A Role for iNOS in Fasting Hyperglycemia and Impaired Insulin Signaling in the Liver of Obese Diabetic Mice

  1. Masaki Fujimoto1,
  2. Nobuyuki Shimizu1,
  3. Kaiko Kunii1,
  4. J.A. Jeevendra Martyn1,
  5. Kohjiro Ueki2 and
  6. Masao Kaneki1
  1. 1Department of Anesthesia and Critical Care, Massachusetts General Hospital, Shriners Hospital for Children, Harvard Medical School, Boston, Massachusetts
  2. 2Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan
  1. Address correspondence and reprint requests to Masao Kaneki, Department of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, 149 13th St., Rm. 6604, Charlestown, MA 02129. E-mail: mkaneki{at}


Chronic inflammation has been postulated to play an important role in the pathogenesis of insulin resistance. Inducible nitric oxide synthase (iNOS) has been implicated in many human diseases associated with inflammation. iNOS deficiency was shown to prevent high-fat diet–induced insulin resistance in skeletal muscle but not in the liver. A role for iNOS in fasting hyperglycemia and hepatic insulin resistance, however, remains to be investigated in obesity-related diabetes. To address this issue, we examined the effects of a specific inhibitor for iNOS, l-NIL, in obese diabetic (ob/ob) mice. iNOS expression was increased in the liver of ob/ob mice compared with wild-type mice. Treatment with iNOS inhibitor reversed fasting hyperglycemia with concomitant amelioration of hyperinsulinemia and improved insulin sensitivity in ob/ob mice. iNOS inhibitor also increased the protein expression of insulin receptor substrate (IRS)-1 and -2 1.5- and 2-fold, respectively, and enhanced IRS-1–and IRS-2–mediated insulin signaling in the liver of ob/ob mice. Exposure to NO donor and ectopically expressed iNOS decreased the protein expression of IRS-1 and -2 in cultured hepatocytes. These results suggest that iNOS plays a role in fasting hyperglycemia and contributes to hepatic insulin resistance in ob/ob mice.


  • Additional information for this article can be found in an online appendix at

    • Accepted February 15, 2005.
    • Received December 9, 2004.
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