title: Stimulating β-cell regeneration by combining a GPR119 agonist with a DPP-IV inhibitor.
abstract: BACKGROUND
  Activating G-protein coupled receptor 119 (GPR119) by its agonists can stimulate glucagon like peptide-1 (GLP-1) release. GLP-1 is rapidly degraded and inactivated by dipeptidylpeptidase-IV (DPP-IV). We studied the efficiency of combining PSN632408, a GPR119 agonist, with sitagliptin, a DPP-IV inhibitor, on β-cell regeneration in diabetic mice.
  
  
  METHODS
  Diabetes in C57BL/6 mice was induced by streptozotocin. PSN632408 and sitagliptin alone or in combination were administered to diabetic mice for 7 weeks along with BrdU daily. Nonfasting blood glucose levels were monitored. After treatment, oral glucose tolerance test (OGTT), plasma active GLP-1 levels, β-cell mass along with α- and β-cell replication, and β-cell neogenesis were evaluated.
  
  
  RESULTS
  Normoglycemia was not achieved in vehicle-treated mice. By contrast, 32% (6 of 19) of PSN632408-treated diabetic mice, 36% (5 of 14) sitagliptin-treated diabetic mice, and 59% (13 of 22) diabetic mice treated with PSN632408 and sitagliptin combination achieved normoglycemia after 7 weeks treatment. Combination therapy significantly increased plasma active GLP-1 levels, improved glucose clearance, stimulated both α- and β-cell replication, and augmented β-cell mass. Furthermore, treatment with combination therapy induced β-cell neogenesis from pancreatic duct-derived cells.
  
  
  CONCLUSIONS
  Our results demonstrate that combining a GPR119 agonist with a DPP-IV inhibitor may offer a novel therapeutic strategy for stimulating β-cell regeneration and reversing diabetes.
authors: The Sanford Project, Children Health Research Center, Sanford Research/USD, Sioux Falls, South Dakota, United States of America.
authors: Ansarullah
authors: Yan
authors: Y
authors: Lu
authors: Martha
authors: M
authors: Holstein
authors: Brittany
authors: B
authors: DeRuyter
authors: Alex
authors: A
authors: Rabinovitch
authors: Zhiguang
authors: Z
authors: Guo
mesh_terms: D000147:Acids, Heterocyclic / Q000008:administration & dosage; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage; D052216:Glucagon-Like Peptide 1 / Q000097:blood; D006801:Humans; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD / Q000235:genetics / Q000378:metabolism*; D010069:Oxadiazoles / Q000008:administration & dosage; D011719:Pyrazines / Q000008:administration & dosage; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000378:metabolism*; D012038:Regeneration / Q000187:drug effects*; D000068900:Sitagliptin Phosphate; D014230:Triazoles / Q000008:administration & dosage
chemical_list: D000147:Acids, Heterocyclic; D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; C519854:GPR119 protein, human; D010069:Oxadiazoles; C534146:PSN 632408; D011719:Pyrazines; D043562:Receptors, G-Protein-Coupled; D014230:Triazoles; D052216:Glucagon-Like Peptide 1; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; D000068900:Sitagliptin Phosphate
references: Endocrinology. 2007 Jun;148(6):2601-9
references: 17289847
references: Curr Med Res Opin. 2008 Feb;24(2):489-96
references: 18182122
references: Nature. 2010 Apr 22;464(7292):1149-54
references: 20364121
references: J Clin Endocrinol Metab. 2010 Oct;95(10):E234-9
references: 20660050
references: Diabetologia. 2009 Aug;52(8):1680-2
references: 19455306
references: Cell. 2012 Mar 16;148(6):1160-71
references: 22424227
references: Diabetes Obes Metab. 2010 May;12(5):421-30
references: 20415690
references: J Clin Pharmacol. 2006 Aug;46(8):876-86
references: 16855072
references: Diabetes. 2009 Jun;58(6):1312-20
references: 19228811
references: Islets. 2011 Nov-Dec;3(6):358-66
references: 21964314
references: Diabetes. 2002 Nov;51(11):3229-36
references: 12401714
references: J Clin Endocrinol Metab. 2006 Nov;91(11):4612-9
references: 16912128
references: Endocr Rev. 2007 Apr;28(2):187-218
references: 17353295
references: Pediatr Diabetes. 2004;5 Suppl 2:16-22
references: 15601370
references: Nat Rev Drug Discov. 2007 Feb;6(2):109-10
references: 17342863
references: Eur J Endocrinol. 2009 Feb;160(2):185-91
references: 19004984
references: Diabetologia. 2006 Nov;49(11):2564-71
references: 17001471
references: Diabetes. 1999 Dec;48(12):2270-6
references: 10580413
references: Diabetes. 2007 Jul;56(7):1802-9
references: 17473224
references: Cell Metab. 2006 Mar;3(3):167-75
references: 16517404
references: Proc Natl Acad Sci U S A. 2003 May 27;100(11):6825-30
references: 12748388
references: Diabetes Obes Metab. 2007 Mar;9(2):153-65
references: 17300591
references: Cell Metab. 2006 Mar;3(3):153-65
references: 16517403
references: Diabetes. 2009 Jun;58(6):1365-72
references: 19265026
references: Endocrinology. 2010 Jul;151(7):3049-60
references: 20444936
references: Biochem Biophys Res Commun. 2006 Dec 15;351(2):474-80
references: 17070774
references: Diabetes Care. 2007 Jun;30(6):1335-43
references: 17337495
references: Biochem Biophys Res Commun. 2005 Jan 28;326(4):744-51
references: 15607732
references: Development. 2005 Aug;132(16):3767-76
references: 16020518
references: Diabetes. 2010 Jul;59(7):1702-8
references: 20413508
references: Endocrinology. 2008 May;149(5):2038-47
references: 18202141
references: Curr Opin Endocrinol Diabetes Obes. 2007 Apr;14(2):98-107
references: 17940427
references: Diabetes. 2006 Jun;55(6):1695-704
references: 16731832
references: Endocrinology. 2010 May;151(5):1984-9
references: 20305008
references: Curr Opin Organ Transplant. 2010 Feb;15(1):79-85
references: 19907327
references: Transpl Int. 2011 Aug;24(8):856-64
references: 21627696
references: Diabetes Res Clin Pract. 2011 Jan;91(1):72-9
references: 21093089
references: J Endocrinol. 2000 Apr;165(1):93-9
references: 10750039
references: Transpl Int. 2011 Nov;24(11):1124-34
references: 21902730
references: Expert Opin Ther Pat. 2009 Oct;19(10):1339-59
references: 19780700
references: J Clin Invest. 2006 Jul;116(7):1802-12
references: 16823478