Medicinal Plants in Management of Diabetes Mellitus: An Overview

Diabetes mellitus has become a global epidemic over the past few decades and is one among the major causes of death worldwide. Although various modern medicines are in the market, herbal medicines have usually maintained worldwide popularity in achieving the primary health care needs of the diabetic population because of the multiple adverse effects related to them. Herbal medicines have a prolonged history of being used as medications and sources of medication for diabetes mellitus. Some of them are enclosed within the modern therapeutic arsenal of medicine, and others are used as complementary therapy or as dietary supplements by patients with diabetes. The present review describes on traditional antidiabetic herbal medicines with an emphasis on scientific investigations conducted on antidiabetic medicinal plants, polypherbal mixtures, isolated compounds and their associated toxicities.


INTRODUCTION
Diabetes mellitus has become a devastating health problems nowadays and millions of people are fighting with this dilemma worldwide. Diabetes mellitus is an endocrine disease characterized by hyperglycaemia which occurs as a result of the inability of the pancreas to secrete insulin, defects in insulin action or both (ADA, 2013). Hyperglycaemia results in both microvascular and macrovascular complications which lead to long-term failure of various organs (Chawla et al., 2016). Although numerous synthetic antidiabetic drugs are available, these medications have limitations in their use due to unwanted side effects (Chaudhury et al., 2017). Hence, herbal products have been accepting a great demand for the management of diabetes due to low cost, high availability and less side effects.
The dependence of human beings on medicinal plants dates back to the beginning of life. Medicinal plants include various types of plants used for numerous medicinal purposes (Jamshidi-Kia et al., 2018). During the past two decades, medicinal plants have become a topic of global importance. World health organization (WHO) estimated that 80% of world population relies on medicinal plants (Gopl et al., 2014). In spite of the presence of effective modern allopathic medicines, herbal medicines have often maintained global popularity in meeting the primary health care needs. Concurrently, many people in developed countries have begun to turn to alternative or complementary therapies with medicinal plants. However, there is a paucity of scientific research data on medicinal plants.
According to WHO reports, around 21,000 plant species have the potential for being used as medicinal plants (Modak et al., 2007). There have been significant developments in the pharmacological evaluation of various medicinal plants used in traditional systems of medicine in the treatment of many of the chronic diseases. Diabetes mellitus is one of them. Importantly, the treatments using medicinal plants are considered safe with little or no side effects independent of the age or gender of the patients. Furthermore, medicinal plants are considered as rich resources of phamacophores which can be used in drug development. In addition, medicinal plants play critical roles as important sources of nutrition.
The present review is an overview of diabetes mellitus, traditional medicines used in the management of diabetes mellitus, summary of antidiabetic medicinal plants, medicinal plants grown in Sri Lanka with scientifically proven antidiabetic activity, polyherbal mixtures with proven antidiabetic activity and toxicities of antidiabetic medicinal plants and polyherbal mixtures.
Diabetes mellitus has become a global epidemic and is considered as one of the emerging global health problems. The prevalence of diabetes has rapidly increased over the past few decades (WHO, 2016). Patients with diabetes have a high risk of morbidity and mortality than the healthy population. Globally, according to the International Diabetic Federation (IDF) Atlas, there were 425 million people with diabetes worldwide in 2016 (Ogurtsova et al., 2017).
Many efforts have been devoted to search and develop optimal therapeutic agents for the management of diabetes mellitus. Due to various side effects associated with currently available oral antidiabetic drugs and their high cost, most of the diabetic patients especially in developing countries tend to use herbal plant remedies as alternative therapies for the management of diabetic mellitus (Ekor, 2014).

Traditional herbal medicines for the management of diabetes mellitus
The use of traditional medicine continues to play a crucial role in the healthcare delivery systems of many parts of the world. Indeed, according to WHO, 40 % of the total population relies on traditional medical systems directly or indirectly (Mazid et al., 2012), while 80% of the population in developing countries depend almost exclusively on traditional medical practices, more specifically, plant medicines for their primary health care needs (Karunamoorthi et al., 2013). Reports from developed countries also indicate that several diabetic patients are gradually turning to herbal remedies as alternatives to modern synthetic drugs (Rani et al., 2015). The literature on medicinal plants with hypoglycaemic activity is vast. More than 1200 species of plants have been used ethnopharmacologically to treat for diabetes mellitus (Delaviz et al., 2017). Traditional systems of medicines always have played a significant role as therapeutic aid for the management of diabetes mellitus. In South East Asia, there is a vast volume of literature on traditional medicine. Generally, civilization has adopted broad cultural aspects which led to create different types of traditional medicine systems for over 3000 years. There are four main systems of traditional medicine in Sri Lanka namely; Ayurveda, Siddha, Unani and Deshiya Chikitsa (Waisundara and Watawana, 2014). The Ayurveda and Deshiya Chikitsa systems use mainly plants and herbal preparations for the treatment of diabetes mellitus as single plants or plant mixtures. Sri Lankan traditional physicians regularly use many antidiabetic plants such as Momordica charantia (Bitter melon), Allium sativum (garlic), Annona squamosa (sugar apple), Gymnema sylvestre (Gymnea), Syzygium cumini (Malabar Plum), Allium cepa (onion) etc. for their daily prescriptions.
Natural products derived from medicinal plants play an important role as useful tools in pharmacological studies in the management of diabetes mellitus (Farzaei et al., 2015). Researchers have proved that the antidiabetic activity of medicinal plants is due to the presence of phenolic compounds, flavonoids, terpenoids, coumarins and other ingredients which demonstrate hypoglycaemic activity (Aswathy and Jessykutty, 2017). In many cases, the detailed mechanisms of action of traditionally used antidiabetic plants are unknown or inconclusive (Patel et al., 2012). As such, many studies are being conducted to elucidate the mechanisms of action of different plants and natural compounds (Grover et al., 2002). Medicinal plant extracts are mainly responsible for regenerating the function of pancreatic tissues by elevating the insulin output or inhibiting the intestinal absorption of glucose or by facilitating metabolites in insulin dependent processes (Patel et al., 2012). Some widely used antidiabetic medicinal plants that were recently scrutinized by scientific investigations are summarized in Table 1.

Antidiabetic compounds reported from medicinal plants
Bioactive compounds isolated from medicinal plants are in much demand than the synthetic compounds as antidiabetic drug leads owing to rich availability, efficacy and less side effects. Among the drugs approved in the therapy of diabetes in the last ten years, 49% are derived from plants (Gothai et al., 2016). More than 1200 antidiabetic compounds from medicinal plants have been discovered by scientists all over the world (Trojan-Rodrigues et al., 2012). The antidiabetic activities of isolated compounds could be varied based on mechanisms of their actions for lowering glucose levels including the inhibition of glucose absorption, improvement in insulin resistance and pancreatic functions (Chang et al., 2013) Quercetin isolated from the aqueous extract of Matricaria recutita has shown high inhibitory effects against glucosidase as yeast α-glucosidase, rat intestinal sucrase, and amylase with IC 50 values as 8.86 μg/mL, 216 μmol/L, and 71 μmol/L respectively (Yin et al., 2014). Mahanine obtained from the fruit pulp of Murraya koenigii showed α-glucosidase inhibitory activity as 21.4 ± 0.4 μmol/L compared with acarbose (IC 50 = 15.2 ± 0.6 μmol/L) (Uvarani et al., 2014). Furthermore, mangiferin (IC 50 = 299.7 ± 42.3 μmol/L) was isolated from 70% aqueous ethanolic leaf extracts of Aquilaria sinensis and showed significant α-glucosidase inhibitory activity than acarbose (IC 50 = 576.2 ± 58.5 μmol/L) (Feng et al., 2011).
The major steps in the discovery of bioactive compounds from plants are solvent extraction, bioassays, isolation, characterization, toxicological evaluation, preclinical and clinical investigation of isolated bioactive compounds (Sasidharan et al., 2011). Table 2 summarizes some common antidiabetic compounds that have been isolated from medicinal plants.

Polyherbal formulations for the management of diabetes mellitus
Medicinal plants with ethnomedicinal value are currently being screened for their therapeutic potential. Herb-herb combinations are basically found in polyherbal therapy and have been used in Ayurvedic medicine for thousands years (Che et al., 2013). In the Ayurvedic literature 'Sarangdhar Samhita', the concept of polyherbalism and combined extracts of plants are chosen rather than individual ones for the treatment of diabetes mellitus in the traditional system of medicine . The Unani medicine has also achieved global acceptance due to the amazing clinical efficiency of the polyherbal formulations (Shailajan, 2015). In the majority of traditional systems, diabetes has been successfully managed by the polyherbal mixtures instead of a single herb because of the powerful synergism and less side effects (Yuan et al., 2017). Combinations often lead to promising effects in the management of diseases over a single drug. Naturally occurring herbs and herbal ingredients are organized into certain formulas that offer potential interactions such as mutual enhancement, mutual assistance, mutual restraint and mutual antagonism (Alabi et al., 2017). Many scientific studies have discovered that polyherbal mixtures produce a greater effect, as compared to individual plant extracts. Combined plant extracts also focus on multiple targets at the same time to provide greater effectiveness (Briskin, 2000). In the preparation of polyherbal mixtures, the extent of individual plants used is less in achieving desirable pharmacological action than in a single herbal preparation. Hence, it reduces the risk of harmful side-effects. In addition, polyherbal formulations also prevent the need to take more than one different single herbal formulation at a time. Therefore, all these benefits has led to the popularity of polyherbal mixtures among patients with diabetes. Many researchers have studied polyherbal mixtures in order to evaluate their effectiveness in acute and long term interventions. These studies have revealed that combined plant mixtures have a wide therapeutic range due to the presence of different phytochemicals. Most of the polyherbal mixtures have shown effectiveness even at low or high doses without any toxic effects (Parasuraman  Kumar et al., 2013Kumar et al., et al., 2014. A summary of recent studies on polyherbal formulation used in the management of diabetes mellitus is shown in Table 3.

Toxicity of medicinal plants and polyherbal mixtures
Toxicology is a branch of science that deals with toxic substances and their effects. Toxicological studies are very important for the development of new safe drugs and for the extension of the therapeutic potential of existing drugs (Parasuraman, 2011). Although medicinal plants play a significant role in the treatment of diseases, many unsafe and fatal side effects have also been reported (Ekor, 2014). These toxic effects might be due to allergic reactions, effects from impurities and interactions with drugs and other herbs (Hussain, 2011). The Organization for Economic Cooperation and Development (OECD) and the International Conference on Harmonization (ICH) have established the guidelines for toxicity studies of pharmacological substances including medicinal plant extracts, herbal mixtures and for isolated compounds (Kiani et al., 2018). Toxicological studies determines whether the plant extract can be accepted for clinical use or not. Even though many phytochemicals are commonly used for health benefits, some of them have been reported as toxic substances and may be present in food or herbal remedies. Arseculeratne and co-workers (1985) have reported some Sri Lankan medicinal plants which are popular in Ayurvedic medicine exerted significant toxic effects such as Terminalia chebula. However, there are many antidiabetic plants extracts which have been documented as toxic free extracts with recent scientific investigations such as Coccinia grandis (Attanayake et al., 2013b). Table 4 describes toxicological studies conducted on medicinal plants with potent antidiabetic activity.

CONCLUSIONS
In the present review we described the traditional antidiabetic herbal medicines with an emphasis on scientific investigations conducted on antidiabetic medicinal plants, polypherbal mixtures, isolated compounds and their associated toxicities. Herbal medicines are used by a large number of patients with diabetes mellitus since ancient times. The indigenous knowledge on herbal medicines can be successfully blended with modern scientific knowledge to develop antidiabetic agents that can be used in the management of diabetes mellitus. The major hindrance in the amalgamation of medicinal plants with modern therapeutic applications is lack of scientific and clinical data proving their efficacy and safety. Many investigations have been carried out to scrutinize the therapeutic benefits of medicinal plants, and polyherbal mixtures used in different traditional medicine systems. However, a considerable number of medicinal plants used in traditional medicines have not been investigated yet. Therefore, there is a crucial need to conduct scientific investigations to scrutinize the therapeutic potency of medicinal plant extracts and polyherbal mixtures in clinical practice, elucidate the antidiabetic principle(s), and to isolate antidiabetic compounds in the near future. antihaemopoietic, hepatotoxic and nephrotoxic Mukinda and Eagles, 2010