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

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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