Journal of Reproductive Immunology · Sep 20, 2026

Metformin (DMBG) ameliorates diabetic erectile dysfunction via the AMPK/mTOR pathway in association with endothelial autophagy reactivation

By Chen J, Hu L, Ding Y et al.

BACKGROUND: Diabetes mellitus erectile dysfunction (DMED) is a prevalent complication with limited treatment efficacy. Metformin (dimethylbiguanide, DMBG) shows therapeutic potential, but its underlying mechanisms remain unclear. This study investigated whether DMBG alleviates DMED in association with restored endothelial autophagy. METHODS: A DMED rat model was induced by streptozotocin and validated by apomorphine screening. Rats were treated with DMBG or Sildenafil (positive control) for 30 days. Erectile function was assessed by intracavernosal pressure (ICP) and mean arterial pressure (MAP). Penile tissues were analyzed histologically and for autophagy markers. To decipher the cellular mechanism, primary cavernosal endothelial cells (PCECs) were isolated from each treatment group and subjected to functional assays including viability, angiogenesis, migration, and apoptosis. The role of the AMPK/mTOR pathway was interrogated through western blot and by using the AMPK inhibitor BAY-3827 in a rescue experiment. RESULTS: DMBG significantly restored erectile function and cavernosal endothelial integrity, comparable to Sildenafil. It downregulated elevated serum VEGF-A and upregulated impaired penile autophagy markers (LC3-II, BECLIN1, ATG5). PCECs from DMBG-treated rats exhibited rescued viability, angiogenesis, migration, and reduced apoptosis, alongside reactivated autophagy. Mechanistically, DMBG activated AMPK and inhibited mTOR phosphorylation in PCECs, increasing eNOS. These protective effects were substantially attenuated by AMPK inhibition. CONCLUSIONS: DMBG ameliorates DMED in association with improved endothelial function and reactivated autophagy. These beneficial effects are associated with activation of the AMPK/mTOR signaling pathway, highlighting a novel mechanistic basis for the use of DMBG in DMED management.

doi.org/10.1016/j.jri.2026.104968PubMed 42950738Interventions