GLP-1 Receptor Agonists Target Autophagy Dysfunction in Diabetic Nephropathy

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Background: Diabetic nephropathy (DN) is a major cause of end-stage kidney disease and current therapeutes remain insufficient to halt disease progression. Dysregulated autophagy emerged as a potential driver of DN pathogenesis. GLP-1 receptor agonists(RA) have demonstrated renoprotective effects beyond glycemic control, but their underlying mechanisms remain unclear. We aimed to assess the impact of GLP-1 RA therapy on autophagy regulation in patients with DN. Methods: Prospective study including adult patients with established DN on SGLT2 inhibitors and RAAS blockers. Patients on insulin or with prior pancreatitis were excluded. All initiated weekly dulaglutide. Clinical and biochemical data were collected at baseline, 3 and 6 months. Autophagy-related markers(Cx43,ATG5,LC3,p62,Beclin-1,AMPK) were measured in extracellular vesicles(EVs) by western blot at each timepoint. Longitudinal changes were analyzed using linear mixed-effects models, adjusted for weight,HbA1c and proteinuria. Results: Six patients were followed for 6 months after GLP-1 RA initiation. Mean proteinuria declined from 968 to 722mg/g, and HbA1c initially dropped from 7.3to6.8% at 3 months, then rose to 7.1% at 6 months. Body weight decreased significantly (95.4to93.0kg; p=0.02). Among autophagy-related markers, ATG5 levels declined significantly (p=0.02), independently of HbA1c, weight, or proteinuria. p62 showed a non-significant increase(p=0.13) but correlated with body weight(p=0.02). Conclusion: GLP-1 RA therapy reduced ATG5 and increased p62 levels in circulating EVs, independent of HbA1c and proteinuria, suggesting direct modulation of basal autophagy.The association between p62 and body weight supports a metabolic-autophagic link. This effects could likely explain renoprotective outcomes, positioning autophagy modulation as a promising therapeutic target. Funding: Private Foundation Support

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