Metformin as a Modulator of Autophagy and Hypoxia Responses in the Enhancement of Wound Healing in Diabetic Rats.

Abstract

The molecular mechanisms underlying delayed wound repair in diabetes involve dysregulation of key cellular processes, including autophagy and hypoxia response pathways. Herein, we investigated the role of topical metformin, an established anti-diabetic drug with potential autophagy-inducing properties, in improving wound healing outcomes under hypoxic conditions. Full-thickness skin wounds were created in streptozotocin-induced diabetic rats, and tissue samples were collected at regular intervals for molecular and histological analysis. The expression levels of autophagy markers LC3B and Beclin-1 were evaluated via immunohistochemistry and qRT-PCR, while the amount of AMP-activated protein kinase (AMPK) and hypoxia-inducible factor-1α (HIF-1α) were determined via ELISA. Our results demonstrated that metformin administration resulted in the upregulation of LC3B and Beclin-1 in the wound bed, suggesting induction of autophagy in response to the treatment. Mechanistically, metformin treatment also led to the increased amount of AMPK, a critical regulator of cellular energy homeostasis, and a subsequent reduction in HIF-1α amount under hypoxic conditions. In conclusion, our findings demonstrate that metformin promotes wound healing in diabetes mellitus by enhancing autophagy through AMPK activation and modulating HIF-1α amount in a hypoxic microenvironment. This study offers a new therapeutic approach by shedding light on the potential benefits of metformin as adjunctive therapy in diabetic wound management.