Abstract 16485: Hyperinsulinemia Reduces Autophagy in Insulin Resistant Hearts Through Insulin Growth Factor 1 Receptor (IGF-1R) Signaling
Bibliographic record
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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".