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. (15th September 2015)

• Record Type: Journal Article
• Authors: Hirukawa, Hidenori; Kaneto, Hideaki; Shimoda, Masashi; Kimura, Tomohiko; Okauchi, Seizo; Obata, Atsushi; Kohara, Kenji; Hamamoto, Sumiko; Tawaramoto, Kazuhito; Hashiramoto, Mitsuru; Kaku, Kohei
• Is Part Of: Molecular and cellular endocrinology. Volume 413(2015)
• Page Start: 49
• Page End: 60
• Publication Date: 2015-09-15
• Subjects: Thiazolidine derivative -- DPP-4 inhibitor -- Pancreatic β-cells -- Cellular kinetics; Pio pioglitazone -- Alo alogliptin -- GSIS glucose-stimulated insulin secretion -- IPITT intraperitoneal glucose tolerance test -- PPARγ peroxisome proliferator-activated receptor γ -- GLP-1 glucagon-like peptide-1 -- GIP glucose-dependent insulinotropicpolypeptide -- DPP-4 dipeptidyl peptidase-4; Endocrinology -- Periodicals; Molecular biology -- Periodicals; Cytology -- Periodicals; Endocrinology -- Periodicals; Hormones -- Periodicals; Endocrinologie -- Périodiques; Cytology; Endocrinology; Molecular biology; Periodicals; 573.4
• DOI: 10.1016/j.mce.2015.06.010
• Languages: English
• ISSNs: 0303-7207

Abstract

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. Highlights: Pioglitazone and/or alogliptin exerted protective effects on pancreatic β-cells. Expression level of IRS-2 was up-regulated after short-term intervention. mRNA and protein levels of IRS-2 were up-regulated in MIN6 cells by the treatment. The additive effect was independent of the alteration of the glycemic control. The protective effects were exerted through the augmentation of IRS-2 expression.