Abstract 16485: Hyperinsulinemia Reduces Autophagy in Insulin Resistant Hearts Through Insulin Growth Factor 1 Receptor (IGF-1R) Signaling

Abstract

Introduction: Diabetes is a leading cause of mortality and morbidity worldwide with over 50% of deaths in diabetic patients being caused by cardiovascular complications. The mechanisms underlying the high incidence of diabetic cardiac dysfunction remain relatively obscure but may involve altered autophagy. Macro-autophagy (referred to as autophagy) is a regulated intracellular catabolic pathway for the turnover of long-lived proteins, macromolecular aggregates, and damaged organelles. Hypothesis: Taking advantage TIRKO mice (a mouse model of total cardiac ablation of insulin receptors [IRs]), we aimed to investigate the impact of myocardial insulin resistance and systemic hyperinsulinemia (SH) on cardiac autophagy. Results: Basal and fasting-induced autophagy were significantly reduced in TIRKO hearts, as evidenced by reduced LC3II/LC3I ratios and increased P62 accumulation. As TIRKO mice develop SH, we next sought to determine whether this reduces autophagy independently of the absence of IRs. Thus, we used mice with cardiomyocytes-specific deletion of IRs (CIRKO mice) but without SH or (ob/ob) mice that have IRs in the heart but develop SH. We demonstrated that cardiac autophagy reduction is indeed caused by systemic SH as its level was unaltered in CIRKO hearts but reduced in (ob/ob) hearts. Because of the absence of IRs in TIRKO hearts and the degree of insulin resistance in (ob/ob) hearts, we hypothesized that the reduction of cardiac autophagy by SH is mediated by the IGF-1R signaling. Indeed, IGF-1R phosphorylation was enhanced in both TIRKO and (ob/ob) hearts but not in CIRKO hearts. To begin to understand the functional role of attenuated autophagy in TIRKO hearts, we further decreased autophagosomes clearance by treating mice with the lysosomal clearance inhibitor chloroquine. Treatment of TIRKO mice with chloroquine for 4 hours massively increased LC3I and P62 levels, promoted cells death and decreased mitochondrial clearance. Conclusions: Taken together, these results suggest that hyperinsulinemia-mediated reduction in cardiac autophagy can be adaptive to suppress sustained autophagy activation by insulin resistance but can become maladaptive if the heart is challenged by a reduction in lysosomal degradation.