Prevention of incipient diabetic nephropathy by high-dose thiamine and benfotiamine.
Accumulation of triosephosphates arising from high cytosolic glucose concentrations in hyperglycemia is the trigger for biochemical dysfunction leading to the development of diabetic nephropathy-a common complication of diabetes associated with a high risk of cardiovascular disease and mortality. Here we report that stimulation of the reductive pentosephosphate pathway by high-dose therapy with thiamine and the thiamine monophosphate derivative benfotiamine countered the accumulation of triosephosphates in experimental diabetes and inhibited the development of incipient nephropathy. High-dose thiamine and benfotiamine therapy increased transketolase expression in renal glomeruli, increased the conversion of triosephosphates to ribose-5-phosphate, and strongly inhibited the development of microalbuminuria. This was associated with decreased activation of protein kinase C and decreased protein glycation and oxidative stress-three major pathways of biochemical dysfunction in hyperglycemia. Benfotiamine also inhibited diabetes-induced hyperfiltration. This was achieved without change in elevated plasma glucose concentration and glycated hemoglobin in the diabetic state. High-dose thiamine and benfotiamine therapy is a potential novel strategy for the prevention of clinical diabetic nephropathy.
Babaei-Jadidi
Roya
R
Department of Biological Sciences, University of Essex, Central Campus, Wivenhoe Park, Colchester, Essex, UK.
Karachalias
Nikolaos
N
Ahmed
Naila
N
Battah
Sinan
S
Thornalley
Paul J
PJ
D000419:Albuminuria / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control; D000818:Animals; D002614:Chelating Agents / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental / Q000150:complications; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000378:metabolism / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D008297:Male; D010427:Pentose Phosphate Pathway / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013831:Thiamine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014174:Transketolase / Q000378:metabolism
D002614:Chelating Agents; D014174:Transketolase; D013831:Thiamine; C013835:benphothiamine