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Discussion

These observations suggest that high dose thiamine repletion suppressed the development of incipient nephropathy in experimental diabetes in which effects on the PKC, glycation and oxidative stress pathways were involved. We found similar effects on human mesangial cells in hyperglycemic culture in vitro - to be published. The primary intervention was the prevention of thiamine deficiency and induction of TK expression with consequent activation of the reductive PPP shunt. It is remarkable that these effects were achieved by increasing the dietary availability of thiamine to diabetic rats by as little as 20 times the minimum daily allowance - although this was sufficient to prevent thiamine deficiency. Diabetes was associated with mild thiamine deficiency due to increased renal clearance of thiamine. This may be due to increased thiamine washout by high diuresis and/or impairment of the proximal tubule thiamine/H+ antiport activity that reclaims thiamine from the glomerular filtrate. Thiamine deficiency exacerbated the development of diabetic nephropathy. Studies of clinical diabetes to date suggest that a significant proportion of diabetic patients have mild thiamine deficiency and this may be corrected by therapy with thiamine and thiamine derivatives [11-13] . However, thiamine supplements are not generally taken by diabetic patients currently. Our study suggests that such thiamine deficiency may exacerbate the risk of developing diabetic nephropathy.

Concluding Remarks

I propose that clinical diabetic subjects should avoid becoming thiamine deficient, even weakly so, and that high dose thiamine repletion should be considered for therapy to prevent the development of clinical diabetic nephropathy.

Acknowledgements

We thank the Juvenile Diabetes Research Fund and the Wellcome Trust (U.K.) for support for research.

Author Contact Details

Contact details for Paul Thornalley are found on the Contact Details section of this site

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