mTOR controls ChREBP transcriptional activity and pancreatic beta cell survival under diabetic stress

作者：Chau Gia Cac; Im Dong Uk; Kang Tong Mook; Bae Jeong Mo; Kim Won; Pyo Suhkneung; Moon Eun Yi^*; Um Sung Hee^*

来源：The Journal of Cell Biology, 2017, 216(7): 2091-2105.

DOI：10.1083/jcb.201701085

Impaired nutrient sensing and dysregulated glucose homeostasis are common in diabetes. However, how nutrient-sensitive signaling components control glucose homeostasis and beta cell survival under diabetic stress is not well understood. Here, we show that mice lacking the core nutrient-sensitive signaling component mammalian target of rapamycin (mTOR) in beta cells exhibit reduced beta cell mass and smaller islets. mTOR deficiency leads to a severe reduction in beta cell survival and increased mitochondrial oxidative stress in chemical-induced diabetes. Mechanistically, we find that mTOR associates with the carbohydrate-response element-binding protein (ChREBP)-Max-like protein complex and inhibits its transcriptional activity, leading to decreased expression of thioredoxin-interacting protein (TXN IP), a potent inducer of beta cell death and oxidative stress. Consistent with this, the levels of TXN IP and ChREBP were highly elevated in human diabetic islets and mTOR-deficient mouse islets. Thus, our results suggest that a nutrient-sensitive mTOR-regulated transcriptional network could be a novel target to improve beta cell survival and glucose homeostasis in diabetes.

• 出版日期2017-7