title: Effects of the combination of a dipeptidyl peptidase IV inhibitor and an insulin secretagogue on glucose and insulin levels in mice and rats.
abstract: 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.
authors.affiliation: Eisai Co., Ltd., Tsukuba, Ibaraki 300-2635, Japan. k5-yamazaki@hhc.eisai.co.jp
authors.forename: Kazuto
authors.initials: K
authors.lastname: Yamazaki
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Yasuda
authors.forename: Takashi
authors.initials: T
authors.lastname: Inoue
authors.forename: Eiichi
authors.initials: E
authors.lastname: Yamamoto
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Sugaya
authors.forename: Tadashi
authors.initials: T
authors.lastname: Nagakura
authors.forename: Masanobu
authors.initials: M
authors.lastname: Shinoda
authors.forename: Richard
authors.initials: R
authors.lastname: Clark
authors.forename: Takao
authors.initials: T
authors.lastname: Saeki
authors.forename: Isao
authors.initials: I
authors.lastname: Tanaka
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis*; D003510:Cyclohexanes / Q000494:pharmacology; D054873:Dipeptidyl-Peptidase IV Inhibitors; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology*; D007328:Insulin / Q000097:blood*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000077715:Nateglinide; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology*; D011724:Pyridazines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014105:Tosyl Compounds / Q000494:pharmacology*
chemical_list: C515375:3-but-2-ynyl-5-methyl-2-piperazin-1-yl-3,5-dihydro-4H-imidazo(4,5-d)pyridazin-4-one tosylate; D001786:Blood Glucose; D003510:Cyclohexanes; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007093:Imidazoles; D007328:Insulin; D011480:Protease Inhibitors; D011724:Pyridazines; D014105:Tosyl Compounds; D000077715:Nateglinide; D010649:Phenylalanine; D052216:Glucagon-Like Peptide 1; D005905:Glyburide