Thiamine Status and Genetic Variability in the Pentose Phosphate Cycle Enzymes as Risk Factors for Diabetic Nephropathy
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| Year of publication | 2008 |
| Type | Conference abstract |
| MU Faculty or unit | |
| Citation | |
| Description | Diabetic complications including diabetic nephropathy (DN) develop due to the complex dysregulation of cellular metabolism during hyperglycemia. Accumulation of proximal glycolytic intermediates provides substrates for several alternative metabolic pathways producing harmful moieties such as advanced glycation end-products, dicarbonyls, sorbitol, hexosamines, reactive oxygen and nitrogen species etc. Pentose phosphate pathway (PPP) represents potentially "protective" mechanism in hyperglycemia since shunting of cumulated glycolytic intermediates (esp. triosephosphates) into the PPP reactions quantitatively limits their processing in alternative metabolic pathways. We hypothesized that genetic variability in genes encoding key enzymes of PPP - transketolase (TKT), transaldolase, TKT-like and glucose-6-phosphate dehydrogenase - together with thiamin status (thiamine and its esters - cofactors of TKT) might contribute to an interindividual variability in the onset and progression of DN. The specific aims of the study were (i) quantification of plasma and erythrocyte levels of thiamines, (ii) haplotype-based association study of DN with haplotypes identified in silico (from genotypes of the most frequent haplotype tagging SNPs) in the 4 candidate genes (iii) for those PPP enzyme genes exhibiting significant association with DN elucidation of event. relationship between genetic variability in a given locus and enzyme erythrocyte activity. A total of 623 diabetic subjects were included in the case (DN) - control (non-DN) study (type 1 or 2 diabetics with parallel DN and gender- and age-matched diabetics without organ complications, respectively, in approx. 1:1 ratio). SNPs (total n = 15) were genotyped by means of PCR using fluorescent-labelled probes (TaqMan, Applied Biosystems). Haplotypes were inferred using Bayesian-based algorithm (PHASE). Concentration of thiamines and TKT catalyzed reaction were determined by HPLC. Haplotype distribution of TKT differed significantly between DN vs. non-DN groups (P<0.05, 10 000 permutations). Common haplotype with frequency 21.3% in the whole study population (risk-haplotype) exhibited the greatest difference. Carrier state of the risk-haplotype was associated with significantly accelerated onset of DN (P<0.05) and lower thiamin concentrations but not with TKT activity. Results suggest that TKT variability and thiamine status play a role in the individual susceptibility to the development of DN. |
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