C332C Genotype of Glyoxalase 1 and its Association with Late Diabetic Complications

Groener, Jan B.; Reismann, Péter; Fleming, Thomas; Kalscheuer, Hannes; Lehnhoff, D; Hamann, Andreas; Roser, Pia; Bierhaus, Angelika; Nawroth, Peter P.; Rudofsky, Gottfried

doi:10.1055/s-0033-1345124

Cited by 29 publications

(23 citation statements)

References 18 publications

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“…Moreover, Glyoxalase 1 (Glo1) acts as a defence system against the AGE's formation by catalysing the detoxification of methylglyoxal (Figure ). An association between the CC genotype of the Glo1 and DPN was documented in type 2 patients together with lower plasma levels of Glo1 in type 1 and type 2 patients with painful DPN . These findings would support the view that methylglyoxal might in fact be a mediator of DPN and its phenotype.…”

Section: Genetics and Diabetic Polyneuropathysupporting

confidence: 58%

Might genetics play a role in understanding and treating diabetic polyneuropathy?

Spallone

2017

Diabetes Metabolism Res

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Despite the high prevalence and impact on quality of life, costs, and survival, there are still unresolved issues regarding diabetic polyneuropathy (DPN): the lack of definite knowledge of its pathogenesis; the limited preventive action of glycaemic control in type 2 diabetes; and the unavailability of evidence-based effective disease-modifying treatment. How can genetics provide the tools to address these gaps? Ziegler et al for the GDS Group explore the novel hypothesis that genetic variability in transketolase (TKT) might contribute to susceptibility to DPN in patients with newly diagnosed type 1 and type 2 diabetes (well characterised for DPN). Transketolase diverts excess glycolytic metabolites from the hexosamine, protein kinase C, and advanced glycation endproduct pathways to the pentose phosphate pathway, with a protective effect against hyperglycaemia-induced damage. Moreover, thiamine and its derivative benfotiamine are among the few disease-modifying agents still under consideration as DPN treatment. The authors find significant associations of single-nucleotide polymorphisms of the TKT gene with the Total Symptom Score and thermal thresholds, in particular in male participants with type 2 diabetes. Moreover, they measure plasma methylglyoxal (a glycating agent, whose availability is hindered by TKT) without however finding a relation with TKT single-nucleotide polymorphisms. The link found between TKT genetic variability and nerve function measures is considered here in the context of DPN genetic studies and of experimental and clinical findings regarding thiamine and benfotiamine. The conclusion is that available data supports the decision to maintain focus on both the search for DPN genetic biomarkers and the therapeutic attempts to target thiamine, TKT, and methylglyoxal.

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Section: Genetics and Diabetic Polyneuropathysupporting

confidence: 58%

Might genetics play a role in understanding and treating diabetic polyneuropathy?

Spallone

2017

Diabetes Metabolism Res

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“…Moreover, in chronic haemodialysis patients, the GLO1 CC variant of the 419A>C (E111A) SNP is significantly associated with the prevalence of peripheral vascular disease, but not with hypertension or diabetes [48]. In contrast, in Type 1 and Type 2 diabetes patients, there was no correlation of GLO1 322A>C ( = rs4746, rs2736654) SNP with diabetic retinopathy or nephropathy [49]. Modulation of Glo1 expression and activity by genetic factors seems to have only marginal impact on susceptibility to diabetic microvascular complications.…”

Section: Glo1 In Diabetic Microvascular Complicationsmentioning

confidence: 99%

Glyoxalase I (Glo1) and its metabolites in vascular disease

Wortmann

Peters

Hakimi

et al. 2014

Biochemical Society Transactions

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Glo1 (glyxoalase I) is a cytosolic protein expressed in all mammalian cells. Its physiological function is the detoxification of MG (methylglyoxal), which is a potent precursor of AGEs (advanced glycation end-products). Although the impact of AGEs on different forms of vascular diseases has been intensively investigated, the evidence for the involvement of Glo1 and MG is still scarce. Recently, several studies have provided significant evidence for Glo1 having a protective effect on microvascular complications in diabetic patients, such as retinopathy and nephropathy. Regarding macrovascular complications, especially atherosclerotic lesions, the impact of Glo1 is even less clear. In the present article, we review the latest findings regarding the role of Glo1 and MG in vascular biology and the pathophysiology of micro- and macro-vascular disease.

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“…Groener et al. () did not find an association with rs4746 with diabetic retinopathy in Caucasian patients.…”

Section: Chronic Hyperglycaemiamentioning

confidence: 92%

Diabetic macular oedema: under‐represented in the genetic analysis of diabetic retinopathy

Broadgate

Kiire

Halford

et al. 2018

Acta Ophthalmologica

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Diabetic retinopathy, a complication of both type 1 and type 2 diabetes, is a complex disease and is one of the leading causes of blindness in adults worldwide. It can be divided into distinct subclasses, one of which is diabetic macular oedema. Diabetic macular oedema can occur at any time in diabetic retinopathy and is the most common cause of vision loss in patients with type 2 diabetes. The purpose of this review is to summarize the large number of genetic association studies that have been performed in cohorts of patients with type 2 diabetes and published in English-language journals up to February 2017. Many of these studies have produced positive associations with gene polymorphisms and diabetic retinopathy. However, this review highlights that within this large body of work, studies specifically addressing a genetic association with diabetic macular oedema, although present, are vastly under-represented. We also highlight that many of the studies have small patient numbers and that meta-analyses often inappropriately combine patient data sets. We conclude that there will continue to be conflicting results and no meaningful findings will be achieved if the historical approach of combining all diabetic retinopathy disease states within patient cohorts continues in future studies. This review also identifies several genes that would be interesting to analyse in large, well-defined cohorts of patients with diabetic macular oedema in future candidate gene association studies.

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C332C Genotype of Glyoxalase 1 and its Association with Late Diabetic Complications

Abstract: Our data suggest a possible association of C332C-genotype of the glyoxalase 1 gene with diabetic neuropathy in type 2 diabetes, supporting the hypothesis that methylglyoxal might be an important mediator of diabetic neuropathy in type 2 diabetes.

Cited by 29 publications

References 18 publications

Might genetics play a role in understanding and treating diabetic polyneuropathy?

Might genetics play a role in understanding and treating diabetic polyneuropathy?

Glyoxalase I (Glo1) and its metabolites in vascular disease

Diabetic macular oedema: under‐represented in the genetic analysis of diabetic retinopathy

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