title: Beta cell specific probing with fluorescent exendin-4 is progressively reduced in type 2 diabetic mouse models.
abstract: Probes based on GLP-1R agonist exendin-4 have shown promise as in vivo β cell tracers. However, questions remain regarding the β cell specificity of exendin-4 probes, and it is unclear if the expression levels of the GLP-1R are affected in a type 2 diabetic state. Using in vivo probing followed by ex vivo imaging we found fluorescent exendin-4 probes to distinctly label the pancreatic islets in mice in a Glp-1r dependent manner. Furthermore, a co-localization study revealed a near 100 percent β cell specificity with less than one percent probing in other analyzed cell types. We then tested if probing was affected in models of type 2 diabetes using the Lepr(db/db) (db/db) and the Diet-Induced Obese (DIO) mouse. Although nearly all β cells continued to be probed, we observed a progressive decline in probing intensity in both models with the most dramatic reduction seen in db/db mice. This was paralleled by a progressive decrease in Glp-1r protein expression levels. These data confirm β cell specificity for exendin-4 based probes in mice. Furthermore, they also suggest that GLP-1R targeting probes may provide a tool to monitor β cell function rather than mass in type 2 diabetic mouse models.
authors.affiliation: a Department of Histology & Imaging , Novo Nordisk A/S , Måløv , Denmark.
authors.forename: Janne
authors.initials: J
authors.lastname: Lehtonen
authors.affiliation: b Department of Protein & Peptide Chemistry , Novo Nordisk A/S , Måløv , Denmark.
authors.forename: Lauge
authors.initials: L
authors.lastname: Schäffer
authors.affiliation: c Department of Antibody Technology , Novo Nordisk A/S , Måløv , Denmark.
authors.forename: Morten Grønbech
authors.initials: MG
authors.lastname: Rasch
authors.affiliation: a Department of Histology & Imaging , Novo Nordisk A/S , Måløv , Denmark.
authors.forename: Jacob
authors.initials: J
authors.lastname: Hecksher-Sørensen
authors.affiliation: a Department of Histology & Imaging , Novo Nordisk A/S , Måløv , Denmark.
authors.forename: Jonas
authors.initials: J
authors.lastname: Ahnfelt-Rønne
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental; D003924:Diabetes Mellitus, Type 2 / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism; D018450:Disease Progression; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008820:Mice, Obese; D010455:Peptides / Q000627:therapeutic use*; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014688:Venoms / Q000627:therapeutic use*
chemical_list: D007004:Hypoglycemic Agents; D010455:Peptides; D018027:Receptors, Glucagon; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide
keywords: Glp-1 receptor; exendin-4; imaging; islets; type 2 diabetes