Medicinal Plants Used in Four Local Government Areas of Southwestern Nigeria for the Management of Diabetes and Its Comorbidities: An Ethnobotanical Survey


 Background:Diabetes mellitus (DM) continues to pose a major global health threat with serious economic burden in sub-Saharan Africa, especially Nigeria. This condition is often worsened with accompanying comorbidities, further putting a strain on patient wellbeing. Medicinal plants are not only effective in DM, but some of them are also have beneficial effects on accompanying disease states. Such plants may be appropriate alternatives or adjuncts to available antidiabetic medications. This study aimed at accessing and documenting the medicinal plants used in four local government of southwestern Nigeria for the management of diabetes and its comorbidities.Methods:Semi-structured questionnaires were used to obtain information from traditional medical practitioners, village elders and herb sellers. The data obtained were analyzed and discussed in relation to previously published literature. Fifty-three respondents mostly males (77.4%) provided information on medicinal plants useful for the management of diabetes and its comorbidities.Results:A total of 77 medicinal plants belonging to 76 genera in 44 plant families were mentioned in the survey. In particular, 53 medicinal plants are mentioned for managing diabetes, 35 for hypertension, 28 for stroke, 17 for heart diseases and 25 for obesity. The most frequently cited plant family was Leguminosae (12%), followed by Euphorbiaceae (8%). The frequently used plant species includesVernonia amygdalina, Citrus aurantifolia, Viscum album, Carica papaya, Allium sativum. It is interesting to note that only Citrus aurantifoliawas mentioned severally for the management of the five ailments. The herbal recipes, methods of herbal preparation and administration were also recorded.Conclusions:The survey shows that a significant number ofmedicinal plants are used for the management of diabetes and its comorbidities in the study area. These plants, apart from their hypoglycemic activity, may be useful against the most common complications of DM and may provide strategies for the development of less expensive therapies especially in low income communities.


Introduction
Medicinal plants have been used for several centuries for the treatment of various ailments and almost seventy thousand species of plant in the world have been screened for their pharmacological activities (1). The importance of the tropical rain forest as a source of raw materials for modern drug development cannot be overemphasized as about 11% of the 252 drugs considered to be essential drugs are exclusively of plant origin with several others synthesised using natural products template (2). In Nigeria, medicinal plants play prominent role in healthcare delivery as many of her residents, especially those dwelling in the rural areas, rely greatly on medicinal plants and visit traditional medical practitioners (TMPs) for their health care need (3). An earlier study reported that the ratio of TMPs to the population was 1:110, while the ratio of medical doctors to the population was 1:16,400; inferring that TMPs are more accessible to the populace (4). Therefore, herbal medicines continue to play vital role in healthcare delivery, especially in third world nations, where most people have great nancial constraints with little or no access to orthodox therapies (3). longitude 4° 89' E with a land mass of 15,500 km 2 and a population of 3, 440,000 as at the 2006 national census (25). The inhabitants of the urban settlers in the study area were mainly educated and involved in high skill jobs, while the rural dwellers were predominately farmers and local traders. The common language spoken by the residents of the study area is Yoruba. The study area has a tropical climate characterised by two distinct weather conditions; rainy season which begins in April and ends in September and the dry season which runs from October to March. The area experiences a relatively high rainfall and humidity for most parts of the year with an average temperature around 32 °C.

Ethnobotanical Survey
Informed consent At the start of the interview, the objective of the study was clearly explained to the intending participants and informed consent to publish the research was sought orally. When the respondents granted consent, the questions contained in the questionnaire were asked and when consent was not given, the individuals were asked no further question.

Plants authentication
Medicinal plants used for the management of hypertension and its co-morbidities were collected with the aid of the TMP and authenticated by comparison with voucher specimens at the Forest Herbarium, Forestry Research Institute of Nigeria, Ibadan. The names of the plants were veri ed at the plant database website (www.theplantlist.org; accessed on September 22, 2018).

Data collection
The study was conducted carried out from May to October, 2014. The ethnomedicinal information of plants used for the management of DM and its comorbidities such as hypertension, obesity, stroke and heart disease were obtained by consulting TMPs, herb sellers and elders in the communities listed above. The use of semi-structured questionnaire via oral interview in the local dialect of the respondents was adopted to obtain the relevant data. Since the interviewer understood the local dialect of the respondents, no interpreter was used in this survey. The questionnaire was divided into three sections. Section 1 deals with demographic information such as age, sex, religion, local tribe, duration of practice, nationality and level of education. Section 2 captures plants used in the treatment of DM and its comorbidities and consisted questions such as frequency of treatment, accompanying side effects and duration of treatment. Section 3 centered on plant parts used, plant availability, local names of diseases, preparation of the recipe and mode of administration of the herbal recipe used in the treatment of diabetes and its comorbidities. Each plant sample was collected at the time of the survey. The botanical names and families of each collected plant samples were authenticated at the Forest Herbarium Ibadan (FHI), Nigeria.

Data analysis
The Microsoft O ce Excel spreadsheet (2016) software was used to conduct descriptive statistical analysis on the socio-demographic data of the respondents, plant part used and plant families. The usementions index (UMi) was also calculated and was taken as the frequency of usage of a particular plant for the treatment of diseases divided by the total number of respondents interviewed.

Results And Discussion
Demographic data and treatment practice of respondents Seventy individuals, including TMPs, herb sellers and village elders, who possess knowledge on the ethnomedicinal use of plants and/or had utilised them for DM and/or its comorbidities in the study area were identi ed and interviewed. However, only 53 respondents agreed to provide their valuable IK. The demographic information of the respondents is summarized in Table 1. As can be seen from the table, the majority of the respondents were male (77.36%), a nding similar to other results obtained from several other ethnobotanical studies within the same region (3,24,26,27). This may be unconnected to the cultural perception that the male gender is the heirloom of family heritage making them to easily acquire IK. In addition, it is perceived that the exhaustive and often dangerous practices associated with traditional medicine as exempli ed with the collection of medicinal plant from the wild where many wild animals reside may also discourage many female individuals from embracing the practice. Most of the respondents (69.8%) were Muslims and more than half of the respondents were elderly. Inheritance was the major source of knowledge acquisition as the results presented in Table 1 revealed that 54.7% of the respondents inherited their knowledge from their parents/ancestors, while only 15.1% obtained their IK through training. In view of this, it is expedient to document the use of medicinal plant in the treatment of various ailments as this will go a long way in the preservation of IK. Majority of the respondents had the basic (primary) level of education (66%) with only four of them having no formal education. In view of the nature of the practice, the respondents commonly referred to DM as 'itosuga' and claimed they were able to diagnose DM in their patients by examining the presence of sugar in urine which is detected when ants surround the spots of their clients' urine few minutes after urination. Other symptoms that also aided them in the diagnosis of DM included excessive urination, sweating and loss of weight.
The respondents referred to hypertension as 'ifunpa giga' and claimed that they normally relied on the laboratory results presented by their patients to diagnose the disease. Stroke, referred to as 'roparose'by the respondents was diagnosed by observing the patient for partial paralysis of a side of the body or the complete paralysis of the body along with impaired speech or vision. For obesity (isanraju), respondents diagnosed the disease by visually observing the fatness of their patients relative to other individuals of the same age and sex.The respondents could not actually differentiate between being overweight and obeseas they claimed the herbal treatments, they prepared were administered to individuals who desired to reduce their body weight, not necessarily obese patients. Heart disease (arunokan) is diagnosed by the respondents when patients have symptoms such as persistent irregular heartbeats, shortness of breath and dizziness. The respondents claimed to have successfully treated many patients suffering from these ailments using the various medicinal plant recipes.

Diversity of medicinal plants, herbal preparation and administration
In the Nigerian ethnomedicine, medicinal plants have been frequently used in the management of human degenerative ailments such as DM and its comorbidities. Medicinal plants have wide patronage due to their accessibility, potency and affordability. There have been several reports of successful treatment of various disease conditions with herbal therapy (28)(29)(30)(31). In the present study, 77 medicinal plants belonging to76 genera in 44 plant families were used by the respondents in the management of DM and its co-morbidities. In particular, 53 medicinal plants were used for the management of DM, 35 for hypertension, 28 for stroke, 17 for heart diseases and 25 for obesity ( Table 2). The plants mentioned in this survey were readily available as they were easily obtained from the forest, around homes and in the market places. Of the plant species encountered in the study for the treatment of various ailments, trees constituted 45% of the plant population, while shrubs, herbs and climbers contributed 33%, 18% and 4%, respectively. The analysis of the plant parts used in this study revealed that the predominant plant part was dominated by leaves (43%), followed by stem (27%) and fruit (10%) (Figure 2). Similar occurrences were recorded in previous ethnobotanical studies in several parts of Nigeria (3,24,(32)(33)(34). This could be connected to the relative availability of leaves for most part of the year and its collection posing the least threat to biodiversity conservation. The most frequently cited plant family was Leguminosae (12%), followed by Euphorbiaceae (8%), Apocynaceae (6%), Compositae (5%) and Anacardiaceae (4%), with the remaining plant families having percentage occurrence less than 3% ( Table 2).
The recipes obtained from the respondents were found to be poly-herbals as they believe it is a more holistic method of managing the illness and they claimed it is more potent than the use of individual plant species. Previous studies have revealed that the combination of several plant species in traditional medicine offers synergistic approach to the management of the ailment as each plant will contribute different quota to the therapeutic e cacy of the recipes (35,36). In this study, twenty-three, nineteen, eleven, ten and seven herbal remedies were mentioned for the treatment of diabetes, hypertension, stroke, heart diseases and obesity, respectively (Supplementary material). Various methods employed for the preparation of the herbal recipes were encountered in this study including decoction (43%), juice (22%), infusion (20%), powder (9%) and paste (6%). The powdered preparations were used when mixed with hot pap, while decoctions and infusions were usually made with water or pap water. The pap water and hot pap were obtained by soaking dried corn in water for three to four days to soften it after which it was ground to form a smooth paste. To get rid of corn shaft that may be contained in the paste, it is sieved and made to stand for three days. The supernatant is called pap water, whereas hot pap was obtained by boiling the sediment in hot water . The liquid preparations were administered using a cup or table spoon, whereas the pastes were applied externally on the affected part.
Data obtained from this study revealed that Vernonia amygdalinaDelile was the most frequently used plant with a user mention index ( Aframomummelegueta(family: Zingiberaceae), commonly referred to as Alligator pepper or grain of paradise, is a tropical plant widely cultivated in many African nations for its edible spicy fruits (37). 6gingerol and oleanolic acid isolated from the fruits of A. melegueta showed strong inhibition of the activity of α-amylase and α-glucosidase, when compared to the standard antidiabetic drug, acarbose, and the antidiabetic effect of the fruits of A. meleguetacould be attributed to these compounds (38). The administration of the seeds of A. meleguetaproduced signi cant reduction in several cardiovascular parameters including the systolic blood pressure and mean arterial pressure (MAP) in normotensive and hypertensive human population (39). Adefegha et al reported that the inclusion of A. meleguetaseeds in the diet of hypercholesterolemic rats for 30 days signi cantly reduced the MAP, attenuated hepatotoxicity and elicited antihypercholesterolemic effect suggesting the plant may have therapeutic usefulness in the management of hypertension and obesity (40). In a similar research, the seeds of A. meleguetaameliorated the increment in serum triacylglycerol, low-density lipoprotein (LDL) cholesterol and total cholesterol as well as the decrease in the activities of superoxide dismutase, glutathione peroxidase and glutathione reductase caused by the administration of Triton X-100 in hyperlipidemic rats (41).
Allium sativum (garlic) is an important functional food and dietary supplement in many parts of the world.. In particular, there is a wide assumption that they confer protective effect on the heart and prevent several cardiovascular diseases and this has been validated scienti cally in several literature (42)(43)(44)(45).
Garlic signi cantly reduced the blood glucose levels of STZ-induced diabetic rats as well as attenuated the progression of diabetic structural nephropathy that was observed in non-treated diabetic rats (43), while another similar research reported that the extract markedly reduces the serum levels of triglycerides, creatinine, total cholesterol and LDL-cholesterol (46).
Bryophyllumpinnatum(family: Crassulaceae), commonly referred to as resurrection plant, is a herbaceous plant native to Madagascar but with widespread use in many parts of the world. Several researches have shown that the chronic administration of the aqueous extract of B. pinnatum produced hypoglycemic effect in STZ-induced diabetic rats as well as elicited a signi cant reduction in the serum cholesterol and triglyceride levels (47)(48)(49). In a recent study, B. pinnatumreduced lipid peroxidation in heart and liver and exerted antihypercholesterolemia in rabbits (50).
Decoctions and infusions obtained from the morphological parts of Carica papayahave been used traditionally in the management of several ailments including cancer, DTN, diarrhea, in ammation and infectious diseases (51). In an early human study, there was an increase in the serum insulin levels of type 2 diabetic patients that took 602 g of C. papaya fruit; a nutritional dose that is equivalent to 50 g of carbohydrate (52). The administration of the methanol extract of C. papaya leaves to Wistar rats at a twice daily dose of 100 mg/kg bw displayed remarkable antihypertensive effect as it reduced the plasma angiotensin converting enzyme (ACE) activity and cardiac hypertrophy at levels similar to the positive control, enalapril (53). Other studies showed that the root extract of the plant reduces the MAP of rats in a renovascular model of hypertension (54).
Citrus aurantifolia is a small tree used in African traditional medicine for the management of anorexia, obesity, malaria, DTN and cancer and cough (3,55). Administration of the C. aurantifoliajuice in rats with high cholesterol diet intake signi cantly reduced the levels of LDL and total cholesterol, while causing an increment in the plasma HDL cholesterol levels. In the same study, the juice of the plant inhibited the activity of ACE in a dose dependent manner and also exerted potent antioxidant potential in various in vitro antioxidant assays including DPPH and nitric oxide scavenging assays (56). In a 45-day study, the simultaneous administration of the essential oils of C. aurantifoliawith ketotifen signi cantly reduced the consumption of food and caused drastic weight loss in experimental mice (57).
Persea americana, a tree of about 20 m and indigenous to South Central Mexico, is used in traditional medicine for the treatment of hypertension (58), DTN (59), renal diseases (60) and obesity (61). Phenolic compounds including protocatechuic acid, kaempferide and vanillic acid present in the methanol extract of the seeds of P. americana were thought to be responsible for the signi cant reduction in the LDL and total cholesterol levels of mice on high hyperlipidemic diet (62). An earlier study revealed that methanol extract of the leaves of P. americana induced a transient reduction in MAP in anaesthetized normotensive rats (63), while another in vivo study demonstrated that the extract displayed signi cant vasorelaxant effect on isolated thoracic rat aorta (64). The chronic administration (28 days) of the hydroethanolic extract of P. americana in STZ-induced diabetic rats decreased the blood glucose levels and enhanced the metabolic activity of the experimental animals; an effect probably due to the activation of the protein kinase B enzymatic pathway (65).
Vernonia amygdalina (Asteraceae), a shrub indigenous to tropical Africa, is probably the most widely used member of the Vernonia genus for medicinal purpose. Several researches have documented the use of V. amygdalinain the management of DTN and vascular diseases. The aqueous extract (80 mg/kg) of the leaves of V. amygdalinawas shown to induce a dose-dependent blood sugar lowering effects in alloxan-induced diabetic rabbits (66), while the chronic administration of its ethanolic extract (400 mg/kg) was reported to elicit a hypoglycemic effect as well as induce the expression of Glut 4 receptors in STZ-induced diabetic rats. In a study demonstrating the lipid lowering effects of the methanolic extract of V. amygdalinaconducted in rats fed with high cholesterol diet, V. amygdalinaat a dose of 200 mg/kg induced 49% dose-dependent decrease in LDL cholesterol, while it increased the levels of HDL by 59%. In addition, the extract signi cantly decreased the levels of plasma and post mitochondrial fraction lipid peroxidation by 42% and 45%, respectively (67).
Viscum album (Loranthaceae), commonly referred to as African mistletoe, is used for the management of abdominal discomfort, anxiety, DTN, epilepsy, hypertension and stroke (68). Nkanuand co-workers reported that the crude extract of V. album at a dose of 150 mg/kg bw signi cantly reduced the blood glucose and MAP of diabetic and hypertensive rats by about 84.2% and 34.5%, respectively (69). The methanol extract of V. album exerted anti-diabetic and anti-hyperlipidemic effects in STZ-induced diabetic rats by decreasing the fasting blood glucose level by 34% and signi cantly reducing the levels of serum triglycerides, lactate dehydrogenase and LDL cholesterol, following a chronic administration (21 days) of the extract at a dose of 100 mg/kg bw(70).
Xylopiaaethiopica'sfruits and seeds are used for culinary purposes in many regions of Africa (71). In a recent study, dietary supplementation of hypercholesterolemic rats with Ethiopian pepper fruits signi cantly reduced the plasma ACE and total cholesterol levels, as well as reversed the elevated serum levels of alanine aminotransferase and aspartate transaminase caused by the high cholesterol diet. Phenolic compounds including rutin, quercetin and ellagic acid were accounted to be responsible for the observed antihypertensive and hypolipidemic properties (72). Administration of a 50:50 mixture of Alstoniacongensisbark and Xylopia aethiopica fruits had a signi cant hypoglycemic effect in normoglycemic rats (73), while the chronic administration of a herbal mixture (Okudiabet®), which contains X. aethiopica as one of its principal constituents, markedly reduced the blood glucose levels in alloxan-induced diabetic rats (74).
Zingiber o cinale (ginger) has a long historical use in traditional medicine in various culture and has been scienti cally validated for the treatment of several diseases including DTN, hypertension and other cardiovascular ailments (75). The ethanolic extract of ginger signi cantly lowered the several serum lipid parameters such as total cholesterol, triglycerides and LDL-cholesterol and also protected the pancreas and liver from lipid peroxidation in STZ-induced diabetic rats (76,77). Administration of the ethanolic extract of Z. o cinalerhizomes produced a dose-dependent reduction in blood glucose levels in normoglycemic and STZ-induced diabetic rats (75), while another study revealed that a single administration of ginger juice attenuated 5-hydroxytryptamine induced hyperglycaemia in diabetic rats (78). Several in vitro studies have reported the inhibitory activity of Z. o cinaleon AA-induced platelet aggregation, COX-derived thromboxanes and prostaglandin synthesis (79)(80)(81).

Conclusion
To summarize our ndings, we present in this report the inventory of medicinal plants in four local government areas of southwestern Nigeria used for the management of DTN and its comorbidities. A total of 77 medicinal plants belonging to 76 genera in 44 plant families were mentioned by the respondents. In particular, 53 medicinal plants were used for the management of DTN, 35 for hypertension, 28 for stroke, 17 for heart diseases and 25 for obesity. The most frequently cited plant family was Leguminosae (12%), followed by Euphorbiaceae (8%), Apocynaceae (6%), Compositae (5%) and Anacardiaceae (4%) with the remaining plant families having percentage occurrence less than 3%..
While only Citrus aurantifoliawas mentioned by several respondents for the management of the ve ailments, review of literature has con rmed the multiple effect of some of the key plants on diabetes and it's commorbidities. As most of the respondents encountered in this study belong to the elderly population, this documentation will serve a great deal in preserving the indigenous traditional knowledge of the local communities.Since most diabetic patients often have one or more accompanying comorbidities, a safe and e cacious herbal preparation that can manage both diabetes and its comorbidities may provide scienti c breakthrough especially for the local communities.

Declarations
Ethics approval and consent to participate.
Informed consent was obtained from each participant according to the guideline of Research Ethics Committee of the University of Ibadan. A copy of the form used is available upon request.  Medicinal plant parts used in the preparation of various remedies for the treatment of diabetes and its comorbidities in four local government areas in southwestern Nigeria.