It has been centuries since diabetes mellitus was first described [1
], however, this metabolic condition continues to greatly impact the quality of life of patients living with diabetes [2
]. Besides being one of the top ten causes of death worldwide [4
], patients with diabetes are at an increased risk of comorbidity of complications associated with metabolic disorders such as neuropathy, retinopathy, and cardiovascular diseases (CVDs). These comorbidities significantly reduce the quality of life, and may even accelerate the rate of permanent disability [5
]. Diabetes is often described in terms of its impact on working-age adults, however, it is of concern that even in older adults (≥60 years old), this condition accelerates the rate of mortality, while also enhancing the risk of institutionalization [7
]. Rapid urbanization that is frequently accompanied by a sedentary lifestyle, mostly identified in developed and developing countries, has notably been responsible for the global rise in cases of type 2 diabetes (T2D) [8
]. T2D is associated with obesity and is a predominant form of diabetes that is characterized by hyperglycemia, insulin resistance and dyslipidemia. Although the pathological mechanisms implicated in the development of diabetes have been partially described [10
], long-term effective therapeutic strategies to contain this metabolic disorder remain scarce.
Several studies have demonstrated that improving blood glucose control can revert diabetes-associated complications, especially by complementing antidiabetic drugs with lifestyle modification intervention, such as regular physical activity [13
]. However, the major challenge has been the limitation of evidence showing the long-term effectiveness of antidiabetic drugs, this coupled with so few individuals that can maintain consistent physical activity could explain the continued rise in new cases of diabetes over the past decades [2
]. Alternatively, there has been great interest in exploring nutritional food products, including plant derived-bioactive compounds, for their ameliorative effects against diabetes-associated complications. For example, regular intake of tea or fruits, due to their rich source of several nutrients and phytochemicals, has been associated with reduced risk of several chronic diseases, including obesity and diabetes [16
]. Consistently, evidence from a meta-analysis of randomized controlled trials (RCTs) has shown that supplementation with resveratrol could effectively improve fasting plasma glucose and insulin levels [19
]. Moreover, the abundant antioxidant properties of resveratrol [20
] further promote its therapeutic value, especially its use as a dietary supplement to manage diabetes-associated complications.
Resveratrol (PubChem CID: 445154) can be found in several food sources including grapes and red wine [21
]. Interestingly, experimental evidence reporting on the comparative or combination use of metformin (PubChem CID: 4091) with well-known bioactive compounds like resveratrol has become of great interest [22
]. Although metformin is a commonly used antidiabetic drug, information on its comparative or combination use with resveratrol has not been assessed to understand the potential synergistic or combination advantages of such a therapy in managing metabolic complications. Thus, the current systematic review aimed to provide a comprehensive synthesis of preclinical studies assessing the comparative effects of metformin with resveratrol against diabetes-associated complications. Information related to the more bioactive compound of the two, as well as evidence linked to adverse or beneficial effects if both compounds are combined is discussed.
Noncommunicable diseases remain the leading cause of death worldwide [2
]. Moreover, metabolic-related complications are known to play a major role in accelerating the global mortality rate [2
]. Thus, highlighting the importance and the need to urgently establish novel and effective therapies to contain metabolic disorders. Metformin is widely considered as a drug of choice in the treatment of T2D [63
], however, the long-term use of this drug seems to be less effective to contain diabetes-associated complications, as evident by the rapidly rising prevalence of diabetes [2
]. As a result, alternative strategies have been progressively explored to contain diabetes and its linked complications.
For example, there is a need to understand the beneficial effects of metformin against diabetes-associated complications when used in combination with other antidiabetic drugs like vildagliptin or sulphonylurea [64
]. Similarly, due to the great interest in understanding the bioactive properties of various naturally-derived compounds such as resveratrol, its combination uses with established oral glucose-lowering drugs like metformin could be of therapeutic benefit to combat diabetes. In fact, in many experimental settings, metformin is widely used as an experimental control to compare the efficacy of other pharmacological compounds for their antidiabetic properties [33
]. To our knowledge, this is the first systematic review to assess and synthesize available evidence reporting on the comparative or combined effects of metformin with resveratrol for their ameliorative effects against diabetes and its associated complications. This is especially important to establish whether resveratrol possesses similar effects to metformin or find out whether this naturally-derived compound can improve the efficacy of metformin in protecting against diabetes.
A systematic search of literature retrieved approximately 34 studies informing on essential information related to the comparative or combination effect of metformin and resveratrol. Significant findings on the comparative use of metformin with resveratrol verified that both compounds possess comparable biological properties in attenuating diabetes-associated complications in vitro [33
]. As displayed in Table 1
, the use of human peripheral blood CD34+ cells or human adrenal H295R cells, consistent with 3T3-L1 adipocytes, HepG2 hepatocytes, and HUVECs as well as INS-1E beta-cells were some of the in vitro models employed to assess the comparative effects of metformin in ameliorating diabetes-related abnormalities. Here, the overall findings support the comparative effects of metformin and resveratrol in reverting β-cell, cardiac, and hepatic damage [34
], preventing hypoxia-induced cellular injury [39
]. It was also evident that high-glucose exposure was the predominant means to explore hyperglycemia-induced stress. Consistently, activation of SIRT1 and AMPK, together with a reduction of intracellular lipid overload, improvement of glucose transport, amelioration of ROS, and attenuation of pro-inflammatory/apoptotic markers such as NF-κB and BAX expression were the predominant mechanism by which metformin and resveratrol could control diabetes-associated complications in vitro [33
While strong antioxidant properties and hypoglycemic effects could be attributed to the beneficial effects of metformin and resveratrol [20
], an interesting finding from an in silico study [43
] demonstrated that both compounds could share a similar activity by interacting with SIRT1. Fascinatingly, SIRT1 together with AMPK are largely involved in the regulation of many cellular processes, including energy metabolism, cell cycle, insulin secretion, and apoptosis during the pathogenesis of diabetes [67
]. Thus, the capability of both metformin and resveratrol to comparable modulate these molecules suggests their strong aptitude to control diabetes-complications. Nevertheless, such evidence was confirmed in vivo [26
], with data supporting the strong potential for both compounds to attenuate diabetes-linked abnormalities equally in STZ or HFD-fed induced models, representing T1D and T2D, respectively. Moreover, some of the data demonstrated that resveratrol might be more protective than metformin in vivo [54
], however, these are only preliminary findings this aspect needs further exploration using well-designed experiments.
In relation to the combination use of metformin with resveratrol, cumulative evidence shows that the combined use of these compounds consistently ameliorates diabetes-associated complications in vitro and in vivo, as displayed in Table 3
. In particular, the combined treatment showed better efficacy in ameliorating oxidative stress, than the use of metformin or resveratrol as a monotherapy. Additionally, the combined treatment attenuated inflammation, while also showing enhanced effect in improving glucose tolerance via activation of the insulin-dependent mechanisms such as the PI3K/protein kinase B (AKT) pathway [23
]. Interestingly, in adult patients on metformin therapy, the use of resveratrol is equally effective in reducing body weight, improving glucose tolerance, and also improving CVD-related outcomes by lowering systolic blood pressure, total cholesterol, triglyceride, urea nitrogen, and total protein [71
]. Although some results showed it could not affect body weight, arterial blood pressure or fasting plasma glucose [73
], supplementation of resveratrol in patients on metformin was still beneficial in improving antioxidant enzymes such as SOD, catalase, reduced GSH levels, while also reducing lipid peroxidation [73
]. Therefore, implying that the combined use of metformin with dietary supplements with glucose-lowering and strong antioxidant properties could be of benefit in containing diabetes-related complications, and is worth further exploration.
In addition to a broadly dissimilar dose selection between reported findings, the evidence presented in this review demonstrates that the duration of treatment with either metformin or resveratrol also varied across in vivo experimental models of diabetes or metabolic syndrome (Table 2
). For instance, although attenuation of diabetes-associated complications was evident as early as seven days of treatment in rodents [39
], constant results were observed with prolonged intervention period lasting up to eight weeks [49
]. Similarly, when the compounds were used in combination, the beneficial effects were observed with the intervention period between four to six weeks (Table 3
), with some studies [22
] showing that the combination treatment was more effective than the use of each compound alone in controlling diabetes-linked pathologies during this period. Such findings are essential to highlight the beneficial effects of the prolonged treatment period with both metformin and resveratrol, especially since it is already known that diabetes and its related complications can induce long-term damage and failure of various organ systems [75
]. Moreover, summarized findings report on the beneficial effects of both metformin and resveratrol in already diabetic animals, further inferring that additional studies are necessary to understand the impact of treating diabetic patients who are at increased risk of developing microvascular and macrovascular complications such as retinopathy and CVDs.