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.