Bioactive Constituents and Toxicological Evaluation of Selected Antidiabetic Medicinal Plants of Saudi Arabia

The purpose of this review is to summarize the available antidiabetic medicinal plants in the Kingdom of Saudi Arabia with its phytoconstituents and toxicological findings supporting by the latest literature. Required data about medicinal plants having antidiabetic activities and growing in the Kingdom of Saudi Arabia were searched/collected from the online databases including Wiley, Google, PubMed, Google Scholar, ScienceDirect, and Scopus. Keywords used in search are in vivo antidiabetic activities, flora of Saudi Arabia, active ingredients, toxicological evaluations, and medicinal plants. A total of 50 plant species belonging to 27 families were found in the flora of Saudi Arabia. Dominant family was found Lamiaceae with 5 species (highest) followed by Moraceae with 4 species. β-Amyrin, β-sitosterol, stigmasterol, oleanolic acid, ursolic acid, rutin, chlorogenic acid, quercetin, and kaempferol are the very common bioactive constituents of these selected plant species. This paper has presented a list of antidiabetic plants used in the treatment of diabetes mellitus. Bioactive antidiabetic phytoconstituents which showed that these plants have hypoglycemic effects and highly recommended for further pharmacological purposes and to isolate/identify antidiabetes mellitus (anti-DM) active agents also need to investigate the side effects of active ingredients.


Introduction
Medicinal plants are used for the treatment of different infections [1,2]. ese plants contributed as a source of inspiration for novel therapeutic compounds [3]. e medicinal value of plants is due to the presence of a wide variety of secondary metabolites including alkaloids, glycosides, tannins, volatile oil, and terpenoids [4,5]. Medicinal plants and their extracts represent a rich source of crude medications that possess therapeutic properties. Indeed, the World Health Organization reports that various plant fractions and their dynamic constituents are utilized as traditional medicines by 80% of the world population [6]. Plants are the primary source for different pharmaceutical, perfumery, flavor, and cosmetics industries; the use of modern drugs dramatically resulted into resistant microorganisms toward different modern drugs; the researchers are now in search for alternate source of treatment of various disorders [7,8]. For this purpose, the medicinal herbs are the best alternate to various drugs. Most of natural products possess interesting biological activities and medicinal potential. Various herbs, fruits, and grains have been found to have different important biological activities such as antioxidant, [9] antitumor, antimutagenic, antidiabetes, antianalgesic, [10] antidementia, inflammation inhibitory effect, [9] antitumor, [11] anticancer, [12] antimicrobial, antileishmanial, and antimalarial properties [13,14]. e consumption of natural antioxidants will reduce risk of many diseases including cancer, cardiovascular disease, diabetes, and other diseases allied with aging [15]. For natural antioxidants, a larger number of medicinal herbs have been evaluated by applying laboratories' developed procedures. Plants derived substances, collectively called phytonutrients or phytochemicals, been recognized as good source of natural antioxidants [16,17].
e Kingdom of Saudi Arabia is a huge arid land with an area of about 2,250,000 km 2 covering the major part of the Arabian Peninsula, characterized by different ecosystems and diversity of plant species. e climate in Saudi Arabia differs greatly between the coast and the interior. High humidity coupled with more moderate temperatures is prevalent along the coast, whereas aridity and extreme temperatures characterize the interior. e flora of Saudi Arabia is one of the richest biodiversities in the Arabian Peninsula and comprises very important genetic resources of crops and medicinal plants. Saudi Arabia contains 97 trees, 564 shrubs, and about 1620 herbs, which cover, respectively, 4.25%, 24.73%, and 71.02% of higher plant diversity of the country [18].
Diabetes mellitus is one of the most prevalent diseases in endocrine gland system with an increasing incidence in human community [19]. Type I diabetes is caused by insulin secretion deficit, while type II diabetes is accompanied with progressive rate of insulin resistance in liver and peripheral tissues, reducing β-cell mass, and deficient insulin secretion [20,21]. is disease brings about acute metabolic side effects including ketoacidosis, hyperosmolar coma accompanied with chronic disorders, and long term, adverse side effects such as retinopathy, renal failure, neuropathy, skin complications, as well as increasing cardiovascular complication risks [22,23]. Also, common symptoms of diabetes are frequent urine, thirsty, and overeating [24]. Diabetes inflicts 100 million people yearly and is recognized as the seventh cause of death in the world [25]. It has been estimated that the number of diabetic people will increase from 150 million individuals in 2003 to 300 million by 2025 [26]. e essential and effective drugs for diabetes mellitus are insulin injection and hypoglycemic agents, but these compounds possess several adverse effects and have no effects on diabetes complications in long term. erefore, it is important to find effective compounds with lower side effects in treating diabetes [27]. Medicinal plants are good sources as alternative or complementary treatments for this and other diseases [28][29][30]. Although various plants have been traditionally used throughout history to reduce blood glucose and improve diabetes complications, there is not enough scientific information about some of them. Herbal medicines are commonly prescribed throughout the world because of low side effects, availability, roughly low cost, and also its effectiveness [31,32].
In Saudi Arabia, the number of people who suffer from DM increased from 890,000 in 2000 to a staggering projection of 2,523,000 in 2030. In 2011, Saudi Arabia reported a prevalence of DM at 30% of the total population, with a rate of 27.6% in women and 34.1% in men [33]. According to 2010 data from several sources (WHO, World Bank, UNESCO, CIA, and individual country databases), DM is the number three disease-related cause of death in Saudi Arabia [34].
In the present situation, herbal medicines' usage has significantly increased and published studies from developed countries emphasize that a paramount proportion of medicines supplied by them have herbal origins, so growing and producing the herbal medicines could be helpful to both economic development and community's health [35]. Keeping in mind the importance of medicinal plants, in the current review various medicinal plants used for antidiabetic treatment around the world, native to or cultivated in Saudi Arabia, are documented for the purpose to provide up-todate insight on medicinal plant used for DM, so that researcher easily selects plant for bioscreening and active constituents' identification purposes. erefore, we invite researchers' attention to carry out detailed ethnopharmacological and toxicological studies on unexplored antidiabetic plants in order to provide reliable knowledge to the patients and develop novel antidiabetic drugs.

Methods
Required data about medicinal plants having antidiabetic activities and growing in the Kingdom of Saudi Arabia were searched/collected from the online databases including Wiley, Google, PubMed, Google Scholar, ScienceDirect, and Scopus. Keywords used in search are in vivo antidiabetic activities, flora of Saudi Arabia, active ingredients, toxicological evaluations, and medicinal plants. Latest published data approximately in the last ten years with the key outcome of change in blood glucose level in animal model were included. One or two articles are selected as references for each plant's species on priority basis from the journals found in web of science and latest years.

Results
e names, families, used parts, location, and antidiabetic properties in animal model of the native/cultivated Saudi medicinal plants are summarized in Table 1. e active ingredients and toxicological effect of these plants in animal model are given in Table 2. A total of 50 plant species belong from 27 families were found in the flora of Saudi Arabia. Dominant family was found Lamiaceae with 5 species (highest) followed by Moraceae with 4 species.

Discussion
e majority of the experiments confirmed the benefits of medicinal plants with hypoglycemic effects in the management of diabetes mellitus. From Table 1, it can be concluded that among the plants used for the treatment of diabetes, H. salicornicum, T. oliverianum, A. cepa, A. herbaalba, Teucrium polium, Sesamum indicum, Z. spina-christi, and U. dioica seem to be most common plants used to treat diabetes and are available everywhere in the world. e leaves were most commonly used plant part, and other parts (root, stem, bark, flower, seed, and whole plant) were also useful for curing. e most common diabetic model that was used was the streptozotocin and alloxan-induced diabetic mouse or rat as diabetic models. e most commonly involved active constituents are flavonoid, alkaloid, saponin, carbohydrate, vitamins, amino acid and its derivatives, phenol and its derivatives, and benzoic acid derivatives. e very common phytoconstituents, targeted metabolic pathways, and its structure are given in Table 3 [194,195]. e native to or cultivated plant species of the kingdom given in Table 1 are selected from the published literature about ethnobotanical value and antidiabetic potential of medicinal Ethanol extract of A. cepa in STZ-induced diabetic rats causes 66% decreased at 200 mg/kg after 24 h in blood glucose level [37]. 0.4 g/100gbw of A. cepa reduced 50% the fasting glucose levels of diabetic rats [38]. Similar results reported by other researchers [39].

Anthemis herbaalba
Compositae/ Asteraceae Aerial parts Farasan Island of Red Sea [40] 72% plasma glucose levels decreased in albino mice by ethyl alcohol extract of Artemisia herbaalba [41] 3. Cichorium intybus Asteraceae Seeds Qassim region [42] C. intybus leaf powder, ethanol, aqueous seed extracts, and hexane extracts led to a decrease in blood glucose levels to near normal value. Hypoglycemic effects of C. intybus were observed in diabetic rats, and a dose of 125 mg of plant extract/kg body weight exhibited the most potent hypoglycemic effect [43][44][45] 4. In streptozotocin-induced diabetic rats, bark aqueous extract, and an isolated compound, α-amyrin acetate exhibited antidiabetic activity by decreasing the blood glucose level and increasing the HDL level [53] 7.

Ficus religiosa Moraceae
Root bark, stem bark, aerial roots Riyadh [52] e aqueous extract of bark and ethanol extract of leaves and fruits had a promising antidiabetic effect in streptozotocin-induced diabetic rats by decreasing the blood glucose, serum triglyceride, and total cholesterol levels and increasing serum insulin, body weight, and glycogen content in the liver and skeletal muscle [53] 8.
Apiaceae or Umbelliferae Seeds Makka [56] Oral administration of cumin seeds crude ethanol extract and glibenclamide to diabetic rats significantly and progressively restored toward normal. Cumin seeds crude ethanol extract and glibenclamide reduced plasma glucose levels by 38.34 and 37.73%, respectively, compared with diabetic control [58]. Other studies also reported similar results [59].

Marrubium vulgare
Lamiaceae Whole plant Widely distributed in Saudi Arabia [60] M. vulgare extracts lower blood glucose level 30 to 60% in dose-dependent manner in streptozotocininduced diabetic rats [60]. Remarkable antidiabetic, anticholinesterase, and antityrosinase effects were recorded for the mint oil [61,62]. Still need to investigate in vivo antidiabetic potential.

Teucrium oliverianum
Lamiaceae Aerial parts roughout Saudi Arabia [65,66] Aqueous and ethanol extract of Teucrium oliverianum were tested for antidiabetic activity in alloxan-induced diabetic mice. Both extracts significantly reduced blood sugar levels [65] 16 Teucrium polium Lamiaceae Leaves Madinah [67] Infusion orally (64% decrease glucose level) and intraperitoneal of different extracts of T. polium caused significant reductions in blood glucose concentration in STZ hyperglycemic rats [68] 17 Achyranthes aspera Amaranthaceae Whole plant Al Hada Road Taif [69] e methanolic and ethanolic extract of A. aspera exhibited significant hypoglycemic activity in streptozotocin-induced diabetic rats [70] 18 Aerva lanata Amaranthaceae Leaves Southwest region of Saudi Arabia [71,72] Extracts of Aerva lanata and glibenclamide were found to significantly (P < 0.01 and P < 0.05) reduce the blood glucose level and lipid profile in streptozotocin-induced diabetic rats [73] 19 Alternanthera sessilis Amaranthaceae Whole plant Hail region, Saudi Arabia [74] In diabetic mice at doses of 50, 100, 200, and 400 mg per kg body weight, the extract reduced blood sugar levels by 22.9, 30.7, 45.4, and 46.1%, respectively, compared to control animals. By comparison, a standard antihyperglycemic drug, glibenclamide, when administered at a dose of 10 mg per kg body weight, reduced blood glucose level by 48.9% [75] 20

Carissa edulis
Apocynaceae Leaves Southern region of Saudi Arabia [76] Oral administration of C. edulis extracts of the leaves significantly reduced the blood glucose level in STZ diabetic rats [77].

Catharanthus roseus Apocynaceae
Flower, leaves, stem, and root Western Saudi Arabia [78] C. roseus (100 mg/kg BW) lowered the glucose level more than metformin-treated group (100 mg/ kg BW) in STZ-induced hyperglycemia rats. C. roseus 200 mg/kg dose was found to be more effective in reducing fasting blood glucose levels [79] 22 Rhazya stricta Apocynaceae Leaves, seeds Middle and western region of Saudi Arabia [80] Extracts Rhazya stricta lowered 37.9% blood glucose level in the streptozotocin-induced diabetic rats. Serum cholesterol and triglyceride levels were significantly (P < 0.05) reduced in the treated diabetic group compared to the untreated diabetic group [81] 23 Calotropis procera Asclepiadaceae Latex Al-Kharj [82] Different extracts of C. procera at dose of 250 mg/ kg were orally administered as single dose per day to diabetes-induced rats for the period of 15 days significantly decreases blood glucose level to the level of standard drug glibenclamide [83] 24 Opuntia dillenii Cactaceae Fruit Jazan Region [84] Researcher observed the significant hypoglycemic activity of Opuntia dillenii extract in streptozotocin-induced diabetic mice and rabbits [85] 4 Evidence-Based Complementary and Alternative Medicine Powder and water extract of O. ficus-indica significantly (in comparison with control group) returned blood glucose level to the initial level, 180 min after administration in STZ-induced diabetic rats [86]. Many studies confirmed the hypoglycemic activities of O. ficus-indica [87] 26 Capparis decidua Capparaceae Fruits, seeds Jazan Region [84] C. decidua extracts at dose level of 200 and 800 mg/ kg significantly reduce sugar level (in a dosedependent manner) compared to standard drug in STZ-induced diabetic and normal rats [88]. I. aquatica ethanol extract at dose level (10, 100, and 1000 µg/ml in streptozotocin-induced diabetic rats significantly (P < .05) exhibited the ability to enhance insulin-mediated glucose uptake into 3T3F442A adipocytes cells compared to insulin alone [97]. Another study confirmed that doses (200 mg/kg and 400 mg/kg) reduced blood glucose level, and it was statistically highly significant (P < 0.001) in comparison with control group [98].

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Jatropha curcas Euphorbiaceae Leaves Jazan Region [84] Ethanolic extract of J. curcas leaves at doses of (250 and 500 mg ml −1 bw by administered orally) reduced glucose level from 219.5 to 116.5 and 237 to 98.8, respectively, in alloxan-induced diabetic rats. e results were comparable to reduction in rats treated with the standard glibenclamide 232-94.5 at 600 μg kg −1 [104].
Evidence-Based Complementary and Alternative Medicine 5 A review article focusing on antidiabetic potential of F. carica confirmed that different extracts and fractions of F. carica and different doses significantly reducing hyperglycemia in streptozotocin-induced diabetic rats compared to standard drug [106]. 37

Ficus sycomorus
Moraceae Leaves Jazan Region [84] Alloxan-induced type 2 diabetic albino Wistar rats treated with 250, 500, and 1000 mg/kg (body weight) of the extract of F. sycomorus intraperitoneally reduced glucose level in diabetic rats almost to the normal as compared to diabetic control [107] 38 Sesamum indicum Pedaliaceae Seeds Jazan Region [84] Alloxan-induced diabetic rats treated with 5% and 10% of Sesamum indicum seed powder significantly decreased blood glucose and increased insulin levels as compared with the positive (diabetic) control group [108] 39

Plantago ovata Plantaginaceae Husk
Northern border region of Saudi Arabia [18] In intravenous administration of alloxan-induced diabetic rabbits glucose level lowering effect observed (time dependent manner) with P. ovata husk extract of dose level (300 mg/kg, orally administered) [109] 40 Polygala erioptera Polygalaceae Aerial part Jazan Region [84] 0.7 g/kg of P. erioptera extract showed significant antidiabetic effect compared to standard drug metformin and glibenclamide in normal and alloxan-induced diabetic rats [110] 41 Polygonum aviculare L Polygonaceae Aerial parts Taif Region [111,112] Many ethnopharmacological investigations reported its antidiabetic potential but still need to study its in vivo and in vitro antidiabetic potential [113,114] 42 Ziziphus spinachristi Rhamnaceae Leaves Eastern region of Saudi Arabia [84,112] e strongest (P < 0.001) antidiabetic activity (25.59 and 39.48% after 7 and 15 days, respectively) was found following treatment with dose level of 500 mg/kg of Z. spina-christi extract in streptozotocin-induced diabetes mice [115].  [112] e strongest (P < 0.001) antidiabetic activity of L. shawii extract of 250 and 500 mg/kg bw was found in a dose-dependent manner in streptozotocin-induced diabetes rats [117]. 45 Solanum nigrum Solanaceae Whole plant Jazan Region [84] S. nigrum extract was given orally in the dose level of 200 and 400 mg/kg/day (7 days) significantly lowering the blood glucose level in fasting compared to standard drug in alloxan-induced diabetic albino Wistar rats [118].
plants around the world. e ethnobotanical information reports about 800 plants that may possess antidiabetic potential [196,197]. Jeeva and Anlin also reported 177 plants belonging to 156 genera and 76 families used traditionally for antidiabetic treatment [198]. In the Middle East countries, there are 129 plant species still in use in traditional Arabic medicine. is indicates that the medicinal plant species require preservation as well as the ethnobotanical and ethnopharmacological knowledge. e preservation of the herbs is an essential requirement for maintaining traditional Arabic medicine as a medicinal and cultural resource [199]. e selected plant species H. salicornicum, T. oliverianum, A. cepa, A. herba-alba, Teucrium polium, Sesamum indicum, Z. spina-christi, and F. religiosa are the native Saudi medicinal plants traditionally used for the treatment of DM [200]. Similarly published data showed that 20 medicinal plants are traditionally used in Tabuk region of Saudi Arabia [201]. Anisotes trisulcus, Artemisia judaica, and Moringa peregrine are used in Al Khobah village, Saudi Arabia, for DM treatment [202]. O. europaea is used in Al Bahah region of KSA for DM treatment [203]. C. roseus, A. cepa, U. dioica, A. aspera, C. intybus, C. cyminum, F. bengalensis, C. colocynthis, and T. polium are the highly investigated medicinal plants for antidiabetic potential [204][205][206].
Desiring to contribute to the conservation priorities of traditional medicine knowledge of various medicinal plants native to or cultivated in Saudi Arabia and to make it easy and familiarized with disease treatment, the present compilation was conducted. According to the International Union for Conservation of Nature and the World Wildlife Fund, there about 15,000 medicinal plant species are threatened with extinction from overharvesting and habitat destruction and 20% of their wild resources have already been nearly exhausted with the increasing human population and plant consumption [207]. Each plant species lost due to extinction phenomena could represent not only the loss of healthcare saving cures for special diseases but also the loss of probable primary metabolite liker protein-or vitamin-rich foods [208]. Medicinal plants have been cited as a potential source of heavy metal toxicity to both man and animals. e most common heavy metals implicated in human toxicity include lead, mercury, arsenic, and cadmium, although aluminum and cobalt may also cause W. somnifera extract oral administration at two doses (200 and 400 mg/kg) reduced the blood glucose level significantly (P < 0.001) in a dosedependent manner in streptozotocin-induced diabetes rats. Only WS treatment did not register any significant change in the blood glucose level when compared to citrate control rats [119]. Another study also confirmed similar results in alloxan-induced diabetic rats [120] 47 Lantana camara Verbenaceae Leaves Jazan Region [84] Literature survey showed that L. camara leaf extract oral administration (200,250, and 500 mg/ kg of bw) showed antidiabetic potential in alloxaninduced diabetic rats [121] 48 Peganum harmala Zygophyllaceae Seeds Taif Region [112] P. harmala seed extract at dose level of (30, 60, and 120 mg/kg, orally administered for four weeks) significantly decreases in blood glucose (in all doses, P < 0.001), in comparison with diabetic group [122].

Ficus carica
Over 100 bioactive compounds have been identified in fig such as rutin, arabinose, chlorogenic acid, β-amyrins, syringic acid, β-carotenes, glycosides, β-sitosterols, and xanthotoxol [131] e rats tested were found healthy with no sign of toxicity up to the dose of 5000, 5500, and 6000 mg/ kg. However, at 5 000 mg/kg, animals were weak and had intense extreme tachycardia and disorientation but no death was recorded.

Anethum graveolens
Carvone, α-phellandrene, limonene, dill ether, myristicin coumarins, flavonoids, phenolic acids, steroids [134] e mice treated with AG of different doses of 1000, 2000, 3000, 4000, and 5000 mg/kg of body showed no toxicity [135] 11 Cuminum cyminum Cuminaldehyde, limonene, α-and β-pinene, 1, 8-cineole, oand p-cymene, α-and c-terpinene, safranal, and linalool [58,59] e acute lethal toxicity test revealed that cumin crude extract was very safe [58] 12 Marrubium vulgare Furanic labdane diterpenes, marrubenol, marrubiin, ladanein [60] An acute toxicity study of M. vulgare (1 g/kg) extract orally administered at a dose of 1 g/kg body weight to the mice and treated mice showed tachycardia 1 h after intake of the infusion and loss of appetite 3 h after intake of the infusion. In another experiment, a single dose of 2000 mg/kg extract of M. vulgare for an acute toxicity study showed no toxicity [60]. 8 Evidence-Based Complementary and Alternative Medicine M. longifolia extract was safe, and no toxicity or mortality was observed in both the oral (3200 mg/ kg) and intraperitoneal (1730 mg/kg) administration in rats. Fourteen days of oral administration of the essential oil (125,250,375, and 500 µL/kg) resulted in the reduction of red blood cells and lymphocytes and elevation of neutrophils and monocytes compared with normal animals [136]. All rats treated with different concentrations of the total extract of TP were alive during the 14 days of observation. e animals did not show visible signs of acute toxicity. It suggested that the LD50 of the total extract was higher than 8 g/kg [138] 17
In vivo toxicity study suggests that the oral administration of Opuntia ficus indica extract at levels up to 2000 mg/kg/day does not cause adverse effects in male and female rats [148].

Beta vulgaris
Betaine, betacyanins, betaxanthins, oxalic acid, and ascorbic acid [89] In acute oral toxicity studies, the BVBF did not show any sign and symptoms of toxicity and mortality up to 2000 mg/kg dose, considered relatively safe [150] 28
U. dioica extracts up to dose level of 2000 mg/kg body weight in animal model showed no mortality or changes/alteration in normal behavior [127].     [209]. Another study conducted on onion bulb showed that the concentrations of Cr in onion bulb and Fe in onion leaf were above the permissible level (2.3 mg/kg, 425.5 mg/kg) set by FAO/WHO at Mojo (4.87 mg/kg, 1090.40 mg/kg), Meki (4.13 mg/kg, 1836.47 mg/ kg), and Ziway (3.33 mg/kg, 764.33 mg/kg), respectively. e results generally indicate that the consumption of these onion bulbs could be the health risk respective to Cr [210]. erefore, it is suggested that the medicinal plant source for the treatment of diabetes must not be taken from heavy metal contaminated areas to avoid their uptake by the plants because migration of these contaminants into noncontaminated areas (or leaching through the soil and spreading of heavy metal contaminated sewage sludge) are a few examples of events contributing to contamination of the ecosystem.

Conclusion and Recommendations
e present review provides a picture of medicinal plants that have been studied as anti-DM drugs, which can be grown either in combination with other medicinal plants or alone as treatment for diabetes and drawbacks should be properly addressed so that medicinal plants can be effectively utilized as anti-DM drugs. Diabetes is a metabolic disorder which can be considered as a major cause of high economic loss which can in turn impede the development of nations. Moreover, uncontrolled diabetes leads to many chronic complications such as blindness, heart failure, and renal failure. In order to prevent this alarming health problem, the development of research into new hypoglycemic and potentially antidiabetic agents is of great interest. In conclusion, this paper has presented a list of anti-DM plants used in the treatment of diabetes mellitus. Bioactive antidiabetic phytoconstituents which showed that these plants have hypoglycemic effects and highly recommended for further pharmacological purposes and to isolate/identify anti-DM active agents also need to investigate the side effects of active ingredients.

Data Availability
is is a review article. All data are taken from published research papers and available online.

Conflicts of Interest
e authors declare no conflicts of interest.

Authors' Contributions
All three authors contributed equally.