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Title: Dysfunctional thiamine metabolism in experimental diabetes and pharmokinetic modelling
Author: Zhang, Fang
ISNI:       0000 0004 2739 9656
Awarding Body: University of Warwick
Current Institution: University of Warwick
Date of Award: 2013
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A dietary-independent thiamine deficiency has been found in experimental and clinical diabetes. Decreased tissue availability of thiamine due to its increased renal clearance is associated with the development of diabetic nephropathy and possibly other microvascular complications of diabetes. Increased thiamine clearance in diabetes is caused by impaired renal reuptake of thiamine. It is proposed that tissue-specific thiamine deficiency may occur in diabetes at sites of complications development – kidney retina and peripheral nerve. The aim of this project was to investigate the involvement of glycaemic control on renal clearance of thiamine and thiamine metabolism in tissues and characterise the pharmacokinetics of thiamine in experimental diabetes – including fitting to a multi-compartment pharmacokinetic model. Thiamine metabolism and pharmacokinetics was studied in streptozotocin (STZ)-induced diabetic rats and normal healthy controls. The effect of correction of hyperglycaemia by intensive insulin therapy and the effect of high dose thiamine therapy was investigated. A multi-compartment model was developed to describe the pharmacokinetics of thiamine metabolism in diabetic and healthy states. This was facilitated by development and validation of a new method of analysis of thiamine by stable isotopic dilution analysis liquid chromatographytandem mass spectrometry (LC-MS/MS). The results show that there is increased renal clearance of thiamine in STZ diabetic rats after only 12 weeks of diabetes and this is corrected by intensive insulin therapy. Depletion of thiamine was found in retina of STZ-diabetic rats and was corrected by intensive insulin therapy. Pharmacokinetic modelling of thiamine revealed in diabetes thiamine inflow of the kidney was increased 2 fold and urinary excretion increased 4 fold; rate constants for thiamine inflow and outflow of the retina were decreased 5 fold and increased 2 fold, respectively, suggesting the retina has decreased uptake and retention of thiamine; and peak [13C3]thiamine content of sciatic nerve was decreased 90% (P < 0.05). Thiamine inflow and outflow of the heart and skeletal muscle were little changed in diabetes. The LC-MS/MS assay detected thiamine and previously unknown physiological metabolites – O-acetylthiamine and oxythiamine. The latter accumulated in clinical renal failure and may impair thiamine pyrophosphate function. I conclude that hyperglycaemia is a key and likely causative factor linked to tissue thiamine deficiency and thiamine washout of the body in diabetes. The kidney, retina and nerve have disturbed thiamine handling in diabetes – increased excretion, decreased uptake and/or accumulation. This may predispose to increased risk of thiamine deficiency and vascular complications of diabetes. These effects are likely mediated by impaired transcriptional regulation and expression of thiamine transporters in diabetes where functional impairment of transcription factors Sp1 and Nrf2 have recently been implicated.
Supervisor: Not available Sponsor: Diabetes UK
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: RC Internal medicine ; RM Therapeutics. Pharmacology