Abstract 17000: Activation of Igf-1 Receptor Signaling by Hyperinsulinemia Suppresses Cardiac Autophagy Through Trb3/p62 Pathway

IntroductionInsulin and insulin-like growth factor (IGF) receptor signaling is a known suppressor of autophagy in the heart. Therefore, one would predict to see higher levels of autophagy in the insulin resistant heart but the opposite is reported in the literature.HypothesisThus, the aim of this study was to investigate the mechanisms involved in autophagy-suppression in insulin resistant hearts.MethodsWe assessed autophagic flux in the hearts of mouse models with either impaired insulin signaling and cardiac insulin resistance (ob/ob mice) or absent insulin signaling specifically in cardiomyocytes (CIRKO mice) or in the entire heart (TIRKO mice).ResultsAutophagic flux was impaired in the hearts of (ob/ob) and TIRKO mice but not in hearts of CIRKO mice. One common characteristic of (ob/ob) and TIRKO mice is that they both exhibit systemic hyperinsulinemia and they both have increased IGF-1 receptor signaling in the heart. Thus, we hypothesized that systemic hyperinsulinema activates IGF-1 receptor signaling to suppress cardiac autophagy. To directly test that, we generated (ob/ob) and TIRKO mice lacking one allele of the IGF-1 receptor in cardiomyocytes and showed that autophagy was restored in these hearts. Furthermore, reduction of IGF-1 receptor signaling in TIRKO hearts reduced p62 accumulation and diminished TRB3 expression.ConclusionTaken together, these results demonstrated for the first time that systemic hyperinsulinemia suppresses cardiac autophagy through IGF-1 receptor signaling to TRB3/p62.