Rikke K Kirk1, Charles Pyke1, Matthias G von Herrath2, Jane P Hasselby3, Lars Pedersen4, Pia G Mortensen1, Lotte B Knudsen5, Ken Coppieters5. 1. Histology and Imaging Department, Global Research, Novo Nordisk A/S, Måløv, Denmark. 2. Type 1 Diabetes Research Center, Global Research, Novo Nordisk Inc., Seattle, Washington. 3. Department of Pathology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. 4. Visiopharm, Hørsholm, Denmark. 5. Metabolic Disease Research, Global Research, Novo Nordisk A/S, Måløv, Denmark.
Abstract
AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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: Olof Eriksson; Irina Velikyan; Torsten Haack; Martin Bossart; Iina Laitinen; Philip J Larsen; Jan Erik Berglund; Gunnar Antoni; Lars Johansson; Stefan Pierrou; Joachim Tillner; Michael Wagner Journal: J Nucl Med Date: 2021-09-09 Impact factor: 10.057
Authors: Steven E Kahn; Yi-Chun Chen; Nathalie Esser; Austin J Taylor; Daniël H van Raalte; Sakeneh Zraika; C Bruce Verchere Journal: Endocr Rev Date: 2021-09-28 Impact factor: 25.261