Transketolase Activity but not Thiamine Membrane Transport Change in Response to Hyperglycaemia and Kidney Dysfunction
received 21. März 2017
revised 16. Juni 2017
accepted 27. Juni 2017
26.September 2017 (eFirst)
Aim Pentose phosphate pathway (PPP) with key enzyme transketolase (TKT), represents a potentially ‘protective’ mechanism in hyperglycaemia. Diabetic kidney disease (DKD), a common complication of both type 1 and type 2 diabetes associated with significant morbidity and mortality, represents the most common cause of chronic kidney disease (CKD). We hypothesized that protective PPP action in diabetes and eventually even more severely in concomitant DKD might be compromised by limited intracellular availability of an active TKT cofactor thiamine diphosphate (TDP).
Methods Effect of hyperglycaemia on gene expression and protein levels of key PPP loci was studied in vitro using human cell lines relevant to diabetes (HUVEC and HRGEC) and (together with measurement of TKT activity, plasma thiamine and erythrocyte TDP concentration) in vivo in diabetic vs. non-diabetic subjects with comparable renal function (n=83 in total).
Results Hyperglycaemia significantly decreased protein levels of RFC-1, THTR1, THTR2 and TKT (P<0.05) in vitro. Analysis of blood samples from CKD patients with and without diabetes and from controls did not reveal any difference in gene expression and protein levels of thiamine transporters while TKT activity and TDP in erythrocytes gradually increased with decreasing kidney function being highest in patients with CKD3-4 of both diabetic and non-diabetic aetiology. Hyperglycaemia and uremic serum mimicking CKD in diabetes did not affect TKT activity in vitro (P<0.05).
Conclusion Both in vitro and human experiments showed decrease or unchanged expression, respectively, of thiamine transporters induced by hyperglycaemia while TKT activity in parallel with intracellular TDP was increased in CKD patients with or without diabetes. Therefore, lack of adaptive increase of thiamine transmembrane transport allowing further increase of TKT activity might contribute to compromised PPP function in diabetes and CKD and to the development of glycotoxic injury.
- 1 Leahy JL. Pathogenesis of type 2 diabetes mellitus. Arch Med Res 2005; 36: 197-209 doi:10.1016/j.arcmed.2005.01.003
- 2 Stincone A, Prigione A, Cramer T. et al. The return of metabolism: Biochemistry and physiology of the pentose phosphate pathway. Biol Rev Camb Philos Soc 2014; DOI: 10.1111/brv.12140.
- 3 Kochetov G, Sevostyanova IA. Binding of the coenzyme and formation of the transketolase active center. IUBMB Life 2005; 57: 491-497 doi:10.1080/15216540500167203
- 4 Ashokkumar B, Vaziri ND, Said HM. Thiamin uptake by the human-derived renal epithelial (HEK-293) cells: Cellular and molecular mechanisms. Am J Physiol Renal Physiol 2006; 291: F796-F805 doi:10.1152/ajprenal.00078.2006
- 5 Thornalley PJ, Babaei-Jadidi R, Al Ali H. et al. High prevalence of low plasma thiamine concentration in diabetes linked to a marker of vascular disease. Diabetologia 2007; 50: 2164-2170 doi:10.1007/s00125-007-0771-4
- 6 Antonysunil A, Babaei-Jadidi R, Rabbani N. et al. Increased thiamine transporter contents of red blood cells and peripheral blood mononuclear leukocytes in type 1 and type 2 diabetic patients. Diabetes 2007; 56: A609-A609
- 7 Hammes HP, Du X, Edelstein D. et al. Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy. Nat Med 2003; 9: 294-299 doi:10.1038/nm834
- 8 Babaei-Jadidi R, Karachalias N, Ahmed N. et al. Prevention of incipient diabetic nephropathy by high-dose thiamine and benfotiamine. Diabetes 2003; 52: 2110-2120
- 9 Karachalias N, Babaei-Jadidi R, Rabbani N. et al. Increased protein damage in renal glomeruli, retina, nerve, plasma and urine and its prevention by thiamine and benfotiamine therapy in a rat model of diabetes. Diabetologia 2010; 53: 1506-1516 doi:10.1007/s00125-010-1722-z
- 10 Rabbani N, Alam SS, Riaz S. et al. High-dose thiamine therapy for patients with type 2 diabetes and microalbuminuria: a randomised, double-blind placebo-controlled pilot study. Diabetologia 2009; 52: 208-212 doi:10.1007/s00125-008-1224-4
- 11 Alkhalaf A, Klooster A, van Oeveren W. et al. A double-blind, randomized, placebo-controlled clinical trial on benfotiamine treatment in patients with diabetic nephropathy. Diabetes Care 2010; 33: 1598-1601 doi:10.2337/dc09-2241
- 12 Alkhalaf A, Kleefstra N, Groenier KH. et al. Effect of benfotiamine on advanced glycation endproducts and markers of endothelial dysfunction and inflammation in diabetic nephropathy. PLoS One 2012; 7: e40427 doi:10.1371/journal.pone.0040427
- 13 Fraser DA, Diep LM, Hovden IA. et al. The effects of long-term oral benfotiamine supplementation on peripheral nerve function and inflammatory markers in patients with type 1 diabetes: A 24-month, double-blind, randomized, placebo-controlled trial. Diabetes Care 2012; 35: 1095-1097 doi:10.2337/dc11-1895
- 14 Harjutsalo V, Groop PH. Epidemiology and risk factors for diabetic kidney disease. Adv Chronic Kidney Dis 2014; 21: 260-266 doi:10.1053/j.ackd.2014.03.009
- 15 Kronenberg F. Emerging risk factors and markers of chronic kidney disease progression. Nat Rev Nephrol 2009; 5: 677-689 doi:10.1038/nrneph.2009.173
- 16 Pácal L, Tomandl J, Svojanovsky J. et al. Role of thiamine status and genetic variability in transketolase and other pentose phosphate cycle enzymes in the progression of diabetic nephropathy. Nephrol Dial Transplant 2011; 26: 1229-1236 doi:10.1093/ndt/gfq550
- 17 Zhang F, Masania J, Anwar A. et al. The uremic toxin oxythiamine causes functional thiamine deficiency in end-stage renal disease by inhibiting transketolase activity. Kidney Int 2016; 90: 396-403 doi:10.1016/j.kint.2016.03.010
- 18 Bukhari FJ, Moradi H, Gollapudi P. et al. Effect of chronic kidney disease on the expression of thiamin and folic acid transporters. Nephrol Dial Transplant 2011; 26: 2137-2144 doi:10.1093/ndt/gfq675
- 19 Bartáková V, Pleskačová A, Kuricová K. et al. Dysfunctional protection against advanced glycation due to thiamine metabolism abnormalities in gestational diabetes. Glycoconj J 2016; 33: 591-598 doi:10.1007/s10719-016-9688-9
- 20 Taylor SC, Posch A. The design of a quantitative western blot experiment. Biomed Res Int 2014; 2014: 361590 doi:10.1155/2014/361590
- 21 Lonergan ET, Semar M, Lange K. Transketolase activity in uremia. Arch Intern Med 1970; 126: 851-854
- 22 Lonergan ET, Semar M, Sterzel RB. et al. Erythrocyte transketolase activity in dialyzed patients. A reversible metabolic lesion of uremia. N Engl J Med 1971; 284: 1399-1403 doi:10.1056/NEJM197106242842503
- 23 Kuriyama M, Mizuma A, Yokomine R. et al. Erythrocyte transketolase activity in uremia. Clin Chim Acta 1980; 108: 169-177
- 24 Pietrzak I, Baczyk K. Erythrocyte transketolase activity and guanidino compounds in hemodialysis patients. Kidney Int Suppl 2001; 78: S97-101 doi:10.1046/j.1523-1755.2001.59780097.x
- 25 Larkin JR, Zhang F, Godfrey L. et al. Glucose-induced down regulation of thiamine transporters in the kidney proximal tubular epithelium produces thiamine insufficiency in diabetes. PLoS One 2012; 7: e53175 doi:10.1371/journal.pone.0053175