Gia Cac Chau, Dong Uk Im, Tong Mook Kang, Jeong Mo Bae, Won Kim, Suhkneung Pyo, Eun-Yi Moon, and Sung Hee Um

J. Cell Biol.; Published June 12, 2017

ABSTRACT

Impaired nutrient sensing and dysregulated glucose homeostasis are common in diabetes. However, how nutrient-sensi-tive 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 associ-ates with the carbohydrate-response element–binding protein (ChREBP)–Max-like protein complex and inhibits its tran-scriptional activity, leading to decreased expression of thioredoxin-interacting protein (TXN IP), a potent inducer of β 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 β  cell survival and glucose homeostasis in diabetes.

See: https://doi.org/10.1083/jcb.201701085

Figure 1: β Cell–specific deficiency of mTOR leads to reduction in islet size and β  cell mass. (A) Immunoblots showing mTOR expression in isolated islets and hypothalamus from WT (mTORflox/flox) or β mTOR knockout (KO) mice (mTORflox/floxRIP Cre). (B) Blood glucose levels were monitored weekly for 8 wk.  (C) Glucose tolerance tests were performed in 12-wk-old mice (2 g glucose per kilogram body weight). (D) Insulin tolerance tests were performed in 12-wk-old mice (0.75 U insulin per kilogram body weight). (E) Serum insulin levels in 12 wk-old WT and mTOR-deficient mice fed standard chow. In B–E, WT, n = 8; knockout, n = 6. (F) Serum insulin levels were measured during glucose tolerance testing (WT, n = 7; knockout, n = 6). (G, left) Representative hematoxylin and eosin staining of pancreatic sections from WT and βmTOR KO mice. Bars, 75 µm. (right) Mean islet volume was calculated in hematoxylin and eosin–stained pancreatic sections. (H, left) Immunofluorescence staining for insulin (green) or glucagon (red) in WT and β mTOR KO mice; Nuclei are shown with Hoechst (blue) staining. Bars, 50 µm. (right) Relative β  cell mass. (I) β  Cell proliferation in WT and β mTOR KO mice. (left) Representative immunofluorescence images of pancreatic sections from WT and β mTOR KO mice using antibodies against insulin (green) or Ki67 (red). Bars, 50 µm. (right) β  Cell proliferation was quantified by percentage of Ki67-positive cells. (J, left) Representative immunofluorescence images of mouse islets stained for TUN EL (green), or insulin (red). Nuclei are stained blue with Hoechst. Bars, 50 µm. (right) Quantification of TUN EL-positive islets in pancreatic sections. In G–J, 18 sections from six WT mice and 15 sections from five knockout mice were stained. In B–J, values are given as mean ± SEM. *, P < 0.05 versus WT  (ANOVA).