Ethnopharmacological review of medicinal plants used to manage diabetes in Morocco

Abstract

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).

Results

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].

Table 1 Plants used in the treatment of diabetes in Morocco, cited in ethnobotanical studies

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 used for medicinal purposes in the study area (32 plant species). According to the authors, Allium sativum L., Salvia officinalis L., Marrubium vulgare L. and Lavandula dentata L were the most frequently used plants to treat diabetes. Six plants were reported for the first time as hypoglycemic plants: Dracaena draco subsp. ajgal, Euphorbia officinarum subsp. officinarum, Eryngium ilicifolium Lam., Pastinaca sativa L., Scorzonera undulata, Ephedra altissima Desf.

In Izarene forest (Northern Morocco), a survey was undertaken in order to inventory the main medicinal plants used in folk medicine to treat diabetes and arterial hypertension. The results obtained allowed an inventory of 40 medicinal plant species used against diabetes. The most cited plants for the treatment of diabetes were: Trigonella foenum-graecum, Artemisia herba-alba, Ammi visnaga, Centaurium erythreae, Myrtus communis, Globularia alypum, Nigella sativa, Tetraena gaetula, Olea europaea, Rosmarinus officinalis, Marrubium vulgare, Allium cepa, Ajuga iva, Salvia officinalis, Artemesia absinthium, Prunus dulcis, Capsicum annuum, Origanum compactum, Nerium oleander, and Urtica dioica [14].

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.

In an ethnobotanical survey by Bousta et al. [16], 22 species of plants belonging to 19 families were reported for the treatment of diabetes in the Middle-Atlas region of Morocco (Sefrou region). The most prominent plants reported were Olea europaea, Salvia officinalis, Trigonella foenum-graecum, Euphorbia officinarum subsp. echinus, Globularia alypum, Coriandrum sativum. Respondents said that they inherited the knowledge of their practices from their parents, traditional healers, some books and nowadays from television programs.

Also in the Central Middle Atlas an ethnobotanical study identified 76 medicinal plants, divided into 67 genus and 40 families. Fourteen plants are reported for the first time intraditional treatment of diabetes in Morocco. They are: Pistacia atlantica, Anacyclus pyrethrum, Ptilotrichum spinosum, Cistus albidus, Juniperus thurifera, Thymus algeriensis, Thymus munbyanus, Thymus zygis, Abelmoschus esculentus, Fraxinus angustifolia, Sorghum bicolor and Eriobotrya japonica [13].

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 semi-structured 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].

Another ethnobotanical survey among the local population in the region of Al Haouz-Rhamna (central Morocco) reported that a total of 150 plant species belonging to 54 families were used for the treatment of diabetes in the area. Among these species recorded 18 are cited for the first time in the region as an antidiabetic plants namely: Chamaerops humilis, Cladanthus arabicus, Centaurea maroccana, Matricaria chamomilla, Tanacetum vulgare, Diplotaxis pitardiana, Berberis vulgaris subsp. australis, Corrigiola litoralis subsp. telephiifolia, Cistus laurifolius, Quercus coccifera, Ballota hirsuta, Buxus balearica, Lavandula stoechas, Ocimum basilicum, Thymus satureioides, Ruta montana, Taxus baccata and Thymelaea virgata [17].

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 medicinal plants used in the treatment of diabetes mellitus, hypertension and cardiac diseases. The most frequently cited medicinal plants used for their antidiabetic effects were Ammi visnaga, Artemesia herba-alba, Trigonella foeniculum-granum, Marrubium vulgare, Nigella sativa, Globularia alypum, Allium sativum, Olea europaea, Citrullus colocynthis, Aloe succotrina, Artemisia absinthium, Rosmarinus officinalis, Thymus vulgaris, Eucalyptus globulus, Mentha pulegium, Myrtus communis, Linum usitatissimum and Carum carvi [21].

Pharmacological and toxicological studies

Among 255 plant species being used, 120 plants have neither been explored experimentally for antidiabetic activity. They are: Mesembryanthemum theurkauffii, Salsola tetragona, Searsia albida, Searsia tripartita, Eryngium ilicifolium, Pastinaca sativa, Ptychotis verticillata, Ridolfia segetum, Apteranthes europaea, Periploca laevigata subsp. Angustifolia, Aristolochia fontanesii, Agave americana, Asparagus albus, Achillea odorata, Antennaria dioica, Anvillea garcinii subsp. radiata, Artemisia abrotanum, Artemisia atlantica, Artemisia mesatlantica, Artemisia reptans, Centaurea maroccana, Cladanthus arabicus, Cynara cardunculus, Dittrichia viscosa, Echinops spinosissimus, Inula conyza, Inula helenium, Launaea arborescens, Pallenis spinosa, Scolymus hispanicus, Scorzonera undulata, Sonchus arvensis, Sonchus tenerrimus, Tanacetum vulgare, Berberis vulgaris subsp. australis, Diplotaxis pitardiana, Eruca vesicaria, Ptilotrichum spinosum, Buxus balearica, Maerua crassifolia, Herniaria glabra, Silene vivianii, Cistus albidus, Cistus creticus, Cistus salviifolius, Androcymbium gramineum, Juniperus thurifera, Tetraclinis articulata, Cynomorium coccineum, Bolboschoenus maritimus, Dracaena draco subsp. ajgal, Ephedra alata, Ephedra altissima, Euphorbia officinarum subsp. echinus, Euphorbia officinarum subsp. officinarum, Hammada scoparia, Euphorbia resinifera, Mercurialis annua, Anagyris foetida, Ceratonia siliqua, Cicer arietinum, Lupinus angustifolius, Lupinus luteus, Ononis natrix, Ononis tournefortii, Retama sphaerocarpa, Vicia faba, Vicia sativa, Quercus coccifera, Juncus maritimus, Ballota hirsuta, Clinopodium alpinum, Clinopodium nepeta subsp. glandulosum, Lavandula dentata, Lavandula maroccana, Lavandula multifida, Mentha pulegium, Mentha spicata, Origanum compactum, Origanum majorana, Origanum vulgare, Thymus algeriensis, Thymus munbyanus, Thymus zygis, Corrigiola litoralis subsp. telephiifolia, Fumaria officinalis, Papaver rhoeas, Globularia repens, Limonium sinuatum, Avena sativa, Castellia tuberculosa, Panicum miliaceum, Panicum turgidum, Polypogon monspeliensis, Triticum durum, Emex spinosa, Fragaria vesca, Rubus vulgaris, Rubia tinctorum, Salix alba, Illicium verum, Taxus baccata, Thymelaea tartonraira, Thymelaea virgata, Aloysia citriodora, Aloe succotrina, Asphodelus microcarpus, Mesembryanthemum theurkauffii, Cladanthus scariosus, Paronychia argentea, Ephedra fragilis, Glycyrrhiza glabra, Origanum elongatum, Thymus broussonetii, Avena sterilis, Lolium perenne, Malus communis, Verbena officinalis, Asphodelus tenuifolius and Tetraena gaetula. 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.

Table 2 In vivo and in vitro studies of medicinal plants used in the treatment of diabetes in Morocco

Plants used most frequently for the treatment of diabetes in Morocco

Trigonella foenum-graecum L.

Trigonella foenum-graecum L. (Fenugreek), is an annual plant, in the family Leguminosae, extensively cultivated in many countries (Morocco, Egypt, China, India, Ethiopia,Turkey, Ukraine, Greece, etc.) [172]. Apart from the usage as an edible species and spice herb, fenugreek is known for its nutraceutical, medicinal, and pharmaceutical features. It has been reported that fenugreek is a valuable medicinal plant with potential for curing abscesses, wounds, arthritis, bronchitis, digestive disorders, fever and sinusitis. It is cited as used in the treatment of diabetes by Moroccan ethnobotanical studies [2, 12,13,14,15,16,17,18,19,20,21,22,23]. Fenugreek is known to have several pharmacological effects such as antidiabetic, lactation aid, antibacterial, gastric stimulant, for anorexia, galactogogue, hepatoprotective effect, anticancer, anticarcinogenic, hypocholesterolemic, antioxidant, and immunological activities. Fenugreek is an excellent source of neutral detergent fiber, proteins, vitamins as well as chemical constituents [172,173,174,175,176].

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.

Administration of Trigonella foenum-graecum seeds (2.5 and 5 g) for 4 weeks to sixty newly diagnosed diabetic patients, improved blood glucose level in dose-dependent. The medium dose (5 g) of fenugreek seeds reduces significantly the glycemia (8.83 vs 6.45, p < 0.05) [179].

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].

Artemisia herba-alba Asso

Artemisia herba-alba Asso. (Compositae), known as the desert wormwood (Shih in arabic), is a dwarf, semi shrub,, strongly aromatic herb, growing widely in arid and semiarid areas of the Mediterranean basin and in Western Asia spreading into middle east, north-western Himalayas and India [181, 182]. This species is used medicinally to treat various diseases such as hypertension, diarrhoea, diabetes, colds, muscle tensions, coughing, intestinal distress and fever [183, 184]. It is cited as used in the treatment of diabetes in Morocco [2, 12, 14,15,16,17,18,19,20,21,22,23].

Numerous scientists have showed various biological and pharmacological effects in Artemisia herba-alba essential oils, especially antibacterial, antispasmodic, anti-diabetic, antioxidant, leishmanicidal, and antifungal properties [185,186,187,188]. In essential oils, monoterpenes were the major components, essentially α- and β-thujones, camphor, 1,8-cineole and chrysanthenyl derivatives, but sesquiterpenes also were found in some countries [189,190,191,192].

Taştekin et al. [79] reported the hypoglycaemic effect of aqueous extract of Artemisia herba-alba in alloxan-induced 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].

A dose of 2 g/kg of hydro-alcoholic extracts of Artemisia herba-alba, orally administered daily for 18 weeks, to male mice fed high fat diet, significantly decreased the blood glucose level (143.8 ± 23.9 vs. 229.0 ± 20.8 mg/dl, p < 0.05), triglyceride (18.9 ± 11.1 vs. 62.8 ± 18.3 mg/dl, p < 0.05), total cholesterol (1.2 ± 0.1 vs. 1.8 ± 1.1 g/L, p < 0.05) and serum insulin concentrations (1.7 ± 0.7 vs. 3.3 ± 14.3 ng/ml, p < 0.05) [194].

Nigella sativa L.

Nigella sativa L. (Family Ranunculaceae), commonly known as black seed or Kalonji seed, is widely grown medicinal plant throughout the world. Seeds and their oil have many food and medicinal uses [195, 196]. It has received attention for its potential application in the treatment and prevention of a number of diseases, such as fever, asthma, diarrhoea, dyslipidaemia, common cold, headache, warts, stings of scorpions, bites of snake and rheumatic diseases [197,198,199]. Moreover, a variety of secondary metabolites has been identified in this species, such as fixed oil, protein, alkaloid, saponin, isochinoline alkaloids (nigellimin and nigellimin-N-oxide), pyrazol alkaloids (nigellidin and nigellicin), thymoquinone, p-cymene, pinene, dithymoquinone, thymohydroquinone, carvacrol, carvone, limonene, 4-terpineol and citronellol [195, 196]. It has been reported to possess potent anti-inflammatory, anti-hyperlipidemic, anti-microbial, anti-cancer, anti-oxidant, anti-diabetic, anti-hypertensive, hepatoprotective, antiparasitic, analgesic, anti-nociceptive, anti-ulcer, anti-histaminic and wound healing activities [196, 200]. Nigella sativa used in Morocco in the treatment of diabetes [2, 13,14,15,16,17,18,19,20,21,22,23].

Alimohammadi et al. [146] reported the hypoglycaemic effect of hydroalcholic extract of Nigella sativa seeds (5, 10, and 20 mg/kg BW) in streptozotocin-induced diabetic rats (STZ). Nigella sativa at 5 mg/kg reduced blood glucose concentration level from (565.4 ± 30.9 mg/dl) to (323.2 ± 32.2 mg/dl), at 10 mg/kg it reduced blood glucose concentration level from (565.4 ± 30.9 mg/dl) to (513.2 ± 42.7 mg/dl), whereas at 20 mg/kg it reduced it from (565.4 ± 30.9 mg/dl) to (517.6 ± 27.3 mg/dl).

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-7-glucoside 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].

Several other studies demonstrated the antidiabetic effect of Olea europaea in streptozotocin diabetic rats [208,209,210,211,212,213,214], in alloxan diabetic rats [215,216,217,218,219], in alloxan diabetic rabbits [215], in human diabetic subjects [209] and in vitro α-amylase and α-glucosidase inhibitory activities [220, 221].

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].

According to traditional medicine experts, Onion is one of the oldest medicinal plants used to relieve several ailments including metabolic disease, wound healer, pneumonia fighters, digestive problems, skin diseases and insect bites, diabetes and asthma [224, 225]. Allium cepa used in Morocco in the treatment of diabetes [2, 12,13,14,15,16,17,18,19,20,21,22].

There are many chemical constituents in Allium cepa, including vitamins and minerals. Moreover, a variety of secondary metabolites has been identified in this species, such as phenolic compounds (particularly ferulic acid, gallic acid, protocatechuic acid, quercetin, and kaempferol), flavonoids (particularly quercetin aglycon, quercetin-3,4′-diglucoside, quercetin-4′-monoglucoside, quercetin-3-monoglucoside, quercetin 3-glycosides, delphinidin 3,5-diglycosides, quercetin 3,7,4′-triglucoside, quercetin 7,4′-diglucoside, quercetin 3,4′-diglucoside and isorhamnetin 3,4′-diglucoside), phytosterols and saponins [226,227,228,229,230].

Recent studies have shown that this plant has different biological properties, such as hypolipidemic, anti-hypertensive, antimicrobial, antioxidant, analgesic, anti-inflammatory, immunoprotective, and anti-diabetic effects [222, 224].

The hypoglycemic effect of Allium cepa was confirmed by aqueous extracts of the whole plant in alloxan (150 mg/Kg BW) rat model of diabetes. Allium cepa at 200 mg/kg reduced fasting blood glucose levels by 62.9% (292.3 ± 29.0 to 108.2 ± 4.6), at 250 mg/kg it reduced fasting blood glucose levels by 69.7 (296.3 ± 37.8 to 89.8 ± 4.3) whereas at 300 mg/kg it reduced it by 75.4% (297.8 ± 37.5 to 73.4 ± 3.0) [45].

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 alloxan-induced 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.

Marrubium vulgare L.

Marrubium vulgare L. is a perennial herb of the Lamiaceae family, popularly known as white horehound. This aromatic plant is native to the Mediterranean Sea region can be found in many temperate regions of Europe, North of Africa and Asia [234, 235]. It could be used to cure and treat several diseases, such as laryngitis, bronchitis, skin abrasions, wounds, bronchial asthma, nonproductive cough, hepatic affections and in phthisis [235, 236]. Marrubium vulgare is rich in phytochemicals like amino acids, polysaccharides, tannins, phenols, flavonoids, alkaloids, steroids, lactones and, in particular, terpenes [237, 238]. The plant is reported to possess hypoglycemic, vasorelaxant, analgesic, antioxidant, antierdematogenic, anti-inflammatory, vasodilator and antihypertensive properties [236, 238]. Horehound used in Morocco in the treatment of diabetes [2, 12,13,14,15,16,17,18,19, 21,22,23].

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.