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Cardio Diabetes Medicine 2017 633

sa University Tokat, in Turkey. They investigated the VARIANTS ASSOCIATED WITH DEFENSE
distributions of the genotype and allele frequencies RESPONSE AND INFLAMMATORY
of the MTHFR gene C677T variant among patients
with DPN and matched control group. They identified RESPONSE IN THE PATHOGENESIS OF
a statistically significant difference of MTHFR gene DPN
C677T polymorphism between the patients with DPN Hur et al., 2011, reported that the molecules which are
and the control group [25]. involved with the process of inflammation such as
chemotactic agents and cytokines are involved with
Decreased levels of peroxisome proliferator activated the development and progression of DPN as well as
receptor alpha (PPARA) in chromosome 22 and lipid diabetic nephropathy [28,].
metabolism-related gene apolipoprotein E (APOE) in
chromosome 19 have been identified confirming the Kakoki et al., 2010, identified that the bradykinin re-
findings that altered lipid metabolism may play a role ceptor B2 (BDKRB2) is of particular interest in disease
in the progression of DPN [26]. Monastiriotis et al., progression of DPN. BDKRB2 gene was found to be
2013, reviewed literature to identify the association involved in progressive glomerulosclerosis and also
between APOE polymorphism and DPN and found susceptibility to DPN .
that the 4 allele of the apolipoprotein E gene is sig- Membrane associated adenosine A3 receptor (ADO-
nificantly associated with pathogenesis of DPN [26].
RA3), is also involved in the pathogenesis of DPN .
The Alpha2B adrenergic receptor encoded by ADR- Variants of DBKRB2 and ADORA3 were found to be
A2B gene located on chromosome 2 is associated involved in enhanced inflammation and dysregulated
with an array of functions. A polymorphism (12Glu9) defense responses, thus contributing to more sub-
resulting in the insertion/deletion of three glutamic stantial nerve damage in patients with progressive
acid residues in the third intracellular loop has been DPN [28,31].
described frequently in the literature [27]. In the ner-
vous system, this polymorphism has been identified VARIANTS ASSOCIATED WITH
to be linked with autonomic nervous dysfunction. This GLUCOSE METABOLIC PROCESSES
is particularly increased with sympathetic nervous AND PPAR SIGNALING PATHWAY IN THE
system activity and Papanas et al., 2007, found a
significant association in this indel allele distribution PATHOGENESIS OF DPN
of alpha2B adrenoceptor gene amongT2D patients According to Hur et al., 2011, PPARG, which encodes
with DPN in comparison with matched T2D patients a nuclear receptor for glitazone, plays a key role in
without neuropathy [27]. regulating glucose and lipid metabolism [28,]. Ag-
onists of PPARG are effective in treatment of DPN
NETWORK OF GENES ASSOCIATED WITH and nephropathy in experimental animal models
COMMON VARIANTS OF DPN [28,]. Another key gene is APOE, encoding an apoli-
poprotein, which regulates the normal catabolism of
Hur et al., 2011, examined two groups of DPN patients. triglycerides and cholesterol. A polymorphism of this
A network of transcription factor jun (JUN), leptin gene is linked to the progression of DPN .
(LEP), serpin peptidase inhibitor E Type 1(SERPINE1),
apolipoprotein E (APOE) and peroxisome proliferator GENETIC VARIANTS INVOLVED IN
activated receptor gamma (PPARG) were examined
to identify their potential relationship. Further subset DIFFERENT PHENOTYPES OF DPN
of genes related to defense response, inflammato- According to Cheng et al., 2015, in an experiment
ry response, regulation of lipid metabolic processes involving both human and animal models, sensory
and PPAR signaling pathways were then analyzed neurodegeneration in the chronic stage of diabetes
to identify the association of gene expression and was found to be associated with early damage to the
development of DPN [28].They demonstrated that in- distal axons of both upper and lower limbs neurons
creased glucose metabolism due to hyperglycaemia showing a pattern that accounts for the distribution
resulted in increased oxidative stress, mitochondrial of ‘‘glove -and-stocking’’ loss of sensation charac-
dysfunction and cell death in both in vitro and in vivo teristically seen in DPN. These changes accompany
models of diabetic neuropathy [28]. widespread abnormalities involving electrophysiolo-
gy and alterations in gene expression that indicate
a degenerative phenotype. However, existing knowl-
edge on the development of DPN which includes
oxidative and nitrergic stress, polyol accumulation,

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