期刊
JOURNAL OF CELL BIOLOGY
卷 216, 期 7, 页码 2091-2105出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.201701085
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资金
- National Research Foundation of Korea [2014R1A2A1A11050734, 2016R1A4A1011189]
- Korea Healthcare Technology Research and Development Project, Ministry for Health, Welfare, and Family Affairs, Korea [HI14C0336]
- National Research Foundation of Korea [2014R1A2A1A11050734] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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.
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