mTOR controls ChREBP transcriptional activity and pancreatic β cell survival under diabetic stress.
Gia Cac ChauDong Uk ImTong Mook KangJeong Mo BaeWon KimSuhkneung PyoEun-Yi MoonSung Hee UmPublished in: The Journal of cell biology (2017)
Impaired nutrient sensing and dysregulated glucose homeostasis are common in diabetes. However, how nutrient-sensitive signaling components control glucose homeostasis and β 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 β cells exhibit reduced β cell mass and smaller islets. mTOR deficiency leads to a severe reduction in β 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 β 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 β cell survival and glucose homeostasis in diabetes.
Keyphrases
- type diabetes
- oxidative stress
- cell proliferation
- binding protein
- cell death
- induced apoptosis
- cardiovascular disease
- transcription factor
- diabetic rats
- glycemic control
- gene expression
- blood glucose
- endothelial cells
- cell cycle arrest
- dna damage
- wound healing
- ischemia reperfusion injury
- stem cells
- poor prognosis
- early onset
- single cell
- blood pressure
- stress induced
- bone marrow
- small molecule
- endoplasmic reticulum stress
- mesenchymal stem cells
- smoking cessation
- adipose tissue
- replacement therapy
- induced pluripotent stem cells
- network analysis