Homocysteine as a non-classical risk factor for atherosclerosis in relation to pharmacotherapy of type 2 diabetes mellitus.

  • Magdalena Anna Borowska Department of Pharmacology, Poznan University of Medical Science
  • Marzena Dworacka Department of Pharmacology, Poznan University of Medical Science
  • Hanna Winiarska Department of Pharmacology, Poznan University of Medical Science
  • Ewa Krzyżagórska Poznan Specialist Center of Medical Care, Diabetology Outpatient Clinic, Serbska 6, Poznan
Keywords: homocysteine, atherosclerosis, pharmacotherapy



The aim of our study was to evaluate which of the pharmacotherapeutic methods that are frequently used to treat type 2 diabetes is associated with the most beneficial profile in relation to pro-atherogenic homocysteine levels.

Patients and methods

We measured the serum homocysteine level in 182 patients with type 2 diabetes treated with metformin (89), treated with insulin in combination with metformin (31), receiving sulfonulureas (31) and treated conventionally with insulin (31). The total homocysteine levels in the serum were assayed using commercial kits (Axis® Human Homocysteine ELISA Kit, IBL). To exclude the influence of selected metabolic and anthropometric factors on the differences between the examined groups, multivariate analysis of covariance was used (ANCOVA). In this analysis, serum homocysteine concentration was the dependent variable, while diabetes duration, waist circumference, HbA1c, 1.5-anhydro-D-glucitol, fasting glycaemia and peptide C were used as covariates.


The serum homocysteine levels in patients treated with insulin in monotherapy was significantly higher than what was observed in the metformin treated subjects and than in the patients receiving insulin combined with metformin. The analysis of covariance confirmed that the differences between the therapeutic groups were affected also by waist circumference and the C-peptide levels.


We conclude that conventional insulin therapy may have negative effect on pro-atherogenic homocysteine levels in patients with type 2 diabetes. This study revealed that not only pharmacotherapy of type 2 diabetes may modify pro-atherogenic homocysteine levels but also beta cell secretory function and abdominal obesity.


Becker A, Smulders YM, van Guldener C (2003) Epidemiology of homocysteine as a risk factor in diabetes. Metab Syndr Relat Disord 1:105-20. PMID: 18370632 DOI: 10.1089/154041903322294434.

Guthikonda S, Haynes WG (2006) Homocysteine: role and implications in atherosclerosis. Curr Atheroscler Rep 8:100-6.

Baszczuk A, Kopczynski Z (2014) Hyperhomocysteinemia in patients with cardiovascular disease. Postepy Hig Med Dosw 68:579. doi: 10.5604/17322693.1102340. [PubMed]

Pushpakumar S, Kundu S, Sen U (2014) Endothelial dysfunction: the link between homocysteine and hydrogen sulfide. Curr Med Chem. 2014;21(32):3662-72.

Signorello MG, Segantin A, Passalacqua M et al (2009) Homocysteine decreased platelet NO level via protein kinase C activation. Nitric Oxide 20:104–113. DOI: 10.1016/j.niox.2008.11.005.

Gurda D, Handschuh L, Kotkowiak W, Jakubowski H (2015) Homocysteine thiolactone and N-homocysteinylated protein induce pro-atherogenic changes in gene expression in human vascular endothelial cells. Amino Acids 47(7):1319-39. doi: 10.1007/s00726-015-1956-7.

Seo H, Oh H, Park H, Park M, Jang Y, Lee M (2010) Contribution of dietary intakes of antioxidants to homocysteine-induced low density lipoprotein (LDL) oxidation in atherosclerotic patients. Yonsei Med J Jul;51(4):526-33. doi: 10.3349/ymj.2010.51.4.526.

American Diabetes Association. Standards of medical care in diabetes – 2007. Diabetes Care 30:4-41.

European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD). Guidelines on diabetes, pre-diabetes, and cardiovascular diseases: executive summary. The Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD) (2007). Eur Heart J 28:88-136.

Rohlfing CL, Little RR (2000) Use of GHb (HbA1c) in screening for undiagnosed diabetes in the US population. Diabetes Care 23:187-91.

Yabuuchi M, Masuda M (1984) Simple enzymatic method for determining 1,5-anhydro-D-glucitol for diagnosis of diabetes mellitus. Clin Chem 35:2039-43.

Dworacka M, Winiarska H (2005) The application of plasma 1.5-anhydro-D-glucitol for monitoring type 2 diabetic patients. Dis Markers 21:127-132.

Refsum H, Smith AD, Ueland M et al (2004) Facts and recommendations about total homocysteine determinations: an expert opinion. Clin Chem Acta 50:3-32 DOI: 10.1373/clinchem.2003.021634.

Sato Y, Ouchi K, Funase Y, Yamauchi K, Aizawa T (2013) Relationship between metformin use, vitamin B12 deficiency, hyperhomocysteinemia and vascular complications in patients with type 2 diabetes. Endocr J 60(12):1275-80.

Dierkes J, Westphal S. Effect of drugs on homocysteine concentrations (2005) Semin Vasc Med 2005 May;5(2):124-39. DOI: 10.1055/s-2005-872398.

Valdés-Ramos R, Guadarrama-López AL, Martínez-Carrillo BE, Benítez-Arciniega AD (2015) Vitamins and type 2 diabetes mellitus. Endocr Metab Immune Disord Drug Targets 15(1):54-63.

Jacobs RL, House JD, Brosnan ME et al (1998) Effects of Streptozotocin-Induced diabetes and of insulin treatment on homocysteine metabolism in the rat. Diabetes 47:1967-1970.

Ratman S, Maclean KN, Jacobs RL et al (2002) Hormonal regulation of cystathionine-synthase expression in liver. J Biol Chem 277:42912-42918. DOI: 10.1016/S2215-0366(14)00081-9.

Vayá A, Rivera L, Hernández-Mijares A et al (2012) Homocysteine levels in morbidly obese patients: its association with waist circumference and insulin resistance. Clin Hemorheol Microcirc 52:49-56. DOI: 10.3233/CH-2012-1544