Glucagon-Like Peptide-1 Gene Therapy in Obese Diabetic Mice Results in Long-Term Cure of Diabetes by Improving Insulin Sensitivity and Reducing Hepatic Gluconeogenesis

  1. Young-Sun Lee,
  2. Seungjin Shin,
  3. Toshikatsu Shigihara,
  4. Eunsil Hahm,
  5. Meng-Ju Liu,
  6. Jaeseok Han,
  7. Ji-Won Yoon and
  8. Hee-Sook Jun
  1. From the Rosalind Franklin Comprehensive Diabetes Center, Department of Pathology, Chicago Medical School, North Chicago, Illinois
  1. Address correspondence and reprint requests to Hee-Sook Jun, PhD, Rosalind Franklin Comprehensive Diabetes Center, Chicago Medical School, 3333 Green Bay Rd., North Chicago, IL 60064. E-mail: hee-sook.jeon{at}rosalindfranklin.edu

Abstract

Long-term treatment with glucagon-like peptide (GLP)-1 or its analog can improve insulin sensitivity. However, continuous administration is required due to its short half-life. We hypothesized that continuous production of therapeutic levels of GLP-1 in vivo by a gene therapy strategy may remit hyperglycemia and maintain prolonged normoglycemia. We produced a recombinant adenovirus expressing GLP-1 (rAd-GLP-1) under the cytomegalovirus promoter, intravenously injected it into diabetic ob/ob mice, and investigated the effect of this treatment on remission of diabetes, as well as the mechanisms involved. rAd-GLP-1–treated diabetic ob/ob mice became normoglycemic 4 days after treatment, remained normoglycemic over 60 days, and had reduced body weight gain. Glucose tolerance tests found that exogenous glucose was cleared normally. rAd-GLP-1–treated diabetic ob/ob mice showed improved β-cell function, evidenced by glucose-responsive insulin release, and increased insulin sensitivity, evidenced by improved insulin tolerance and increased insulin-stimulated glucose uptake in adipocytes. rAd-GLP-1 treatment increased basal levels of insulin receptor substrate (IRS)-1 in the liver and activation of IRS-1 and protein kinase C by insulin in liver and muscle; increased Akt activation was only observed in muscle. rAd-GLP-1 treatment reduced hepatic glucose production and hepatic expression of phosphoenolpyruvate carboxykinase, glucose-6-phosphatase, and fatty acid synthase in ob/ob mice. Taken together, these results show that a single administration of rAd-GLP-1 results in the long-term remission of diabetes in ob/ob mice by improving insulin sensitivity through restoration of insulin signaling and reducing hepatic gluconeogenesis.

Footnotes

  • Published ahead of print at http://diabetes.diabetesjournals.org on 16 March 2007. DOI: 10.2337/db06-1182.

    J.-W.Y. is deceased.

    The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted March 2, 2007.
    • Received August 23, 2006.
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  1. Diabetes vol. 56 no. 6 1671-1679
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