The Potential Role of Thiamine (Vitamin B1) in Diabetic Complications

Abstract

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.

Increased protein damage in renal glomeruli, retina, nerve, plasma and urine and its prevention by thiamine and benfotiamine therapy in a rat model of diabetes

“…Increased tissue content of AGEs in diabetes leads to impairment of protein function, linked to vascular cell detachment and anoikis [16,17], oxidative stress [18], low-grade inflammation [18,19] and other cell dysfunctions implicated in the development of microvascular complications [20]. Thiamine and benfotiamine proba- Data are means±SD; units are mmol/mol lysine for FL, CML and CEL and mmol/mol arginine for G-H1, MG-H1 and 3DG-H Rat study group key as in Table 1 *p<0.05, **p<0.01 and ***p<0.001 with respect to normal control † p<0.05, † † p<0.01 † † † p<0.001 with respect to diabetic controls bly decrease AGE and oxidation and nitration adduct formation by increasing transketolase expression and activity in tissues [3,4,21]; this counters metabolic dysfunction and oxidative stress in hyperglycaemia, maintains antioxidant and dicarbonyl-metabolising enzyme activities and thereby prevents protein damage [2]. This is the first application of quantitative 'gold standard' stable isotopic dilution analysis LC-MS/MS to quantify a comprehensive range of glycation, oxidation and nitration adducts in tissues, plasma and urine in experimental diabetes.…”

“…This is probably related to the thiol intermediate formed by thioester hydrolysis of benfotiamine [2]. This may participate in thiol/disulfide exchange reactions, preserve thiol status and thereby prevent formation of MetSO and maintain levels of thioredoxin cofactor for MetSO reductase [31].…”

“…Benfotiamine was also more effective than thiamine in reversal of increased urinary excretion of dityrosine but had similar potency to thiamine in reversal of increased urinary excretion of 3-NT free adduct in diabetic rats. Benfotiamine uses the reduced folate carrier-1 (RFC-1) and phosphatase activity for thiamine delivery [2]. Decreased production of RFC-1 in diabetes and loading of tissues with TMP by benfotiamine approaching levels that inhibit thiamine pyrophosphokinase may impair thiamine delivery by benfotiamine in diabetes [9,33].…”

“…A therapeutic intervention to resist and reverse early-stage vascular complications beyond that achieved with current therapy is high-dose supplementation of thiamine. This counters multiple pathways of biochemical dysfunction linked to the development of vascular complications with doses of the vitamin markedly higher than the dietary reference intake [2]. High-dose therapy with thiamine and the thiamine monophosphate (TMP) derivative benfotiamine prevented the development of microvascular complications in experimental diabetes [3][4][5].…”

The uremic toxin oxythiamine causes functional thiamine deficiency in end-stage renal disease by inhibiting transketolase activity

“…35 The latter is associated with stimulation of mitochondrial dysfunction and formation of oxidative stress, increased diacylglycerol formation and activation of protein kinase C, activation of the hexosamine pathway and increased formation of methylglyoxal and AGEs. 36 Further disturbance of thiamine metabolism in renal failure occurs by decreased expression of thiamine transporters in small intestine, heart, liver and brain and likely decreased availability of thiamine at these sites. 37 Herein we showed that incubation of red blood cells from HD patients ex vivo with thiamine restored normal levels of transketolase activity and R5P concentration, consistent with correction of impaired pentose pathway activity.…”