Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes.

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.
Authors	Umut Ozcan, Erkan Yilmaz, Lale Ozcan, Masato Furuhashi, Eric Vaillancourt, Ross O Smith, Cem Z Görgün, Gökhan S Hotamisligil
Journal	Science (New York, N.Y.) (Science) Vol. 313 Issue 5790 Pg. 1137-40 (Aug 25 2006) ISSN: 1095-9203 [Electronic] United States
PMID	16931765 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References	Blood Glucose Eukaryotic Initiation Factor-2 Insulin Phenylbutyrates Taurochenodeoxycholic Acid ursodoxicoltaurine 4-phenylbutyric acid Receptor, Insulin PERK kinase eIF-2 Kinase JNK Mitogen-Activated Protein Kinases Glucose
Topics	Adipose Tissue (metabolism) Animals Blood Glucose (metabolism) Cell Line, Tumor Diabetes Mellitus, Type 2 (drug therapy, metabolism) Disease Models, Animal Endoplasmic Reticulum (drug effects, metabolism) Enzyme Activation Eukaryotic Initiation Factor-2 (metabolism) Glucose (administration & dosage, metabolism) Glucose Tolerance Test Homeostasis Insulin (blood, pharmacology) Insulin Resistance JNK Mitogen-Activated Protein Kinases (metabolism) Liver (metabolism) Mice Mice, Obese Phenylbutyrates (pharmacology, therapeutic use) Phosphorylation Receptor, Insulin (metabolism) Signal Transduction Taurochenodeoxycholic Acid (pharmacology, therapeutic use) eIF-2 Kinase (metabolism)

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