Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes.
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.
Ozcan
Umut
U
Department of Genetics and Complex Diseases, Harvard School of Public Health, Harvard University, Boston, MA 02115, USA.
Yilmaz
Erkan
E
Ozcan
Lale
L
Furuhashi
Masato
M
Vaillancourt
Eric
E
Smith
Ross O
RO
Görgün
Cem Z
CZ
Hotamisligil
Gökhan S
GS
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D045744:Cell Line, Tumor; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism*; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D004789:Enzyme Activation; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005947:Glucose / Q000008:administration & dosage / Q000378:metabolism*; D005951:Glucose Tolerance Test; D006706:Homeostasis; D007328:Insulin / Q000097:blood / Q000494:pharmacology; D007333:Insulin Resistance; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008820:Mice, Obese; D010654:Phenylbutyrates / Q000494:pharmacology* / Q000627:therapeutic use; D010766:Phosphorylation; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology* / Q000627:therapeutic use; D019892:eIF-2 Kinase / Q000378:metabolism
D001786:Blood Glucose; D015852:Eukaryotic Initiation Factor-2; D005947:Glucose; D007328:Insulin; D048031:JNK Mitogen-Activated Protein Kinases; D010654:Phenylbutyrates; D011972:Receptor, Insulin; D013655:Taurochenodeoxycholic Acid; D019892:eIF-2 Kinase; C031655:ursodoxicoltaurine; C075773:4-phenylbutyric acid