Pharmacokinetics of thiamine in streptozotocin-induced diabetic rats reveals thiamine mishandling in the kidney, retina and peripheral nerve exposing these tissues to increased risk of thiamine deficiency
F Zhang, ND Evans, JR Larkin, L Godfrey, N Yamada-Fowler, MJ Chappell, N Rabbani and PJ Thornalley
Poster at Diabetes UK Annual Professional Meeting, Manchester, UK (2013)
Background and aims: Experimental and clinical diabetes are associated with increased clearance of thiamine linked to development of nephropathy. In this study we investigated the pharmacokinetics of thiamine in diabetic and healthy rats fitting data to a multicompartment model to describe changes in thiamine tissue handling in diabetes.
Materials and methods: Diabetes was induced by streptozotocin (55 mg/kg) in male Sprague-Dawley rats, 6-8 weeks old, and thereafter body weight and moderate hyperglycaemia maintained by daily insulin injections (4 U, glargine) for 6 weeks. A healthy control group was also studied. Control and diabetic rats were randomised to 7 subgroups (n = 5), [thiazolium-4,5,5-methyl-13C3]thiamine tracer (0.25 mg/kg) given i.p. and sacrificed over 0.75-48 h post-injection. Total and [13C3]thiamine content of plasma and tissues was determined by mass spectrometry. [13C3]Thiamine content was fitted to a multi-compartment model solving for rate constants for thiamine entry and efflux from tissues and urinary excretion.
Results: 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.
Conclusions: In experimental diabetes the kidney, retina and nerve have disturbed thiamine handling—increased excretion, decreased uptake and/or accumulation of thiamine. This is likely associated with increased risk of thiamine deficiency and vascular complications.