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Abstract

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.
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References and Notes

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We thank J. Kim and G. I. Shulman for training and advice on the hyperinsulinemic-euglycemic clamp experiments and R. J. Foote for administrative assistance. Supported by NIH grant DK52539 to G.S.H. M.F is supported by a postdoctoral fellowship from the Japan Society for the Promotion of Science. L.O. is supported by the American Diabetes Association mentor-based postdoctoral fellowship.

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Published In

Science
Volume 313 | Issue 5790
25 August 2006

Submission history

Received: 4 April 2006
Accepted: 27 June 2006
Published in print: 25 August 2006

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Authors

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Umut Özcan
Department of Genetics and Complex Diseases, Harvard School of Public Health, Harvard University, Boston, MA 02115, USA.
Erkan Yilmaz
Department of Genetics and Complex Diseases, Harvard School of Public Health, Harvard University, Boston, MA 02115, USA.
Lale Özcan
Department of Genetics and Complex Diseases, Harvard School of Public Health, Harvard University, Boston, MA 02115, USA.
Masato Furuhashi
Department of Genetics and Complex Diseases, Harvard School of Public Health, Harvard University, Boston, MA 02115, USA.
Eric Vaillancourt
Department of Genetics and Complex Diseases, Harvard School of Public Health, Harvard University, Boston, MA 02115, USA.
Ross O. Smith
Department of Genetics and Complex Diseases, Harvard School of Public Health, Harvard University, Boston, MA 02115, USA.
Cem Z. Görgün
Department of Genetics and Complex Diseases, Harvard School of Public Health, Harvard University, Boston, MA 02115, USA.
Gökhan S. Hotamisligil*
Department of Genetics and Complex Diseases, Harvard School of Public Health, Harvard University, Boston, MA 02115, USA.

Notes

* To whom correspondence should be addressed. E-mail: [email protected]

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