Accumulation of triosephosphates arising from high cytosolic
glucose concentrations in
hyperglycemia is one likely or potential trigger for biochemical dysfunction leading to the development of
diabetic complications. This may be prevented by disposal of excess triosephosphates via the reductive pentosephosphate pathway. This pathway is impaired in experimental and clinical diabetes by mild
thiamine deficiency. The expression and activity of the
thiamine-dependent
enzyme,
transketolase--the pacemaking
enzyme of the reductive pentosephosphate pathway, is consequently decreased. Correction of
thiamine deficiency in experimental diabetes by high dose
therapy with
thiamine and the
thiamine monophosphate prodrug,
Benfotiamine, restores disposal of triosephosphates by the reductive pentosephosphate pathway in
hyperglycemia. This prevented multiple mechanisms of biochemical dysfunction: activation of
protein kinase C, activation of the
hexosamine pathway, increased glycation and oxidative stress. Consequently, the development of incipient
diabetic nephropathy, neuropathy and retinopathy were prevented. Both
thiamine and
Benfotiamine produced other remarkable effects in experimental diabetes: marked reversals of increased diuresis and glucosuria without change in glycemic status. High dose
thiamine also corrected
dyslipidemia in experimental diabetes--normalizing
cholesterol and
triglycerides. Dysfunction of beta-cells and
impaired glucose tolerance in
thiamine deficiency and suggestion of a link of
impaired glucose tolerance with dietary
thiamine indicates that
thiamine therapy may have a future role in prevention of
type 2 diabetes. More immediately, given the emerging multiple benefits of
thiamine repletion, even mild
thiamine deficiency in diabetes should be avoided and
thiamine supplementation to high dose should be considered as adjunct nutritional
therapy to prevent
dyslipidemia and the development of vascular complications in clinical diabetes.