Diabetes is one of the most prevalent chronic diseases in the world. Based on the reports, about 425 million diabetic patients, between 20 -79 years of old, were identified in 2017. It has been predicted that millions of new patients will be added to this number by 2045. There are reports that about 46.1% of diabetes patients under 60 years died because of diabetes complications (1). Considering the rise in the number of patients, the increment in diabetics' mortality rate is predictable, and represents a global challenge for human health (2).
 Hyperglycemia is one of the preponderant complications of diabetes that results in a number of other complications including heart attack, stroke, kidney disease, limb amputations, poor vision, and nerve damage(3). Diabetes may be treated through lifestyle adaptations (such as diet therapy and physical activity), oral medication (such as biguanides, sulfonylureas, and a-glucoside drugs inhibitors), injected drugs (such as insulin and glucagon-like peptide-1amide [GLP-1] agonists), surgical treatment, and complementary and alternative medicines (4). Currently, one of the most effective treatments for diabetes is injecting insulin and taking oral hypoglycemic medications which most probably would leave a lot of side effects(5). There is a huge dating back to herbal medicine. Also, the curiosity about their functional details raises more than before; mainly because they are most efficient, have the least side effects, and cost lower than chemical and synthetic drugs. It has been investigated that herbal medicine is the first option for the treatment of various diseases, for almost 80% of the developing countries population (6, 7).
Securigera securidaca (L.), colloquially termed, goat pea, hatchet vetch, scorpion vetch, ax, or weed seed, is a type of herb part of the Leguminosae family. It is native to Western Asia, Europe, Australia, and Iran, especially in Tehran and Khuzestan provinces (8). Securigera securidaca (L.) is an annual, glabrous, 10–40 cm long herb, with wide branches in an upright form or occasionally dispersed on the ground. It has four to six slightly thick, full, and fleshy leaflet pairs. Morphologically, Securigera securidaca (L.) is similar to the chickpea and has light brown fruits and each of them has several red-brownish square flat seeds. Having the ability to grow in any kind of climate is one of its advantageous properties. Although this plant is usually growing near rivers, gardens, and wheat farms (9).
Flavonoids, steroidal and pentacyclic triterpenoid-type saponins, cardenolides, and tannins have been found in S. securidaca extract through its phytochemical analysis (10). Securidaca seeds have been recommended as a traditional herbal medicine for treating multiple complications by specialists in traditional medicine such as hypertension, hypercholesterolemia, hyperglycemia, wound healing, gastric reflux, malaria, and inflammation (11, 12). Besides, some other advantages of it are under discussion including positive effects on seizure (13), hypoglycemia, ulcers (14), and also, its antioxidative, antiviral, antitumor, and anti-parasite effects are considerable (15, 16).
Various studies have worked on the hypoglycemic effects of S. securidaca seeds, but some of them have not demonstrated significant impacts on the blood glucose level. This study aims to make a comprehensive review of the articles that investigated Securigera securidaca usage in the treatment of hyperglycemia in animal models.
 

 
Figure 1. Flow diagram of selection of studies

 
Table 2. The methodological quality according to CAMARADES 10-item checklist

Studies fulfilling the criteria of A: Publication in a peer-reviewed journal; B: Statement of control of temperature; C: Randomization of treatment or control; D: Allocation concealment; E: Blinded assessment of outcome; F: Avoidance of anesthetics with marked intrinsic properties; G: Use of animals with diabetes; H: Sample size calculation; I: Statement of compliance with regulatory requirements; J: Statement regarding possible conflict of interest.
 

N/I- Non informed, SS- Securigera securidaca
 
Table 4. Diabetes induction procedure, protocol experimental, outcomes, and conclusion.

Discussion

Even in the era of highly advanced biomedicine, herbal medicines remain of contemporary interest for researchers around the world for their ability to complement modern drugs and as sources for the development of novel drugs. The mechanism of most of the named plants has not been approved yet; however, various herbs and their derived bioactive compounds are currently consumed for their advantage on diabetic patients. This may be attributed to the efficacy of new plant-based remedies and increased attention to natural products, concomitant to the presence of deleterious side effects, high-cost, and lack of access to modern antidiabetic drugs for people who live in the countryside, specifically in developing countries (30).
The findings of this review are consistent with the results of studies conducted on Securigera securidaca across many regions with different experimental animals. The information about serum glucose levels collected from these critically reviewed articles obviously indicates that the various Securigera securidaca significantly reduced hyperglycemia in alloxan and STZ-induced diabetic animals through various possible mechanisms.  Indeed, their hypoglycemic effect was comparable with that of the usual hypoglycemic drugs: gliclazide, tolbutamide, insulin, and glibenclamide.
Most included studies demonstrated that SS seed hydroalcoholic extract can significantly reduce serum glucose levels in diabetic animals (10, 18-22, 27-30). GC-MS analysis showed that, in SS seeds hydroethanolic extract, most bioactive components are fatty acids with antidiabetic and antioxidative effects with a total of 43.1 % content. Also, phenol, polyol, and sterol compounds (total content: 34.86 %) in this extract may represent another reason for the greater hypoglycemic activities of the extract (19). Ahmadi et al. (18, 19) reported a significant blood glucose lowering effect of the intervention compared to the control group, at all time-points.  Another article by Tofighi et al. (26) further confirmed the antidiabetic activity of SS seed extract's chloroformic and methanolic fractions. Following isolation of three cardenolide glycosides as active compounds, the authors were able to indicate that blood glucose lowering effects of these cardiac glycosides are related to increasing insulin level in blood.
Two of the included studies in this review assessed the anti-hyperglycemic activity of S.securidaca flowers, and reported a marked decrease in blood glucose level, advocating considering SS flowers as an anti-diabetic treatment, which could be based on the noticeable phenolic content (18, 22).
In contrast, in Minaiyan et al. study (24), S. securidaca has been shown as a non-effective agent in decreasing blood glucose of STZ-induced diabetic samples. It seems that the presence of phenolic components, fatty acids, flavonoids, and sterols in S. securidaca is the reason for the antihyperglycemic and antioxidative effects of this plant. Investigations suggested that the blood glucose lowering effect of SS seeds is probably distinct from sulfonylurea and insulin-like factors, and has no effect on gastrointestinal absorption of glucose. Nevertheless, some properties related to biguanides such as gluconeogenesis suppression, glycolysis stimulation, serum glucose depletion, or enhancing insulin functions may be involved in SS seeds mechanisms of actions (19). Phenolic and flavonoid compounds take part in blood glucose regulation similar to α- 12 amylase and α-glucosidase suppressors in diabetes, along with synthetic analogs. Moreover, there are multiple other possibilities for phenolic and flavonoid compounds anti-diabetic mechanisms including suppressing gastrointestinal glucose absorption because of suppression of Na+-dependent resorption, stimulating β-cell to increase insulin secretion, increasing the number of insulin receptors which leads to more glucose uptake, inhibition in fatty acid synthesis, and anti-gluconeogenesis activity. Aside from antidiabetic effects of the phenolic and flavonoid compounds, they have shown significant antioxidative effects. The protective effect of these metabolites against oxidative damage depends on the redox potential of phenolic hydroxyl groups that allow them to act as hydrogen donators and reducing agents, singlet oxygen scavengers, and metal chelators (20). Previous investigations suggested fatty acids as a basis for glucose-stimulated insulin release from pancreatic β-cells. In addition, β-cells glucose-induced apoptosis regulated by fatty acids, plus, they adjust β-cell proliferation and reduce insulin resistance, which could be connected to mitochondrial, endoplasmic reticulum (ER) stress, and Fas signal pathways, respectively. The sterols have a variety of pharmacological functions that regulate plasma cholesterol and increase antioxidant capacity by activating an estrogen receptor/PI3-kinase-dependent pathway with an ROS scavenger role.
Furthermore, reductions in glucose, nitric oxide (NO), and HbA1c generally occur after an increase in insulin level and improvement in insulin sensitivity, and show protective effects on the pancreas due to its antioxidant activity, which means protecting beta-cells from free radical-induced damage, resulting in the prevention and improvement of diabetes (19).
 

Limitations and strengths

There are multiple limitations in this study that must be considered in the conclusion. It is suggested that caution be taken in generalizing these consequences, based on the evidence that the analyzed publications have methodological variations about the species of the animals, the kind of extract of Securigera securidaca, and the type of the protocols. Moreover, although we tried to retrieve the articles following the selected keywords, it is plausible that articles may have been missed if they were not published in English or Persian and published in journals that were not indexed in the PubMed, Google scholar or Scopus database. Despite the aforementioned limitations, the study has multiple strengths points: Firstly, to the authors' knowledge, the present study represents the first study to comprehensively review the use of Securigera securidaca in the treatment of hyperglycemia in animal models. Furthermore, we followed stringent guidelines, and we conducted a detailed methodological quality assessment.
 
 

Conclusion

In this systematic review, we found that various extracts of Securigera securidaca elicit antidiabetic effects in animal models. Although current chemical drugs are significantly successful in diabetes treatment, recently, herbal medicines have gotten noticeable attention as diabetes treatments because of their desired efficiency and fewer side effects. Given the prevalence, importance, and efficacy of Securigera securidaca for treating and managing diabetes in animal models, a detailed assessment of the general toxic profile and formulation for eventual use in humans is advisable.
 
 

Acknowledgements

None.

 

Conflicts of Interest

The authors declare that they have no conflict of interests.