Ethnopharmacological review of medicinal plants used to manage diabetes in Morocco

Diabetes is a chronic metabolic disorder which affects millions of people every year. If diabetes is not controlled, it can cause serious damage and a number of health complications. The aim of this paper was to review published ethnobotanical and ethnopharmacological evidences of Moroccan plants with antidiabetic potentials. Publications describing the medicinal plants used for the treatment of diabetes in Morocco were searched from the databases, including Google Scholar, Elsevier, Medline, Web of Science, SCOPUS and Pubmed. Other literature source was also used including books and theses available in library. About 750 literature references were studied, and only 240 research publications based on data from different Moroccan provinces published until June 2019 were included in this review. In total, 255 plants species belonging to 70 families were reported. Compositae and Lamiaceae were mentioned as the most represented families. The frequently used plant species in the dwellers of most regions of Morocco are Trigonella foenum-graecum, Artemesia herba-alba, Nigella sativa, Olea europaea, Allium cepa and Marrubium vulgare. This review provides useful information and current scientific knowledge on the medicinal plants used to manage diabetes in Morocco. Medicinal plants reported should be submitted to chemical, pharmacological and clinical studies to identify pharmacologically active metabolites and to confirm their antidiabetic activity.


Introduction
Type 2 diabetes mellitus (T2DM), generally termed as diabetes, is one of the major endocrine diseases which affects millions of people in the industrial and developing countries [1,2]. It is projected that the total number of people with diabetes worldwide is expected to increase to 592 million by 2035 [3]. Diabetes is a metabolic disease characterized by insufficient insulin secretion, impaired cellular action of the insulin or both [2,4]. The characteristic symptoms of diabetes are pruritus, polydipsia, weight loss, polyphagia, wasting, blurred vision, polyuria, tachycardia and hypotension [5,6]. Dietary and lifestyle factors (Obesity, weight gain, physical inactivity and low fiber diet with a high glycemic index) play a significant role in the development of diabetes [7]. Prolonged uncontrolled hyperglycemic level causes an increase in oxidative stress activation of the polyol pathway, coronary artery disease, peripheral arterial disease, stroke, diabetic nephropathy, neuropathy, peripheral neuropathy, retinopathy, retinopathy leading to vision loss, chronic kidney disease, urinary problems, sexual dysfunction, and skin infections [3,8,9]. The treatment of diabetes mellitus is based on insulin, diet modification and oral hypoglycemic agents. Herbal medicine has developed as an alternative for the treatment of diabetes because oral hypoglycemic agents are expensive and tagged with several side effects (nausea, skin reactions, liver disease, heart failure diarrhea, etc.) [10,11]. In Morocco, there are numerous medicinal plants described for treatment of diabetes [2,[12][13][14][15][16][17][18][19][20][21][22][23].
The aim of this review article was to collect data for species wellknown for their antidiabetic effect in Morocco.

Method
Three researchers searched Google Scholar, Elsevier, Medline, Web of Science, SCOPUS and Pubmed bibliographic databases from January 2019 to July 2019 to extract all data about the use of plants in folklore medicine for treatment and management of diabetes in Morocco published in the period from January 1980 to June 2019, using English, French and Arabic keywords. The search terms used were "Ethnobotanical survey", "Moroccan medicinal plants", "anti-diabetic medicinal plants in Morocco", "hypoglycemic plants in Morocco", "diabetes in Morocco". We reviewed the literature and collected data on the explored regions of Morocco (Beni Mellal region, Rabat, Western Anti-Atlas, Izarene forest, Oriental Morocco, Northwestern Morocco, Sefrou region, Central Middle Atlas, Tizi n' Test Region, Al Haouz-Rhamna, Tan-Tan, Meknes-Tafilalet and Fez-Boulemane). About 750 literature references were studied, and only 240 ethnobotanical articles and pharmacology papers were included in this review. We did not included articles related to taxonomy, morphological characters, pharmacology, toxicity, ethnobotany, phytochemistry, clinical studies, cultivation, physiological, and anatomical aspects of all the medicinal plants mentioned. We studied in detail only the six plants most used for the treatment of diabetes in Morocco. We also excluded the articles without accessible full text and duplicate articles. Plant taxonomy is confirmed through data available on site (www.theplantlist.org).

Ethnobotanical studies
A total of 255 plant species belonging to 70 families were reported as being used in the treatment and management of diabetes in Morocco (Table 1). Among plant families, Compositae had the highest number of species followed by Lamiaceae, Leguminosae, Apiaceae, Poaceae and Brassicaceae. Compositae was the most frequently cited plant family, which is consistent with the predominance of this plant family in the results of various studies conducted in other countries [3,27,28]. Compositae has been designated as the largest plant family of flowering plants worldwide, comprising 23,000 species and 1535 genera, including many with considerable medicinal importance [29,30]. The traditional medicinal applications of several Compositae species have been recorded in the literature. Several bioactive compounds have been evaluated for their biological activities [31]. A wide use of Compositae family plants in Morocco could be due to the large number of plant species belonging to this family. Further, plants belonging to the Compositae family contain a group of active phytochemical constituents and some bitter-tasting secondary metabolites such as sesquiterpene lactones [8,30].
Our evaluation of literature showed that indigenous people used 19 plant parts (leaf, aerial part, fruit, leafy stem, seed, root, bark, calyce, flower, stem, clove, gum, inflorescence, bark, pericarp, rhizome, stigma, tuber and young sprout) as herbal therapies for curing diabetes, but with, however, some preference for the leaves. Several procedures modes are used by the population to create medicinal formulations (decoction, cooked, infusion, powder, maceration, juice, raw and cataplasm). However, extractions by decoction, powder or infusion remain the most common processes. Most medicinal formulations were used internally via oral route. The dose used varied considerably according to the patients questioned. The patients did not respect the precision of doses (some diabetics use specific doses, and others use non-specific doses). Often, people use a mixture of plants to treat diabetes. The duration of the use of plants was badly defined ranging from a few days to several years. The majority of people with diabetes have recourse in medicinal plants to treat diabetes. The percentage of use of phytotherapy varies between 51% and 90%, depending on the regions. The use of herbal medicine among certain diabetics was done in combination with their conventional treatment. Women frequently used more medicinal plants than men. Diabetics have discovered the disease by suggestive symptoms or by a screening test.
An ethnobotanical study was conducted out among 400 herbalists from the Beni Mellal region in order to identify the medicinal plants used for the traditional treatment by the diabetic patients. The results identified 45 species belonging to 25 botanical families. The most used species are: Olea europaea, Salvia officinalis, Allium sativum and Trigonella foenum-graecum. Leaves and roots are the most used parts [24].
To collect some information about antidiabetic plants used in Rabat (capital city of Morocco), a survey was undertaken from March 1st to April 30th 2018. The investigations revealed 30 species of plants belonging to 18 families. Lamiaceae and Leguminosae were the most commonly reported plant families. Interview results showed that the most frequently used plants were Trigonella foenumgraecum, Salvia officinalis and Olea europaea [25].
A survey was conducted by Barkaoui et al. [2], in Tiznit (Western Anti-Atlas), in central Morocco. This study showed the importance of the use of medicinal plants by local population in the treatment of diabetes. Results have identified 48 medicinal plant species, belonging to 25 families and 44 genera, used for treating diabetes in the region. Plants growing in wild are most commonly  [18] Amaryllidaceae Allium ampeloprasum L.
An ethnobotanical survey by Ziyyat et al. [23] in different areas of Oriental Morocco reported that 34 plant species were used for the treatment of diabetes, of which the most used were Trigonella foenum-graecum, Globularia alypum, Artemisia herba-alba, Citrullus colocynthis and Tetraclinis articulata. Also a study was carried out in Oriental Morocco with 279 diabetic patients at the Department of Endocrinology and Metabolism of Mohammed VI Uneversity Hospitalin Oujda. The results showed that the local population uses medicinal plants for the treatment of diabetes. Fifty plants are reported to be used in the region for the treatment of diabetes. The five most common herbal medicines used were Salvia officinalis, Trigonella foenum-graecum, Olea europaea, Artemisia herba-alba and Origanum vulgare [15].
A study by Laadim et al. [12] in Sidi Slimane (northwestern Morocco) reported that 59 plant species were cited by 700 diabetic patients for management of diabetes. Five plants, Trigonella foenum-graecum, Oreganum vulgare, Salvia officinalis, Marrubium vulgare and Olea europaea, were most used. The survey revealed that seeds and leaves are the part of the plant most often used in herbal preparations.
To inventory the medicinal plants used in traditional medicine to treat diabetes in the Tizi n' Test Region (Taroudant Province), a survey was carried using semistructured and structured questionnaires. Thirty-nine plant species belonging to 24 botanical families were recorded for the treatment of diabetes. The most important species were Artemisia herba-alba, Cistus creticus, Lavandula maroccana, Salvia officinalis and Olea europaea. Leaves were the parts predominantly used and decoction was the most common method to prepare the formulations [26].
In the region of Tan-Tan (South of Morocco), a survey reported that 129 medicinal species belonging to 53 families were cited by 350 people for the treatment of diabetes with the dominance of the most represented families in the flora of Morocco. Some of the inventoried plant species are endemic to the Sahara such as Cynomorium coccineum, Atriplex halimus and Salsola tetragona, but others are toxic including Aristolochia fontanesii, Euphorbia officinarum and Nerium oleander [18].
In the region of Meknes-Tafilalet (North-central Morocco), an ethnobotanical study was undertaken in order to inventory the main medicinal plants used in folk medicine to treat diabetes. In this region, the most frequently used plants include Allium cepa, Artemisia herba-alba and Trigonella foenum graecum [19]. Also in the North central region of Morocco (Fez-Boulemane), an ethnobotanical study reported that 90 medicinal species are used in the treatment of diabetes, hypertension and renal diseases. Among these species, 9 plants are toxic at high doses. For diabetes, 54 plants were cited, of which the most cited were: Artemesia herba alba, Trigonella foenum-graecum and Tetraena gaetula [22].
In the Errachidia province (South-eastern Morocco), a survey was carried out to catalog the plants traditionally used in the treatment of hypertension and diabetes mellitus. The authors have inventoried 64 species belonging to 33 families, of which 45 plants were used in the treatment of diabetes. The most frequently cited plant species by the local population for management of diabetes are Ajuga iva, Allium cepa, Artemisia herba-alba, Carum carvi, Lepidium sativum, Nigella sativa, Olea europaea, Peganum harmala, Phoenix dactylifera, Rosmarinus officinalis, and Tetraena gaetula [20]. Also in south-eastern Morocco (Tafilalet region), an ethnobotanical study identified 92  It is essential to study the effects of unexplored plant species on diabetes in more detail and to identify the active components and especially to study the mechanisms of action of these plant extracts, in order to obtain further data on the pharmacological effects of these plants.
Despite the therapeutic effects of medicinal plants, excessive consumption of some of the inventoried plants might lead to harmful effects which are related to a variety of causes. To avoid danger to patients, prudent use as well as safety precautions is required, such as using lower doses. The main toxic plants are, Citrullus colocynthis [32], Datura stramonium [33], Euphorbia officinarum [34], Myristica fragrans [35], Artemisia herba alba [36], Peganum harmala [37], Ricinus communis [38], Tetraena gaetula [39], Nigella sativa [40] and Nerium oleander [32]. Despite their toxic properties, patients do not suffer any adverse consequences. This indicates that the patients or the provider of the plants are skilled in recognizing the potential for toxicity and taking the appropriate precautions.
Of all medicinal plants reported in this study, 137 medicinal plants have been documented to demonstrate a potent anti-diabetic effect in vitro or in vivo or in clinical studies. We present in Table 2 pharmacological studies which have investigated directly or indirectly medicinal plants used in Morocco to treat diabetes. Trigonella foenum-graecum, Artemesia herba-alba, Nigella sativa, Olea europaea, Allium cepa and Marrubium vulgare were the most frequently used plants to treat diabetes based on number of citations. These plants are discussed in detail below. Apiaceae Ammi visnaga (L.) Lam.
Bachnikha / Barghanisse Aqueous extract of fruits 20 mg/kg BW Streptozotocin-induced diabetic rats (STZ) Significant decrease of blood glucose in normal rats 6 h after a single oral administration (P < 0.005) and 9 days after repeated oral administration (P < 0.05). [49] Apiaceae
Kamoun soufi Aqueous extract of fruits 10 mg/kg BW Streptozotocin-induced diabetic rats (STZ) Significant reduction in blood glucose levels after four (p < 0.01) and 6 h (p < 0.001) of treatment. This effect was more pronounced than glibenclamide which caused a significant decrease in blood glucose at the fourth (p < 0.05) and sixth (p < 0.01) hour after oral administration [50] Apiaceae Apium graveolens L.    The administration of Artemisia herba-alba indicates significant (P < 0.05) reduction of blood glucose concentration and was found to be antidiabetic [79] Compositae Chamaemelum nobile (L.) All.
Lgerta/ Kawkaw Aqueous extract of the seeds 2 ml Alloxan-induced diabetic rats The extract caused a significant (P < 0.05) decrease of fasting blood glucose of both normal and alloxan-induced diabetic rats [116] Leguminosae The extract decreased (p < 0,025) plasma glucose in diabetic (27.9 ± 4.5 mmol/L to 19.6 ± 9.9 mmol/L) while not in normal rats [128] Moraceae Morus alba L. diabetic rats (STZ) The aqueous extract exhibited a significant and dose-dependent effect on the blood glucose levels (P < 0.001). The highest dose (300 mg/kg) produced the most pronounced lowering of blood glucose levels [133] Myrtaceae Myrtus communis L.

Rihane
Hydroalcoholic, water, and ethanol extracts of the leaves 2 and g/kg BW Streptozotocin-induced diabetic rats (STZ) The ethanolic extract of leaves (2 g/kg) had a better hypoglycemic effect in diabetic rats compared with the aqueous extract (p < 0.05) [134] Myrtaceae

Janjlan
Ethanolic extract of the seeds 500 mg/kg BW Streptozotocin-induced diabetic rats (STZ) A significant decrease in the elevated blood glucose and increase in the lowered insulin and glycogen levels [138] Plantaginaceae Globularia alypum L.

Njem
Aqueous extract of the whole plant 250, 500 and 1000 mg/kg BW Streptozotocin-induced diabetic rats (STZ) The dose of 500 mg/kg was identified as the most effective dose. It lowers blood glucose level around 31% after 4 h of administration in normal rats [140] Poaceae Hordeum vulgare L.
Chair/Zraa Hydroalcoholic extract of the seeds 0.1, 0.25, 0.5 g/ kg BW Streptozotocin-induced diabetic rats (STZ) The extract at doses of 0.25 and 0.5 g/kg, were only effective in detracting blood glucose levels of diabetic rats after 11 days of continued daily therapy [141] Poaceae Pennisetum glaucum (L.) R.Br.

Illan
Hexane, ethylacetate, methanolic and aqueous extracts of the seeds 250 mg/kg BW Streptozotocin-induced diabetic rats (STZ) The aqueous extract has shown maximal blood glucose lowering effect in diabetic rats [142] Poaceae The extract exerted a significant (P < 0.05) hypoglycaemic effect in normal rabbits which was however short-lived. The hypoglycaemic effect was not significant (P > 0.1) in alloxan-treated rabbits [150]    Plants used most frequently for the treatment of diabetes in Morocco Trigonella foenum-graecum L.
Hypoglycaemic activity of alcoholic extract of seeds of Trigonella foenum-graecum was tested in both normal and alloxan-induced diabetic rats. Significant decrease in glycaemia was seen with alcoholic extract (74.33 ± 4.77 to 60.56 ± 1.9 in normal rats and 201.25 ± 7.69 to 121.25 ± 6.25 in diabetic rats) (P < 0.001) [122].
Fenugreek water seed extract was found to increase the body weight and decrease the fasting blood glucose in streptozocin-induced diabetic rats [177]. Similar results were obtained in the study done by Abdelatif et al. [178] who found that there was a weight gain in fenugreek treated rabbits as compared to the group that received only alloxan monohydrate. Plasma glucose level was reduced as compared to the alloxan monohydrate induced diabetic rabbits.
An active compound (G II ), isolated from water extract of seeds of fenugreek orally administered to the subdiabetic and mild diabetic rabbits, was capable of reduce blood glucose in glucose tolerance test [180].
Taştekin et al. [79] reported the hypoglycaemic effect of aqueous extract of Artemisia herba-alba in alloxaninduced diabetic rats. Aqueous extract of the aerial parts at the dose of 0.39 g/kg BW (body weight) significantly reduced (P < 0.05) blood glucose concentration. Its hypoglycaemic effect was comparable with that of insulin and repaglinide.
In vitro screening of hypoglycemic activity of Artemisia herba-alba using α-amylase inhibition technique emphasized its activity in hypoglycemic remedy. The 70% ethyl alcohol extract and mucilage of 70% ethyl alcohol inhibited the activity of α-amylase by 11% and 2% respectively [193].
The antidiabetic activity of methanolic crude extract and the commercial oil of Nigella sativa seeds in alloxan-induced diabetic rats was examined by Houcher et al. [201]. Administration of the crude methanolic extract at a dose of 810 mg/kg/day and the oil at a dose of 2.5 ml/kg/day decreased significantly the blood glucose (decreases of 58.09 and 73.27% respectively) after 10 days of treatment.
Administration of the volatile oil extracted from Nigella sativa seeds experimentally caused a significant decrease in blood glucose level in alloxan-diabetic rabbits (2% and 21% decreases in the fasting glucose levels at the 4 h and the 6 h time intervals, respectively) [202].

Olea europaea L.
Olea europaea L. (Olive) belongs to the plant family Oleaceae, is a small tree that produces the olive fruit, cultivated in the coastal areas of the eastern Mediterranean basin, the contiguous coastal areas of southeastern Europe, northern Iran at the south end of the Caspian Sea, western Asia, and northern Africa [203,204]. Phytochemical investigations on Olea europaea have revealed the presence of various phytochemicals including phenolic compounds (oleuropein, hydroxytyrosol, verbascoside, apigenin-7glucoside and luteolin-7-glucoside), flavonoids, secoiridoids, triterpenes, biophenols, benzoic acid derivatives, xylitol, sterols, isochromans and sugars [204,205]. Olea europaea has a variety of medicinal properties and traditional uses. The plant has been used to treat diabetes, high blood pressure, cardiovascular diseases, influenza, chronic fatigue syndrome, to support time of recovery, immune system, stomach and intestinal diseases, common cold, malaria, dengue, severe diarrhoea, respiratory and urinary tract infections, and as mouth cleanser [204,206]. Various biological activities of Olea europaea have been extensively studied like antihypertensive, analgesic, antimicrobial, anticancer, antihyperglycemic, antidiabetic, anticonvulsant, antioxidant, anti-inflammatory, immunomodulatory, antiviral, antinociceptive, and gastroprotective activities [203,204]. It is cited in the ethnobotanical surveys that the plant is used in the treatment of diabetes in Morocco [2,12,13,[15][16][17][18][19][20][21][22][23].
Eidi et al. [137] showed the antidiabetic effect of alcohol extract of Olea europaea leaves in normal and streptozotocin-induced diabetic rats. Rats were divided into nine groups, group1: normal control rats, groups 2, 3, 4: normal ratstreated with Olea europaea, group 5: diabetic control rats, group 6, 7, 8: diabetic rats treated with Olea europaea, group 9: diabetic rats treated with glibenclamide. The administration of extract at a dose of 0.1, 0.25 and 0.5 g/kg BW for 14 days significantly decreased the blood glucose in diabetic rats (p < 0.05).
Another study was conducted to check the antidiabetic potential of oleanolic acid (an agonist for TGR5), isolated from Olea europeaea leaves in mice fed with a high fat diet. Oleanolic acid cause a decrease in blood glucose concentration and insulin levels and it enhances glucose tolerance [207].

Allium cepa L.
Allium cepa L., commonly known as onion, botanically classified under the Amaryllidaceae family, is a biennial plant widely cultivated around the world. Onion is utilized as both vegetable and flavouring [222,223].
Another study showed the hypoglycemic effect of onion juice on alloxan-induced diabetic rats. After 4 week treatment of onion juice (1 ml/100 g body weight), significant anti-hyperglycaemic effect were observed in treated rats [231].
The antidiabetic effect of 200 mg/kg body weight for 60 days of S-methyl cysteine sulfoxide (SMCS) isolated from Allium cepa was studied and compared in alloxaninduced diabetic rats. Results suggested that the administration of SMCS reduced blood glucose level [232].
In another experiment conducted by El-Soud and Khalil [233], they found that treatment with onion essential oil caused a significant decrease in serum lipids, lipid peroxide formation, blood glucose and increase in serum insulin in streptozotocin induced diabetic albino rats.
Elberry et al. [102] showed that methanolic extract of the aerial parts of Marrubium vulgare can have beneficial effect in diabetes and its complication. They showed on a streptozotocin rat model the antidiabetic effect of a daily single oral dose of 500 mg/kg/day of Marrubium vulgare for 28 days. The methanolic extract produced a significant decrease in blood glucose starting on the second week and a significant increase in plasma insulin and tissue glycogen contents.
The administration of an aqueous extract from aerial parts infusion at dose 100, 200 and 300 mg/kg BW to alloxan-induced diabetic rats decreased significantly the blood glucose level in a dose dependent manner (a decrease by 50% for the dose 100 mg/kg and more than 60% for doses 200 and 300 mg/kg) [239].
The antidiabetic activity of various ethanolic extracts (root, leaf and stem) from Marrubium vulgare on normoglycemic rats was examined by Vergara-Galicia et al. [240].The intragastric administration of both extracts (root and stem), at 100 mg/kg BW, significantly reduced blood glucose level in healthy rat. Furthermore, the increase in plasma glucose level was significantly suppressed by the ethanolic root extract after substrate oral administration.

Conclusion
Many Moroccan medicinal plants are reported to have blood sugar lowering properties that make them useful for the management of diabetes. We have reported 255 medicinal plants species belonging to 70 families in this study for the treatment of diabetes. Plants from the Compositae family were used most often in Morocco. The role of 135 Moroccan medicinal plants in the treatment of diabetes has been reviewed by several authors. However, 120 medicinal plants that are used for the treatment of diabetes in Morocco have not yet been studied in great detail for their antidiabetic properties. Furthermore, there are very few scientific reports of toxicological properties of these plants which would guarantee the safety of patients. In general, the literature search showed that some users of medicinal plants have only little information about toxic plants. In order to prevent the usage of toxic plants by the greater population, we have reported the major plants that have side effects according to toxicological documentations. Despite the therapeutic effects of medicinal plantsthey may have a toxicity risk which is related to a variety of causes including, contamination, misidentification, mistaken use of the wrong species, incorrect dosing and errors in use. Another problem, which may occur, is the possibility of adverse interaction between conventional medication and plant remedies. In conclusion, this review provides baseline data for plant species that have the potential antidiabetic activity and their associated knowledge in Morocco. However, many of the plant species mentioned require further pharmacological and clinical studies in order to validate any effective plant remedies to treat diabetes.