Journal
JOURNAL OF PHARMACOLOGICAL SCIENCES
Volume 113, Issue 4, Pages 343-352Publisher
JAPANESE PHARMACOLOGICAL SOC
DOI: 10.1254/jphs.09359FP
Keywords
thiamine; pyruvate dehydrogenase (PDH) activity; phosphorylated PDH E1 alpha; O-glycosylated protein; diabetic rat heart
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Funding
- Ministry of Education, Culture, Sports, Science, and Technology of Japan
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The activity of pyruvate dehydrogenase (PDH) is reduced in diabetic patients. Phosphorylation of the PDH E1 alpha 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 alpha 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 alpha. PDH inhibition in RCFs was not accompanied by an increase in the PDH E1 alpha 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 alpha may be involved in the regulation of the PDH activity.
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