title: Enhanced beta cell function and anti-inflammatory effect after chronic treatment with the dipeptidyl peptidase-4 inhibitor vildagliptin in an advanced-aged diet-induced obesity mouse model.
abstract: OBJECTIVE
  Studies have shown that dipeptidyl peptidase-4 (DPP4) inhibitors stimulate insulin secretion and increase beta cell mass in rodents. However, in these models hyperglycaemia has been induced early on in life and the treatment periods have been short. To explore the long-term effects of DPP4 inhibition on insulin secretion and beta cell mass, we have generated a high-fat diet (HFD)-induced-obesity model in mice of advanced age (10 months old).
  
  
  METHODS
  After 1 month of HFD alone, the mice were given the DPP4 inhibitor vildagliptin for a further 11 months. At multiple time points throughout the study, OGTTs were performed and beta cell area and long-term survival were evaluated.
  
  
  RESULTS
  Beta cell function and glucose tolerance were significantly improved by vildagliptin with both diets. In contrast, in spite of the long treatment period, beta cell area was not significantly different between vildagliptin-treated mice and controls. Mice of advanced age chronically fed an HFD displayed clear and extensive pancreatic inflammation and peri-insulitis, mainly formed by CD3-positive T cells, which were completely prevented by vildagliptin treatment. Chronic vildagliptin treatment also improved survival rates for HFD-fed mice.
  
  
  CONCLUSIONS
  In a unique advanced-aged HFD-induced-obesity mouse model, insulin secretion was improved and the extensive peri-insulitis prevented by chronic DPP4 inhibition. The improved survival rates for obese mice chronically treated with vildagliptin suggest that chronic DPP4 inhibition potentially results in additional quality-adjusted life-years for individuals with type 2 diabetes, which is the primary goal of any diabetes therapy.
authors: Department of Clinical Sciences, Lund University, Lund, Sweden. bilal.omar@med.lu.se
authors: B A
authors: BA
authors: Omar
authors: J
authors: J
authors: Vikman
authors: M S
authors: MS
authors: Winzell
authors: U
authors: U
authors: Voss
authors: E
authors: E
authors: Ekblad
authors: J E
authors: JE
authors: Foley
authors: B
authors: B
authors: Ahrén
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D059305:Diet, High-Fat / Q000009:adverse effects*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000627:therapeutic use*; D005260:Female; D007150:Immunohistochemistry; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009570:Nitriles / Q000627:therapeutic use*; D009765:Obesity / Q000188:drug therapy* / Q000209:etiology* / Q000378:metabolism; D011759:Pyrrolidines / Q000627:therapeutic use*; D000077597:Vildagliptin
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D009570:Nitriles; D011759:Pyrrolidines; D000077597:Vildagliptin; D000218:Adamantane
references: Eur J Endocrinol. 2002 May;146(5):717-27
references: 11980629
references: Methods Mol Biol. 2007;380:285-311
references: 17876100
references: Mediators Inflamm. 2010;2010:592760
references: 20652060
references: Nature. 2000 Nov 9;408(6809):239-47
references: 11089981
references: Immunol Rev. 1998 Feb;161:55-70
references: 9553764
references: Diabetes Care. 2012 Oct;35(10):2076-82
references: 22688551
references: Diabetologia. 1996 Jan;39(1):54-9
references: 8720603
references: Diabetes Obes Metab. 2010 May;12(5):421-30
references: 20415690
references: Diabetologia. 2012 Feb;55(2):404-12
references: 22072158
references: Diabetologia. 2011 Aug;54(8):1985-91
references: 21547496
references: Diabetologia. 2010 Feb;53(2):321-30
references: 19855953
references: Diabetes. 2009 Jun;58(6):1312-20
references: 19228811
references: Islets. 2010 Nov-Dec;2(6):353-6
references: 21099337
references: Diabetes Obes Metab. 2011 Apr;13(4):337-47
references: 21205126
references: Diabetes. 2009 Mar;58(3):641-51
references: 19073764
references: Autoimmun Rev. 2005 Jul;4(6):373-9
references: 16081028
references: Diabetes Obes Metab. 2011 Sep;13(9):775-83
references: 21507182
references: Eur J Pharmacol. 2012 Sep 15;691(1-3):297-306
references: 22820107
references: Horm Metab Res. 2010 Sep;42(10):731-5
references: 20625970
references: J Clin Invest. 1983 Jun;71(6):1544-53
references: 6134752
references: Am J Physiol Endocrinol Metab. 2011 Feb;300(2):E410-21
references: 21081706
references: Diabetes. 2009 Jun;58(6):1365-72
references: 19265026
references: Endocrinology. 2010 Jul;151(7):3049-60
references: 20444936
references: Am J Med. 1998 Jul 6;105(1A):20S-26S
references: 9707264
references: Ann Fam Med. 2005 Jan-Feb;3(1):60-3
references: 15671192
references: Diabetes. 2006 Jun;55(6):1695-704
references: 16731832
references: Toxicol Pathol. 1995 Sep-Oct;23(5):570-82
references: 8578100
references: Eur J Pharmacol. 2011 Jan 15;650(2-3):703-7
references: 21070766
references: Methods Mol Biol. 2009;560:19-36
references: 19504240
references: Diabetes Obes Metab. 2011 Oct;13 Suppl 1:158-66
references: 21824270
references: Diabetes Care. 2006 Mar;29(3):717-8
references: 16505537
references: Diabetes Obes Metab. 2010 Oct;12 Suppl 2:66-75
references: 21029302
references: Int J Clin Pract Suppl. 2008 Mar;(159):8-14
references: 18269436
references: Diabetes. 2003 Jun;52(6):1475-84
references: 12765960
references: Diabetes. 2003 Jan;52(1):102-10
references: 12502499
references: Eur J Pharmacol. 2009 Nov 25;623(1-3):148-54
references: 19765579