The Endoplasmic Reticulum Chaperone Improves Insulin Resistance in Type 2 Diabetes

  1. Kentaro Ozawa1,
  2. Mayuki Miyazaki12,
  3. Munehide Matsuhisa3,
  4. Katsura Takano14,
  5. Yoshihisa Nakatani3,
  6. Masahiro Hatazaki3,
  7. Takashi Tamatani1,
  8. Kazuya Yamagata5,
  9. Jun-ichiro Miyagawa5,
  10. Yasuko Kitao1,
  11. Osamu Hori1,
  12. Yoshimitsu Yamasaki3 and
  13. Satoshi Ogawa1
  1. 1Department of Neuroanatomy, Kanazawa University Medical School, Kanazawa, Ishikawa, Japan
  2. 2Department of Discovery Pharmacology II, Pharmacology and Microbiology Research Laboratories, Drug Research Division, Dainippon Pharmaceutical Company, Suita, Osaka, Japan
  3. 3Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
  4. 4Laboratory of Molecular Pharmacology, Kanazawa University Graduate School of Natural Science and Technology, Kanazawa, Ishikawa, Japan
  5. 5Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
  1. 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.

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.
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