**5. Impact of genetic polymorphism on GSTs for patients with microvascular diabetic complications**

Diabetic nephropathy (DN) is the main secondary complication of diabetes. Associated with an increased risk for cardiovascular disease and high mortality rates, DN is the leading kidney disease worldwide. Approximately 40% of diabetic patients are affected by this microvascular complication [46].

The mechanisms related to the development of DN are unclear and probably involve a number of dynamic events occurring early and with the progression of diabetes. It is known that the clinical characterization of this pathology is preceded by an established morphological renal lesion that results in imbalance of normal renal homeostasis [47]. These lesions are triggered by functional and metabolic changes. A common metabolic manifestation in the body of a diabetic individual is the picture of oxidative stress [31].

There are several factors that are involved in generating oxidative stress during diabetes. There is strong evidence that hyperglycemia results in the activation of PKC in diabetic glomeruli and, as a consequence, mesangial expansion, glomerular basement membrane thickening, endothelial cell dysfunction leading to diabetic renal disease, inflammation, apoptosis [48–50]. Diabetic renal disease, on the other hand, intensifies the formation and activation of ROS, worsening renal disease [51].

ROS, generated by hyperglycemia, also interfere with other biochemical pathways [39]. The Krebs cycle, which, due to oxidative stress, favors the increase of the number of proton donors in the mitochondria, the main source of free radicals [37, 40]. This generates an even greater

**Figure 4.** Main complications of *Diabetes mellitus.* NADH, nicotinamide and adenine dinucleotide; ROS, oxygen-reactive

This mitochondrial production is the primary cause of long-term complications of diabetes. The cascade signaling also suffers from oxidative stress in that it affects the activation of protein kinase C (PKC) [37], a serine/threonine kinase pathway that forms part of the mitogenic protein kinase (MAPK) [42] and plays an important role in several intracellular processes such as signal transduction, response to specific hormonal, neuronal and growth factor stimuli [28, 40].

−

ratio (**Figure 4**). The substrates of this alteration are directed to the polyol pathway,

which, at normal glucose concentrations, is not active [38]. In excess, in the polyol pathway, glucose is reduced to sorbitol, an osmotically active compound [37]. These disorders result in changes in redox homeostasis and in a variety of known effects for pathogenesis and progres-

The accumulation of sorbitol in the ocular tissue, for example, contributes to the development of diabetic cataracts (**Figure 4**). In nerve tissue, high concentrations of this component

) and hydroxyl compounds (OH−

ratio and decreases the NADPH/

) [41].

accumulation of free radicals, mainly superoxide (O2

species; AGE, advanced glycation end product; DN, diabetic neuropathy.

Furthermore, hyperglycemia increases the NADH/NAD<sup>+</sup>

NADP<sup>+</sup>

sion of diabetes.

54 Glutathione in Health and Disease

Considering that, in situations of oxidative stress, GSTs play an important role in cellular detoxification, studies of polymorphisms in the genes encoding these enzymes have been gaining prominence and arousing curiosity about a possible association with the susceptibility of this complication [52–54]. In this context, the deletions of *GSTM1* and *GSTT1* together with the *GSTP1* Ile105Val polymorphism are among the most studied isoforms in the GSTs group [55, 56].

It is described that individuals with *GSTM1* deletion polymorphisms are unable to produce the GSTM1 protein. On the other hand, the conversion of adenine to guanine at position 313 at codon 105 in the *GSTP1* gene causes the amino acid isoleucine (Ile) to be replaced with valine (val), which results in a lower activity of this isoform [56].

In the last decade, some investigations have made DM associations and their complications with the genetic polymorphism in GSTs. Notably, the expression of the GST gene has been described in different variations among ethnic populations. Studies with Egyptian children and adolescents, for example, show that the null genotype of *GSTT1* conferred a 4.2-fold increased risk for the occurrence of DM, and in this case, associations with some biochemical variables and laboratory data were also observed (lipid profile and HbA1c). In this study, no investigation was performed when susceptibility to DN; however, the results are clear and show that gene polymorphisms encoding GSTs are associated with the development of type 1 DM and disease-related risk factors [31].

on clinical and biochemical changes did not indicate a significant association, and this suggests that the *GSTT1* null polymorphism may be associated with the risk of developing the

Impact of Oxidative Changes and Possible Effects of Genetics Polymorphisms of Glutathione…

http://dx.doi.org/10.5772/intechopen.76222

57

Considering all the information described above, it is concluded that DM is among the main health concerns in the world. Hyperglycemia is the main characteristic of this pathology, and this unusual situation favors the imbalance between the reactive oxygen species and the antioxidant defense line produced by the individual. This condition is called oxidative stress and Glutathione and GSTs enzymes are fundamental for the reestablishment of redox homeostasis. The progression of diabetes and, consequently, prolonged exposure to this condition, favor the development of secondary complications of DM. DN is the main secondary compli-

Expression of polymorphic GST genes within several ethnic populations is remarkable. Some studies have suggested an association between genetic polymorphism of GSTs M1, T1 and P1 susceptibility to DM and its microvascular complications, and others do not. As the results are

The authors would like to thank the National Council for Scientific and Technological

, Ana Cristina Silva Rebelo5

2 Department of Biochemistry and Molecular Biology, Institute of Biological Sciences (ICB II),

1 Laboratory of Molecular Pathology, Institute of Biological Sciences (ICB II), Federal

3 Department of Natural Sciences (LEdoC), Special Academic Unit of Human Sciences,

4 Department of Physiology, Institute of Biological Sciences (ICB II), Federal University of

5 Department of Morphology, Institute of Biological Sciences (ICB III), Federal University of

, Gustavo Rodrigues Pedrino4

,

disease, but not with the biochemical alterations analyzed.

still scarce and inconsistent, more studies need to be done.

Development (CNPq) (Grant: 448905/2014-0 to A.A.S.R.).

Rodrigo da Silva Santos1,3 and Angela Adamski da Silva Reis1,2\*

\*Address all correspondence to: angeladamski@gmail.com

Federal University of Goiás (UFG), Goiânia, GO, Brazil

Federal University of Goiás (UFG), Goiás, GO, Brazil

University of Goiás (UFG), Goiânia, GO, Brazil

**6. Conclusion**

cation that arises as result of DM.

**Acknowledgements**

**Author details**

Laura Raniere Borges dos Anjos1

Goiás (UFG), Goiânia, GO, Brazil

Goiás (UFG), Goiânia, GO, Brazil

More specific studies addressing end-stage renal failure developed as a complication of DM show that this secondary complication is more common in the Asian population than in the UK population. In addition, the data are consistent and indicate that all patients of Asian origin who developed end-stage renal failure had non-insulin-dependent diabetes [57].

A meta-analysis performed by *Saadat* (2017) [58] brought together 18 studies with a total of 5483 subjects (healthy and diabetic). Overall analysis did not indicate a significant association between *GSTP1* and type 2 DM polymorphisms. Subgroup analyzes stratified by ethnicity, year of publication, and sample size also did not reveal a significant association between study polymorphism and DM2 risk.

In contrast, another meta-analysis by *Orlewski* and *Orlewska* (2015) [29] reports strong evidence of association between the genes glutathione-S-transferase (GST) and diabetic nephropathy (DN) polymorphisms. The results of this study reveal that significantly increased risks were found for the occurrence of DN in individuals with *GSTM1* genotype null. However, this same study does not observe correlation between the DN and the *GSTT1* genotype null or the presence of val alleles. Despite this, the genotype combination results indicate interaction between *GSTT1* null and *GSTM1* null, suggesting a possible summation in the deficiencies of these enzymes.

These findings differ from those found in a previous study by *Fujita* et al. (2000), where no associations between DN and genotype *GSTM1* null were observed. This study was performed with two groups of Japanese patients with or without diabetic nephropathy. Statistical analyses show that the frequency of the null genotype *GSTM1* was not significantly higher in the group of patients with nephropathy than in the group of patients without nephropathy, suggesting that the null *GSTM1* genotype does not contribute to the development of DN in this population [59].

More recent studies with the Romanian population suggest that the polymorphism of the *GSTP1* Ile105Val gene was associated with the risk of developing type 2 DM, but not with the risk of developing DN. For polymorphisms in the *GSTM1* and GSTT1 genes, the results did not indicate an increased risk of developing DM or DN [30].

Studies with the Brazilian population do not indicate an association of *GSTM1* deletion polymorphism with type 2 DM susceptibility. However, the *GSTM1* null and *GSTT1* null polymorphisms reveal an influence on some observed clinical parameters (blood glucose and blood pressure). This suggests that both polymorphisms may contribute to the clinical course of patients with type 2 DM [60].

On the other hand, other studies with the population of Central Brazil [61] suggest that individuals with null *GSTT1* polymorphism present an increased risk of approximately 2.9-fold for DN development. For the same population, no association of *GSTM1* null and DN was found. In this same study, the analysis of the influence of the deletion of *GSTT1* and *GSTM1*

on clinical and biochemical changes did not indicate a significant association, and this suggests that the *GSTT1* null polymorphism may be associated with the risk of developing the disease, but not with the biochemical alterations analyzed.
