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

J. Biol. Chem., Vol. 280, Issue 25, 23653-23659, June 24, 2005

This Article Full Text Full Text (PDF) All Versions of this Article: 280/25/23653    most recent M412113200v1 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 HighWire Citing Articles via Google Scholar Google Scholar Articles by Fukuen, S. Articles by Shimomura, I. Search for Related Content PubMed PubMed Citation Articles by Fukuen, S. Articles by Shimomura, I. Social Bookmarking                      What's this?

Sulfonylurea Agents Exhibit Peroxisome Proliferator-activated Receptor Agonistic Activity^*

Shuichi Fukuen¶, Masanori Iwaki¶, Atsutaka Yasui, Makoto Makishima||, Morihiro Matsuda**, and Iichiro Shimomura¶¶

From the Department of Medicine and Pathophysiology, Graduate School of Frontier Bioscience, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan, the Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan, PREST, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan, and the 21st Century COE Program, the Japan Society for the Promotion of Science, Tokyo, Japan

Sulfonylurea (SU) agents, including glimepiride and glibenclamide, are the most widely used oral hypoglycemic drugs, which stimulate insulin secretion primarily by binding to the SU receptor on the plasma membrane of pancreatic -cells. Thiazolidinediones, such as pioglitazone and rosiglitazone, are other hypoglycemic agents that effectively improve peripheral insulin resistance through activation of peroxisome proliferator-activated receptor (PPAR). In the present study, we found that glimepiride specifically induced the transcriptional activity of PPAR in luciferase reporter assays. Glimepiride enhanced the recruitment of coactivator DRIP205 and dissociation of corepressors such as nuclear receptor corepressor and silencing mediator for retinoid and thyroid hormone receptors. In addition, glimepride directly bound to PPAR in a manner competitive to rosiglitazone, which is a proven ligand for PPAR. Furthermore, in 3T3-L1 adipocytes, glimepiride stimulated the transcriptional activity of the gene promoter containing PPAR-responsive element and altered mRNA levels of PPAR target genes including aP2, leptin, and adiponectin. Finally, glimepiride induced adipose differentiation in 3T3-F442A cells, which was known to differentiate into adipocytes in a PPAR-dependent manner. Most effects observed with glimepiride were also seen with glibenclamide. These data strongly suggest that glimepiride and glibenclamide, both of which belong to SU agents, should have PPAR agonist activity, whose potencies were 16–25% of the maximum level achieved by pioglitazone. Our observation that glimepiride and glibenclamide could act not only on SU receptor but also on PPAR may give an important clue to the development of novel antidiabetic drugs, which can enhance both insulin secretion from pancreatic -cells and peripheral insulin sensitivity.

Received for publication, October 26, 2004 , and in revised form, February 9, 2005.

^* This work was supported in part by a grant from the Ministry of Health, Labor and Welfare, Japan, and grants from the Ministry of Education, Culture, Sports, Science, and Technology, Japan. 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.

^¶ These authors contributed equally to this work.

^|| Present address: Dept. of Biochemistry, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan.

^** To whom correspondence may be addressed: Dept. of Medicine and Pathophysiology, Graduate School of Frontier Bioscience, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. Tel.: 81-6-6879-3272; Fax: 81-6-6879-3279; E-mail: mmatsuda{at}fbs.osaka-u.ac.jp. ¶¶ To whom correspondence may be addressed: Dept. of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. Tel.: 81-6-6879-3730; Fax: 81-6-6879-3739; E-mail: ichi{at}imed2.med.osaka-u.ac.jp.

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

This article has been cited by other articles:

				A. Gastaldelli, E. Ferrannini, Y. Miyazaki, M. Matsuda, A. Mari, and R. A. DeFronzo Thiazolidinediones improve beta-cell function in type 2 diabetic patients Am J Physiol Endocrinol Metab, March 1, 2007; 292(3): E871 - E883. [Abstract] [Full Text] [PDF]

				M. Scarsi, M. Podvinec, A. Roth, H. Hug, S. Kersten, H. Albrecht, T. Schwede, U. A. Meyer, and C. Rucker Sulfonylureas and Glinides Exhibit Peroxisome Proliferator-Activated Receptor {gamma} Activity: A Combined Virtual Screening and Biological Assay Approach Mol. Pharmacol., February 1, 2007; 71(2): 398 - 406. [Abstract] [Full Text] [PDF]