The role of the kidney in diabetic thiamine deficiency
Larkin, James Robert (2010) The role of the kidney in diabetic thiamine deficiency. PhD thesis, University of Warwick.
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Official URL: http://webcat.warwick.ac.uk/record=b2483049~S15
Diabetes is a chronic epidemic compounded by a burden of vascular complications
including diabetic nephropathy. Diabetic nephropathy affects ~40% of patients and is characterised
by increased urinary albumin excretion and decreased glomerular filtration rate.
Diabetic patients exhibit ~75% decreased plasma thiamine concentration, linked
to increased renal thiamine clearance. In streptozotocin-induced diabetic rats, decreased
plasma thiamine concentration was also associated with a reduction in expression and activity
of transketolase. Transketolase is a thiamine pyrophosphate-dependent enzyme and a
critical component of the reductive pentose phosphate pathway, a metabolic pathway leading
from glycolysis involved with the synthesis of ribose sugars. It is proposed that increasing
flux of glucose through the pentose phosphate pathway can ameliorate hyperglycaemic
damage. This thesis investigates mechanisms mediating the increased renal thiamine
clearance and the effects of thiamine therapy on type 2 diabetic patients with nephropathy.
The hypothesis that hyperglycaemia increases
flux through the hexosamine pathway, leading
to increased O-glycosylation of the transcription factor Sp1 and subsequent decreased
expression of thiamine transporters is investigated.
Thiamine transporters in normal human kidney sections were found to be localised to
the proximal tubule. Investigations in primary cultures of human proximal tubule epithelial
cells and the HK-2 cell line have shown that there is a decreased expression (-48 to -80%) and abundance (-52 to -77%) of thiamine transporters in cells cultured in high glucose
concentrations (26mM) with respect to low glucose concentrations (5 mM). There is only
limited evidence supporting the involvement of the hexosamine pathway in these decreases.
A double-blind, placebo-controlled study investigated the effect of thiamine supplementation
on type 2 diabetic patients with microalbuminuria. Thiamine therapy restored
plasma thiamine concentrations from 11nM to 98nM, exceeding the published median concentration
observed in normal patients (64nM). After three months, thiamine therapy,
but not placebo, caused a decrease in the urinary albumin excretion rate relative to baseline
(-18 mg day-1). These results show promise for thiamine as a therapy for diabetic
|Item Type:||Thesis or Dissertation (PhD)|
|Subjects:||Q Science > QP Physiology
R Medicine > RC Internal medicine
|Library of Congress Subject Headings (LCSH):||Non-insulin-dependent diabetes, Diabetic nephropathies -- Treatment, Vitamin B1 -- Therapeutic use, Vitamin B1 -- Physiological transport, Kidneys -- Physiology|
|Official Date:||November 2010|
|Institution:||University of Warwick|
|Theses Department:||Warwick Medical School|
|Supervisor(s)/Advisor:||Thornalley, Paul J.|
|Extent:||xxiii, 266 p. : ill., charts|
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