Genetic variability in the pentose phosphate cycle enzymes as a treatment-independent modifier of hyperglycemia toxicity in diabetic nephropathy



Year of publication 2008
Type Conference abstract
MU Faculty or unit

Faculty of Medicine

Description Introduction and Aims: Variable degree of more or less permanent hyperglycemia characterising diabetes mellitus (DM) is causally responsible for the development of diabetic complications including diabetic nephropathy (DN). Complex dysregulation of cellular metabolism during hyperglycemia - especially accumulation of proximal glycolytic intermediates - provides substrates for certain alternative metabolic pathways (polyol, hexosamine, non-enzymatic glycation etc.) giving rise to harmful moieties (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 supposedly disburdens glycolysis and quantitatively limits processing of glycolytic intermediates in the alternative metabolic pathways. Transketolase (TKT), transaldolase (TALDO) and potentially TKT-like (TKTL1) are key enzymes of non-oxidative branch of PPP while glucose 6 phosphate dehydrogenase (G6PDH) - a rate-limiting enzyme of the oxidative branch of the PPP - might contribute to the protection by providing NADPH equivalents for the regeneration of oxidised glutathione. We hypothesized that genetic variability in the TKT, TALDO, TKTL1 and G6PDH genes contribute to an interindividual variability in the onset and progression of DN. The specific aims of the study were (i) in silico reconstruction of haplotypes in the four candidate genes studied based on genotypes of the most frequent haplotype tagging SNPs, (ii) association study of identified haplotypes with DN and (iii) detail characterisation of the eventual haplotype-specific risk. Methods: SNPs in the candidate genes were selected using SNPbrowser based on following criteria: (i) MAF more than 10% in Caucasian population and (ii) location in different haplotype block (htSNPs). SNPs (total n = 15) were genotyped by means of polymerase chain reaction (PCR) using fluorescent-labelled probes (TaqMan, Applied Biosystems). Haplotypes were inferred from genotype data using Bayesian-based algorithm (PHASE). A total of 434 diabetic subjects were included in the case - control study. Cases (approx. half of the total number) were subjects with DM and parallel DN (DM+DN); controls were gender- and age-matched diabetics without organ complications (DM non-DN). Logistic regression, survival analysis (Kaplan-Meier) and Cox proportional hazard regression were be used to assess the risk of particular haplotypes eventually exhibiting association with DN. Results: Haplotype distribution of TKT differed significantly between DN vs. non-DN groups (P=0.046, 10 000 permutations). Common haplotype with frequency 0.22 in the whole study population was identified as a risk-haplotype by means of logistic regression (OR = 2.1). Carrier state of the risk-haplotype was associated with significantly accelerated onset of DN (P=0.05). Conclusions: Results suggest that TKT variability might play a role in the individuals susceptibility to the development of DN. This finding might be an important determinator of the benefit from the treatment with lipid-soluble TKT activator (benfothiamin).
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