MTOR controls ChREBP transcriptional activity and pancreatic ? cell survival under diabetic stress.

ABSTRACT: Impaired nutrient sensing and dysregulated glucose homeostasis are common in diabetes. However, how nutrient-sensitive signaling components control glucose homeostasis and ? 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 ? cells exhibit reduced ? cell mass and smaller islets. mTOR deficiency leads to a severe reduction in ? 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 (TXNIP), a potent inducer of ? cell death and oxidative stress. Consistent with this, the levels of TXNIP 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 ? cell survival and glucose homeostasis in diabetes.

SUBMITTER: Chau GC 

PROVIDER: S-EPMC5496625 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature