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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on November 8, 2006; DOI: 10.1124/jpet.106.112011

0022-3565/07/3202-738-746$20.00
JPET 320:738-746, 2007
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ENDOCRINE AND DIABETES

Effects of the Combination of a Dipeptidyl Peptidase IV Inhibitor and an Insulin Secretagogue on Glucose and Insulin Levels in Mice and Rats

Kazuto Yamazaki, Nobuyuki Yasuda, Takashi Inoue, Eiichi Yamamoto, Yukiko Sugaya, Tadashi Nagakura, Masanobu Shinoda, Richard Clark, Takao Saeki, and Isao Tanaka

Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan

Several combination therapies have been tried for treating of type 2 diabetes to control more effectively fasting hyperglycemia and postprandial hyperglycemia. In this study, we have examined the effects of combining a novel, selective, and competitive dipeptidyl peptidase IV (DPP-IV) inhibitor, 3-but-2-ynyl-5-methyl-2-piperazin-1-yl-3,5-dihydro-4H-imidazo[4,5-d]pyridazin-4-one tosylate (E3024), with a representative of one of two types of insulin secretagogues, i.e., either glybenclamide (a sulfonylurea) or nateglinide (a rapid-onset/short-duration insulin secretagogue), on glucose and insulin levels in an oral glucose tolerance test (OGTT) using mice fed a high-fat diet. In addition, we have investigated the effects of these combinations on blood glucose levels in fasting rats. Two-way analysis of variance showed that the combination of E3024 and glybenclamide improved glucose tolerance additively and also caused a synergistic increase in insulin levels in the OGTT in mice fed a high-fat diet. In a similar way, the combination of E3024 and nateglinide ameliorated glucose tolerance additively and raised insulin levels additively. In fasting rats, coadministration of E3024 with glybenclamide or nateglinide treatment did not affect the glucose-lowering effects of the insulin secretagogues. Therefore, a DPP-IV inhibitor in combination with glybenclamide or nateglinide may be a promising option for the treatment of type 2 diabetes, and particularly, for controlling postprandial hyperglycemia in the clinic.

Received August 3, 2006; accepted November 7, 2006.

Address correspondence to: Dr. Kazuto Yamazaki; Tsukuba Research Laboratories, Eisai Co., Ltd., 5-1-3, Tokodai, Tsukuba, Ibaraki 300-2635, Japan. E-mail: k5-yamazaki{at}hhc.eisai.co.jp






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