Diabetes form of folate also act as

Diabetes Mellitus type 2 (DM2) is
showing an increasing prevalence worldwide and is

known as potential health burden,
with a range of systemic complications including,

neuropathies. Neuropathies,
particularly diabetic peripheral neuropathy (DPN) is

recognized as the most frequent
chronic complications of diabetes. DPN affects up to 50%

of patients with type 2 diabetes
at age >60 and is responsible for significant mortality and

morbidity as well as decline in
quality of life. Approximately half of the cases of DPN

might be asymptomatic while
patients are at risk of severe foot injury 1-2.

Methylene-tetrahydrofolate
reductase (MTHFR) is an enzyme encoded by the MTHFR

gene in human1.MTHFR is an
enzyme with major role in folate and homocysteine

metabolism. Hyper-homocysteinemia
is the result of diminished activity of MTHFR.

Mutations of the MTHFR gene might
lead to reduced enzymatic activity. In vitro studies

revealed that
hyper-homocysteinemia damages nervous function through direct cytotoxic

effects or as a result of
oxidative injuries of endothelial cell. Therefore, in diabetes macroand

microvascular complications
associated with higher hyper-homocysteinemia plasma

level might be associated with
nervous injuries3.

MTHFR acts in catalyzingthe
conversion of 5, 10-methylenetetrahydrofolate to the active

form of
folate5-methyltetrahydrofolate (5-MTHF), which is co-substrate for

homocysteine(Hcy) remethylation
to methionine 1.5-MTHF which is a circulating form

of folate also act as
peroxynitrite scavenger and conduct several effect on endothelial

function thorough by diminishing
generation of vascular superoxide and enhancement in

nitric oxide (NO) level 4.
MTHFR gene is located on chromosome 1p36.3 in humans,

consisting of 11 exons5.Several
single nucleotide polymorphisms (SNPs) within this

gene have been defined and C677T
(rsl80ll33) and Al298C (rsl80ll31) variants are the

two most explored ones 1.They
both are functional polymorphisms which cause

decreased enzyme activity,
resulting in diminished amount of folate, vitamins B6, B12 and

higher plasma level of
homocysteine. It has been demonstrated that each copy of the 677T

allele causes substitution of the
amino acid alanine to valine at amino acid 222 in the

catalytic domain of MTHFR1 and
result in a 35% decline in enzyme activity6.

Individuals with two copies T
allele (677TT) (homozygous) have MTHFR deficiency1.In

comparison to the normal C/C genotype,
approximately 35% and 70% enzyme activity

have been reported in the
heterozygous individuals with C/T genotype and the

homozygous T/T genotypes,
respectively7. Based on its biological functions, this variant

which is common in various
populations has been considered as a potential candidate

polymorphism for studying T2DM
and neuropathies 8-9.The frequency of 677C>T, has

been approximately estimated as
33%–37% heterozygous and about 10% homozygous in

Europeans6.In a meta-analysis
in order to examine whether frequencies of the C677T

MTHFR gene polymorphism were
population dependent, van der Puta and colleagues

(1997) reported that prevalence
of homozygosity for this polymorphism was 5% to 16% in

various populations and appeared
to be very common in Hispanics 10.

Peripheral neuropathy is an
unusual feature during the course of MTHFR deficiency

11.Recently, a number of case–control
studies have been surveyed the association

between the 677C>T
polymorphism in the MTHFR gene and T2DM or diabetes-related

complications. Nevertheless,
these studies have presented conflicting results, which has

prevented a
definitive conclusion to date