Abstract 368: The GLP-1 Receptor Agonist Liraglutide Improves Autophagy Impairment in the Diabetic Heart
Bibliographic record
Abstract
Background: Diabetes mellitus is a well-recognized risk factor for the development of heart failure. Although studies with the glucagon-like pepide-1 analog liraglutide—an approved treatment for type 2 diabetes—have demonstrated substantial cardioprotective effects of the drug in both human and experimental diabetes, the underlying mode of action/mechanism of liraglutide remains unclear. Here, we investigate the impact of liraglutide on autophagy—an evolutionary conserved mechanism thought to play an essential role in cell survival during stress—using a rodent model of type 2 diabetes, the Goto Kakizaki (GK) rat. Methods: Thirty-two weeks old male GK rats and sex/age-matched Wistar controls were treated with liraglutide (0.2 mg/kg/day) or PBS twice daily for 8 consecutive weeks. At 40-weeks of age, cardiac structure/function were assessed by echocardiography and LV tissue samples were collected to assess the expression of inducers/markers of autophagy (mTOR, phospho-mTOR, LC3-I/II, p62, and Beclin-1). Results: Autophagy was inhibited in the heart of diabetic GK animals when compared to Wistar controls, as confirmed by a significant increase in mTOR expression/activation—a negative regulator of autophagy. This was further confirmed by an observed decrease in the LC3 II/I ratio in diabetic GK animals when compared to controls (p<0.05). P62 expression levels, however, were found to be significantly upregulated in GK animals with respect to controls (p<0.01); suggesting an impairment or defect in basal autophagy in diabetic GK animals. Liraglutide-treatment—which was associated with an improvement in both HbA1C level and LV hypertrophy in GK animals—resulted a significant reduction in mTOR expression/activation in GK animals when compared to their untreated counterparts. This improvement in autophagy status was further corroborated by an observed increase in LC3 II/I ratio and Beclin-1, as well as a reduction in p62 expression levels. Conclusion: Overall, our data suggests that the cardioprotective effects of liraglutide may stem from its ability to activate autophagy in the diabetic heart and improve autophagy impairment in the setting of type 2 diabetes.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 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 | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 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".