Thiamine ameliorates diabetes-induced inhibition of pyruvate dehydrogenase (PDH) in rat heart mitochondria: Investigating the discrepancy between PDH activity and PDH E1 α phosphorylation in cardiac fibroblasts exposed to high glucose

The activity of pyruvate dehydrogenase (pdh) is reduced in diabetic patients. phosphorylation of the pdh e1 α subunit by pdh kinase contributes to the suppression of pdh activity. pdh requires thiamine as a coenzyme. we investigated the exact mechanism of diabetes-induced pdh inhibition,and the effect of thiamine in both in vivo and in vitro experiments. treatment of rats with thiamine significantly,although partially,recovered streptozotocin (stz)-induced reductions in mitochondrial pdh activity. nevertheless,we found that pdh e1 α phosphorylation in the thiamine-treated stz group was perfectly diminished to the same level as that in the control group. stz treatment significantly caused enhancements of the expression of o-glycosylated protein in the rat hearts,which was decreased by thiamine repletion. next,the rat cardiac fibroblasts (rcfs) were cultured in the presence of high glucose levels. thiamine dramatically recovered high glucose-induced pdh inhibition. high glucose loads did not alter the phosphorylated pdh e1 α. pdh inhibition in rcfs was not accompanied by an increase in the pdh e1 α phosphorylation. the o-glycosylated protein was markedly increased in rcfs exposed to high glucose,which was inhibited by thiamine. these results suggest that thiamine ameliorates diabetes-induced pdh inhibition by suppressing the increased expression of the o-glycosylated protein. the o-glycosylation of pdh e1 α may be involved in the regulation of the pdh activity. © 2010 the japanese pharmacological society.