Pharmacologically Active Phytomolecules Isolated from Traditional Antidiabetic Plants and Their Therapeutic Role for the Management of Diabetes Mellitus

Diabetes mellitus is a chronic complication that affects people of all ages. The increased prevalence of diabetes worldwide has led to the development of several synthetic drugs to tackle this health problem. Such drugs, although effective as antihyperglycemic agents, are accompanied by various side effects, costly, and inaccessible to the majority of people living in underdeveloped countries. Medicinal plants have been used traditionally throughout the ages to treat various ailments due to their availability and safe nature. Medicinal plants are a rich source of phytochemicals that possess several health benefits. As diabetes continues to become prevalent, health care practitioners are considering plant-based medicines as a potential source of antidiabetic drugs due to their high potency and fewer side effects. To better understand the mechanism of action of medicinal plants, their active phytoconstituents are being isolated and investigated thoroughly. In this review article, we have focused on pharmacologically active phytomolecules isolated from medicinal plants presenting antidiabetic activity and the role they play in the treatment and management of diabetes. These natural compounds may represent as good candidates for a novel therapeutic approach and/or effective and alternative therapies for diabetes.


Introduction
Diabetes mellitus is one of the most common endocrine metabolic disorders characterized by chronic hyperglycemia caused by varying degrees of insulin resistance, deficiency in insulin secretion, or both [1]. Nearly 10.5% of the worldwide population is affected by diabetes, with its prevalence increasing at an alarming rate. According to data collected from the International Diabetes Federation (IDF), about 783.2 million people are estimated to be diagnosed with diabetes by 2045 [2]. Diabetes mellitus can be classified into two major categories: Type 1 and Type 2 diabetes, where Type 2 diabetes accounts for about 90% of all cases. Type 1 diabetes, previously known as insulin-dependent diabetes, is an autoimmune disorder that occurs due to the destruction of the pancreatic beta cells leading to significantly reduced secretion of insulin [3]. It is a non-hereditary genetic condition that mainly affects the juvenile under thirty years of age. Type 2 diabetes, also known as non-insulin-dependent diabetes, is the most common form of diabetes, with its prevalence rapidly rising worldwide [4]. It is a hereditary condition caused as a result of insulin resistance, insufficient insulin secretion, or a combination of both, largely affecting an older population than Type 1 diabetes [5]. Both forms of diabetes alter carbohydrate, protein, and fat metabolism. The effect of insulin resistance leads to high blood sugar levels

Pharmacological Activity of Plant-Based Medicines
Although knowledge of many plant-based therapies has been transmitted through generations, only a few of these have started to come to the fore recently. However, there is still some uncertainty regarding their pharmacological activity as well as their acute/chronic side effects due to such medicines being broadly underreported [40]. Few plants have proven to be efficacious for which they were intended, whilst some were not strongly therapeutically effective and/or sufficient scientific data were lacking to support their expected effects [41]. The increase in the widespread use of plant-based therapies has led to an urgent need for a detailed scientific examination of the chemicals responsible for pharmacological activity. Indeed, such a study of the pharmacological properties and phytoconstituents of plant-based medicines may lead to the discovery of new pharmacological characteristics previously unknown or used in traditional medicine [42]. Herbal medicines have been suggested to exert their mechanism of action by concurrently targeting multiple physiological processes via interactions between different biochemicals and cellular proteins [43].
Herbal medications may be able to alter the biological systems from disease to a healthy state by causing the interactions between multi-component and multi-target. Because of the therapeutic properties of the phytomolecules, a lower dosage may be used, resulting in less toxicity and adverse effects. [43]. The antidiabetic activity of medicinal plants is dependent upon the phytochemicals that act through multiple pathways, such as cAMP: which stimulates insulin secretion without affecting the K ATP channel [44]; PI3K: which facilitates glucose uptake by the translocation of the glucose transporter in skeletal muscles, adipose tissue, or liver [45]; AMPK: The activation of 5 -adenosine monophosphate-activated protein kinase pathway improves insulin sensitivity by limiting lipolysis and lipogenesis, and AMPK also enhances glucose uptake in skeletal muscles by translocating GLUT4-containing intracellular vesicles across the plasma membrane [46,47]. For example, phlorizin obtained from the bark of apple and pear trees increases glucose excretion in urine by decreasing glucose reabsorption in the kidneys via the inhibition of SGLT and thus, lowers plasma glucose concentration [48]. Some of the phytomolecules have the potential to regenerate and protect pancreatic beta cells from destruction by reducing the glucose load [49], inhibiting α-amylase and α-glucosidase activity, inducing glucose uptake in 3T3L1 cells [50,51], inhibiting aldose reductase enzyme activity, glycogen metabolizing enzymes, exerting hepato-pancreatic protective activity, inhibiting glucose-6-phosphate and DPP-IV, reducing lactic dehydrogenase, γ-glutamyl transpeptidase, glycosylated hemoglobin levels, and inhibiting glycogenolysis and gluconeogenesis in the liver [20,52]. As an example, a summary of the different pathways involved in the antidiabetic activity of flavonoids is illustrated in Figure 1. A summary of antidiabetic medicinal plants and their pharmacological actions has been shown in Table 1.

Phytochemicals and Their Impact on Diabetes
Plants are the primary source of biologically active compounds that may ultimately lead to the discovery and development of potential new drugs [238]. Plants produce both primary and secondary metabolites. Carbohydrates, proteins, and lipids are considered primary metabolites, necessary for the growth and development of plants and involved in essential metabolic pathways, such as photosynthesis and glycolysis. Secondary metabolites are not required for the growth and development of plants; rather, they are responsible for interactions between plant species and the environment and have highly specific functions in plants [239].
Over 13,000 secondary metabolites have been purified and isolated from medicinal plants. These phytochemicals can be categorized into various chemical classes such as alkaloids, flavonoids, terpenoids, phenolics, tannins, saponins, xanthones, and glycosides [78]. Many of these phytochemicals are known to exhibit medicinal properties, including antidiabetic activity [78]. Several phytochemicals isolated from various plant species have been scientifically validated for their contribution to treating and managing diabetes by exerting antihyperglycemic activity and reducing the complications associated with diabetes [171]. For example, the flavonoid rutin, present in the leaves of numerous plants, including Annona squamosa and Azadirachta indica (neem), has been reported to possess many beneficial effects such as anti-inflammatory, anti-cancer, anti-allergic, antiviral, and antioxidative properties [240]. Rutin-containing plants have also been shown to protect against heart disease, hepatotoxicity, and diabetes mellitus [240]. Rutin exerts its antidiabetic effect by lowering plasma glucose, improving the function of pancreatic β-cells, and enhancing glucose tolerance [10]. Two other flavonoids found in the leaves of Annona squamosa, namely quercetin and isoquercetin, have also been reported to possess antihyperglycemic activity by inhibiting α-glucosidase and lowering blood glucose levels [241]. Alongside rutin and quercetin, the tetranortriterpenoid meliacinolin, isolated from the leaves of A. indica, has been found to inhibit α-glucosidase and α-amylase in Type 2 diabetic mice [98]. Nimbidin, extracted from neem seeds, is another phytochemical exhibiting hypoglycemic properties [98]. Quercetin, allicin, allyl-propyl disulfide, cysteine sulfoxide, and S-allyl cysteine sulfoxide from Allium sativum (garlic) have been reported to stimulate insulin secretion from pancreatic β-cells, increase insulin sensitivity to target cells, and prevent insulin activation triggered by the liver [71]. Alliin, from garlic, has been reported to mimic the function of glibenclamide and insulin [71]. Epigallocatechin-3-gallate, epigallocatechin, epicatechin-3-gallate, and epicatechin present in Camellia sinensis (tea) leaves can also lower plasma glucose levels by improving β-cell function, increasing insulin secretion, and enhancing glucose metabolism [117]. These phytomolecules may exert their antidiabetic activity in multiple manners, most commonly by being insulinotropic, insulin-mimetic, and by improving β-cell function, increasing insulin sensitivity, improving glucose tolerance and metabolism, as well as inhibiting various enzyme activities. A summary of antidiabetic medicinal plants and their phytochemicals with potential antidiabetic effects is provided in Table 2. The chemical structures of the antidiabetic phytoconstituents of medicinal plants are given in Table 3.

Plant-Based Drug Formulations Available on the Market and Their Role in Diabetes
For the past few decades, there has been an increasingly growing trend in many European countries to develop and sell plant-based medicines [370]. The latter are known as herbal formulations or phytomedicines. These preparations have been standardized and confirmed for their safety profile and effectiveness in the treatment of various diseases. Similar to any other allopathic medicine, herbal formulations can also be prepared as diverse formulations such as tablets, capsules, elixirs, suspensions, solutions, emulsions, and powders [371]. Phytomedicines can either be single herb-or polyherbal formulations [35]. Several phytomedicines have been marketed worldwide for the control and management of diabetes. These include Antibetic, Di-

Plant-Based Drug Formulations Available on the Market and Their Role in Diabetes
For the past few decades, there has been an increasingly growing trend in many European countries to develop and sell plant-based medicines [370]. The latter are known as herbal formulations or phytomedicines. These preparations have been standardized and confirmed for their safety profile and effectiveness in the treatment of various diseases. Similar to any other allopathic medicine, herbal formulations can also be prepared as diverse formulations such as tablets, capsules, elixirs, suspensions, solutions, emulsions, and powders [371]. Phytomedicines can either be single herb-or polyherbal formulations [35]. Several phytomedicines have been marketed worldwide for the control and management of diabetes. These include Antibetic, Diabetics, Diabetica, Diabet, Diasol, Diabecon, Diasulin, Dia-Care, Diabecure, Diabeta, Diabeta Plus, Dianex, Diashis, GlucoCare, GlycoNase, Glyoherb, Karmin Plus, SugarMax, and Sugar Loss [35,372]. These products comprise a combination of individual constituents from several antidiabetic plants. Many of these preparations are sold with directions about diet, rest, and physical activities to enhance their effectiveness [35,372].

The Future of Plant-Based Antidiabetic Medicines
Nearly 75% of the globally used herbal medicines have been developed based on traditional medicine practitioners [24]. Medicinal plants will continue to be used for their natural safety and potency in many remedies, as well as cosmetics, perfumes, and in the food and beverages industry [373]. Biologically active components derived from traditional medicinal plants have yielded several clinically used drugs and still play a key role in the discovery of new medicines. Thus, it is reasonable to assume that plants used in folk medicine can be used as a potential source for the discovery of new drugs to treat diabetes. The most frequently recommended synthetic drug, metformin, has blood glucoselowering properties in Type 2 diabetes and the search for many such drugs persists [370]. Moreover, any plant-derived antidiabetic drug with a novel mode of action compared to existing antidiabetic agents has a high potential to be used in clinics [374]. Although the use of plant-based medicines is widespread in developing countries, recently, developed countries have also shown interest in using herbal drugs and therapies. With the rise in the incidence of diabetes mellitus, the demand for plant-based antidiabetic medicines is increasing worldwide. It is expected that countries such as China, India, and Japan, which have an abundance of medicinal plant species and are the greatest exporters of medicinal plants worldwide, will be the most sought [375]. More studies are required regarding the pharmacokinetics/pharmacodynamics of different phytoconstituents in laboratory animals and in clinical use to establish the benefits and mode(s) of action of these compounds in the treatment and management of diabetes. Extensive investigations into the pharmacology, toxicology, metabolism, and tissue distribution of medicinal plants and their phytomolecules are necessary for the development of new potent antidiabetic drugs [376].

Conclusions
Diabetes mellitus has risen as a major public health crisis, particularly in underdeveloped countries. Thus, recent research efforts have been centered on the discovery of new natural sources of antidiabetic therapies for the treatment and management of diabetes. As traditional medicinal plants with antidiabetic activity may be considered potential candidates for diabetes management in the long run, they are being extensively researched for novel targets, mechanisms of action, and routes of administration. Plant-based antidiabetic medicines are inexpensive, readily available, and hold low risks of side effects. This makes them promising new antidiabetic agents. With the progression of medicinal plant-based research, scientists and physicians have started to develop newer classes of antidiabetic drugs based on the pharmacology of the phytochemicals isolated from these plants. However, more studies are required for in-depth investigation of these newly discovered antidiabetic drugs at the molecular, therapeutic, and physiological levels in order to control and manage diabetes mellitus worldwide.

Acknowledgments:
We would like to extend our appreciation to Peter R Flatt, School of Biomedical Sciences, Ulster University, UK and Independent University, Bangladesh for his aid, guidance, and support in creating the innovative ideas.

Conflicts of Interest:
The authors declare no conflict of interest.