Metformin accelerates wound healing in type 2 diabetic db/db mice

Abstract

Wound healing impairment is increasingly recognized to be a consequence of hyperglycemia-induced dysfunction of endothelial precursor cells (EPCs) in type 2 diabetes mellitus (T2DM). Metformin exhibits potential for the improvement of endothelial function and the wound healing process. However, the underlying mechanisms for the observed beneficial effects of metformin application remain to be completely understood. The present study assessed whether metformin, a widely used therapeutic drug for T2DM, may accelerate wound closure in T2DM db/db mice. Genetically hyperglycemic db/db mice were used as the T2DM model. Metformin (250 mg/kg/day; intragastric) was administered for two weeks prior to EPC collection and wound model creation in db/db mice. Wound healing was evaluated by alterations in the wound area and the number of platelet endothelial cell adhesion molecule-positive cells. The function of the isolated bone marrow-derived EPCs (BM-EPCs) was assessed by a tube formation assay. The number of circulating EPCs, and the levels of intracellular nitric oxide (NO) and superoxide (O2−) were detected by flow cytometry. Thrombospondin-1 (TSP-1) expression was determined by western blot analysis. It was observed that treatment with metformin accelerated wound healing, improved angiogenesis and increased the circulating EPC number in db/db mice. In vitro, treatment with metformin reversed the impaired BM-EPC function reflected by tube formation, and significantly increased NO production while decreasing O2− levels in BM-EPCs from db/db mice. In addition, TSP-1 expression was markedly attenuated by treatment with metformin in cultured BM-EPCs. Metformin contributed to wound healing and improved angiogenesis in T2DM mice, which was, in part, associated with stimulation of NO, and inhibition of O2− and TSP-1 in EPCs from db/db mice.

AMPK Activation by 5-Amino-4-Imidazole Carboxamide Riboside-1-β-D-Ribofuranoside Attenuates Alkali Injury-Induced Corneal Fibrosis

“…Indeed, the systemic administration of AICAR and metformin, another pharmacological AMPK activator, in the treatment of type 2 diabetes mellitus and in wound healing is premised on their anti-inflammatory actions in addition to their major modes of action. [58][59][60][61] Taken together with our results, AICAR may be inhibiting alkali injury-induced cornea inflammation and accelerating corneal wound healing by reduc-ing the production of angiogenic factors and inflammatory cytokines.…”

The Treatment of Impaired Wound Healing in Diabetes: Looking among Old Drugs

“…These effects were correlated with increased function of endothelial precursor cells and nitric oxide (NO) levels as well as antioxidant activity. Metformin was also able to restore basal levels of thrombospondin 1, an endogenous antiangiogenic mediator known to be involved in vascular complications in diabetes [81]. Notably, metformin was effective in accelerating wound healing by improving epidermis, hair follicles, and collagen deposition also when applied topically in young rats undergoing an excision wound [82,83] and confirmed its efficacy also in patients carrying non-healing lower limb traumatic wounds or ulcers [82].…”

“…Accordingly, topically applied metformin in a pluronic gel formulation accelerated healing of excisional wounds in rat skin with a parallel increased polarization of M2 macrophages through activation of AMPK and ensuing downregulation of the mTOR/NLRP3 inflammasome signaling pathway [80]. Faster wound healing and increased angiogenesis were observed in db/db diabetic rats following systemic administration of metformin for 14 days [81]. These effects were correlated with increased function of endothelial precursor cells and nitric oxide (NO) levels as well as antioxidant activity.…”

Diabetes pharmacotherapy and effects on the musculoskeletal system

“…At the same time, bone marrow adipose expansion, characteristic of mice fed a high‐fat diet, was also correctible with metformin . Finally, metformin treatment appears to accelerate wound healing and angiogenesis in hyperglycemic rodents . These findings, however, may be indirectly mediated by the insulin‐sensitizing and/or glucose‐lowering efficacy of metformin in these studies.…”