Thesis Abstract

<p>&nbsp;                <b>ABSTRACT&nbsp;</b>&nbsp;</p><p>Diabetes mellitus is one of the major health problems in the world, the incidence and associated mortality are increasing. Inadequate regulation of the blood sugar imposes serious consequences for health. Conventional antidiabetic drugs are effective, however, also with unavoidable side effects. On the other hand, medicinal plants may act as an alternative source of antidiabetic agents. Examples of medicinal plants with antidiabetic potential are described, with focuses on preclinical and clinical studies. The beneficial potential of each plant matrix is given by the combined and concerted action of their profile of biologically active compounds. Keywords Diabetes mellitus; medicinal plants; antidiabetic; hypoglycemic; antihyperglycemic <br></p>

Thesis Overview

<p> <b>1.1 INTRODUCTION</b></p><p>Diabetes mellitus (DM) is a serious, chronic, and complex metabolic disorder of multiple aetiologies with profound consequences, both acute and chronic [1]. Also known only as diabetes, DM and its complications affect people both in the developing and developed countries, leading to a major socioeconomic challenge. It is estimated that 25% of the world population is affected by this disease [2]. Genetic and environmental factors contribute significantly to the development of diabetes [3]. During the development of diabetes, the cells of the body cannot metabolize sugar properly due to deficient action of insulin on target tissues resulting from insensitivity or lack of insulin (a peptide hormone that regulates blood glucose). The inability of insulin to metabolize sugar occurs when the pancreas does not produce enough insulin or when the body cannot effectively use the insulin it produces. This triggers the body to break down its own fat, protein, and glycogen to produce sugar, leading to the presence of high sugar levels in the blood with excess by-products called ketones being produced by the liver [4,5]. Diabetes is distinguished by chronic hyperglycemia with disturbances in the macromolecules’ metabolism as a result of impairments in insulin secretion, insulin action, or both. Diabetes causes long-term damage, dysfunction, and failure of various organ systems (heart, blood vessels, eyes, kidneys, and nerves), leading to disability and premature death [6]. The severity of damage triggered by hyperglycemia on the respective organ systems may be related to how long the disease has been present and how well it has been controlled. Several symptoms such as thirst, polyuria, blurring of vision, and weight loss also accompany diabetes [7]. <br></p><p><b>1. 2. TYPE OF DIABETES, PREVALENCE AND MANAGEMENT</b></p><p>There are various types of diabetes of which type 1 DM (T1DM) and type 2 DM (T2DM) were the most usually discussed. The T1DM is also known as insulin-dependent diabetes. It is primarily due to pancreatic islet beta cell destruction and is characterized by deficient insulin production in the body [6]. Patients with T1DM are prone to ketoacidosis and need daily administration of insulin to control the amount of glucose in their blood. The majority of T1DM occurs in children and adolescents [5]. On the other hand, T2DM, also known as non-insulin-dependent diabetes, results from the body’s ineffective use of insulin and hyperglycemia [8,9] and accounts for the vast majority of people with diabetes around the world. Insulin resistance is due to a reduced responsiveness of target tissues to normal circulating levels of insulin [9]. Ethnicity, family history of diabetes, and previous gestational diabetes, older age, overweight and obesity, unhealthy diet, physical inactivity, and smoking increase diabetes risk. Most people with diabetes are affected by T2DM diabetes (90%), usually occur nearly entirely among adults but, in these days, is increasing in children [5]. The universal prevalence of diabetes has nearly doubled since 1980, rising from 4.7% to 8.5% in the adult population. Moreover, the prevalence of diabetes has also been found to steadily increase for the past 3 decades and has risen faster in low- and middle-income countries compared to high-income countries. The increase in the prevalence of diabetes is parallel with an increase in associated risk factors such as being overweight or obese. If not properly treated or controlled, diabetes may cause blindness, kidney failure, lower limb amputation, and other long-term consequences that impact significantly on the quality of life [10]. Interestingly, the WHO also projects that diabetes will be the seventh leading cause of death in 2030 [11]. The incidence and prevalence of diabetes have continued to increase globally, despite a great deal of research with the resulting burden resting more heavily on tropical developing countries [12,13]. Based on demographic studies, by 2030, the number of people older than 64 years with diabetes will be greater in developing countries (≥82 million) in comparison to that in developed countries (≥48 million). The greatest relative increases are projected to occur in the Middle East crescent, sub-Saharan Africa, and India [14,15]. Amongst all people with diabetes, T2DM accounts for the majority (90%) of cases, and these can be prevented as well as treated easily, while T1DM cannot be prevented with current knowledge. Since management of diabetes is complex and multidisciplinary, it should include primary prevention through promotion of a healthy diet and lifestyle (such as exercise). Dietary management and exercise represent important pillars of care and are crucial in the treatment of T2DM, and both may be adequate to attain and retain the therapeutic goals to normolipidemic and normoglycemia. <br></p><p>1.3.&nbsp;<b>ANTIDIABETIC DRUGS AND THEIR SIDE EFFECTS</b></p><p>There are several classes of oral hypoglycemic drugs that exert antidiabetic effects through different mechanisms, namely sulfonylureas, biguanides, α-glucosidase inhibitors, thiazolidinediones, and non-sulfonylureas secretagogues. Oral sulfonylureas, such as glimepiride and glyburide, act to reduce blood sugar, mainly by elevating insulin release from islets of Langerhans. This is achieved through binding with the sulfonylurea receptor onβcells resulting in adenosine triphosphate-dependent potassium channels closure. As a result, the cell membrane depolarizes and the following calcium influx accompanied by secretion of stored insulin from secretory granules within the cells takes place. This mechanism works only in the presence of insulin [16,17]. Another oral hypoglycemic drug, the biguanides, acts to reduce hepatic gluconeogenesis and to replenish peripheral tissues’ sensitivity to insulin, actions that are achieved through elevation of insulin-stimulated uptake and use of sugar. Nevertheless, biguanides are ineffective in insulin absence. The best example of this class is metformin. The α-glucosidase inhibitors, such as acarbose and miglitol, impede certain enzymes responsible for the breakdown of carbohydrates in the small intestine. This class of hypoglycemic agents acts mostly by reducing the absorption rate of carbohydrates in the body. Also, acarbose reversibly inhibits both pancreatic α-amylase and α-glucosidase enzymes by binding to the carbohydrate-binding region and by interfering with their hydrolysis into monosaccharides, which leads to a slower absorption together with a reduction in postprandial blood sugar levels [16,18].&nbsp;</p><p>Another important class of oral hypoglycemic agents is the thiazolidinediones (TZDs), such as pioglitazone and rosiglitazone, of which the mechanism of action primarily includes improving muscle and adipose tissue sensitivity to insulin and, to a smaller extent, reducing liver glucose production. TZDs also are potent and selective agonists to the nuclear peroxisome proliferator-activated receptor gamma (PPARγ) present in liver, skeletal muscle, and adipose tissue. Activation of PPARγ receptors controls the transcription of insulin-responsive genes involved in the regulation of transportation, production, and glucose use. Also, TZDs have been reported to augment β-cell function by lowering free fatty acid levels that ultimately lead to β-cell death [19]. <br></p><p> The last class of oral hypoglycemic agents is the non-sulfonylureas secretagogues, which include meglitinide and repaglinide and which increases the secretion of insulin from active β cells by a similar mechanism as sulfonylureas. However, this class of oral antidiabetic agents binds to different β-cell receptors [20]. Although synthetic oral hypoglycemic drugs alongside insulin are the main route for controlling diabetes, they fail to reverse the course of its complications completely and further worsen it by the fact that they also demonstrate prominent side effects. This forms the main force for discovering alternative sources of antidiabetic agents [21]. Despite the significant progress made in the treatment of diabetes using oral antidiabetic agents in the past three decades, the results of treatment of diabetic patients are still far from perfect. Several disadvantages have been reported related to the use of those oral hypoglycemic agents, including drug resistance (reduction of efficiency), adverse effects, and even toxicity. For example, sulfonylureas lose their effectiveness after 6 years of treatment in approximately 44% of patients, whereas glucose-lowering drugs are reported to be not able to control hyperlipidemia [22]. Due to the several limitations associated with the use of existing synthetic antidiabetic drugs, the search for newer antidiabetic drugs from natural source continues [23]. <br></p><p>1.4.&nbsp;&nbsp;<b>MEDICINAL PLANTS AS AN ALTERNATIVE SOURE OF ANTIDIABETIC</b></p><p>Agents Natural products, particularly of plant origin, are the main quarry for discovering promising lead candidates and play an imperative role in the upcoming drug development programs [24–26]. Ease of availability, low cost, and least side effects make plant-based preparations the main key player of all available therapies, especially in rural areas [27]. Moreover, many plants provide a rich source of bioactive chemicals, which are free from undesirable side effects and possess powerful pharmacological actions [28–34]. Plants also have always been an exemplary source of drugs with many of the currently available drugs being obtained directly or indirectly from them [2,29–31]. The recent review of Durazzo et al. [35] gives a current snapshot of the strict interaction between the main biologically active compounds in plants and botanicals by giving a mini overview of botanicals features, a definition of the study, and examples of innovative (i.e., an assessment of the interaction of bioactive compounds, chemometrics, and the new goal of biorefineries) and a description of existing databases (i.e., plant metabolic pathways, food composition, bioactive compounds, dietary supplements, and dietary markers); in this regard, the authors marked the need for categorization of botanicals as useful tools for health research [35]. <br></p><p> For centuries, many plants have been considered a fundamental source of potent antidiabetic drugs. In developing countries, particularly, medicinal plants are used to treat diabetes to overcome the burden of the cost of conventional medicines to the population [2]. Nowadays, treatments of diseases including diabetes using medicinal plants are recommended [36] because these plants contain various phytoconstituents such as flavonoids, terpenoids, saponins, carotenoids, alkaloids, and glycosides, which may possess antidiabetic activities [37]. Also marked by Durazzo et al. [35], the combined action of biologically active compounds (i.e., polyphenols, carotenoids, lignans, coumarins, glucosinolates, etc.) leads to the potential beneficial properties of each plant matrix, and this can represent the first step for understanding their biological actions and beneficial activities. Generally, the main current approaches of study [38,39] of the interactions of phytochemicals can be classified: (i) model system development of interactions [40–42]; (ii) study of extractable and nonextractablecompounds [43,44]; or (iii) characterization of biologically active compound-rich extracts [45,46]. The antihyperglycemic effects resulting from treatment with plants are usually attributed to their ability to improve the performance of pancreatic tissue, which is done by increasing insulin secretions or by reducing the intestinal absorption of glucose [2]. The number of people with diabetes today has been growing and causing increasing concerns in the medical community and the public. Despite the presence of antidiabetic drugs in the pharmaceutical market, the treatment of diabetes with medicinal plants is often successful. Herbal medicines and plant components with insignificant toxicity and no side effects are notable therapeutic options for the treatment of diabetes around the world [47]. Most tests have demonstrated the benefits of medicinal plants containing hypoglycemic properties in diabetes management. Ríos et al. [48] described medicinal plants (i.e., aloe, banaba, bitter melon, caper, cinnamon, cocoa, coffee, fenugreek, garlic, guava, gymnema, nettle, sage, soybean, green and black tea, turmeric, walnut, and yerba mate) used for treating diabetes and its comorbidities and the mechanisms of natural products as antidiabetic agents, with attention to compounds of high interest such as fukugetin, palmatine, berberine, honokiol, amorfrutins, trigonelline, gymnemic acids, gurmarin, and phlorizin. The current review of Bindu and Narendhirakannan [49] has categorized and described from literature 81 plants native to Asian countries with antidiabetic, antihyperglycemic, hypoglycemic, anti-lipidemic, and insulin-mimetic properties. <br></p><p> Traditional knowledge of antidiabetic Asian plants: (1) Review in Iran [50–54]; (2) Review in Jordan [55–57]; (3)Review in Malaysia [58,59]; (4) Review in Mongolia [60]; (5) Review in Philippines [61,62]; (6) Review in Saudi Arabia [63–65]; (7) Review in Korea [66–68]; (8) Review in Sri Lanka [69]; (9) Review in Syria [70]; (10) Review in Thailand [71–75]; (11) Review in Turkey [76–82]; (12) Review in Vietnam [83–85]; (13) Review in India [86–105]; and (14) Review in China [99,106–112]. The biological activities considered in this review are antidiabetic, antihyperglycemic, and hypoglycemic activities as well as α-amylase and α-glucosidase inhibition. A majority of the plant species was tested for antidiabetic activity. The methodology followed while collecting the plant species should influence the treatment of diabetes. Accordingly, the plants screened from the Asian region were selected. Then, the genus name was searched to identify whether any species belonging to the same genus are reported elsewhere. Such plants are listed in Table 1. Those plants where only one species is available are reported in Table 2. <br></p><p> Table 1 has 509 plants belonging to 140 genera. Among these 140 genera, some of them have more than ten species exhibiting an antidiabetic property. Ficus with 18 species, Artemisia with 13, Solanum with 12, Terminalia with 11, and Euphorbia with 10 are some of the genera which have a large number of species exhibiting an antidiabetic property. In the Ficus genus, among 18 plants, the prominent species having relevance to traditional medicines are Ficus benghalensis, Ficus hispida, and Ficus elastica. Ficus benghalensis, also known as Indian Banyan tree, is one of the most frequently used plants for the treatment of diabetes [89] and is used in folk medicines, Ayurveda, Unani, Siddha [113], and homeopathy [114]. It is worth mentioning the recent review of Deepa et al. [115] on the role of Ficus species in the management of diabetes mellitus: F. benghalensis, F. carica, F. glomerata, F. glumosa, F. racemosa, and F. religiosa exhibited remarkable antidiabetic properties with various mechanisms of action. The leaves and edible fruits of Ficus hispida are used for the treatment of diabetes [116] and is used in Ayurveda [117], Siddha [118], and traditional African medicine [119]. Ficus elastica, an ethnomedicinal Filipino plant, exhibits less toxicity [62], which is used in diabetes treatment. In the Artemisia genus, Artemisia absinthium is one of the traditional medicinal plant used for diabetes treatment [120]. Artemisia afra is one of the popular herbal medicines used in the southern part of Africa [121]. Artemisia herba-alba is a traditional medicinal plant [122], and its aqueous extract of the leaves and barks reduces blood glucose levels [123]. Solanum americanum is a traditional medicine used in Guatemala [124], while Solanum viarum is used in India [125]. Terminalia arjuna is a plant used in India and Bangladesh [126] and exhibits amylase inhibition (IC50 value of 302 µg/mL) [127]. Terminalia chebula is a medicinal plant used in India [128], Bangladesh [129], Thailand [75], and Iran [130]. Euphorbia ligularia [104], Euphorbia neriifolia [131], and Euphorbia caducifolia [132] are some of the plants traditionally used in India. Similarly, Euphorbia thymifolia and Euphorbia hirta are used in Bangladesh [116,133], and Euphorbia kansui is a Korean traditional medicinal plant used for diabetes treatment [134]. Allium cepa, Mangifera indica, Murraya koenigii, and Phyllanthus amarusreduce triglycerides (TG), total cholesterol (TC), and very low-density lipoproteins (VLDL) levels and exhibit antidiabetic and hypolipidemic effects [135]. <br></p>