title: Taspoglutide, a novel human once-weekly GLP-1 analogue, protects pancreatic β-cells in vitro and preserves islet structure and function in the Zucker diabetic fatty rat in vivo.
abstract: OBJECTIVE
  Glucagon-like peptide-1 (GLP-1) has protective effects on pancreatic β-cells. We evaluated the effects of a novel, long-acting human GLP-1 analogue, taspoglutide, on β-cells in vitro and in vivo.
  
  
  METHODS
  Proliferation of murine pancreatic β (MIN6B1) cells and rat islets in culture was assessed by imaging of 5-ethynyl-2'-deoxyuridine-positive cells after culture with taspoglutide. Apoptosis was evaluated with the transferase-mediated 2'-deoxyuridine 5'-triphosphate nick-end labelling assay in rat insulinoma (INS-1E) cells and isolated human islets exposed to cytokines (recombinant interleukin-1β, interferon-γ, tumour necrosis factor-α) or lipotoxicity (palmitate) in the presence or absence of taspoglutide. Islet morphology and survival and glucose-stimulated insulin secretion in perfused pancreata were assessed 3-4 weeks after a single application of taspoglutide to prediabetic 6-week-old male Zucker diabetic fatty (ZDF) rats.
  
  
  RESULTS
  Proliferation was increased in a concentration-dependent manner up to fourfold by taspoglutide in MIN6B1 cells and was significantly stimulated in isolated rat islets. Taspoglutide almost completely prevented cytokine- or lipotoxicity-induced apoptosis in INS-1E cells (control 0.5%, cytokines alone 2.2%, taspoglutide + cytokines 0.6%, p < 0.001; palmitate alone 8.1%, taspoglutide + palmitate 0.5%, p < 0.001) and reduced apoptosis in isolated human islets. Treatment of ZDF rats with taspoglutide significantly prevented β-cell apoptosis and preserved healthy islet architecture and insulin staining intensity as shown in pancreatic islet cross sections. Basal and glucose-stimulated insulin secretion of in situ perfused ZDF rat pancreata was normalized after taspoglutide treatment.
  
  
  CONCLUSIONS
  Taspoglutide promoted β-cell proliferation, prevented apoptosis in vitro and exerted multiple β-cell protective effects on islet architecture and function in vivo in ZDF rats.
authors.affiliation: F. Hoffmann-La Roche AG, Grenzacherstrasse 124, Basel, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Uhles
authors.forename: H
authors.initials: H
authors.lastname: Wang
authors.forename: A
authors.initials: A
authors.lastname: Bénardeau
authors.forename: M
authors.initials: M
authors.lastname: Prummer
authors.forename: M
authors.initials: M
authors.lastname: Brecheisen
authors.forename: S
authors.initials: S
authors.lastname: Sewing
authors.forename: L
authors.initials: L
authors.lastname: Tobalina
authors.forename: D
authors.initials: D
authors.lastname: Bosco
authors.forename: C B
authors.initials: CB
authors.lastname: Wollheim
authors.forename: C
authors.initials: C
authors.lastname: Migliorini
authors.forename: E
authors.initials: E
authors.lastname: Sebokova
mesh_terms: D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D003857:Deoxyuridine / Q000031:analogs & derivatives; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000473:pathology*; D052216:Glucagon-Like Peptide 1 / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000494:pharmacology; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D007150:Immunohistochemistry; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000473:pathology* / Q000502:physiology; D008297:Male; D010455:Peptides / Q000008:administration & dosage* / Q000494:pharmacology; D051381:Rats; D011924:Rats, Zucker; D018027:Receptors, Glucagon / Q000008:administration & dosage*
chemical_list: C000593833:GLP1R protein, human; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D010455:Peptides; D018027:Receptors, Glucagon; C541736:taspoglutide; D052216:Glucagon-Like Peptide 1; C031086:5-ethynyl-2'-deoxyuridine; D003857:Deoxyuridine