MATRIX METALLOPROTEINASE-2 (MMP-2 )
AND-9 (MMP-9) GENE VARIANTS AND MICROVASCULAR
COMPLICATIONS IN TYPE 2 DIABETES PATIENTS
Andjelic Jelic M٭ˡ, Radojkovic D², Nikolic A², Rakicevic Lj², Babic T², Jelic D³, Lalic NM⁴
*Corresponding Author: Marina Andjelic Jelic, Department of Endocrinology, Diabetes and Metabolic
Diseases, Clinical Medical Centre Zvezdara, Dimitrija Tucovica 161, 11000 Belgrade, Serbia, Phone +381 64 122 2010 Fax +381 11 3088733, E mail: drmajelic@gmail.com
page: 6
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INTRODUCTION
Globally, diabetes mellitus (DM) is a growing medical
and social problem. It is estimated that the number of
people affected by diabetes will rise from 463 million in
2019 to 700 million by 2045 [1]. Vascular complications
lead to increased morbidity and mortality of these patients.
The incidence is growing of diabetic microvascular complications,
including diabetic retinopathy (DR), diabetic
polyneuropathy (DPN), and diabetic nephropathy (DN)
[2-4]. The pathological mechanisms that are responsible
for developing these complications are very complex and
not fully understood. It seems that genetic susceptibility
plays a role in developing such complications [5]. It has
been postulated that zinc-dependent endopeptidases called
matrix metalloproteinases (MMPs), are very important in
remodelling the extracellular matrix, and therefore they
have an impact on the onset and progression of diabetic
vascular complications [6-7]. The regulation of MMPs is
very complex, depending not only on the regulation of
their tissue inhibitors, but also on the regulation of MMP
gene expressions by transcriptional factors and epigenetic
modifications [8]. Matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) are enzymes
which are responsible for the degradation of the basal
membrane through collagen IV cleveage and therefore
have a role in angiogenesis.
Diabetic retinopathy is a very common microvascular
diabetic complication, affecting up to one third of
patients with diabetes [9-10]. It can lead to seriuous vision
impairments and vision loss, especially in the adult
working population [11]. The duration of diabetes and
poor metabolic control, as well as elevated blood pressure
can contribute to the development of DR [12-14]. Genetic
factors also seem to have an important role, and they account
for 25% to 50 % of the risk of developing DR [15].
The role of MMP-2 and MMP-9 is recognized even in the
early phases of DR [16] as well as in the latter stages or in
the proliferative retinopathy [17-18]. In the pathogenesis
of DR, activated MMPs cause the damage of mitochondria
and augment retinal capillary cell apoptosis [19]. Only a
few studies regarding the MMPs gene single nucleotide
polymorphism (SNP) studies have been completed, and the
results of their correlation with DR are conflicting [20-21].
Diabetic polyneuropathy (DP) is the most prevalent
diabetic complication which affects almost half of the
patients with diabetes [22]. It can lead to major disability
due to foot amputation, and DP significantly reduces the
quality of life [23]. It has been shown that MMPs and their
inhibitors may have a role in the process of the demyelization
and the regeneration of axons [24-25]. MMP-2 and
MMP-9 play a critical role in the pathogenesis of DP [26].
A single genetic study has shown that SNP -1562C>T
in the promoter of the MMP-9 gene is seen in patients with
diabetic foot ulcers and that increased MMP-9 production
from the high expressing T allele may promote matrix
degradation [27].
Diabetic nephropathy (DN) develops in 20-40 %
patients with diabetes [28] and is the leading cause of
end-stage renal disease [29]. Genetic studies regarding the
association of MMP gene polymorphism and DN provide
conflicting results. Some show that certain polymorphisms
of MMP-9 may be predictive factors in the development
of diabetic nephropathy [30] and some suggest the protective
role of the T allele SNP - 1562C>T of MMP-9 against
diabetic nephropathy [31, 32]. It has also been shown that
MMP-2 gene polymorphism is associated with susceptibility
and disease progression of DN [33].
The objectives of our study were to assess
the frequencies of the MMP-2 gene variant
NC_000016.9:g.55511806C>T (-1306C>T) and MMP-9
variant NC_000020.10:g.44635976C>T (-1562C>T) in
type 2 diabetes patients and healthy subjects and to study
whether there is a possible association with the presence
of microvascular complications in type 2 diabetes patients.
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