AP20187-mediated activation of a chimeric insulin receptor results in insulin-like actions in skeletal muscle and liver of diabetic mice

Gabriella Cotugno, Pietro Formisano, Ferdinando Giacco, Pasqualina Colella, Francesco Beguinot, Alberto Auricchio

Research output: Contribution to journalArticle

3 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)106-117
Number of pages12
JournalHuman Gene Therapy
Volume18
Issue number2
DOIs
StatePublished - Feb 1 2007

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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