title: Immunohistochemical assessment of glucagon-like peptide 1 receptor (GLP-1R) expression in the pancreas of patients with type 2 diabetes.
abstract: Glucagon-like peptide-1 (GLP-1) is an incretin hormone which stimulates insulin release and inhibits glucagon secretion from the pancreas in a glucose-dependent manner. Incretin-based therapies, consisting of GLP-1 receptor (GLP-1R) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors, are used for the treatment of type 2 diabetes (T2D). Immunohistochemical studies for GLP-1R expression have been hampered previously by the use of unspecific polyclonal antibodies. This study aimed to assess the expression levels of GLP-1R in a set of T2D donor samples obtained via nPOD.
  
  
  
  This study used a new monoclonal antibody to assess GLP-1R expression in pancreatic tissue from 23 patients with T2D, including 7 with a DPP-4 inhibitor and 1 with a history of GLP-1R agonist treatment. A software-based automated image analysis algorithm was used for quantitating intensities and area fractions of GLP-1R positive compartments.
  
  
  
  The highest intensity GLP-1R immunostaining was seen in beta-cells in islets (average signal intensity, 76.1 [±8.1]). GLP-1R/insulin double-labelled single cells or small clusters of cells were also frequently located within or in close vicinity of ductal epithelium in all samples and with the same GLP-1R immunostaining intensity as found in beta-cells in islets. In the exocrine pancreas a large proportion of acinar cells expressed GLP-1R with a 3-fold lower intensity of immunoreactivity as compared to beta-cells (average signal intensity 25.5 [±3,3]). Our studies did not unequivocally demonstrate GLP-1R immunoreactivity on normal-appearing ductal epithelium. Pancreatic intraepithelial neoplasia (PanINs; a form of non-invasive pancreatic ductular neoplasia) was seen in most samples, and a minority of these expressed low levels of GLP-1R.
  
  
  
  These data confirm the ubiquity of early stage PanIN lesions in patients with T2D and do not support the hypothesis that incretin-based therapies are associated with progression towards the more advanced stage PanIN lesions.
authors.affiliation: Histology and Imaging Department, Global Research, Novo Nordisk A/S, Måløv, Denmark.
authors.forename: Rikke K
authors.initials: RK
authors.lastname: Kirk
authors.affiliation: Histology and Imaging Department, Global Research, Novo Nordisk A/S, Måløv, Denmark.
authors.forename: Charles
authors.initials: C
authors.lastname: Pyke
authors.affiliation: Type 1 Diabetes Research Center, Global Research, Novo Nordisk Inc., Seattle, Washington.
authors.forename: Matthias G
authors.initials: MG
authors.lastname: von Herrath
authors.affiliation: Department of Pathology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Jane P
authors.initials: JP
authors.lastname: Hasselby
authors.affiliation: Visiopharm, Hørsholm, Denmark.
authors.forename: Lars
authors.initials: L
authors.lastname: Pedersen
authors.affiliation: Histology and Imaging Department, Global Research, Novo Nordisk A/S, Måløv, Denmark.
authors.forename: Pia G
authors.initials: PG
authors.lastname: Mortensen
authors.affiliation: Metabolic Disease Research, Global Research, Novo Nordisk A/S, Måløv, Denmark.
authors.forename: Lotte B
authors.initials: LB
authors.lastname: Knudsen
authors.affiliation: Metabolic Disease Research, Global Research, Novo Nordisk A/S, Måløv, Denmark.
authors.forename: Ken
authors.identifier: 0000-0003-3037-0806
authors.initials: K
authors.lastname: Coppieters
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal; D000918:Antibody Specificity; D015415:Biomarkers / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005934:Glucagon / Q000378:metabolism; D000067757:Glucagon-Like Peptide-1 Receptor / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D054795:Incretins / Q000627:therapeutic use; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D014015:Tissue Banks; D055815:Young Adult; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
chemical_list: D000911:Antibodies, Monoclonal; D015415:Biomarkers; C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D054795:Incretins; D007328:Insulin; D005934:Glucagon; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
keywords: 
  GLP-1; incretin; liraglutide; type 2 diabetes