Division of Endocrinology, Diabetes and Metabolism, University of Miami, Miller School of Medicine, Miami, Florida 33136, USA.
Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, Brehm Center for Diabetes Research, University of Michigan Medical Center, Ann Arbor, Michigan 48105, USA.
Nat Commun. 2017 Jul 12;8:16014. doi: 10.1038/ncomms16014.
Deregulation of mTOR complex 1 (mTORC1) signalling increases the risk for metabolic diseases, including type 2 diabetes. Here we show that β-cell-specific loss of mTORC1 causes diabetes and β-cell failure due to defects in proliferation, autophagy, apoptosis and insulin secretion by using mice with conditional (βraKO) and inducible (MIP-βraKO) raptor deletion. Through genetic reconstitution of mTORC1 downstream targets, we identify mTORC1/S6K pathway as the mechanism by which mTORC1 regulates β-cell apoptosis, size and autophagy, whereas mTORC1/4E-BP2-eIF4E pathway regulates β-cell proliferation. Restoration of both pathways partially recovers β-cell mass and hyperglycaemia. This study also demonstrates a central role of mTORC1 in controlling insulin processing by regulating cap-dependent translation of carboxypeptidase E in a 4EBP2/eIF4E-dependent manner. Rapamycin treatment decreases CPE expression and insulin secretion in mice and human islets. We suggest an important role of mTORC1 in β-cells and identify downstream pathways driving β-cell mass, function and insulin processing.
mTOR 复合物 1（mTORC1）信号的失调增加了代谢疾病的风险，包括 2 型糖尿病。在这里，我们通过使用条件性（βraKO）和诱导性（MIP-βraKO）raptor 缺失的小鼠，显示β细胞特异性的 mTORC1 缺失会导致糖尿病和β细胞衰竭，原因是增殖、自噬、凋亡和胰岛素分泌缺陷。通过对 mTORC1 下游靶标的遗传重建，我们确定 mTORC1/S6K 途径是 mTORC1 调节β细胞凋亡、大小和自噬的机制，而 mTORC1/4E-BP2-eIF4E 途径调节β细胞增殖。两条途径的恢复部分恢复了β细胞质量和高血糖。这项研究还表明，mTORC1 通过调节羧肽酶 E 的 cap 依赖性翻译，以 4EBP2/eIF4E 依赖的方式，在控制胰岛素加工方面起着核心作用。雷帕霉素治疗可降低小鼠和人胰岛中 CPE 的表达和胰岛素分泌。我们提出 mTORC1 在β细胞中的重要作用，并确定驱动β细胞质量、功能和胰岛素加工的下游途径。
