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