation and Development. Cardiovascular Disease and Diabetes: Policies for Better Health and Quality of Care. Paris: Organisation for Economic Co-operation and Development;2015. p. 111–131.

23. Durga J, Bots ML, Schouten EG, Grobbee DE, Kok FJ, Verhoef P. Effect of 3 y of folic acid supplementation on the progression of carotid intima-media thickness and carotid arterial stiffness in older adults. Am J Clin Nutr. 2011; 93:941–949.

24. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972; 18:499–502.

25. Lauer M, Clarke R. Factors affecting the relationship between childhood and adult cholesterol levels: the Muscatine Study. Pediatrics. 1988; 82:309–318.

26. Yamashina A, Tomiyama H, Takeda K, Tsuda H, Arai T, Hirose K, Koji Y, Hori S, Yamamoto Y. Validity, reproducibility, and clinical significance of noninvasive brachial-ankle pulse wave velocity measurement. Hypertens Res. 2002; 25:359–364.

27. Kweon SS, Shin MH, Park KS, Nam HS, Jeong SK, Ryu SY, Chung EK, Choi JS. Distribution of the ankle-brachial index and associated cardiovascular risk factors in a population of middle-aged and elderly koreans. J Korean Med Sci. 2005; 20:373–378.

28. Millán J, Pintó X, Muñoz A, Zúñiga M, Rubiés-Prat J, Pallardo LF, Masana L, Mangas A, Hernández-Mijares A, González-Santos P, Ascaso JF, Pedro-Botet J. Lipoprotein ratios: physiological significance and clinical usefulness in cardiovascular prevention. Vasc Health Risk Manag. 2009; 5:757–765.

29. da Luz PL, Favarato D, Faria-Neto JR Jr, Lemos P, Chagas AC. High ratio of triglycerides to HDL-cholesterol predicts extensive coronary disease. Clinics (Sao Paulo). 2008; 63:427–432.

30. Keser I, Ilich JZ, Vrkić N, Giljević Z, Colić Barić I. Folic acid and vitamin B(12) supplementation lowers plasma homocysteine but has no effect on serum bone turnover markers in elderly women: a randomized, double-blind, placebo-controlled trial. Nutr Res. 2013; 33:211–219.

31. Aboyans V, Criqui MH, Abraham P, Allison MA, Creager MA, Diehm C, Fowkes FG, Hiatt WR, Jönsson B, Lacroix P, Marin B, McDermott MM, Norgren L, Pande RL, Preux PM, Stoffers HE, Treat-Jacobson D. American Heart Association Council on Peripheral Vascular Disease. Council on Epidemiology and Prevention. Council on Clinical Cardiology. Council on Cardiovascular Nursing. Council on Cardiovascular Radiology and Intervention. Council on Cardiovascular Surgery and Anesthesia. Measurement and interpretation of the ankle-brachial index: a scientific statement from the American Heart Association. Circulation. 2012; 126:2890–2909.

32. Wu L, Wang Y, Zheng L, Li J, Hu D, Xu Y, Hasimu B, Yuan H, Yang J, Sun Y, Ma Y. Distribution of brachial-ankle pulse wave velocity values and optimal cut-off in distinguishing subjects with clinical condition in Chinese population. Int Angiol. 2012; 31:252–259.

33. Tehlivets O. Homocysteine as a risk factor for atherosclerosis: is its conversion to s-adenosyl-L-homocysteine the key to deregulated lipid metabolism? J Lipids. 2011; 2011:702853.

34. Young IS, Woodside JV. Folate and homocysteine. Curr Opin Clin Nutr Metab Care. 2000; 3:427–432.

35. Banerjee RV, Matthews RG. Cobalamin-dependent methionine synthase. FASEB J. 1990; 4:1450–1459.

36. Bostom AG, Shemin D, Lapane KL, Nadeau MR, Sutherland P, Chan J, Rozen R, Yoburn D, Jacques PF, Selhub J, Rosenberg IH. Folate status is the major determinant of fasting total plasma homocysteine levels in maintenance dialysis patients. Atherosclerosis. 1996; 123:193–202.

37. Title LM, Ur E, Giddens K, Mcqueen MJ, Nassar BA. Folic acid improves endothelial dysfunction in type 2 diabetes--an effect independent of homocysteine-lowering. Vasc Med. 2006; 11:101–109.

38. Liao D, Tan H, Hui R, Li Z, Jiang X, Gaubatz J, Yang F, Durante W, Chan L, Schafer AI, Pownall HJ, Yang X, Wang H. Hyperhomocysteinemia decreases circulating high-density lipoprotein by inhibiting apolipoprotein A-I Protein synthesis and enhancing HDL cholesterol clearance. Circ Res. 2006; 99:598–606.

39. Namekata K, Enokido Y, Ishii I, Nagai Y, Harada T, Kimura H. Abnormal lipid metabolism in cystathionine beta-synthase-deficient mice, an animal model for hyperhomocysteinemia. J Biol Chem. 2004; 279:52961–52969.

40. Werstuck GH, Lentz SR, Dayal S, Hossain GS, Sood SK, Shi YY, Zhou J, Maeda N, Krisans SK, Malinow MR, Austin RC. Homocysteine-induced endoplasmic reticulum stress causes dysregulation of the cholesterol and triglyceride biosynthetic pathways. J Clin Invest. 2001; 107:1263–1273.

41. Adaikalakoteswari A, Jayashri R, Sukumar N, Venkataraman H, Pradeepa R, Gokulakrishnan K, Anjana RM, McTernan PG, Tripathi G, Patel V, Kumar S, Mohan V, Saravanan P. Vitamin B12 deficiency is associated with adverse lipid profile in Europeans and Indians with type 2 diabetes. Cardiovasc Diabetol. 2014; 13:129.

42. Shargorodsky M, Boaz M, Pasternak S, Hanah R, Matas Z, Fux A, Beigel Y, Mashavi M. Serum homocysteine, folate, vitamin B₁₂ levels and arterial stiffness in diabetic patients: which of them is really important in atherogenesis? Diabetes Metab Res Rev. 2009; 25:70–75.

43. Nappo F, De Rosa N, Marfella R, De Lucia D, Ingrosso D, Perna AF, Farzati B, Giugliano D. Impairment of endothelial functions by acute hyperhomocysteinemia and reversal by antioxidant vitamins. JAMA. 1999; 281:2113–2118.

44. el-Swefy SE, Ali SI, Asker ME, Mohamed HE. Hyperhomocysteinaemia and cardiovascular risk in female ovariectomized rats: role of folic acid and hormone replacement therapy. J Pharm Pharmacol. 2002; 54:391–397.

45. Xia XS, Li X, Wang L, Wang JZ, Ma JP, Wu CJ. Supplementation of folic acid and vitamin B₁₂ reduces plasma levels of asymmetric dimethylarginine in patients with acute ischemic stroke. J Clin Neurosci. 2014; 21:1586–1590.

46. Sibal L, Agarwal SC, Home PD, Boger RH. The role of asymmetric dimethylarginine (ADMA) in endothelial dysfunction and cardiovascular disease. Curr Cardiol Rev. 2010; 6:82–90.

47. Protopsaltis I, Foussas S, Angelidi A, Gritzapis A, Sergentanis T, Matsagos S, Tzirogiannis K, Panoutsopoulos GI, Dimitriadis G, Raptis S, Melidonis A. Impact of ADMA, endothelial progenitor cells and traditional cardiovascular risk factors on pulse wave velocity among prediabetic individuals. Cardiovasc Diabetol. 2012; 11:141.

48. Koyama K, Ito A, Yamamoto J, Nishio T, Kajikuri J, Dohi Y, Ohte N, Sano A, Nakamura H, Kumagai H, Itoh T. Randomized controlled trial of the effect of short-term coadministration of methylcobalamin and folate on serum ADMA concentration in patients receiving long-term hemodialysis. Am J Kidney Dis. 2010; 55:1069–1078.