title: Transgenic Expression of Glucagon-Like Peptide-1 (GLP-1) and Activated Muscarinic Receptor (M3R) Significantly Improves Pig Islet Secretory Function.
abstract: Porcine islets show notoriously low insulin secretion levels in response to glucose stimulation. While this is somehow expected in the case of immature islets isolated from fetal and neonatal pigs, disappointingly low secretory responses are frequently reported in studies using in vitro-maturated fetal and neonatal islets and even fully differentiated adult islets. Herein we show that β-cell-specific expression of a modified glucagon-like peptide-1 (GLP-1) and of a constitutively activated type 3 muscarinic receptor (M3R) efficiently amplifies glucose-stimulated insulin secretion (GSIS). Both adult and neonatal isolated pig islets were treated with adenoviral expression vectors carrying sequences encoding for GLP-1 and/or M3R. GSIS from transduced and control islets was evaluated during static incubation and dynamic perifusion assays. While expression of GLP-1 did not affect basal or stimulated insulin secretion, activated M3R produced a twofold increase in both first and second phases of GSIS. Coexpression of GLP-1 and M3R caused an even greater increase in the secretory response, which was amplified fourfold compared to controls. In conclusion, our work highlights pig islet insulin secretion deficiencies and proposes concomitant activation of cAMP-dependent and cholinergic pathways as a solution to ameliorate GSIS from pig islets used for transplantation.
authors.forename: Nizar I
authors.initials: NI
authors.lastname: Mourad
authors.forename: Andrea
authors.initials: A
authors.lastname: Perota
authors.forename: Daela
authors.initials: D
authors.lastname: Xhema
authors.forename: Cesare
authors.initials: C
authors.lastname: Galli
authors.forename: Pierre
authors.initials: P
authors.lastname: Gianello
mesh_terms: D000818:Animals; D052216:Glucagon-Like Peptide 1 / Q000235:genetics / Q000378:metabolism*; D005941:Glucokinase / Q000378:metabolism; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism* / Q000648:ultrastructure; D008854:Microscopy, Electron; D043587:Receptor, Muscarinic M3 / Q000235:genetics / Q000378:metabolism*; D013552:Swine
chemical_list: D007328:Insulin; D043587:Receptor, Muscarinic M3; D052216:Glucagon-Like Peptide 1; D005941:Glucokinase