- Research
- Open access
- Published:
Type II diabetes mellitus and hyperhomocysteinemia: a complex interaction
Diabetology & Metabolic Syndrome volume 9, Article number: 19 (2017)
Abstract
Background
Elevated homocysteine (Hc) levels have a well-established and clear causal relationship to epithelial damage leading to coronary artery disease. Furthermore, it is strongly associated with other metabolic syndrome variables, such as hypertension, which is correlated with type II diabetes mellitus (T2DM). Studies on T2DM in relation to Hc levels have shown both positive and negative associations. The aim of the present study is to examine the relationship between Hc levels and risk of T2DM in the Lebanese population.
Methods
We sought to identify whether Hc associates positively or negatively with diabetes in a case–control study, where 2755 subjects enrolled from patients who had been catheterized for coronary artery diagnosis and treatment. We further sought to identify whether the gene variant MTHFR 667C>T is associated with T2DM, and how Hc and MTHFR 667C>T also impact other correlates of T2DM, including the widely used diuretics in this study population.
Results
We found that Hc levels were significantly reduced among subjects with diabetes compared to those without diabetes when adjusted for all potential confounders (OR 0.640; 95% CI [0.44–0.92]; p = 0.0200). The associations between Hc levels and other variates contradicted the result: hypertension associates positively with high Hc levels, and with T2DM. The MTHFR 667C>T only associated significantly with high Hc levels.
Conclusion
These results suggest population-specific variations among a range of mechanisms that modulate the association of Hc and T2DM, providing a probe for future studies.
Background
The prevalence of type II diabetes mellitus (T2DM) continues to increase worldwide [1, 2]. A recent study estimated the prevalence of diabetes in the Middle East to be 9.3% [3], already more elevated than worldwide estimates of 8.3% in 2014 [4], with a rapid emergence due to recent dietary changes [5]. Given the significant healthcare-related expenditures, identifying modifiable factors is essential for the prevention of diabetes. T2DM is known to be a complex and heterogeneous disease resulting from a set of interacting factors that can be genetic or environmental, each with a variable contribution to disease causation. Many cultural, dietary, behavioral, contextual and lifestyle factors are also primary determinants of risk for T2DM [6].
Recent studies have increasingly been showing interactions between plasma Hc levels and T2DM and its vascular complications [7–9]. Correlation with T2DM remains unconvincing however, with studies reporting variability in plasma Hc levels between people with diabetes and people without diabetes [10–14]. Hc is a sulfur-containing, toxic non-proteinogenic amino-acid biosynthesized from methionine. It is located at a branch-point of multiple metabolic pathways and is produced from methionine as a product of a number of transmethylation reactions [15]. The most common inherited disorder leading to hyperhomocysteinemia is the 5-methylenetetrahydrofolate reductase (MTHFR) polymorphism [16, 17]. Individuals with deficiencies of folic acid (B9), pyridoxine (B6), or cobalamin (B12) can as well develop hyperhomocysteinemia [18, 19].
To date, the mechanisms behind the T2DM correlation with Hc levels have been difficult to identify. MTHFR converts 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. Mutations in MTHFR impair the function of the enzyme, and the 677C → T polymorphism (MTHFR, MIM # 607,093) is an enzyme reducing activity variant associated with elevated plasma Hc levels as well as insulin resistance. [20–22]. It is believed that the decreased insulin secretory responsiveness, caused by the destructive production of reactive oxygen species (ROS) as a result of elevated Hc levels, leads to insulin resistance [23, 24]. It has also been suggested that in patients with insulin resistance, there is hepatic acceleration of glucocorticoid secretion that also leads to enhanced Hc catabolism and decreased plasma Hc levels [14].
Genetic modifiers of significant biological effect could promote our understanding of the mechanisms of action by which Hc levels and MTHFR variants contribute to T2DM. These mechanisms of interactions have not yet been comprehensively elucidated, and explanations of these interactions have been contradictory. The aim of the present study is to examine the relationship between Hc levels and risk of T2DM in a phenotypically well-characterized group of patients and controls. We further investigate whether a dose–response relationship exists in our study population by assessing the interaction between the MTHFR 677C>T and Hc levels on T2DM. The Lebanese population may offer some unique features due to the rapid emergence of T2DM in Lebanon.
Methods
Subjects were recruited from several hospitals in Lebanon between May 2007 and June 2013. We developed a questionnaire to measure the impact of T2DM risk factors and collected family history after obtaining an informed consent from participants, as approved by the Lebanese American University Institutional Review Board (IRB). Annotations were coded from medical charts for data such as laboratory tests, prescribed medications, and presence of other clinical conditions. Venous blood samples were drawn in ethylenediaminetetraacetic acid (EDTA) tubes from 7709 subjects. A diagnosis of T2DM was made when a patient had a hemoglobin A1C (HbA1C) value of 48 mmol/mol (6.5%) or higher and/or by an ascertained physician supported by documentation in the patient’s medical records. DNA was extracted using a standard phenol–chloroform extraction procedure. The single-nucleotide polymorphism (SNP) rs1801133 from MTHFR was determined for 1824 of the 2755 study samples, having been analyzed using the Illumina Human610 and 660 W Quad beadchip and the Illumina Human Omni EXP-12v1 multi-use.
Plasma homocysteine level was determined for the 2643 subjects by a microparticle enzyme immunoassay (MEIA) method (Abbott). The assay was carried out following the instructions of the manufacturer. Hyperhomocysteinemia was defined as a concentration of ≥15 μmol/l, and elevated Hc level as ≥10 μmol/l. 1007 of these samples were genotyped. Dyslipidemia was defined as low high-density lipoprotein (HDL) (≤40 for men, 50 for women), high triglycerides (≥200), and diagnosis of hyperlipidemia (DxHL). Since most subjects had controlled low-density lipoprotein (LDL) with a protective effect against LDL levels ≥120 given a diagnosis of hyperlipidemia (OR 0.730, 95% CI = 0.60–0.89, p = 0.0014), elevated LDL levels were not included for analysis. Diagnoses of T2DM (DxT2DM) and hypertension (DxHTN) were also included. BMI in excess of 30 (obesity) was also analyzed.
Besides summary statistics (Table 1), we sought to identify dominating covariates associated with hyperhomocysteinemia. Noting T2DM negatively associated with hyperhomocysteinemia, we considered whether the structure of enrollment induced Berkson’s bias, and tested for interaction with enrollment categories. Prediction of T2DM by hyperhomocysteinemia was performed given adjustment variables, first by including only the adjustment variables, then including hyperhomocysteinemia and finally including interactions between hyperhomocysteinemia with DxHTN. The adjustment variable analysis provides a baseline to identify shifts due to inclusion of hyperhomocysteinemia and its interaction with DxHTN. Following that, the same analysis of T2DM was repeated except that hyperhomocysteinemia was replaced by elevated Hc levels. Finally, rs1801133 in MTHFR, known to promote hyperhomocysteinemia, was tested for its effects on other metabolic syndrome variables and for elevated Hc and hyperhomocysteinemia.
Results
Table 1 shows summary statistics for metabolic syndrome, and Hc for the study population. It is notable that males make up most of the population and the average Hc levels were either borderline or fully hyperhomocysteimic. Figure 1 shows the interaction between hypertension diagnosis and T2DM diagnosis on Hc levels in our study population. Hypertension diagnosis has a stronger impact on Hc levels among diabetics than among non-diabetics. The difference in Hc levels between diabetics and non-diabetics is clearly greater than the difference in Hc levels between hypertensive and non-hypertensive subjects.
We tested for the presence of Berkson’s bias by examining whether the association between Hc levels and T2DM interacted with subjects’ enrollment. There was no significant association between enrollment and elevated Hc levels (OR 0.870, 95% CI 0.72–1.05, p = 0.153), or hyperhomocysteinemia (OR 0.869, 95% CI 0.74–1.02, p = 0.0947). Table 2 shows very significant associations of hyperhomocysteinemia and elevated Hc with age and sex. Associations of hyperhomocysteinemia and elevated Hc with other variants were analyzed with and without adjustment with sex and age. T2DM is suppressed among subjects with elevated Hc with and without adjustment, but not among subjects with hyperhomocysteinemia. Hypertension is significantly promoted both by hyperhomocysteinemia and elevated Hc.
Table 3A shows the impact of hyperhomocysteinemia on T2DM considering adjustments from the other covariates. Inclusion of the strongest covariates (age, sex included as adjustment variables but not reported), DxHL, obesity, and DxHTN were all highly significant. Inclusion of hyperhomocysteinemia tended to shift the other adjustment variable odds ratios marginally, with BMI losing high significance, yet remaining significant; hyperhomocysteinemia was significant. Inclusion of the interaction with hypertension was not significant, but hyperhomocysteinemia remained significant. Table 3B shows patterns similar to that of 3A except that elevated Hc levels had more pronounced OR values and were more highly significant.
Table 4 summarizes the allele frequencies of rs1801133 in the study population, with Hardy–Weinberg disequilibrium almost significant. Table 5 repeats Table 2, except that Hc levels are replaced by rs1801133 in an additive logistic regression. All associations were not statistically significant except for those involving Hc. Hyperhomocysteinemia was highly significant (OR 1.483, 95% CI 1.20–1.83, p = 0.000237), with elevated Hc being only significant (OR 1.287, 95% CI 1.05–1.59, p = 0.0173).
Discussion
To our knowledge, this is the first study done on the Lebanese population to examine the correlation of homocysteine levels and T2DM. The mean Hc plasma levels in patients without diabetes in our study population (15.3 ± 8.7) was elevated and found to be higher than what has been reported in previous studies (range = 12–14 mmol/l) [25]. We observed a significantly negative correlation between hyperhomocysteinemia and T2DM. This negative correlation remained significant whether Hc plasma levels where ≥10 or ≥15, indicating a consistent threshold association. Given the correlation of T2DM and coronary artery disease (CAD), a previous study conducted on our study subjects showed an association of hyperhomocysteinemia with the degree of coronary artery stenosis in CAD patients [26].
Our results are not aligned with the overwhelming majority of previous studies that have reported a positive correlation between elevated Hc and T2DM and its complications [27–29]. A recent meta-analysis study conducted on more than 8000 subjects provided strong support for a causal association of elevated Hc levels and T2DM [30]. This meta-analysis study, however, used published data from various studies that may have had different patient recruitment criteria and clinical definitions with many including small number of subjects. Measurements of Hc levels were not homogenous across all populations with each having a distinct genetic background hence leading to significant heterogeneity. This data variability may explain some of the difference in their findings compared to ours. One study in particular, conducted on 105 subjects with diabetes and 120 controls matched for sex showed that the mean fasting Hc was significantly lower in patients with diabetes than control subjects [13]. A study conducted on Mediterranean patients with T2DM did not show a difference in Hc levels between diabetic and non-diabetic patients [31], while a study done by Russo et al. [32] did not show a difference between total Hc among diabetic and non-diabetic women, suggesting a possible gender effect on this association. Moreover, despite the strong evidence showing the causal association of Hcy level with the development of T2DM [30], the Prospective Investigation of the Vasculature study in Uppsala Seniors (PIVUS) cohort (n  =  1016) showed no evidence of a causal relationship of levels of plasma homocysteine with fasting glucose, fasting insulin, or T2DM [33].
The reduction of Hc levels among subjects with diabetes could possibly be attributed to two factors. First, Hc is located at a branch-point of multiple metabolic pathways and is produced from methionine as a product of a large number of transmethylation reactions [15]. Homocysteine methyltransferase (MTHFR) and cystathionine beta synthase (CBS) carry out a chemical reaction that converts Hc to methionine when Hc is methylated by N-5-methyltetrahydrofolate. This remethylation reaction is the main regulator of plasma Hc levels. Second, it was consistently shown that in rats with diabetes, the expression of CBS is significantly increased. Hc levels were significantly increased when these rats with diabetes received insulin. These results strongly suggest a regulatory role of insulin in the hepatic trans-sulfuration pathway that metabolizes Hc. In vitro studies conducted on cultured hepatocytes also demonstrated an increased activity of CBS [34].
It has been postulated that as modulators of Hc, MTHFR variants that inactivate MTHFR or lower its activity may be directly associated with increased risk of T2DM. Although previous studies have shown an association between MTHFR 677C>T and complications of diabetes like retinopathy [35, 36] and nephropathy [37], none could recognize this activity lowering variant as a risk factor for T2DM, and therefore the negative association that we observe remains questionable. Moreover, mild hyperhomocysteinemia and the MTHFR TT genotype were not shown to be significant risk factors for the development of microangiopathy in patients with T2DM in one prospective cohort study by Russo et al. [38]. This suggests that there are other confounding variables not yet identified that may be impacting Hc levels and T2DM, which are not related to MTHFR mutations. In a recent meta-analysis study, a link between MTHFR 677C>T and T2DM was established, showing that subjects with the T allele of the MTHFR 677C>T variant have significantly higher risk of having diabetes (OR 1.31, p = 0.032) than carriers of the C allele [30].
In our study we failed to show a direct association between the MTHFR 677C>T variant and T2DM. This suggests that there are other causes to hyperhomocysteinemia acting in our population that impact its association either directly or through high Hc levels with hypertension not accounted for by MTHFR 677C>T. We did not resolve an interaction between diuretics and MTHFR 677C>T in predicting hyperhomocysteinemia, but additive regression showed both contributed highly significant OR’s. Yet, MTHFR 677C>T shows no significant association with T2DM. One possible reason behind the difference observed from the various studies associating MTHFR with T2DM is the genetic heterogeneity of the various populations studied. The frequencies of the MTHFR 677 alleles vary significantly from one population to another. The T allele ranges from 8.8% in Moroccans [39] to 19.1% in Chinese [40] population while it was 34.3% in our study, which although yields increased power, but limitations in the number genotyped restrict power. A systematic review by Zhong et al. [41] showed that rs1801133 polymorphism of the MTHFR gene was not consistently associated with either increased or reduced risk of T2DM.
Limitations
All enrolled subjects were catheterized. Catheterization was performed for myocardial infarction, unstable angina, and subjects warranting workup due to high CAD risk factors. We therefore tested whether the negative association between hyperhomocysteinemia and T2DM might be due to Berkson’s bias, and found that there was no association between reason for catheterization and the relationship between homocysteine levels with T2DM. Another limitation of the study is the absence of data related to levels of vitamins B9 (folate) and B12 or creatinine levels reflecting kidney functions; thus these parameters were not included in the final multivariate analysis despite being associated with homocysteinemia.
Conclusion
We speculate that the role of MTHFR and their interaction with insulin and glucose levels in the blood shows mixed pressures on both positive and negative associations between Hc levels and T2DM, and the conditions reflected in populations producing these disparate results need to be further elucidated. The expression regulation of these enzymes is a complex process that may involve the activity of other enzymes as well as the cellular environment that is affected by diet, cellular stress and genomic background and the epigenetic milieu. The interaction between glucose metabolism, insulin resistance and the pathogenicity of hyperhomocysteinemia remains to be unraveled.
Abbreviations
- BMI:
-
body-mass index
- CAD:
-
coronary artery disease
- CBS:
-
cystathionine beta synthase
- DxHL:
-
diagnosis of hyperlipidemia
- DxHTN:
-
diagnosis of hypertension
- DxT2DM:
-
diagnosis of type 2 diabetes mellitus
- EDTA:
-
ethylenediaminetetraacetic
- HbA1C:
-
hemoglobin A1C
- Hc:
-
homocysteine
- HD:
-
hemodialysis
- HDL:
-
high-density lipoprotein
- LDL:
-
low-density lipoprotein
- MEIA:
-
microparticle enzyme immunoassay
- MIM:
-
mendelian inheritance in man
- MTHFR:
-
5-methylenetetrahydrofolate reductase
- ROS:
-
reactive oxygen species
- SNP:
-
single-nucleotide polymorphism
- Tg:
-
triglyceride
- T2DM:
-
type 2 diabetes mellitus
References
Guariguata L, Whiting DR, Hambleton I, Beagley J, Linnenkamp U, Shaw JE. Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res Clin Pract. 2014;103:137–49.
International Diabetes Federation. International Diabetes Federatio. IDF Diabetes Atlas. 6th ed. Brussels: International Diabetes Federation; 2013.
Shaw JE, Sicree RA, Zimmet PZ. Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract. 2010;87:4–14.
Costanian C, Bennett K, Hwalla N, Assaad S, Sibai AM. Prevalence, correlates and management of type 2 diabetes mellitus in Lebanon: findings from a national population-based study. Diabetes Res Clin Pract. 2014;105:408–15.
Al-Khudairy L, Stranges S, Kumar S, Al-Daghri N, Rees K. Dietary factors and type 2 diabetes in the Middle East: what is the evidence for an association?–a systematic review. Nutrients. 2013;5:3871–97.
Ghassibe-Sabbagh M, Deeb M, Salloum AK, Mouzaya F, Haber M, Al-Sarraj Y, Chami Y, Akle Y, Hirbli K, Nemr R, et al. Multivariate epidemiologic analysis of type 2 diabetes mellitus risks in the Lebanese population. Diabetol Metab Syndr. 2014;6:89.
Buysschaert M, Dramais AS, Wallemacq PE, Hermans MP. Hyperhomocysteinemia in type 2 diabetes: relationship to macroangiopathy, nephropathy, and insulin resistance. Diabetes Care. 2000;23:1816–22.
Hoogeveen EK, Kostense PJ, Beks PJ, Mackaay AJ, Jakobs C, Bouter LM, Heine RJ, Stehouwer CD. Hyperhomocysteinemia is associated with an increased risk of cardiovascular disease, especially in non-insulin-dependent diabetes mellitus: a population-based study. Arterioscler Thromb Vasc Biol. 1998;18:133–8.
Meigs JB, Jacques PF, Selhub J, Singer DE, Nathan DM, Rifai N, D’Agostino RB Sr, Wilson PW, Framingham Offspring S. Fasting plasma homocysteine levels in the insulin resistance syndrome: the Framingham offspring study. Diabetes Care. 2001;24:1403–10.
Agullo-Ortuno MT, Albaladejo MD, Parra S, Rodriguez-Manotas M, Fenollar M, Ruiz-Espejo F, Tebar J, Martinez P. Plasmatic homocysteine concentration and its relationship with complications associated to diabetes mellitus. Clin Chim Acta. 2002;326:105–12.
Folsom AR, Nieto FJ, McGovern PG, Tsai MY, Malinow MR, Eckfeldt JH, Hess DL, Davis CE. Prospective study of coronary heart disease incidence in relation to fasting total homocysteine, related genetic polymorphisms, and B vitamins: the atherosclerosis risk in communities (ARIC) study. Circulation. 1998;98:204–10.
Hoogeveen EK, Kostense PJ, Jakobs C, Dekker JM, Nijpels G, Heine RJ, Bouter LM, Stehouwer CD. Hyperhomocysteinemia increases risk of death, especially in type 2 diabetes: 5-year follow-up of the Hoorn Study. Circulation. 2000;101:1506–11.
Mazza A, Bossone E, Mazza F, Distante A. Reduced serum homocysteine levels in type 2 diabetes. Nutr Metab Cardiovasc Dis. 2005;15:118–24.
Emoto M, Kanda H, Shoji T, Kawagishi T, Komatsu M, Mori K, Tahara H, Ishimura E, Inaba M, Okuno Y. Impact of insulin resistance and nephropathy on homocysteine in type 2 diabetes. Diabetes Care. 2001;24:533–8.
Finkelstein JD. Methionine metabolism in mammals. J Nutr Biochem. 1990;1:228–37.
Fowler B. Disorders of homocysteine metabolism. J Inherit Metab Dis. 1997;20:270–85.
Goyette P, Sumner JS, Milos R, Duncan AM, Rosenblatt DS, Matthews RG, Rozen R. Human methylenetetrahydrofolate reductase: isolation of cDNA mapping and mutation identification. Nat Genet. 1994;7:551.
Manolescu BN, Oprea E, Farcasanu IC, Berteanu M, Cercasov C. Homocysteine and vitamin therapy in stroke prevention and treatment: a review. Acta Biochim Pol. 2010;57:467–77.
Saposnik G, Ray JG, Sheridan P, McQueen M, Lonn E, Heart Outcomes Prevention Evaluation I. Homocysteine-lowering therapy and stroke risk, severity, and disability: additional findings from the HOPE 2 trial. Stroke. 2009;40:1365–72.
Harmon DL, Doyle RM, Meleady R, Doyle M, Shields DC, Barry R, Coakley D, Graham IM, Whitehead AS. Genetic analysis of the thermolabile variant of 5, 10-methylenetetrahydrofolate reductase as a risk factor for ischemic stroke. Arterioscler Thromb Vasc Biol. 1999;19:208–11.
Lievers KJ, Boers GH, Verhoef P, den Heijer M, Kluijtmans LA, van der Put NM, Trijbels FJ, Blom HJ. A second common variant in the methylenetetrahydrofolate reductase (MTHFR) gene and its relationship to MTHFR enzyme activity, homocysteine, and cardiovascular disease risk. J Mol Med (Berl). 2001;79:522–8.
Kluijtmans LA, Whitehead AS. Methylenetetrahydrofolate reductase genotypes and predisposition to atherothrombotic disease; evidence that all three MTHFR C677T genotypes confer different levels of risk. Eur Heart J. 2001;22:294–9.
Patterson S, Flatt PR, Brennan L, Newsholme P, McClenaghan NH. Detrimental actions of metabolic syndrome risk factor, homocysteine, on pancreatic beta-cell glucose metabolism and insulin secretion. J Endocrinol. 2006;189:301–10.
Scullion SM, Gurgul-Convey E, Elsner M, Lenzen S, Flatt PR, McClenaghan NH. Enhancement of homocysteine toxicity to insulin-secreting BRIN-BD11 cells in combination with alloxan. J Endocrinol. 2012;214:233–8.
Motti C, Gnasso A, Bernardini S, Massoud R, Pastore A, Rampa P, Federici G, Cortese C. Common mutation in methylenetetrahydrofolate reductase. Correlation with homocysteine and other risk factors for vascular disease. Atherosclerosis. 1998;139:377–83.
Ghassibe-Sabbagh M, Platt DE, Youhanna S, Abchee AB, Stewart K, Badro DA, Haber M, Salloum AK, Douaihy B, el Bayeh H, et al. Genetic and environmental influences on total plasma homocysteine and its role in coronary artery disease risk. Atherosclerosis. 2012;222:180–6.
Sonkar SK, Sonkar GK, Soni D, Soni D, Usman K. Plasma Homocysteine level and its clinical correlation with type 2 diabetes mellitus and its complications. Int J Diabetes Develop Ctries. 2014;34:3–6.
Soinio M, Marniemi J, Laakso M, Lehto S, Ronnemaa T. Elevated plasma homocysteine level is an independent predictor of coronary heart disease events in patients with type 2 diabetes mellitus. Ann Intern Med. 2004;140:94–100.
Looker HC, Fagot-Campagna A, Gunter EW, Pfeiffer CM, Narayan KM, Knowler WC, Hanson RL. Homocysteine as a risk factor for nephropathy and retinopathy in type 2 diabetes. Diabetologia. 2003;46:766–72.
Huang T, Ren J, Huang J, Li D. Association of homocysteine with type 2 diabetes: a meta-analysis implementing Mendelian randomization approach. BMC Genom. 2013;14:867.
Diakoumopoulou E, Tentolouris N, Kirlaki E, Perrea D, Kitsou E, Psallas M, Doulgerakis D, Katsilambros N. Plasma homocysteine levels in patients with type 2 diabetes in a Mediterranean population: relation with nutritional and other factors. Nutr Metab Cardiovasc Dis. 2005;15:109–17.
Russo GT, Di Benedetto A, Alessi E, Giandalia A, Gaudio A, Ientile R, Horvath KV, Asztalos B, Raimondo G, Cucinotta D. Menopause modulates homocysteine levels in diabetic and non-diabetic women. J Endocrinol Invest. 2008;31:546–51.
Kumar J, Ingelsson E, Lind L, Fall T. No Evidence of a causal relationship between plasma homocysteine and type 2 diabetes: a Mendelian randomization study. Front Cardiovasc Med. 2015;2:11.
Dicker-Brown A, Fonseca VA, Fink LM, Kern PA. The effect of glucose and insulin on the activity of methylene tetrahydrofolate reductase and cystathionine-beta-synthase: studies in hepatocytes. Atherosclerosis. 2001;158:297–301.
Ksiazek P, Bednarek-Skublewska A, Buraczynska M. The C677T methylenetetrahydrofolate reductase gene mutation and nephropathy in type 2 diabetes mellitus. Med Sci Monit. 2004;10:Br47–51.
Maeda M, Yamamoto I, Fukuda M, Nishida M, Fujitsu J, Nonen S, Igarashi T, Motomura T, Inaba M, Fujio Y, Azuma J. MTHFR gene polymorphism as a risk factor for diabetic retinopathy in type 2 diabetic patients without serum creatinine elevation. Diabetes Care. 2003;26:547–8.
Chen H, Wei F, Wang L, Wang Z, Meng J, Jia L, Sun G, Zhang R, Li B, Yu H, et al. MTHFR gene C677T polymorphism and type 2 diabetic nephropathy in Asian populations: a meta-analysis. Int J Clin Exp Med. 2015;8:3662–70.
Russo GT, Di Benedetto A, Magazzu D, Giandalia A, Giorda CB, Ientile R, Previti M, Di Cesare E, Cucinotta D. Mild hyperhomocysteinemia, C677T polymorphism on methylenetetrahydrofolate reductase gene and the risk of macroangiopathy in type 2 diabetes: a prospective study. Acta Diabetol. 2011;48:95–101.
Benrahma H, Abidi O, Melouk L, Ajjemami M, Rouba H, Chadli A, Oudghiri M, Farouqui A, Barakat A. Association of the C677T polymorphism in the human methylenetetrahydrofolate reductase (MTHFR) gene with the genetic predisposition for type 2 diabetes mellitus in a Moroccan population. Genet Test Mol Biomarkers. 2012;16:383–7.
Sun J, Xu Y, Zhu Y, Lu H. Genetic polymorphism of methylenetetrahydrofolate reductase as a risk factor for diabetic nephropathy in Chinese type 2 diabetic patients. Diabetes Res Clin Pract. 2004;64:185–90.
Zhong JH, Rodriguez AC, Yang NN, Li LQ. Methylenetetrahydrofolate reductase gene polymorphism and risk of type 2 diabetes mellitus. PLoS ONE. 2013;8:e74521.
Authors’ contributions
Conceived and designed the experiments: DEP HES PAZ ABA MH DG. Performed the statistical analysis: MH. Analyzed the data: MGS AKS PS FM DEP HES PAZ. Contributed reagents/materials/genotyping: MGS AS DG YAS HES. Wrote the paper: DEP EH PAZ ABA and with help from all co-authors. All authors read and approved the final manuscript.
Acknowledgements
We thank the patients for agreeing to participate in the study. This publication was made possible by a grant from the Qatar National Research Fund under its National Priorities Research program (NPRP) award number NPRP 09-215-3-049. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the Qatar National Research Fund.
Competing interests
The authors declare that they have no competing interests.
Consent for publication
Informed consent was obtained from all patients for being included in the study and for using their data for publication.
Funding
The authors declare no source of funding was available for this study.
Statement of human and animal rights
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008 (5). The study was approved by the Lebanese American University Institutional Review Board (IRB).
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
About this article
Cite this article
Platt, D.E., Hariri, E., Salameh, P. et al. Type II diabetes mellitus and hyperhomocysteinemia: a complex interaction. Diabetol Metab Syndr 9, 19 (2017). https://doi.org/10.1186/s13098-017-0218-0
Received:
Accepted:
Published:
DOI: https://doi.org/10.1186/s13098-017-0218-0