Ozcan Umut, Cao Qiong, Yilmaz Erkan, Lee Ann-Hwee, Iwakoshi Neal N, Ozdelen Esra, Tuncman Gürol, Görgün Cem, Glimcher Laurie H, Hotamisligil Gökhan S
Department of Genetics and Complex Diseases, Harvard Medical School, Boston, MA 02115, USA.
Science. 2004 Oct 15;306(5695):457-61. doi: 10.1126/science.1103160.
Obesity contributes to the development of type 2 diabetes, but the underlying mechanisms are poorly understood. Using cell culture and mouse models, we show that obesity causes endoplasmic reticulum (ER) stress. This stress in turn leads to suppression of insulin receptor signaling through hyperactivation of c-Jun N-terminal kinase (JNK) and subsequent serine phosphorylation of insulin receptor substrate-1 (IRS-1). Mice deficient in X-box-binding protein-1 (XBP-1), a transcription factor that modulates the ER stress response, develop insulin resistance. These findings demonstrate that ER stress is a central feature of peripheral insulin resistance and type 2 diabetes at the molecular, cellular, and organismal levels. Pharmacologic manipulation of this pathway may offer novel opportunities for treating these common diseases.
肥胖会促使2型糖尿病的发展，但其潜在机制却知之甚少。通过细胞培养和小鼠模型，我们发现肥胖会引发内质网（ER）应激。这种应激反过来会通过c-Jun氨基末端激酶（JNK）的过度激活以及随后胰岛素受体底物-1（IRS-1）的丝氨酸磷酸化，导致胰岛素受体信号传导受到抑制。缺乏X-box结合蛋白-1（XBP-1）的小鼠（XBP-1是一种调节内质网应激反应的转录因子）会出现胰岛素抵抗。这些发现表明，内质网应激在分子、细胞和机体水平上是外周胰岛素抵抗和2型糖尿病的核心特征。对该途径进行药物调控可能为治疗这些常见疾病提供新的机会。
