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Dysfunctional thiamine metabolism in experimental diabetes and pharmokinetic modelling
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Zhang, Fang, (Researcher in medical sciences) (2013) Dysfunctional thiamine metabolism in experimental diabetes and pharmokinetic modelling. PhD thesis, University of Warwick.
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Official URL: http://webcat.warwick.ac.uk/record=b2661607~S1
Abstract
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.
Item Type: | Thesis (PhD) | ||||
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Subjects: | R Medicine > RC Internal medicine R Medicine > RM Therapeutics. Pharmacology |
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Library of Congress Subject Headings (LCSH): | Vitamin B1 deficiency, Vitamin B1 -- Metabolism -- Disorders, Diabetes, Pharmacokinetics -- Mathematical models | ||||
Official Date: | February 2013 | ||||
Dates: |
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Institution: | University of Warwick | ||||
Theses Department: | Warwick Medical School | ||||
Thesis Type: | PhD | ||||
Publication Status: | Unpublished | ||||
Supervisor(s)/Advisor: | Rabbani, Naila; Thornalley, Paul J. | ||||
Sponsors: | Diabetes UK | ||||
Extent: | xxxiii, 327 leaves : charts. | ||||
Language: | eng |
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