SGLT2 Inhibitors Promote Diabetic Wound Healing Via AMPK/AKT/mTORC1-Regulated Endothelial Angiogenesis

BACKGROUND: Approximately 25% of patients with type 2 diabetes are at risk of developing diabetic ulcers, which can progress to amputations. A key challenge in diabetic wound healing is impaired angiogenesis. Although SGLT2 (sodium-glucose transporter 2) inhibitors are known for their cardiovascular and renal benefits, their role in wound healing and angiogenesis, remains incompletely understood. METHODS: We evaluated the effects of empagliflozin, dapagliflozin, and canagliflozin on wound healing in db/db mice by measuring wound closure, granulation tissue thickness, and perfusion. Angiogenesis and proliferation were assessed by CD31 and Ki67 immunostaining. Ex vivo studies used human skin organoids, sprouting assays from human microvessels and murine aortic explants. In vitro studies were performed in human umbilical vein endothelial cells (ECs). RESULTS: Empagliflozin and dapagliflozin significantly improved wound healing, perfusion, angiogenesis, and cell proliferation while canagliflozin showed limited benefit. In human skin organoids and ECs, empagliflozin and dapagliflozin but not canagliflozin improved wound closure, angiogenesis, proliferation, and migration. Sprouting angiogenesis of human vascular explants and mice aorta showed significantly increased branching and junction formation in response to empagliflozin and dapagliflozin. All 3 SGLT2 inhibitors similarly suppressed inflammation and improved EC barrier function, while empagliflozin and dapagliflozin selectively increased tissue remodeling gene expression. Mechanistically, canagliflozin significantly increased AMPK (AMP-activated protein kinase) phosphorylation while decreasing AKT/mTORC1 (mechanistic target of rapamycin complex 1) activation compared with empagliflozin, dapagliflozin. AMPK inhibition with compound C, or dose reduction of canagliflozin, partially restored AKT/mTORC1 signaling and wound closure. CONCLUSIONS: These findings uncover distinct angiogenic effects among SGLT2 inhibitors. Empagliflozin and dapagliflozin promote EC-angiogenic functions through balanced AMPK/AKT/mTORC1 signaling, whereas canagliflozin impaired these processes via excessive AMPK activation and suppression of AKT/mTORC1 signaling. AMPK inhibition or dose reduction restored AKT/mTORC1 signaling and partially rescued wound healing, underscoring the importance of balanced AMPK/AKT/mTORC1 signaling for EC-angiogenic function in diabetic wounds.