title: Combination of DPP-4 inhibitor and PPARγ agonist exerts protective effects on pancreatic β-cells in diabetic db/db mice through the augmentation of IRS-2 expression.
abstract: We investigated the effects of long- and short-term treatment with pioglitazone (Pio) and/or alogliptin (Alo) on β-cells in diabetic db/db mice. Six-week-old male db/db mice received Pio (25 mg/kg, oral) and/or Alo (30 mg/kg, oral) for 4 weeks and for 2 days. Blood glucose levels were decreased after 4-week intervention, but not after 2-day intervention. Pio increased adiponectin levels, and Alo decreased glucagon levels and increased active GlP-1 levels. Insulin sensitivity was restored by Pio. After 4-week treatment, β-cell mass was increased (over 2-fold increase) and expression levels of various β-cell-related factors were restored. Expression levels of IRS-2 and various downstream factors were up-regulated by Pio and Alo after 2-day and 4-week intervention. In addition, mRNA and protein levels of IRS-2 and various downstream factors were up-regulated in MIN6 cells after 24-h exposure to Pio and exendin-4. These results suggest that Pio and Alo additively up-regulate IRS-2 expression independently of the alteration of glycemic control. Taken together, combination of Pio and Alo exerts protective effects on β-cells in diabetic db/db mice, at least in part, through the augmentation of IRS-2 expression.
authors.affiliation: Division of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, 577 Matsushima, Kurashiki-city, Okayama 701-0192, Japan. Electronic address: hirukawa@med.kawasaki-m.ac.jp.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Hirukawa
authors.affiliation: Division of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, 577 Matsushima, Kurashiki-city, Okayama 701-0192, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Kaneto
authors.affiliation: Division of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, 577 Matsushima, Kurashiki-city, Okayama 701-0192, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Shimoda
authors.affiliation: Division of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, 577 Matsushima, Kurashiki-city, Okayama 701-0192, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Kimura
authors.affiliation: Division of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, 577 Matsushima, Kurashiki-city, Okayama 701-0192, Japan.
authors.forename: Seizo
authors.initials: S
authors.lastname: Okauchi
authors.affiliation: Division of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, 577 Matsushima, Kurashiki-city, Okayama 701-0192, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Obata
authors.affiliation: Division of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, 577 Matsushima, Kurashiki-city, Okayama 701-0192, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kohara
authors.affiliation: Division of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, 577 Matsushima, Kurashiki-city, Okayama 701-0192, Japan.
authors.forename: Sumiko
authors.initials: S
authors.lastname: Hamamoto
authors.affiliation: Division of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, 577 Matsushima, Kurashiki-city, Okayama 701-0192, Japan.
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Tawaramoto
authors.affiliation: Division of Diabetes and Endocrinology, Yodogawa Christian Hospital, Osaka, Japan.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Hashiramoto
authors.affiliation: Division of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, 577 Matsushima, Kurashiki-city, Okayama 701-0192, Japan; Department of General Internal Medicine 1, Kawasaki Hospital, Kawasaki Medical School, Okayama, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Kaku
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000096:biosynthesis*; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D000077205:Pioglitazone; D010880:Piperidines / Q000494:pharmacology*; D045162:Thiazolidinediones / Q000494:pharmacology*; D014498:Uracil / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D055504:Insulin Receptor Substrate Proteins; C526298:Irs2 protein, mouse; D047495:PPAR gamma; D010880:Piperidines; D045162:Thiazolidinediones; D014498:Uracil; D018819:Dipeptidyl Peptidase 4; C545245:Dpp4 protein, mouse; C520853:alogliptin; D000077205:Pioglitazone
keywords: Cellular kinetics; DPP-4 inhibitor; Pancreatic β-cells; Thiazolidine derivative