The Endoplasmic Reticulum Chaperone Improves Insulin Resistance in Type 2 Diabetes

• Published in: Diabetes (New York, N.Y.) Vol. 54; no. 3; pp. 657 - 663
• Main Authors: OZAWA, Kentaro, MIYAZAKI, Mayuki, HORI, Osamu, YAMASAKI, Yoshimitsu, OGAWA, Satoshi, MATSUHISA, Munehide, TAKANO, Katsura, NAKATANI, Yoshihisa, HATAZAKI, Masahiro, TAMATANI, Takashi, YAMAGATA, Kazuya, MIYAGAWA, Jun-Ichiro, KITAO, Yasuko
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.03.2005
• Subjects: Adenoviruses; Animals; Biological and medical sciences; Cell Line; Diabetes; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - physiopathology; Diabetes research; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Endoplasmic reticulum; Endoplasmic Reticulum - physiology; Food Deprivation; Gene Expression; Genomes; Glucose; Glucose Intolerance; Heterozygote; HSP70 Heat-Shock Proteins; Hyperglycemia; Hypoxia; Insulin Resistance; Kinases; Liver - metabolism; Medical sciences; Mice; Mice, Transgenic; Molecular Chaperones - genetics; Molecular Chaperones - physiology; Muscle, Skeletal - metabolism; Musculoskeletal system; Nitric oxide; Oxidation; Oxidative Stress; Pancreas; Pancreas - metabolism; Proteins; Proteins - genetics; Proteins - physiology; Risk factors; Transgenic animals; Type 2 diabetes; Japan; Endocrinopathy; Type 2 diabetes; Metabolic diseases; Insulin resistance; Endoplasmic reticulum
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/diabetes.54.3.657

The Endoplasmic Reticulum Chaperone Improves Insulin Resistance in Type 2 Diabetes Kentaro Ozawa 1 , Mayuki Miyazaki 1 2 , Munehide Matsuhisa 3 , Katsura Takano 1 4 , Yoshihisa Nakatani 3 , Masahiro Hatazaki 3 , Takashi Tamatani 1 , Kazuya Yamagata 5 , Jun-ichiro Miyagawa 5 , Yasuko Kitao 1 , Osamu Hori 1 , Yoshimitsu Yamasaki 3 and Satoshi Ogawa 1 1 Department of Neuroanatomy, Kanazawa University Medical School, Kanazawa, Ishikawa, Japan 2 Department of Discovery Pharmacology II, Pharmacology and Microbiology Research Laboratories, Drug Research Division, Dainippon Pharmaceutical Company, Suita, Osaka, Japan 3 Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan 4 Laboratory of Molecular Pharmacology, Kanazawa University Graduate School of Natural Science and Technology, Kanazawa, Ishikawa, Japan 5 Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan Address correspondence and reprint requests to Kentaro Ozawa, MD, PhD, Department of Neuroanatomy, Kanazawa University Medical School, 13-1, Takara-machi, Kanazawa City, Ishikawa, 920-8640, Japan. E-mail: k.ozawa{at}mbi.nifty.com Abstract To determine the role of the endoplasmic reticulum (ER) in diabetes, Akita mice, a mouse model of type 2 diabetes, were mated with either heterozygous knockout mice or two types of transgenic mice of 150-kDa oxygen-regulated protein (ORP150), a molecular chaperone located in the ER. Systemic expression of ORP150 in Akita mice improves insulin intolerance, whereas the exclusive overexpression of ORP150 in pancreatic β-cells of Akita mice did not change their glucose tolerance. Both an insulin tolerance test and hyperinsulinemic-euglycemic clamp revealed that ORP150 enhanced glucose uptake, accompanied by suppression of oxidized protein. Furthermore, ORP150 enhanced the insulin sensitivity of myoblast cells treated with hydrogen peroxide. These data suggest that ORP150 plays an important role in insulin sensitivity and is a potential target for the treatment of diabetes. ALA, α-lipoic acid CAG, chicken β-actin Chop, C/EBP homologous protein eIF, eukaryotic initiation factor GRP, glucose-regulated protein ER, endoplasmic reticulum IPGTT, intraperitoneal glucose tolerance test IRS, insulin receptor substrate ITT, insulin tolerance test ORP150, 150-kDa oxygen-regulated protein PERK, PKR-like ER kinase TM, tunicamycin Footnotes K.O., M.Mi., and M.Ma. contributed equally to this work. Additional information for this article can be found in an online appendix at http://diabetes.diabetesjournals.org . Accepted November 30, 2004. Received March 17, 2004. DIABETES