Common Microvascular Complication Of Diabetes

Published Date: 02 Nov 2017

In Chinese population No individual SNP nor any haplotype was found to be associated with DR in our study. This is the first study to report TNF-alpha polymorphisms in patients with DR in the Chinese population. The results suggest that the variants among the promoter of TNF-alpha are unlikely to play a major role in the susceptibility to DR in Chinese patients with type 2 diabetes.(Wang et al 2008)

http://www.ncbi.nlm.nih.gov/pubmed/18398712?dopt=Abstract

another http://www.ncbi.nlm.nih.gov/pubmed/18575614?dopt=Abstract

Under normal physiological circumstances, there is a tight balance between free radical production and their inactivation by antioxidant defense system of the body [Maritim, 2003]. But in the course of different diseases like diabetes, this balance is impaired resulting in oxidative stress accompanied by organ damage [Peuchant 1997].

High oxidative stress may result in activation of stress sensitive pathways that cause cellular damage accompanied by injury to beta cells of pancreas in T1DM and decreased function of insulin (insulin resistance) in T2DM [West & Rousselot 2000].

Selective damage of vascular endothelial cells and neurons by increased glucose levels is due to the fact that these cells lack efficient glucose transport mechanism that other body cells posses. High glucose inside these cells leads to activation of pathological mechanisms that ultimately result in diabetic complications. The main mechanism of which is production of free radicals by the endogenous source i.e. mitochondria of the cells.

Reactive oxygen moieties produced by mitochondria result in release of cytochrome c from mitochondria that lead to activation of apoptotic enzymes and direct the apoptosis of capillary endothelial cells and nerve cells in the retina [Mizutani et al 1996; Kristal et al 1997; Barber et al 1998; Kern et al 2000; Podesta et al 2000; Anuradha et al 2001 and Phaneuf & Leeuwenburgh 2002].

One of the previous study revealed that there is an association between TNFα -308 G>A polymorphism and late diabetic complications have been studied showing that the allele was associated with increased risk for macrovascular complications in T2DM (OR 1.53 [1.04–2.25], p = 0.03, but not in T1DM patients [Lindholm et al 2008].

Another study was performed on the widespread distribution of TNFα and the nature of the adhesion molecules expressed by vascular endothelial cells in PDR membranes suggesting the local activation of TNFα and enhanced expression of vascular cell adhesion molecules may play an important role in the development of the proliferative phase of DR [Limb et al 1996].

In the current study it has been revealed that there is no association of TNFα -313G>A polymorphism with DR, but gender studies showed a marginal association of the polymorphism with male DR patients while no association was seen in females. Likewise there was an association with the PDR suggesting that the variation in this gene may be a cause for its development and progression towards the complications of the DR. This polymorphism lies in the promoter region, therefore due to the presence of the variant A allele, there must be a negative effect on the promoter activity leading to reduced protein levels.

It has been previously seen that there are higher levels of Hsp70 in diabetic patients and this increase is directly related to the duration of the disease [Nakhjavani 2010].

Our specific interest was to study the stress-mediated responses and their association with DR. We thus chose the -27 (G/C) polymorphism for genotypic studies, as this polymorphism has not since been investigated with DR. Functional analyses of the -27 (G/C) polymorphism, which maps to the 5′ UTR region of HSP70, have revealed that compared with the G allele, the variant C allele causes reduced promoter activity and lower HSP70 protein levels [He et al 2009].

Our study revealed that HSP70 polymorphism is not only associated with diabetes but also with its microvascular complications and disease progression. As the polymorphism is in the promoter region, so polymorphism in it causes lower protein levels in the cell, and hence will not be able to cope with the apoptosis leading to disease progression.

As long as the gender differences are concerned, it has previously been reported that due to estrogen, females have high levels of HSPs as compared to males [Voss et al 2003]. So our findings suggest that there was no association of HSP70 polymorphism with the females but there was association seen in males.

Previous studies have shown that the MMP9 SNPs revealed no significant association with PDR. This group studied two polymorphisms in MMP9 (-1562C/T and R279Q) [Beranek et al 2008].

Another study on MMPs has pointed that the higher levels of glucose causes increased production of MMP9 in retinal endothelial cells, suggesting that the higher levels of MMPs in the retina of the diabetic animals cause increase in the vascular permeability by a mechanism which involves proteolytic degradation of occludin which is a tight junction protein or other junctional proteins [Giebel et al 2005].

In the current study there was no association of the polymorphism of MMP9 seen with DR but there was an association seen in the females in DR as well as DNR groups suggesting that the polymorphism is associated with female diabetic patients as compared to males. rs17576, also known as Gln279Arg or Q279R, is a SNP in exon 6 of the MMP9 gene. The rs17576(G) allele encodes the Arg (R). So our study has shown similar results with the previous study showing no significant association with PDR in this polymorphism.

One possible manner in which HSPs might contribute to DR is by affecting the expression of MMPs. Hence, the polymorphism we studied in HSP70 and MMP9 may have a role in progression of DR. It must be pointed out that to fully understand the role of HSPs in the regulation of MMPs, it is important to conduct further expression and activity assays.