title: Protective effects of dipeptidyl peptidase-4 (DPP-4) inhibitor against increased β cell apoptosis induced by dietary sucrose and linoleic acid in mice with diabetes.
abstract: Chronic exposure to high glucose and fatty acid levels caused by dietary sugar and fat intake induces β cell apoptosis, leading to the exacerbation of type 2 diabetes. Oleic acid and linoleic acid are two major dietary fatty acids, but their effects in diabetes are unclear. We challenged β cell-specific glucokinase haploinsufficient (Gck(+/-)) mice with a diet containing sucrose and oleic acid (SO) or sucrose and linoleic acid (SL) and analyzed β cell apoptosis. In Gck(+/-) but not wild-type mice, SL significantly decreased the β cell mass and β cell proportion in islet cells arising from increased apoptosis to a greater degree than did SO. The mRNA expression of SREBP-1c was significantly higher, and that of E-cadherin was significantly lower in the islets of Gck(+/-) mice fed SL compared with mice fed SO. We next evaluated monotherapy with desfluorositagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, in these mouse groups. DPP-4 inhibitor protected against β cell apoptosis, restored the β cell mass, and normalized islet morphology in Gck(+/-) mice fed SL. DPP-4 inhibition normalized the changes in the islet expression of SREBP-1c and E-cadherin mRNA induced by the SL diet. Furthermore, linoleic acid induced β cell apoptosis to a greater degree in the presence of high glucose levels than in the presence of low glucose levels in vitro in islets and MIN6 cells, whereas a GLP-1 receptor agonist prevented apoptosis. In conclusion, SL exacerbated β cell apoptosis in diabetic Gck(+/-) mice but not in euglycemic wild-type mice, and DPP-4 inhibition protected against these effects.
authors: Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan.
authors: Jun
authors: J
authors: Shirakawa
authors: Kikuko
authors: K
authors: Amo
authors: Hirokazu
authors: H
authors: Ohminami
authors: Kazuki
authors: K
authors: Orime
authors: Yu
authors: Y
authors: Togashi
authors: Yuzuru
authors: Y
authors: Ito
authors: Kazuki
authors: K
authors: Tajima
authors: Megumi
authors: M
authors: Koganei
authors: Hajime
authors: H
authors: Sasaki
authors: Eiji
authors: E
authors: Takeda
authors: Yasuo
authors: Y
authors: Terauchi
references: J Biol Chem. 2008 Mar 28;283(13):8723-35
references: 18216022
references: Endocrinology. 2006 Jul;147(7):3398-407
references: 16601139
references: Diabetes. 2010 Feb;59(2):479-85
references: 19934000
references: Diabetes. 2008 Sep;57(9):2382-92
references: 18458149
references: Endocrinology. 2010 May;151(5):2019-29
references: 20219981
references: Diabetes. 2009 Dec;58(12):2851-62
references: 19720788
references: J Endocrinol. 2007 Apr;193(1):65-74
references: 17400804
references: Endocrinology. 2002 Nov;143(11):4397-408
references: 12399437
references: Diabetologia. 2009 Jul;52(7):1298-307
references: 19288077
references: J Nutr. 2007 Aug;137(8):1908-15
references: 17634263
references: Diabetes Obes Metab. 2009 Nov;11 Suppl 4:159-67
references: 19817798
references: Diabetes. 2008 Jan;57(1):190-8
references: 17928394
references: Prog Lipid Res. 2008 Mar;47(2):147-55
references: 18198131
references: Horm Metab Res. 2004 Nov-Dec;36(11-12):842-5
references: 15655717
references: Am J Med. 2002 Dec 30;113 Suppl 9B:25S-29S
references: 12566135
references: Nature. 1998 Mar 12;392(6672):190-3
references: 9515965
references: J Endocrinol. 2007 Jul;194(1):21-9
references: 17592017
references: Can J Biochem Physiol. 1959 Aug;37(8):911-7
references: 13671378
references: Diabetologia. 2007 Apr;50(4):752-63
references: 17268797
references: J Med Chem. 2005 Jan 13;48(1):141-51
references: 15634008
references: Cell Physiol Biochem. 2007;20(6):987-94
references: 17982281
references: Horm Metab Res. 2006 Feb;38(2):98-105
references: 16523410
references: Diabetes. 1999 Dec;48(12):2270-6
references: 10580413
references: Endocrine. 2005 Mar;26(2):107-15
references: 15888922
references: Diabetes. 2011 Apr;60(4):1246-57
references: 21330637
references: J Biol Chem. 2010 Feb 26;285(9):6693-705
references: 20032468
references: J Clin Invest. 2007 Jan;117(1):246-57
references: 17200721
references: Prog Lipid Res. 2008 Sep;47(5):348-80
references: 18435934
references: Cell Metab. 2006 Nov;4(5):391-406
references: 17084712
references: Diabetes. 2000 Dec;49(12):2056-62
references: 11118007
references: Diabetologia. 2004 May;47(5):806-15
references: 15095038
references: J Cell Sci. 2005 Sep 1;118(Pt 17):3905-15
references: 16091421
references: Diabetes. 2000 May;49(5):741-8
references: 10905482
references: J Biol Chem. 2002 Dec 20;277(51):49676-84
references: 12393870
references: Diabetologia. 2004 Mar;47(3):581-589
references: 14767595
references: Diabetes. 2006 Jun;55(6):1695-704
references: 16731832
references: J Biol Chem. 1995 Dec 22;270(51):30253-6
references: 8530440
references: Cell Death Differ. 2004 Apr;11(4):381-9
references: 14685163
references: J Cell Sci. 2008 Jul 15;121(Pt 14):2308-18
references: 18559892
references: Curr Opin Genet Dev. 2006 Feb;16(1):51-9
references: 16377174
references: PLoS One. 2009;4(3):e4954
references: 19305497
references: Diabetes Care. 2006 Mar;29(3):717-8
references: 16505537
references: J Biol Chem. 2008 Dec 12;283(50):34819-32
references: 18936091
references: Diabetes. 2003 Jan;52(1):102-10
references: 12502499