Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes
Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes
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DOI：
10.1126/science.1128294
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发表时间：
2006-08-25
期刊：
影响因子：
56.9
通讯作者：
Hotamisligil, Goekhan S.
中科院分区：
文献类型：
--
作者：
Oezcan, Umut;Yilmaz, Erkan;Hotamisligil, Goekhan S.
内质网（ER）应激是肥胖、胰岛素抵抗和2型糖尿病之间的关键联系。在这里，我们提供的证据表明，这种机制的联系可以利用口腔活性化学分子伴侣的治疗目的。4-苯丁酸和牛磺酸结合的熊去氧胆酸减轻细胞和整个动物的ER应激。用这些化合物治疗肥胖和糖尿病小鼠导致高血糖症正常化，全身胰岛素敏感性恢复，脂肪肝疾病消退，以及肝脏、肌肉和脂肪组织中胰岛素作用增强。我们的研究结果表明，化学分子伴侣增强了ER的适应能力，并作为有效的抗糖尿病模式，在2型糖尿病的治疗中具有潜在的应用。
Endoplasmic reticulum ( ER) stress is a key link between obesity, insulin resistance, and type 2 diabetes. Here, we provide evidence that this mechanistic link can be exploited for therapeutic purposes with orally active chemical chaperones. 4-Phenyl butyric acid and taurine-conjugated ursodeoxycholic acid alleviated ER stress in cells and whole animals. Treatment of obese and diabetic mice with these compounds resulted in normalization of hyperglycemia, restoration of systemic insulin sensitivity, resolution of fatty liver disease, and enhancement of insulin action in liver, muscle, and adipose tissues. Our results demonstrate that chemical chaperones enhance the adaptive capacity of the ER and act as potent antidiabetic modalities with potential application in the treatment of type 2 diabetes.