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J. Biol. Chem., Vol. 282, Issue 26, 19113-19121, June 29, 2007

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 282/26/19113    most recent M610759200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map 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 Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Sloop, K. W. Articles by Michael, M. D. Search for Related Content PubMed PubMed Citation Articles by Sloop, K. W. Articles by Michael, M. D. Social Bookmarking                      What's this?

Specific Reduction of Hepatic Glucose 6-Phosphate Transporter-1 Ameliorates Diabetes while Avoiding Complications of Glycogen Storage Disease^*

Kyle W. Sloop¹, Aaron D. Showalter, Amy L. Cox, Julia X. C. Cao, Angela M. Siesky, Hong Yan Zhang, Armando R. Irizarry, Susan F. Murray^¶, Sheri L. Booten^¶, Eleftheria A. Finger^¶, Robert A. McKay^¶, Brett P. Monia^¶, Sanjay Bhanot^¶, and M. Dodson Michael

From the Endocrine Discovery, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, Pathology and Toxicology, Lilly Research Laboratories, Eli Lilly and Company, Greenfield, Indiana 46140, and ^¶Isis Pharmaceuticals, Carlsbad, California 92008

D-Glucose-6-phosphatase is a key regulator of endogenous glucose production, and its inhibition may improve glucose control in type 2 diabetes. Herein, 2'-O-(2-methoxy)ethyl-modified phosphorothioate antisense oligonucleotides (ASOs) specific to the glucose 6-phosphate transporter-1 (G6PT1) enabled reduction of hepatic D-Glu-6-phosphatase activity in diabetic ob/ob mice. Treatment with G6PT1 ASOs decreased G6PT1 expression, reduced G6PT1 activity, blunted glucagon-stimulated glucose production, and lowered plasma glucose concentration in a dose-dependent manner. In contrast to G6PT1 knock-out mice and patients with glycogen storage disease, excess hepatic and renal glycogen accumulation, hyperlipidemia, neutropenia, and elevations in plasma lactate and uric acid did not occur. In addition, hypoglycemia was not observed in animals during extended periods of fasting, and the ability of G6PT1 ASO-treated mice to recover from an exogenous insulin challenge was not impaired. Together, these results demonstrate that effective glucose lowering by G6PT1 inhibitors can be achieved without adversely affecting carbohydrate and lipid metabolism.

Received for publication, November 20, 2006 , and in revised form, April 26, 2007.

^* 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1 and 2.

¹ To whom correspondence should be addressed: Endocrine Discovery, Lilly Research Laboratories, Drop Code 0424, Indianapolis, IN 46285. Tel.: 317-651-2856; Fax: 317-276-9086; E-mail: sloop_kyle_w{at}lilly.com.

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