Role of thiamine status and genetic variability in transketolase and other pentose phosphate cycle enzymes in the progression of diabetic nephropathy.
BACKGROUND
Pentose phosphate pathway (PPP) represents a potentially 'protective' mechanism in hyperglycaemia due to shunting of glycolytic intermediates into PPP reactions. We hypothesized that thiamine status (plasma and erythrocyte levels of thiamine and its esters) together with genetic variability in key PPP enzymes-transketolase (TKT), transaldolase and TKT-like-might contribute to the progression of diabetic nephropathy (DN) and mortality of diabetics.


METHODS
A total of 240 diabetic subjects with variable degree of kidney disease were included at baseline and were followed up for a median of 26 (IQR 21-50) months. Concentrations of thiamine in plasma and whole blood and TKT-catalysed reaction were determined by HPLC. Single-nucleotide polymorphisms (SNPs) (n = 14) were genotyped by means of PCR using TaqMan chemistry (Applied Biosystems, Foster City, CA, USA).


RESULTS
Significant differences in pTh, pThDP, eryThDP and eryTKT between DN-stage groups were ascertained (P < 0.05) with advancing stage of DN being accompanied with increasing values of pTh, pThDP and eryTKT but not eryThDP. A highly significant negative correlation (r = - 0.41, P < 0.001) was found between pThDP and eryThDP, and the tertiles of the ratio of eryThDP/pThDP were significantly associated with all-cause mortality rates (P = 0.0072). We also identified significant differences in the rate of DN progression between different pTDP tertile groups (P = 0.0017). No significant genetic effects were found.


CONCLUSIONS
The results support the role of 'functional' thiamine deficiency in the development of hyperglycaemia-related pathology. Limited intracellular availability of active TKT co-factor seems to be a dominant abnormality.
Pácal
Lukás
L
Department of Pathophysiology, Masaryk University, Brno, Czech Republic.
Tomandl
Josef
J
Svojanovsky
Jan
J
Krusová
Darja
D
Stepánková
Sona
S
Rehorová
Jitka
J
Olsovsky
Jindrich
J
Belobrádková
Jana
J
Tanhäuserová
Veronika
V
Tomandlová
Marie
M
Muzík
Jan
J
Kanková
Katerina
K
D000328:Adult; D000368:Aged; D003430:Cross-Sectional Studies; D003928:Diabetic Nephropathies / Q000201:enzymology* / Q000235:genetics* / Q000401:mortality; D004912:Erythrocytes / Q000201:enzymology; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D005947:Glucose / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D010427:Pentose Phosphate Pathway; D010428:Pentosephosphates / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D015996:Survival Rate; D013831:Thiamine / Q000378:metabolism*; D014153:Transaldolase / Q000235:genetics*; D014174:Transketolase / Q000235:genetics*
D010428:Pentosephosphates; C505431:TKTL1 protein, human; D014174:Transketolase; D014153:Transaldolase; D005947:Glucose; D013831:Thiamine