Harnessing the Power of Non-diabetic Benefits of Metformin Derived from Galega officinalis: Focus on Wound Healing
Article information
Abstract
This review explores the potential of metformin, a widely used type 2 diabetes medication, in accelerating wound healing. Derived from guanidine compounds found in Galega officinalis, a plant with a long history in traditional medicine, metformin has been recognized for its minimal side effects. Beyond its primary role in diabetes treatment, metformin shows promising non-diabetic benefits, particularly in wound healing. Research indicates that metformin enhances wound healing through multiple mechanisms. It increases circulating endothelial progenitor cells, improves vascular function, and regulates thrombospondin-1 levels. Metformin also modulates the AMPK/mTOR/NLRP3 inflammasome signaling pathway, promoting M2 macrophage polarization, which is crucial for tissue repair. Additionally, it reduces pro-inflammatory cytokines, increases growth factors, and decreases matrix metalloproteinases. Studies have shown that topical application of metformin accelerates wound contraction, closure, and overall healing. Furthermore, it has been found to reduce fibrosis-related gene expression and improve collagen synthesis. With chronic wounds affecting millions globally and causing significant healthcare costs, there is a pressing need for improved wound healing agents. This review advocates for further research to establish clinical guidelines on using metformin to enhance wound healing. By harnessing metformin’s pleiotropic effects, healthcare providers may offer personalized treatments that not only manage diabetes but also promote wound healing.
Introduction
Chronic, non-healing wounds affect millions of people worldwide and present a major medical challenge. According to the Global Wound Care Market report, chronic wounds account for an estimated $28 billion in treatment costs each year in the United States alone. Furthermore, chronic skin ulcers such as venous ulcers lead to decreased mobility, loss of productivity, and a reduced quality of life [1]. With an aging population and increasing rates of diabetes, venous insufficiency, and peripheral vascular disease, experts expect the incidence of chronic wounds to rise significantly over the next decade [2].
This highlights the need for improved wound healing agents to properly treat injuries, stimulate regenerative processes, prevent infections, and reduce healing times. One promising natural compound that research indicates may aid wound healing is Galega officinalis, also known as goat’s rue, Italian fitch, Spanish sainfoin, French lilac, and professor’s weed [3].
G. officinalis is an herbaceous plant of the Leguminosae family that has long been used in herbal medicine. Native to Europe and Western Asia, G. officinalis has been part of traditional medical systems for centuries [4]. In medieval Europe, G. officinalis was used as a remedy for plague, fever, and wound healing. It has also been utilized in Ayurvedic medicine and traditional Chinese medicine as a treatment for diabetes and malnutrition [5].
The alkaloid galegine isolated from G. officinalis has shown anti-inflammatory, antioxidant, and wound healing properties in preliminary research [6]. Galegine displays potent anti-inflammatory effects by inhibiting tumor necrosis factor α (TNF-α) and interleukin (IL)-1β, which reduces inflammation during the proliferative phase of wound healing. Galegine also stimulates collagen synthesis by activating fibroblasts, encouraging the formation of connective tissue. Furthermore, galegine has been shown to activate vascular endothelial growth factor (VEGF), promoting angiogenesis to improve blood flow to wound sites. However, galegine is not the only substance obtainable from G. officinalis that can be beneficial in wound healing: tannins isolated from G. officinalis exhibit antimicrobial properties against common wound pathogens like Staphylococcus aureus, preventing infection [7]. Through these combined mechanisms, the phytochemical constituents of G. officinalis offer promising wound healing benefits [8].
Various drugs commonly used in managing diabetes, including insulin, certain sulfonylureas, thiazolidinediones, and dipeptidyl peptidase 4 inhibitors, have demonstrated a wide array of effects that could be beneficial in treating chronic wounds. Metformin, derived from G. officinalis, is also included in this list [9]. Metformin is widely used in clinical practice, with a well-established safety profile. It also appears to enhance collagen synthesis, potentially accelerating wound closure [10]. Its ease of oral administration and minimal adverse effects make it an attractive option for wound healing interventions [11].
The anti-inflammatory properties and impact on wound healing of metformin are some of the most extensively researched non-diabetic benefits of metformin. This review seeks to offer a comprehensive understanding of metformin’s role in wound healing.
Search strategy
To assess the supporting and opposing evidence for the supposed actions and mechanisms of metformin and its potential clinical advantages, we conducted a narrative review. This review included publications found via searches on Web of Science, PubMed, and Scopus.
Metformin
Metformin (1,1-dimethylbiguanide hydrochloride), as a biguanide, is widely used as a first-line drug for the treatment of type 2 diabetes (T2D) due to minimal side effects [7]. The history of metformin is connected to G. officinalis which is naturally rich in guanidine. In 1918, it was demonstrated that guanidine could reduce blood glucose levels. Guanidine derivatives, including metformin, were created. Some of these (excluding metformin) were used in the treatment of diabetes during the 1920s and 1930s. However, they were discontinued due to their toxicity and the growing accessibility of insulin [12].
The long-term findings from the UK Prospective Diabetes Study in 1998 paved the way for metformin to become the favored initial treatment for managing hyperglycemia in T2D. Interestingly, the extensive application of this medication in treating diabetes has been associated with a decreased occurrence of various cancer types, due to its reported influence on inhibiting cancer cell proliferation [13].
Recently, metformin has garnered increased interest due to its anti-inflammatory properties [14,15]. Newly surfacing evidence in scientific literature supports the innovative theory that metformin possesses immune-regulating properties [16]. Table 1 enumerates the various clinical trials where metformin has been employed as a treatment for diverse diseases.
Clinical trials show metformin’s reparative effects in various diseases
Metformin and its relation to improved wound healing
Conventional wound management includes methods such as wound dressings, negative pressure wound therapy, and cell therapy. These methods promote tissue repair and prevent infection [17]. However, there is growing interest in natural compounds like honey, aloe vera, curcumin, and green tea extracts for their wound healing properties. These compounds have anti-inflammatory, antimicrobial, and antioxidant effects. Researchers are exploring the synergy between conventional treatments and natural compounds to improve wound healing outcomes. By combining the strengths of both, we can potentially improve wound healing outcomes [18].
Chen et al. [19] showed that metformin can increase the number of circulating endothelial progenitor cells (EPCs) and enhance their cellular function in patients with T2D. In a 2008 study, Dabir et al. [20] demonstrated that thrombospondin-1 (TSP-1), a newly discovered antiangiogenic adipokine, is expressed in animal models prone to diabetes, including those exhibiting obesity and insulin resistance. There has been a noted increase in the mRNA expression of TSP-1 in cases of T2D.
In 2014, Tie et al. [21] showed that TSP-1 has a detrimental impact on the function of EPCs, with a negative correlation observed with nitric oxide regeneration in endothelial cells studied in vitro. While metformin has been identified as a regulatory factor for TSP-1 in patients with polycystic ovarian syndrome, there is currently limited data available regarding its role in diabetes [22].
In a 2013 study, Desouza et al. [23] demonstrated that metformin can speed up the healing of wounds and increase the number of circulating EPCs and the function of bone marrow-derived EPCs in diabetes. However, Ochoa-Gonzalez et al. [24] published results to the contrary in 2016, stating that metformin treatment did not change the number of circulating EPCs and even slowed down wound healing in diabetes. Later in 2017, Han et al. [15] revealed that metformin treatment sped up wound healing and enhanced angiogenesis in diabetic mice.
Venna et al. [25] discovered that metformin directly enhances VEGF A expression and promotes microvessel density. Goggi et al. [26] demonstrated that a combination of simvastatin and metformin significantly enhanced blood vessel growth in the limbs, increased VEGF expression, improved capillary density (CD31+), enhanced foot function, and slowed disease progression in diabetic mice.
Yu et al. [27] conducted experiments to determine whether metformin could enhance wound healing by improving the impaired function of EPCs in streptozotocin-induced diabetic mice. According to their results, metformin accelerated wound closure, promoted angiogenesis, and increased the number of circulating EPCs.
Xu et al. [28] found that metformin enhances VEGF signaling through the RasGRP1 (RAS guanyl releasing protein 1) pathway, improving impaired angiogenesis induced by high glucose in human umbilical vein endothelial cells.
In a 2018 study, Jing et al. [29] demonstrated that the pleiotropic effects of metformin are linked to the activation of a protein called AMP-activated protein kinase (AMPK). Furthermore, AMPK is recognized as being upstream of mammalian target of rapamycin (mTOR), which has a significant role in controlling inflammation. Recent research has shown that metformin primarily suppresses immune responses by directly affecting the cellular functions of various types of immune cells. This is achieved through the induction of AMPK and the subsequent inhibition of mTOR. Hence, metformin can enhance wound healing by promoting the polarization of M2 macrophages, a process that is involved in the AMPK/mTOR/NLRP3 inflammasome signaling pathway.
The NLR family pyrin domain containing 3 (NLRP3) inflammasome is a complex made up of multiple proteins, including NLRP3, caspase-1, and apoptosis-associated speck-like protein containing an apoptosis repressor with caspase recruitment domain. This complex regulates the activity of caspase-1 and the release of inflammatory cytokines IL-1β and IL-18 within the innate immune system. It has been discovered that inflammasome signaling, along with the cytokine responses it triggers, plays a role in the wound healing process [30]. In a 2014 study, Bitto et al. [31] found strong evidence that blocking the NLRP3 inflammasome significantly speeds up wound healing in diabetic mice.
Zhao et al. [32] demonstrated that topical application of metformin sped up wound healing, leading to improvements in the epidermis, hair follicles, and collagen accumulation in young rodents. These discoveries shed light on the varying effects of anti-aging treatments on wound healing. They pinpointed key mechanisms for angiogenesis and rejuvenation through the AMPK pathway in both young and old skin. Furthermore, they revealed that the chronic local use of metformin is an optimal and promising treatment for healing skin wounds.
The effects of metformin on M2 macrophages and their role in the wound healing process have been established in various studies. Wynn and Vannella [33] suggested that the polarization of M2 macrophages, which control revascularization, myofibroblasts differentiation, fibroblast regeneration, and collagen production during the wound healing process, is linked to the resolution of tissue repair processes. Okizaki et al. [34] indicated that a decrease in M2 macrophage levels results in lower levels of growth factors, such as transforming growth factor β (TGF-β), insulin-like growth factor 1, and VEGF. These factors regulate the proliferative stage of repair during the healing process of diabetic wounds. Furthermore, it has been found that elevated levels of pro-inflammatory cytokines and mediators, such as IL-1β, IL-17, TNF-α, and inducible nitric oxide synthase, contribute to delayed or impaired wound healing [35]. The study by Qing et al. [36] published in 2019 states that metformin aids in the polarization of pro-inflammatory macrophages (M1 subtype) into the healing-associated macrophage (M2 subtype). This process involves the AMPK/mTOR/NLRP3 inflammasome signaling pathway. Subsequently, these M2 macrophages enhance wound healing by releasing VEGF (Fig. 1).
Model of metformin activation of M2 macrophages. When the NLR family pyrin domain containing 3 (NLRP3) inflammasome was activated, it kept the macrophages in a pro-inflammatory state (M1) and prevented them from switching to a pro-healing state (M2). However, metformin has been shown to control the AMPK/mTOR/NLRP3 inflammasome pathway to make the macrophages more pro-healing (M2), which would accelerate wound healing. AMPK, AMP-activated protein kinase; mTOR, mammalian target of rapamycin; IL, interleukin; TNF-α, tumor necrosis factor-α; STAT3, signal transducer and activator of transcription 3; ATF-3, activating transcription factor 3.
Tombulturk et al. [10] demonstrated that metformin enhances cell growth and inhibits cell death by boosting the expression of collagen type 1/3 (Col-I/III) and reducing the levels of p53/c-jun. This effect is particularly noticeable in both diabetic and normal wounds. The results of their study imply that applying metformin topically to diabetic wounds counteracts the negative impacts of diabetes, accelerates the healing process, and enhances wound healing.
In a 2019 study by El-Ridy et al. [37], biological testing on diabetic rats indicated that a niosomal gel of metformin HCl, administered every 2 days, maintained a more consistent antidiabetic effect than daily oral doses. Additionally, diabetic rats treated with metformin formulations exhibited enhanced wound healing compared to those that were not treated. Bagheri et al. [38] also demonstrated in 2020 that treatments with photobiomodulation and metformin significantly sped up the healing process during the inflammation and proliferation stages of skin injury repair in a non-genetic model of T2D.
Chogan et al. [39] showed that the local use of metformin-HCl significantly reduced the expression of fibrosis-related genes such as α-SMA (α-smooth muscle actin), TGF-β1, fibronectin, and Col-I/III. This helped reduce scar formation but also slowed wound healing. To counteract this delay, an engineered dual function scaffold was used. This study was the first to introduce a metformin slow-releasing scaffold that both reduces fibrosis and accelerates wound healing.
In a 2020 study Shi et al. [40] demonstrated that in cell coculture, metformin can lower the production of collagen I in mice embryonic fibroblast (NIH 3T3) cells. It does this by reducing the amount of TGF-β1 that the mouse mononuclear macrophage (RAW 264.7) cells secrete into the spaces between cells. As a result, metformin could be clinically useful in managing the healing process of deep burn wounds.
Vazquez-Ayala et al. [41] demonstrated that sponges made of chitosan and loaded with metformin were able to regenerate skin tissue after 21 days of treatment. This underscores the accelerated in vivo wound healing process when exopolysaccharide, which aids in tissue regeneration, was included.
Conclusions and future directions
This review highlighted the potential of metformin, a widely used T2D medication, in accelerating wound healing. The mechanisms by which metformin enhances wound healing include increasing circulating EPCs, improving vascular function, regulating TSP-1 levels, modulating the AMPK/mTOR/NLRP3 inflammasome signaling pathway, and promoting M2 macrophage polarization. Studies have shown that topical application of metformin accelerates wound contraction, closure, and overall healing. Furthermore, it has been found to reduce fibrosis-related gene expression and improve collagen synthesis. Future studies should focus on establishing the efficacy of metformin in clinical settings, particularly in the treatment of chronic wounds. The optimal dosage and duration of metformin treatment for wound healing should be determined. Additionally, the combination of metformin with other natural compounds or conventional treatments should be explored to enhance wound healing outcomes. The role of metformin in modulating the NLRP3 inflammasome and its impact on macrophage polarization should be further investigated. Furthermore, the potential of metformin in treating other conditions, such as cancer and cardiovascular disease, should also be explored. By harnessing the pleiotropic effects of metformin, healthcare providers may offer personalized treatments that not only manage diabetes but also promote wound healing, ultimately improving patient outcomes and quality of life.
Notes
No potential conflict of interest relevant to this article was reported.