title: Glucose-induced down regulation of thiamine transporters in the kidney proximal tubular epithelium produces thiamine insufficiency in diabetes.
abstract: Increased renal clearance of thiamine (vitamin B(1)) occurs in experimental and clinical diabetes producing thiamine insufficiency mediated by impaired tubular re-uptake and linked to the development of diabetic nephropathy. We studied the mechanism of impaired renal re-uptake of thiamine in diabetes. Expression of thiamine transporter proteins THTR-1 and THTR-2 in normal human kidney sections examined by immunohistochemistry showed intense polarised staining of the apical, luminal membranes in proximal tubules for THTR-1 and THTR-2 of the cortex and uniform, diffuse staining throughout cells of the collecting duct for THTR-1 and THTR-2 of the medulla. Human primary proximal tubule epithelial cells were incubated with low and high glucose concentration, 5 and 26 mmol/l, respectively. In high glucose concentration there was decreased expression of THTR-1 and THTR-2 (transporter mRNA: -76% and -53% respectively, p<0.001; transporter protein -77% and -83% respectively, p<0.05), concomitant with decreased expression of transcription factor specificity protein-1. High glucose concentration also produced a 37% decrease in apical to basolateral transport of thiamine transport across cell monolayers. Intensification of glycemic control corrected increased fractional excretion of thiamine in experimental diabetes. We conclude that glucose-induced decreased expression of thiamine transporters in the tubular epithelium may mediate renal mishandling of thiamine in diabetes. This is a novel mechanism of thiamine insufficiency linked to diabetic nephropathy.
authors.affiliation: Warwick Medical School, Clinical Sciences Research Laboratories, University of Warwick, University Hospital, Coventry, United Kingdom.
authors.forename: James R
authors.initials: JR
authors.lastname: Larkin
authors.forename: Fang
authors.initials: F
authors.lastname: Zhang
authors.forename: Lisa
authors.initials: L
authors.lastname: Godfrey
authors.forename: Guerman
authors.initials: G
authors.lastname: Molostvov
authors.forename: Daniel
authors.initials: D
authors.lastname: Zehnder
authors.forename: Naila
authors.initials: N
authors.lastname: Rabbani
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Thornalley
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003920:Diabetes Mellitus / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000378:metabolism* / Q000473:pathology; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013831:Thiamine / Q000378:metabolism*; D013832:Thiamine Deficiency / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D026901:Membrane Transport Proteins; C120043:SLC19A2 protein, human; C492291:SLC19A3 protein, human; D005947:Glucose; D013831:Thiamine