HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: db06-1182v1 56/6/1671    most recent Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Lee, Y.-S. Articles by Jun, H.-S. Search for Related Content PubMed PubMed Citation Articles by Lee, Y.-S. Articles by Jun, H.-S. Social Bookmarking                What's this?

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

From the Rosalind Franklin Comprehensive Diabetes Center, Department of Pathology, Chicago Medical School, North Chicago, Illinois

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

Abbreviations: FAS, fatty acid synthase; FFA, free fatty acid; G6Pase, glucose-6-phosphatase; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; GLP, glucagon-like peptide; IRS, insulin receptor substrate; PEPCK, phosphoenolpyruvate carboxykinase; PKC, protein kinase C; rAd-ßgal, recombinant adenovirus expressing ß-galactosidase; rAd-GLP-1, recombinant adenovirus expressing GLP-1

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 ß-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.

CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?