Efficacy, safety and phytochemistry of medicinal plants used for the management of diabetes mellitus in Ethiopia: a systematic review

Despite tremendous developments in synthetic medicine, medicinal plants are still commonly used for the management of diabetes mellitus. This study synthesized scientific evidence on commonly used medicinal plants for the management of diabetes mellitus (DM) in Ethiopia. Databases (PubMed, Cochrane, CINAHL and Google Scholar) have been thoroughly sought and evidence was synthesized. Thirty studies conducted anti-diabetic activities studies on 19 medicinal plants in Ethiopia. Most of the studies were in vivo studies (25). Others include; clinical study (1), in vitro studies (2), and both in vivo and in vitro study (2). Trigonella foenum-graecum L., clinical study, showed an improved lipid profile in type II diabetic patients. Comparable blood sugar level (BSL) lowering effect to glibenclimide was observed with Persea Americana and Moringa stenopetala. Noteworthy in vitro half maximal inhibitory concentration (IC 50) of Aloe megalacantha B and Aloe monticola R were observed. Animal model studies demonstrated the relative safety of the plants extract and phytochemistry studies showed various components. Medicinal plants used for management of diabetes mellitus in Ethiopia are worthy for further study for pharmacologically active ingredients and clinical evaluation.


Background
Diabetes mellitus (DM) is a metabolic disorder characterized by hyperglycemia due to impaired insulin secretion, defective insulin action or both. Chronic hyperglycemia is associated with long term microvascular complications affecting the cardiovascular, eyes, kidneys, and nerves [1]. The complications include nephropathy, retinopathy, nephropathy, peripheral vascular disease and coronary heart diseases [2]. The complications cause major impact on the lives and wellbeing of individuals, families and societies.
No successful cure for DM has yet been found but can be managed using insulin, diet modification and oral anti-diabetic agents. Herbal medicines could provide an alternative management. Compromised effectiveness, cost, accessibility, affordability, and tolerability are some of the limitations of current conventional anti-diabetic medicine. African medicinal plants are commonly used in the management of DM and provide an alternative therapy. Research is required on different indigenous plant and herbal formulations. The research will shed light on effectiveness and safety of herbal medicines. The findings will help to discover novel drugs and/or optimize the traditional use.
In Ethiopia, there are numerous medicinal plants used for DM and a number of these were assayed for their anti-diabetic activity. An estimated 80 to 90% of Ethiopians use herbal medicine as a primary form of health care [3] and many rural communities continue to depend on it [4]. There are preliminary studies on the scientific evidence of commonly used medicinal plants in Ethiopia though evidences were not synthesized. With a lack of critical appraisal on the currently evidence studies, this study aimed at reviewing information on the reported scientific evidence for effectiveness of medicinal plans used in Ethiopia in the management of DM.

Study design
This systematic review and meta-Analysis was conducted using databases searches and the reporting adhered to the Preferred Reporting Items for Systematic Review and Meta-Analysis [5]. PRISMA checklist was included as additional file (see Supplementary file 1).

Search strategy
Databases, PubMed, CINAHL, the Cochrane Central Register of Controlled Trials and clinical trial.gov and Google scholar, were searched from inception to May 25, 2020. The reference lists of all identified articles were searched for additional studies. Flow diagram was used to summarize the number of studies identified, screened, excluded and finally included in the study. Key words used in the search include (Diabetes mellitus OR T1DM OR type I diabetes mellitus OR T2DM OR type 2 diabetes mellitus) AND (Plant* OR herb* OR dietary supplement* OR traditional medicine*) AND (Ethiopia).

Study selection and data extraction
Three reviewers (SS, KE and EW) independently carried out a literature search and examined relevant studies and sequentially screened their titles and abstracts for eligibility. The full texts of potentially eligible studies were retrieved. Disagreements were resolved on discussion with the fourth author (SD). A screening guide was used to ensure that all review authors reliably apply the selection criteria. Human, animal and in-vitro studies which were conducted to examine anti-diabetic effect of medicinal plants in Ethiopia were included. Data extraction was performed using a pre-designed format. Extracted data include first author, study area, scientific, family and local name, study model used, the animal type used, extraction method used, a component of the extract used, duration of treatment, and change in BSL (from diabetic control, from normal control and standard control). A study is included if the effect on diabetic control is reported, otherwise it is excluded.

Definition of terms
Diabetic control refers animals with DM but no standard or experimental treatment is given which could refer a  placebo control. Whereas standard controls are animals with induced DM and treated with standard treatment most commonly glibenclamide. Normal controls are animal being followed and managed in the same was as experimental conduction but no induction of Dm or treatment is given.

In vitro studies
In vitro half-maximal carbohydrate digestive enzyme inhibitory concentration (IC 50) of Aloe megalacantha B, Aloe monticola R, Moringa Stenopetala, and Terminalia brownie Fresen were evaluated. The IC50 was less than100 μg/ml except ethanolic extract of Moringa Stenopetala and aqueous extract of Terminalia brownie Fresen. All extract and fractions showed less effect compared to a standard control (acarbose), Table 2.

In vivo studies
There was a significant difference in duration of treatment among in vivo studies, ranges from 4h to 30 days. Fifteen studies used mice, three used rats, and two studies used both rats and mice. In eight of the studies the plant was extracted using methanol, in six ethanol extract and in other six aqueous extract was used, Table 3.

Clinical studies
Trigonella foenum-graecum L. showed noteworthy effect on lipid profile of newly diagnosed type II diabetic patients [6]. Out of 114, 95 completed the study, 49 in the treatment group and 46 in the control group. Both treatment and control groups had abnormal FBG (≥180 mg/dL) and abnormal lipid profile (TC, TG, HDL-C, and LDL-C) at baseline. Trigonella foenum-graecum administered (25 mg seed powder solution for 30 consecutive days) showed a significant reduction (13.6%) in serum TC level as compared to baseline TC level. Yet, no significant difference in TC level in the control group. The treatment group showed a statistically significant decrease (23.53%) in serum TG level compared to baseline TG level but the control group had no significant difference in TG level. HDL-C level was significantly increased in the treatment group by 21.7% as compared to the baseline HDL-C level within the group. LDL-C level had a significantly reduced by 23.4% as compared to the baseline LDL-C level. Trigonella foenum-graecum produced a significant reduction in TC, TG, and LDL-C levels and an increase in HDL-C level compared to baseline.     [10, 12-15, 21, 22, 26, 28]. Other plants showed LD 50 greater than 5000 mg/ kg [11,16,19,20,23]. The LD50 of Moringa stenopetalla were 50.6 g/kg [11] and 50 g/kg [23]. The LD 50 of Persea Americana was greater 1000 mg/kg [23]. The sub-chronic toxicity of Moringa Stenopetala showed normal hematological, significantly higher platelet counts compared to controls, significant changes were observed in the clinical chemistry parameters (urea, creatinine, CA125, TSH, FT3, ALT, TGs, and cholesterol), FT4 significantly reduced, and AST were significantly higher in the mice received the treatment [7].

Phytochemistry
Preliminary phytochemical investigation were given in Table 4 and Tekulu et al, 2019 [25] further studied TLC isolates, AM1 and AG1, separated from leaves latexes of A. megalacantha and A. monticola respectively. AM1 and AG1are considered to be more polar compounds than AM2 and AG2 as they have small Rf values during isolation using silica gel coated TLC plate with chloroform: methanol (80:20) solvent system [25]. They could be assigned as glycosides of anthraquinones or its derivatives as they have similar Rf with previously isolated anthraquinone glycosides from leaf latex and root extracts of different Aloe species [38][39][40].

Discussion
This study reviewed twenty three articles on plants with anti-diabetic activity. Most of the studies (20) were conducted in an animal model, in vitro studies (2) and both in vitro and in vivo study (1). Noteworthy glycemic control was observed with T. brownie Fresen compared to a diabetic control. Carbohydrate digestion inhibitory effect was demonstrated in in vitro studies. The possible mechanism for hypoglycemic effect could be decreasing the absorption of ingested sugars as shown in in vitro αamylase/α-glucosidase inhibitory activity. The human study was primarily focused on the effect of body weight and lipid profile in patients with type 2 diabetes mellitus [6]. Numbers of studies conducted on anti-diabetic activity of Ethiopian medicinal plants were lower compared to studies conducted in many African countries. For example, a systematic review in Nigeria showed 103 plants have experimental evaluation of their blood sugar reducing effects, either in vivo or in vitro [41].
Several medicinal plants are being used traditionally for treatment of diabetes mellitus in Ethiopia for a long period of time but the number of plants studied is limited. This review summarized studies conducted so far and highlighting the need for further studies. Moringa stenopetala is the most commonly studied plant and other plants remain scantly studied. Inhibition of αamylase, a potential target to control diabetes mellitus for more than 30 years is considered a strategy for the treatment of diabetes mellitus [42].
The effect exerted by Moringa stenopetala could most probably be carbohydrate absorption inhibition resulting in hypoglycemia which could give an insight into the mechanism of the hypoglycemic activity of the antidiabetic plants. Herbal medicines are often complex mixtures of various phytochemicals that work synergistically to achieve a desired therapeutic outcome [43] and therefore several mechanisms of action could be expected including protecting and repairing cells. The mechanism of lowering BSL could also be stimulating insulin secretion and action.
Natural products are promising lead candidates for discovering and also easily available, affordable and tolerable [44,45]. Plants provide a rich source of bioactive molecules and possess diverse pharmacological actions including anti-diabetic activity. The activity is attributed to either a single component or mixture of phytochemicals. The phytochemicals responsible for anti-diabetic properties could mainly be alkaloids, phenolics, flavonoids, glycosides, saponins, polysaccharides, stilbenes, and tannins [46] and phytochemical investigation of current study showed the presence of this component in most studied plants. Several animal studies reported a wide variation in composition between the extraction methods. Phytochemical compositions are also highly dependent on several endogenous and exogenous factors, environment, genetics, and plant part used, growing, drying, and storing conditions [47].
Investigations of phytochemicals responsible for the anti-diabetic activity have progressed in the last few decades and treating diabetes mellitus with plantderived compound seems highly attractive as they are accessible and do not require laborious pharmaceutical synthesis.

Strengths and limitation of the studies
The evidence synthesized from in vitro/ in vivo studies will have paramount for further studies in human studies. It will show directions of further the studies and promote the traditional use. The limitation of this study arises from the limitation of the included primary studies. The methods used for the induction of diabetic mellitus were streptozotocin or alloxan which mostly induces type 1 diabetes mellitus. The methodological challenge in an animal model study is as induction method mostly induces type 2 diabetes mellitus. With its limitation this study provides preliminary activity assay showed further study direction in other plants, identification and isolation of most active components that could join the adventure of modern drug discovery.
It is also worth noting that only one plant has been studied for efficacy in humans in Ethiopia. No clinical trials were conducted and also no clearly defined preparation for clinical trials in Ethiopia. Furthermore, majority of studies did not report the composition of the formulation, standardization protocols and preparation procedures.

Conclusion
This review demonstrated medicinal plants used for management of diabetes mellitus in Ethiopia are worthy for further investigation of pharmacologically active ingredients and clinical study. Further in vitro, in vivo and clinical studies are warranted to confirm the claimed activity of commonly used medicinal plant species. Studies should also focus on the identification of the active ingredient(s) of potent plant species for the development of modern medicine. The present review provides useful information to researchers, students, health professionals, policymakers and, traditional medicine practitioners.