Besides its classical function as an orchestrator of calcium and phosphorus homeostasis, vitamin D also affects insulin secretion and tissue efficiency. A number of studies have consistently reported the inverse relationship between vitamin D deficiency and type 2 diabetes. Activation of certain metabolic pathways and down-stream transcription factors may protect from glucolipotoxicity and their targeted activation -e.g. by vitamin D - might explain the detrimental role of vitamin D deficiency in diabetes. The aim of the study was to quantify gene and protein expression of selected enzymes involved in the protection from glucolipotoxicity, specifically glyoxalase 1 (GLO1), and other enzymes with antioxidant activity - hemoxygenase (HMOX), thiamin pyrophosphokinase (TPK1) and transketolase (TKT), under normo- and hyperglycemic conditions and upon addition of vitamin D in peripheral blood mononuclear cells (PBMCs) and human umbilical vein endothelial cells (HUVEC). The results of our study indicate that the active form of vitamin D regulates gene expression of enzymes opposing the harmful effect of glucolipotoxicity whose activities appear to be suppressed by hyperglycemia. However, we were unable to confirm this effect on protein expression. While we cannot speculate on the effect of vitamin D on diabetes itself our results support its role in the protection against existing glucolipotoxicity therefore possibly translating into the prevention of development of diabetic complications.
- MeSH
- endoteliální buňky pupečníkové žíly (lidské) účinky léků enzymologie MeSH
- homeostáza účinky léků MeSH
- inzulin sekrece MeSH
- kultivované buňky MeSH
- laktoylglutathionlyasa genetika metabolismus MeSH
- leukocyty mononukleární účinky léků enzymologie MeSH
- lidé MeSH
- regulace genové exprese MeSH
- thiaminpyrofosfokinasa genetika metabolismus MeSH
- transketolasa genetika metabolismus MeSH
- vitamin D farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: We hypothesized that genetic variability in genes encoding enzymes metabolizing glycolytic intermediates produced in excess under hyperglycemic conditions [i.e., transketolase (TKT), transaldolase, TKT-like protein 1, fructosamine 3-kinase (FN3K), glyoxalase 1 and glucose-6-phosphate dehydrogenase] could influence progression of diabetic nephropathy (DN) and diabetes-related morbidity and mortality. METHODS: A total of 19 single nucleotide polymorphisms (SNPs) in six candidate genes were studied in 314 type 2 diabetic subjects with variable stage of kidney disease (normo- and microalbuminuria, proteinuria, end-stage renal disease). SNP selection criteria were based on known functional effect and gene coverage. SNPs were detected using polymerase chain reaction based methods. Subjects were followed up for median of 38 months. Time-to-event analysis considered three end-points: 1) DN progression by at least one stage; 2) major cardiovascular event; and 3) all-cause mortality. RESULTS: We found combined effect of TKT SNP rs11130362 and FN3K SNP rs1056534 on DN progression (p<0.01). Additionally, TKT rs3736156 alone and also in combination with the previous two SNPs exhibited significant effect on incidence of major cardiovascular events (p<0.01 and p=0.01, respectively). CONCLUSIONS: Genetic variability in rate-limiting enzymes of pathways proposed to confer hypothetical protection against hyperglycemia might act as an important determinant of hyperglycemia toxicity in long-standing diabetes.
- MeSH
- alely MeSH
- diabetes mellitus 2. typu * enzymologie genetika mortalita MeSH
- diabetické nefropatie etiologie metabolismus mortalita MeSH
- fosfotransferasy s alkoholovou skupinou jako akceptorem * genetika MeSH
- genotyp MeSH
- jednonukleotidový polymorfismus MeSH
- Kaplanův-Meierův odhad MeSH
- kardiovaskulární nemoci MeSH
- lidé středního věku MeSH
- lidé MeSH
- metabolické sítě a dráhy MeSH
- nemoci ledvin komplikace MeSH
- senioři MeSH
- stupeň závažnosti nemoci MeSH
- transketolasa * genetika MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
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.
- MeSH
- diabetické nefropatie enzymologie genetika mortalita MeSH
- dospělí MeSH
- erytrocyty enzymologie MeSH
- genotyp MeSH
- glukosa metabolismus MeSH
- jednonukleotidový polymorfismus genetika MeSH
- lidé středního věku MeSH
- lidé MeSH
- míra přežití MeSH
- následné studie MeSH
- pentosafosfáty metabolismus MeSH
- pentózofosfátový cyklus MeSH
- průřezové studie MeSH
- senioři MeSH
- thiamin metabolismus MeSH
- transaldolasa genetika MeSH
- transketolasa genetika MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
