Phytomedicines Used for Diabetes Mellitus in Ghana: A Systematic Search and Review of Preclinical and Clinical Evidence

Background Available data indicate that diabetes mellitus leads to elevated cost of healthcare. This imposes a huge economic burden on households, societies, and nations. As a result many Ghanaians, especially rural folks, resort to the use of phytomedicine, which is relatively less expensive. This paper aims at obtaining information on plants used in Ghana to treat diabetes mellitus, gather and present evidence-based data available to support their uses and their mechanisms of action, and identify areas for future research. Method A catalogue of published textbooks, monographs, theses, and peer-reviewed articles of plants used in Ghanaian traditional medicine between 1987 and July 2018 for managing diabetes mellitus was obtained and used. Results The review identified 76 plant species belonging to 45 families that are used to manage diabetes mellitus. Leaves were the part of the plants frequently used for most preparation (63.8%) and were mostly used as decoctions. Majority of the plants belonged to the Euphorbiaceae, Lamiaceae, Asteraceae, and Apocynaceae families. Pharmacological data were available on 23 species that have undergone in vitro studies. Forty species have been studied using in vivo animal models. Only twelve plants and their bioactive compounds were found with data on both preclinical and clinical studies. The records further indicate that medicinal plants showing antidiabetic effects did so via biochemical mechanisms such as restitution of pancreatic β-cell function, improvement in insulin sensitivity by receptors, stimulating rate of insulin secretion, inhibition of liver gluconeogenesis, enhanced glucose absorption, and inhibition of G-6-Pase, α-amylase, and α-glucosidase activities. Conclusion This review contains information on medicinal plants used to manage diabetes mellitus, including their pharmacological properties and mechanisms of action as well as models used to investigate them. It also provides gaps that can form the basis for further investigations and development into useful medications for effective treatment of diabetes mellitus.


Introduction
Diabetes mellitus is a metabolic and/or hormonal condition that is usually described by persistent hyperglycemia, as a result of defects in insulin secretion by pancreatic -cells, and reduced sensitivity of cell surface receptors to insulin or both [1]. There are four main types of diabetes mellitus: type-1, type-2, gestational diabetes mellitus, and "other specific types of diabetes mellitus" [2]. Inadequate management or uncontrolled hyperglycemia manifests into signs and symptoms that can also be referred to as acute complications. When these signs and symptoms are overlooked or not detected Most of these orthodox drugs used are either bedeviled with many side effects such as hypoglycemia, weakness, diarrhea, shortness of breath, fatigue, nausea, dizziness, lactic acidosis, weight gain, increase in LDL-cholesterol levels, hepatotoxicity and kidney toxicity, and lactic acid intoxication or are relatively expensive [9,10]. The high cost of managing diabetes mellitus compels many Ghanaians to patronize herbal medicine that is less expensive. This calls for intensive research to provide needed information, including the efficacy and safety of these medicinal plants. Managing diabetes mellitus using herbal remedies is not uncommon in Ghanaian rural and urban communities [11]. According to WHO, the number of people that choose traditional herbal medicines in most African countries is driven by amalgamation of factors which include economic hardships, difficult geographical approachability of the populace to conventional antidiabetics, inadequacy of healthcare systems, ease of accessibility of herbal medicine, and indigenous knowledge of the people in addition to the role of traditional healers [12].
Ghana is endowed with a rich floral diversity and likewise rich plant ethnomedicinal tradition. Several herbal preparations have been used in folklore for the management of diabetes mellitus that are purported to possess hypoglycemic effect. This assertion has heightened the interest in plant medicines as alternatives for orthodox medicines. Despite the progress made in the development of plant-based antihyperglycemic agents by many countries [13], Ghana is yet to fully harness its plant biodiversity for this purpose. Though Ghana has a rich history of herbal medicine usage, pharmacological efficacy data on these plants are highly fragmented, which underscores the need for compilation of evidence-based data on the subject. Proper documentation of these traditional medicinal plants used in managing diabetes mellitus constitutes an important task.
This review aimed to compile ethnopharmacological data on medicinal plants found in Ghana and brings together findings available on their bioactive compounds, efficacy, safety, and clinical trials. Information gathered is expected to assist in preserving indigenous knowledge and biodiversity and enhance awareness on medicinal plants and consequently access to information on medicinal plants to serve as a resource to facilitate the development of new and standardized herbal-based drugs. The availability of one-stop data on antihyperglycemic plants in Ghana is crucial for identifying gaps in knowledge and stimulating research that could lead to identification of lead compounds. This piece thus focuses on medicinal plants used in Ghana to manage diabetes mellitus and synthesizes research findings on the bioactive phytoconstituents and efficacy of medicinal plants concerned.
Evidence-Based Complementary and Alternative Medicine 3 Table 1: Summary of studies included in this review.

Characteristics of paper used
Number of articles source Ethnomedicinal report 11 Table 2  In vitro mechanism  26  Table 3  In vivo mechanism  53  Table 4  Clinical studies  12  Table 5 Bioactive compounds with anti-diabetic activity 12 Table 6 One study can fall into more than one grouping.

Method and Literature Search Strategy
A catalogue of textbooks, monographs, published theses, and published peer-reviewed articles of plants used in Ghanaian traditional medicine was sourced [14-16, 19, 21, 21, 23, 24, 26, 26]. Electronic databases, namely, ScienceDirect, Scopus, PubMed, Springer Nature, Web of Science, and Google Scholar were used to gather information. English language articles were the sole source of information for this review.
The key terms that were used in the search were "Antidiabetic", "Hypoglycemic effect", "Ethnomedicine", "Traditional medicine", and "Ghana". All retrieved articles were reviewed to obtain the needed information on Ghanaian antidiabetic medicinal plants. For each plant material identified to be used to treat diabetes mellitus in Ghana, peer-reviewed or published theses between 1987 and July 2018 were scrutinized of which the active components attributed/reported to possess antidiabetic effect were considered. Synthesized or isolated active compounds of respective plants that have been used to carry out antidiabetic studies with significant success were considered. In addition, plants with information on preclinical and clinical studies were the ones that were expatiated on. All articles accessed were evaluated for information on methods employed by investigators in their studies such as preclinical in vitro, in vivo (rodents and human) data or clinical trials and mechanism of action. Plants that did not show any marked antidiabetic effects experimentally were not included in the study. Bibliographies of ultimately used articles were appraised for other relevant information to the type of plant extract, scientific names, plant part used, active principles, category of diabetes mellitus, and disease animal model. Only peer-reviewed or published theses were used as sources for this piece. A summary of the main sources consulted is shown in Table 1.

Results
. . Overview of Characteristics of Studies Included in is Review. A summary of source of materials used for the review process is shown in Table 1. A major barrier to understanding the diversity and uses of medicinal plants in Ghana has been the lack of research and available data on these plants. In this review, efforts have been made to gather information regarding herbs used to manage diabetes in Ghana. About ten identified plants with data on preclinical and clinical trials met inclusion criteria and have been discussed. Information gathered is summarized in Tables  2-6. Table 2 presents information on reported plants used in Ghana for the management of diabetes mellitus. Tables 3-5 depict data for in vitro, in vivo, and clinical trials for medicinal plants used in managing diabetes mellitus. Table 6 provides information on plants with their corresponding bioactive ingredients responsible for the hypoglycemic effect. Figure 1 shows chemical structures of bioactive compounds isolated from plants experimentally shown to possess antidiabetic property. Also evidence-based data relating to in vitro, animal, and human studies aside from their bioactive compounds have been described in this piece.

. . Preclinical and Clinical Data on Plants with Antidiabetic
Effects. Phytomedicines have been used for the management of different ailments, and many populations in the world depend entirely on plants medicines for their healthcare needs such as management of diabetes mellitus. From the ethnobotanical studies, many plants found to possess antidiabetic activities were used for dietary purposes with no comprehension of their proper functions and active principles. This practice may have continued due to their fewer side effects compared to orthodox drugs.
Although many orthodox synthetic drugs have been developed to manage diabetes mellitus, few of them are available for use in managing diabetes mellitus. Over 200 pure compounds from plants shown to possess antihyperglycemic effects [118] in different classes of natural products such as flavonoids and alkaloids are available.
This report presents information on plants that possess antidiabetic properties from which bioactive compounds have been isolated and tested. The families of plants showing some level of potency with regard to their hypoglycemic effects include Passifloraceae, Liliaceae, Asphodelaceae, Meliaceae, Cucurbitaceae, Fabaceae, Lauraceae, Costaceae, Anacardiaceae, Scrophulariaceae, and Zingiberaceae.
Allium cepa. Allium cepa, commonly known as onion, is a plant grown in Ghana. The bulb and leaves, which are used for cooking, possess nutritional and medicinal benefits [18]. It serves as a rich source of protein, fibre, fat, folic acid, sodium, vitamin C, vitamin B 6 , and many other micronutrients [119]. The health benefits of onion include management of a number of diseases including diabetes mellitus. Jung and colleagues in a study involving streptozotocin-induced diabetic rats showed that onion peel extract improves glucose control and insulin resistance associated with type-2-diabetes mellitus [120]. Additionally, research work carried out by Ojieh and colleagues [56] demonstrated the hypoglycemic  [14,18,21] Evidence-Based Complementary and Alternative Medicine 5

Abelmoschus esculentus
Peel and Seed Streptozotocin induced exert blood glucose normalization and lipid profiles lowering activity [28] Adenia lobata Stem Streptozotocin induced provide protective mechanism against reactive oxygen species associated with chronic hyperglyceamia and diabetic complications [15] Ageratum conyzoides

Leaves
Glucose induced exert extra pancreatic action by stimulating insulin secretion [53] Ageratum conyzoides

Leaves
Streptozotocin induced possess blood glucose lowering effect [54] Allium cepa Bulb Alloxan-induced Stimulates insulin release and action to enhance glucose cellular uptake and utilization [55] Allium cepa Bulb Streptozotocin induced Ameliorate possible complications associated with diabetes mellitus. [56] Allium sativum Bulb Streptozotocin-induced Restores delayed insulin response by reacting with endogenous thiol containing molecules [57] Aloe barbadensis Leaves Alloxan induced useful and safe agent in reducing hyperglycemia induced by alloxan [58] Alstonia boonei Leaves Alloxan induced exert significant antidiabetic activity [59] Alstonia boonei

Leaves
Streptozotocin induced restore glucose levels to near normal level [39] Mangifera indica Leaves Alloxan induced Insulin like effect by Inhibiting hepatic gluconeogenesis or glucose absorption in muscles or adipose tissues [84] Mangifera indica Leaves Streptozotocin induced -amylase and -glucosidase inhibitory activity [85] Mimosa pudica L  [98,99] Evidence-Based Complementary and Alternative Medicine 9   Figure 1: Chemical structures of isolated compounds listed in Table 6.
Evidence-Based Complementary and Alternative Medicine 13 effects of Allium cepa and its ability to ameliorate complications associated with diabetes mellitus. Babu and Srinivasan [121] also reported that feeding onion powder-containing diet to diabetic animals produces marked reduction in their hyperglycaemic status. Petroleum ether extract of onion was demonstrated to reduce blood glucose levels in normal rabbits. Prolonged addition of freeze-dried onion powder in the diet of STZ-diabetic rats produced antihyperglycemic, hypolipidemic, and antioxidant effects [122]. Kelkar and colleagues also reported a higher hypoglycemic potential of onion callus cultures over natural onion bulb [123]. Onion juice administered to alloxan induced diabetic rats for a period of one month showed characteristics of antihyperglycemia [124].
The presence of quercetin, allyl propyl disulphide oxide (dipropyl disulphide oxide), S-methylcysteine sulphoxide, and S-allyl cysteine sulphoxide in onion is reported to be responsible for the drop in glucose level and lipid profile. Allyl propyl disulphide oxide also aids in insulin secretion [14,120]. S-allyl cysteine sulphoxide from onion also markedly decreased blood glucose level of diabetic rats [125]. Daily oral administration of about 200 mg of S-methylcysteine sulphoxide for 45 days to alloxan diabetic rats controlled their blood glucose and lipid levels. The same study also reports improvement in the activities of liver glucose-6-phosphatase, hexokinase, and HMG CoA reductase. The observed effect of S-methylcysteine sulphoxide was analogous to that of insulin and glibenclamide [126]. Oral administration of S-methyl cysteine sulphoxide to alloxan diabetic rats for one-month period ameliorated hyperglycaemia and was similar to animals treated with glibenclamide and insulin [121].
In a clinical study of individuals with diabetes mellitus administered with juice of onion bulb, a decrease in blood glucose concentration was observed [127]. Our search did not find any published work on any reported case of adverse toxicity associated with the consumption of onion. Meanwhile there are reports of unfavorable effects of excessive intake such as abdominal bloating, heartburn, hypotension, allergies, and bad breath [128].
Allium sativum. Allium sativum commonly known as garlic is one of the oldest known medicinal spices in existence. It is cultivated all over Ghana. It is used to manage many disorders, which include diabetes mellitus. The bulb is washed, dried, and chewed as required for the management of diabetes mellitus [18]. The cloves of the plant are reported to possess a sulphur-containing chemical compound called allicin that is also responsible for its pungent smell [128]. The bulb is reported to contain other principles such as S-allyl cysteine sulphoxide, allicin, Bis (allixinato) oxovanadium (IV), vitamins C and B 6 , and manganese [128,129].
Administration of extract of garlic orally to normal and STZ-diabetic rats daily for 5 weeks controlled hyperglycemia [130]. A study by Kumar et al. [101] found that garlic plus metformin treatment in patients with type-2-diabetes mellitus for a duration of 12 weeks produced a drastic decline in blood glucose level. In alloxan induced diabetic rabbits, different solvent extracts produced antihyperglycemic effect [131]. Alloxan induced diabetic rats put on a diet containing garlic for a period of 15 days recorded a significant reduction in blood glucose as compared to the control group [132]. Oral administration of diet containing ajoene (obtained from garlic) for two months was also reported to reduce blood glucose in genetically transformed diabetic mice [133]. Garlic oil and diallyl trisulfide given for 3 weeks to diabetic rats markedly elevated the basal insulin levels and also increased its sensitivity [134]. Oral administration of S-allyl cysteine sulphoxide isolated from garlic to alloxan diabetic rats for one month ameliorated hyperglycaemia in treated rats, which was comparable to glibenclamide and insulin treated rats [125]. Furthermore, S-allyl cysteine sulphoxide was reported to significantly stimulate insulin secretion from beta cells isolated from healthy rats [135]. Intraperitoneal injection and oral administration of Bis (allixinato) oxovanadium (IV) to type-1-diabetic mice showed potential as a potent antidiabetic agent [136]. According to Mathew et al. [137], oral administrations of 0.25 mg of allicin to mild diabetic rabbits exhibited pronounced antihyperglycemic effect.
A clinical study has confirmed that garlic improves glycemic status by decreasing fasting blood glucose concentration and postprandial blood glucose level in humans [102]. According to Miron et al. [110], allicin acts to restore delayed insulin response by reacting with endogenous thiol molecules and to lower insulin resistance in diabetic patients. It has the ability to freely permeate through phospholipid bilayers of membranes and this enhances its intracellular interaction with thiols. Toxicity studies have shown that excessive intake of garlic is considered toxic due to the sulphone hydroxyl ion constituent. This constituent is capable of penetrating the blood-brain barrier and can cause damage to brain cells. A study by Johnson et al. [138] on alloxan induced diabetic Wistar rats demonstrated that high doses of garlic extract greater than 400-mg/kg body weight per day induced morphological changes that presented severe threats to the heart, kidney, and liver of Wistar rat. However, low doses of 250-350 mg/kg body weight/day had no deleterious effects on the organs mentioned. Raw garlic is reported to also promote botulism, inhibit blood clotting, and trigger allergic reactions by the skin and mucous membrane [17].
Aloe vera (Aloe barbadensis). This plant is commonly referred to as Aloe. Aloe barbadensis: the plant is widely distributed, cultivated, and used in many homes in Ghana for several purposes. It is believed to have originated from Sudan. The sap consists largely of D-glucose, Dmannose, tannins, steroids, phytosterols [lophenol, 24methyl-lophenol, 24-ethyl-lophenol, cycloartenol, and 24methylene-cycloartanol], amino acids, vitamins, and minerals. Fresh aloe juice from the inner leaf parenchyma contains 96 % water.
Dry sap of the plant produced conspicuous antihyperglycemic response in alloxan induced diabetic albino mice [139]. Aloe vera leaf pulp extract showed antihyperglycemic activity on both types of diabetes in rat models, with the outcome enhanced in type-2-diabetes compared with the positive control-glibenclamide [140]. Extracts of aloe vera orally administered produced antihyperglycemic activity in oral glucose fed and STZ-diabetic rats [141]. Oral administration of ethanolic extract to diabetic rats for three weeks resulted in a conspicuous decrease in fasting blood glucose along with enhanced plasma insulin levels [142]. Oral administration of aloe vera gel extract for three weeks to diabetic rats ensued in a substantial reduction of blood glucose and improved the plasma insulin level [141]. Aqueous leaf extract of Aloe vera was reported to be useful and safe for reducing blood glucose levels in alloxan induced diabetes mice [58]. Administration of some phytosterols isolated from aloe vera to type-2-diabetic mice for 28 days resulted in a reduction in blood glucose levels [111,143]. A clinical study reported that oral administration of aloe vera was beneficial in lowering blood glucose concentration in diabetic patients [104,144]. It could be adduced that the antihyperglycemic effect of aloe vera and its principles may be through stimulating synthesis and/or release of insulin from the beta cells.
Momordica charantia. This plant commonly referred to as bitter gourd is an annual climber grown in Ghana for use as vegetable. It has a wide array of medicinal uses; however it is widely known for its use in the management of diabetes in Ghana. In Ghanaian traditional medicine, the aerial part is crushed and boiled and the strained liquid drunk as required [18]. Research has shown that [115,145] bitter gourd extracts from the fruit, seeds, and leaves contain several bioactive compounds that have hypoglycemic activity in both diabetic rats and humans. The hypoglycemic ameliorative effects of the fruit extract of the plant are reported to be closely linked to the increase in hepatic glycogen, peripheral tissue's glucose transporter (GLUT-4) expression, and higher insulin sensitivity through downregulating the expression of suppressor of cytokine signaling 3 (SOCS-3) and c-Jun N-terminal kinase (JNK) [90]. Fruit aqueous extract administered orally for 6 weeks with exercising decreased blood glucose of type-2 diabetic rats [146]. Blood glucose level dropped when about 4000 mg of Momordica charantia fruit extract was orally used to treat alloxan diabetic rats for 8 weeks [147]. Seed aqueous extract showed conspicuous decrease in blood glucose, glycated haemoglobin, glucose-6-phosphatase, lactate dehydrogenase, fructose-1, 6bisphosphatase, and glycogen phosphorylase coupled with a rise in glycogen content, hexokinase, and glycogen synthase activities [148]. Ethanolic extract of Momordica charantia also produced antihyperglycemic effects in streptozotocin diabetic rats [149].
Bioactive principles reported to be found in Momordica charantia are charantin, oleanolic, vicine, and momordicin [115]. Charantin, a sterol isolated from Momordica charantia seeds, induced hypoglycemic effect by stimulating the release of insulin [150]. Momordica charantia has also been reported to inhibit gluconeogenesis [151]. Its antidiabetic effect is similar to sulfonylurea-like medicines. According to Matsuda et al. [152], an experiment conducted using rat intestine showed that oleanolic acid and momordin from the plant exhibit antihyperglycemic activity through inhibition of glucose transport in the intestine. These compounds could be considered for use as dietary supplements for people with diabetes mellitus. In a clinical study of people with diabetes mellitus, polypeptide-p obtained from fruit, seed, and tissue exhibited antihyperglycemic effects with no adverse reactions [153].
Data available shows that extracts and the main isolated bioactive compounds [charantin, vicine, polypeptide-p, and momordicin] from Momordica charantia are considered to produce their antidiabetic effects through diverse physiological and biochemical processes [145].
The ethanolic extract of the fruit is reported to be safe in Sprague-Dawley rats at 2000 mg and below, whereas doses higher than 2000 mg could pose safety problems to delicate organs like the liver [154]. The seeds have been shown to decrease fertility in male Wistar rats and also produce side effects such as fever and coma. Momordica charantia is also reported to induce abortion in pregnant women [155]; thus care must be taken in usage.
Cinnamomum zeylanicum. Cinnamon is a spice derived from the stems of the C. zeylanicum tree. It is widely used in food preparations as a spice particularly in baking and for culinary purposes. The plant is not only used for making food taste better, but also used as home remedies and medicines. The dried bark has golden-yellow colour with pungent taste and scent due to the active constituent cinnamaldehyde and eugenol [113]. Cinnamon is reported to reduce blood glucose through decrease of insulin resistance and upsurge in the rate of hepatic glycogenesis [156,157]. Cinnamaldehyde possesses antioxidant and antidiabetic properties. Moreover, cinnamaldehyde demonstrated antihyperglycemic and antihyperlipidemic effects in rodent models [158]. Cinnamaldehyde is also reported to markedly and dose-dependently decrease plasma glucose concentration in streptozotocininduced diabetic rats [113]. All these evidence supports the fact that cinnamaldehyde from cinnamon extract is a potential antidiabetic agent and thus more research is needed in that direction.
Clinical investigation shows that cinnamon is useful in the management of both type-1 and type-2 diabetes mellitus [159]. Daily consumption of cinnamon regulates high triglyceride or cholesterol levels tremendously. It also aids in controlling elevated glucose level in type-2 diabetic patients. Toxicity studies conducted with ethanolic extracts of C. zeylanicum bark did not exert any observable adverse effects. Although the ethanolic extracts of C. zeylanicum bark have no reported acute or chronic oral toxicity in mice, it has been reported to cause reduction in liver weight as well as haemoglobin levels [160].
Costus afer Ker-Gawl. Costus afer Ker-Gawl (bush cane or ginger lilly) is herbaceous monocot, tropical plant with creeping rhizome commonly found in moist and shady forest of West and Tropical Africa. It is often planted in home gardens. The leaves are edible and the rhizome is sometimes used as a spice. In Ghana, all parts of the plant are used in traditional medicine, but the stem is the part mostly used for treatment of diabetes [75]. In an alloxan induced rat, there was a marked reduction in the blood glucose level when Costus afer aqueous leaf extract with concentrations 375, 750, and 1125 mg/kg and control drug (glibendamide Evidence-Based Complementary and Alternative Medicine 15 (5 mg/kg)) were orally given [76]. A dose of 375 mg/kg of the extract had a preservative effect on -cells [161]. This report is consistent with work by ThankGod et al. [162] that also reported on the regeneration of islet cells on administration of Costus afer stem extract to streptozotocin-induced rats. Moreover, the oral administration of 750 and 1125 mg/kg of Costus afer extract produced a more prominent regeneration of pancreatic islet cells and exocrine cell [163]. This therefore indicates that C. afer extract has a pancreatic (islet cells) curative property, which could help manage type I diabetes mellitus. This was consistent with the histopathological study of Costus afer extract on damaged pancreatic cells as reported by Ezejiofor et al. [161]. When stem extract was orally given to streptozotocin-induced rat, there was a marked drop in blood glucose level at extract dosage of 500, 1000, and 1500 mg in a concentration dependent manner [164]. In an in vitro study of the effect of solvents [hexane, ethyl acetate, methanol, and water] extracts of Costus afer stem, leaf, and rhizome on the activity of -glucosidase and -amylase activity, there was a significant inhibition of the enzymes. Ethyl acetate rhizome and methanolic leaf extract showed the highest inhibitory effect of the activity of the aforementioned enzymes with an IC 50 value of 0.10 and 5.99 mg/mL [36].
The stem and seeds are reported to contain several steroids and sapogenins; thus, diosgenin, saponins aferosides A-C, diosin, parphyllin c, flavonoid, and glycoside with diosgenin are the most potent [75]. Diosgenin ameliorates insulin resistance by increasing glucose usage and intracellular glycogen synthesis [165]. This is achieved by restoring pancreatic -cell function, alteration of hepatic enzymes, enhancement of adipocyte differentiation, inhibition of macrophage infiltration into adipose tissue, and decreased expression of inflammatory genes [165]. It is also reported to decrease the expression of the C/EBP homologous protein (CHOP) leading to reduced stress of endoplasmic reticulum in pancreatic -cells.
Also the effectiveness of diosgenin as an antidiabetic agent was evident by its effect on the renal antioxidant system and oxidative markers such as myeloperoxidase and lipid peroxidation. Diosgenin is reported to exhibit a protective effect on the kidney of diabetic rats and therefore serves as a potential candidate for treatment of diabetes mellitus with renal associated problems [165,166]. There is no reported toxic effect of diosgenin isolated from Costus afer in liver. Meanwhile a study conducted by Ezejiofor et al. [167] to investigate the subchronic toxic effect of the aqueous extract of Costus afer leaves on the liver and kidney of albino rats reported that it may be toxic to the liver but not to the kidney. This implies that much work needs to be done to provide more information on its toxicological effects.
Mangifera indica. Mango is a delicious and succulent fruit that has immense health benefits. It is popular in every part of the world including Ghana due to its delicious fruit. It is the major traditional fruit that is exported from the country. The leaf is traditionally used to treat diabetes in Ghana. Traditionally, a decoction of the leaves is drunk after meals [17]. Ganogpichayagrai et al. [42] demonstrated that leaf extract of mango tree possesses alpha amylase and alpha glucosidase inhibitory activity. Intraperitoneal administration of aqueous extract of stem bark produced a marked antihyperglycemic effect in streptozotocin-induced diabetic rats in a dose dependent manner. The oral administration of peel extract to streptozotocin-induced diabetic rats exhibited a significant antidiabetic effect [168].
Bioactive compound, mangiferin (MGF), mostly found in the leaves is reported to have alpha amylase and alpha glucosidase inhibitory effects [85]. Furthermore, mangiferin is reported to have antidiabetic as well as hypolipidemic potential effects in type-2-diabetic model rats. MGF inhibits anaerobic metabolism of pyruvate to lactate but enhances pyruvate oxidation suggesting that one of the targets of MGF is pyruvate dehydrogenase [169]. These observations highlight the therapeutic potential of activation of carbohydrate utilization in the correction of metabolic syndrome and emphasize the potential of MGF to serve as a model compound that can elicit fuel-switching effects. Mangiferin, a polyphenol isolated from M. indica, significantly prevents progression of diabetic nephropathy and improves renal function in diabetic nephropathy rat model and cultured rat mesangial cells [170]. Implicitly mangiferin is likely to possess beneficial effects in the management of type-2diabetes mellitus with hyperlipidemia.
Scoparia dulcis. Scoparia dulcis, commonly referred to as sweet broomweed, is an annual erect herb with many medicinal uses. It is a rich source of flavones, terpenes, and steroids. Some compounds found include coxicol, glutinol, scoparic acid D, luteolin, and apigenin; they are the main constituents found in the leaves and they have various pharmacological activities. The whole plant is used as a remedy for many ailments including diabetes mellitus. The fresh or dried leaves are used to manage hypertension and diabetes mellitus [171]. In Ghanaian traditional medicine, the dried leaves are boiled with water and strained and the decoction is drunk when needed [17].
An in vitro study performed to assess the -amylase and -glucosidase inhibitory potentials of the plant extract showed that the methanol extract of Scoparia dulcis effectively reduces postprandial glucose levels [172]. Investigation of the effect of the aqueous extract of Scoparia dulcis on streptozotocin-induced diabetes mellitus showed that the plant extract-mediated reduction in blood glucose was significant and was similar to that of glibenclamide [173]. According to Latha et al. [174], Scoparia dulcis possesses insulin-secretagogue activity. The administration of an aqueous extract of Scoparia dulcis to streptozotocin diabetic rats at a dose of 200 mg markedly reduced the blood glucose with significant increase in plasma insulin level during a 15-day period of treatment. The mechanisms of action of Scoparia dulcis plant extracts possessing antidiabetic effect have also been reported. According to Latha et al. [174], the antidiabetic activity of the aqueous extracts of S. dulcis may be attributable to its insulin-secretagogue activity. Also, S. dulcis imparts its antidiabetic effects via altering the levels of many antioxidant enzymes and enzymes of the polyol pathway. In fact, Latha et al. showed, using streptozotocin-induced diabetic rats, that the aqueous extract of S. dulcis significantly decreases the level of sorbitol dehydrogenase while increasing the levels of the antioxidant enzymes [173]. Beh et al. [175] demonstrated using L6 rat myoblasts (CRL-1458) that the TLC fraction seven of the aqueous extract of S. dulcis possesses glucose uptake activity comparable to that of insulin.
Luteolin, a flavonoid isolated from Scoparia dulcis, is reported to inhibit alpha glucosidase better than acarbose, a standard drug. Luteolin, an active constituent in the leaves of Scoparia dulcis, is reported to improve hepatic insulin sensitivity by suppressing expression of sterol regulatory element-binding transcription protein 1 (SREBP1) that modulates insulin receptor substrate 2 (Irs2) expression through its negative feedback and gluconeogenesis. Scoparic acid D has also been reported to possess antidiabetic effects [176].
The data supports the traditional use of Scoparia dulcis as an antidiabetic medicinal plant. Furthermore, luteolin and apigenin, flavonoids of Scoparia dulcis, have been shown to influence glucose metabolism by activating the transcription factor FOX O1 (forkhead-box gene O1) in human cells [177,178].
Zingiber officinale. Ginger is one of the most ancient spices cultivated for its edible rhizome. The rhizome serves a variety of purposes including culinary and medicinal applications. Medicinal properties attributed to ginger include hypolipidemic, hypocholesterolemic, and antidiabetic effects. In a study based on STZ induced diabetic rat model reported, oral administration of ethanolic extract of ginger markedly reduced blood glucose level [179]. Another study demonstrated that there is a substantial blood glucose lowering effect of ginger juice in diabetic animals [180]. Ahmed and Sharma have also shown that administration of ginger extract in rats recorded a significant hypoglycemic effect [181].
Several constituents are reported to be present in ginger that include terpenes and oleoresin, which are generally called ginger oil. Ginger also contains volatile oils and nonvolatile pungent components such as oleoresin [182]. The major identified components from terpene are sesquiterpene hydrocarbons and phenolic compounds, which are gingerol and shogaol.
The major bioactive constituent reported to be present in ginger is gingerol. Studies on ginger show that it increases glucose uptake through promotion of GLUT-4 translocation via adenosine monophosphate-activated protein kinase (AMPK) activation in L6 myocytes. It has been reported that gingerol protects pancreatic -cells from oxidative stress, increases insulin receptors sensitivity, and enhances -cell function to decrease insulin resistance [117]. Gingerol has also been shown to regulate in vivo hepatic gene expression of enzymes involved in glucose metabolism, leading to a decrease in glucose production and an increase in glycogen synthesis, which contributes to the antihyperglycemic effect of gingerol. Studies have shown that gingerol could provide therapeutic as well as prophylactic benefit for type-2 diabetes individuals [117]. Ginger has no known reported toxic dose. However overconsumption can cause some minor side effects. For example, some people have experienced side effects including heartburn, diarrhea, and general stomach discomfort following consumption of ginger. High dose of ginger can also interact with certain drugs such as warfarin used in the treatment of heart condition and increase their effect to result in symptoms such as irregular pulse, palpitations, confusion, loss of appetite, diarrhea, nausea, and vomiting. Large doses may also cause dizziness and minor sedation and increase the risk of bleeding in women as well [17].

Discussion
The adoption of a Western lifestyle and urbanization is cited as a major cause for the tremendous increase in metabolic diseases such as diabetes mellitus in Africa, including Ghana [183]. Currently, there is no known cure for diabetes mellitus despite the availability of various classes of pharmacological agents for management of diabetes mellitus. Currently, issues related to efficacy, safety, and affordability of existing pharmacological agents for management of diabetes are driving patients to turn to complementary and alternate medicine (CAM), including plant medicines for the management of diabetes mellitus. Indeed, it has been estimated that up to one-third of diabetic patients use CAM to manage their condition. A growing number of phytomedicines and their chemical constituents have been studied in the treatment of diabetes mellitus. Despite the increased use of phytomedicines, with over 70% of the world's population using some form of it, according to WHO [184] many still lack thorough experimental investigation data to support their use.
Plant medicine remains an important means by which humans have treated ailments, prevented diseases, and maintained health for centuries. Traditional knowledge and use of plant-based medicines remain important in Ghana because Traditional Medical Practice (TMP) is readily available and is affordable to rural communities in Ghana. Various plants are used for managing diabetes mellitus in Ghanaian Traditional Medicine Practice [14,17,18,21,185] but not much is known about the plants used.
Of the plants discussed Aloe vera has the highest evidence supporting its use in diabetes mellitus, with multilateral level of support from in vitro, animal, and clinical studies and elucidation of active principle and testing in an animal model [103,111,143,185]. Other findings also support its use in the treatment of various complications that arise from diabetes mellitus demonstrating broad clinical utility. Thus Aloe vera remains the hallmark of phytomedicine for diabetes mellitus though there are minor concerns over toxicity. Momordica charantia and Zingiber officinale offer the next most extensive evidence for use in managing diabetes mellitus with preclinical studies in animal models, with human studies showing clinical efficacy.
In this review, information on Ghanaian medicinal plants used for diabetes mellitus has been compiled (Tables 2 and  3). The information gathered demonstrates that some of these plants and/or their preparations show promise in managing diabetes mellitus. The review provides information on pharmacological mechanisms of some of the plants. The study shows that some of the plants and their bioactive compounds ( Figure 1) act by reducing glucose absorption through inhibition of the action of enzymes such as sucrase, -glucosidase, and maltase. Others act through cellular mechanisms such as regeneration of pancreatic -cell by inhibiting the atrophy of pancreatic islet tissue. Some medicinal plants have also been shown to suppress accumulation of fat and dyslipidemia through the enhancement of energy expenditure enzymes such as carnitine palmitoyl-transferase1 and acyl CoA oxidase and also attenuating enzymes involved in fatty acid synthesis that occurs in the liver. Furthermore, some of the plants have antioxidant and anti-inflammatory potentials and thus may be playing a central role in acting against diabetes associated with metabolic disorders of liver and kidney. Others reduce hepatic glucose output and enhance glycolysis, glycogenesis, and reduction in glycogen breakdown and gluconeogenesis.
This review has also identified various experimental studies that have examined the efficacy of antidiabetic medicinal plants. Results obtained from clinical trials revealed that using medicinal plants notably improves levels of biochemical indices of people with diabetes. Moreover, some principles isolated from these plants indicated antidiabetic activity with better efficacy than orthodox oral hypoglycemic agents. This piece provides scientific evidence of the effectiveness and efficacy of phytomedicines in the management of diabetes mellitus. Most of these studies did not reveal any major adverse effects consequent to the use of these medicinal plants suggesting that they are generally safe.

Concluding Remarks and Future Direction
Ghana is bestowed with abundance of plant biodiversity; several are used in managing diabetes mellitus in Traditional Medicine Practice. This review indicates that there is substantial preclinical evidence and some clinical data to support the usefulness of some of these herbs as antihyperglycaemic agents. The provision of information on medicinal plants used for the management of diabetes mellitus in Ghana in this narrative can serve to promote a more rational medicinal use of these plants. These can also offer evidence-based data for clinical development of many of these potential medicinal plants. Further phytochemical elucidation and pharmacological research should be carried out on many ethnomedicinal plants used in Ghana to standardize these traditional medicines with definite antidiabetic or antihyperglycaemic activity. Ultimately, in giving credibility to the preclinical data, clinical trial studies ought to be carried out in order to validate their medicinal usefulness in people with diabetes mellitus. It is believed that, this way, the pharmacotherapeutic potential of these plants could be harnessed towards a possible all-inclusive integration into the healthcare system.

Conflicts of Interest
The authors declare that there are no conflicts of interest.