title: AP20187-mediated activation of a chimeric insulin receptor results in insulin-like actions in skeletal muscle and liver of diabetic mice.
abstract: Diabetes mellitus (DM) derives from either insulin deficiency (type 1) or resistance (type 2). Insulin regulates glucose metabolism and homeostasis by binding to a specific membrane receptor (IR) with tyrosine kinase activity, expressed by its canonical target tissues. General or tissue-specific IR ablation in mice results in complex metabolic abnormalities, which give partial insights into the role of IR signaling in glucose homeostasis and diabetes development. We generated a chimeric IR (LFv2IRE) inducible on administration of the small molecule drug AP20187. This represents a powerful tool to induce insulin receptor signaling in the hormone target tissues in DM animal models. Here we use adeno-associated viral (AAV) vectors to transduce muscle and liver of nonobese diabetic (NOD) mice with LFv2IRE. Systemic AP20187 administration results in time-dependent LFv2IRE tyrosine phosphorylation and activation of the insulin signaling pathway in both liver and muscle of AAV-treated NOD mice. AP20187 stimulation significantly increases hepatic glycogen content and muscular glucose uptake similarly to insulin. The LFv2IRE-AP20187 system represents a useful tool for regulated and rapid tissue-specific restoration of IR signaling and for dissection of insulin signaling and function in the hormone canonical and noncanonical target tissues.
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), 80131 Naples, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Cotugno
authors.forename: Pietro
authors.initials: P
authors.lastname: Formisano
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Giacco
authors.forename: Pasqualina
authors.initials: P
authors.lastname: Colella
authors.forename: Francesco
authors.initials: F
authors.lastname: Beguinot
authors.forename: Alberto
authors.initials: A
authors.lastname: Auricchio
mesh_terms: D000818:Animals; D000229:Dependovirus; D005822:Genetic Vectors / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D019000:Phosphotyrosine / Q000378:metabolism; D011972:Receptor, Insulin / Q000737:chemistry / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D016559:Tacrolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D014161:Transduction, Genetic
chemical_list: C463061:AP20187; D007328:Insulin; D011993:Recombinant Fusion Proteins; D019000:Phosphotyrosine; D006003:Glycogen; D011972:Receptor, Insulin; D005947:Glucose; D016559:Tacrolimus