YALE JOURNAL OF BIOLOGY AND MEDICINE 93 (2020), pp.307-325. Review Antidiabetic Potential of Syzygium sp.: An Overview Azrin S. Zulcafli, Chooiling Lim, Anna P. Ling, Soimoi Chye, and Rhunyian Koh* Division of Applied Biomedical Science and Biotechnology, School of Health Sciences, International Medical University, Kuala Lumpur, Malaysia Diabetes, characterized by hyperglycemia, is one of the most significant metabolic diseases, reaching alarming pandemic proportions. It can be due to the defects in insulin action, or secretion, or both. The global prevalence of diabetes is estimated at 425 million people in 2017, and expected to rise to 629 million by 2045 due to an increasing trend of unhealthy lifestyles, physical inactivity, and obesity. Several treatment options are available to diabetics, however, some of the antidiabetic drugs result in adverse side effects such as hypoglycemia. Hence, there has been a proliferation of studies on natural products with antidiabetic effects, including plants from the Myrtaceae family, such as Psidium guajava, Eucalyptus globulus, Campomanesia xanthocarpa, and more significantly, Syzygium sp. Previous studies have shown that a number of Syzygium species had potent antidiabetic effects and were safe for consumption. This review aims to discuss the antidiabetic potential of Syzygium sp., based on in vitro and in vivo evidence. INTRODUCTION obesity, drugs, and as a pregnancy-related complication. Symptoms of diabetes are polyuria, polyphagia, slow- Diabetes, characterized by hyperglycemia, is one of wound healing, and polydipsia. Furthermore, diabetes the most significant metabolic diseases, reaching alarm- can lead to a host of complications such as neuropathy, ing pandemic proportions. It can be due to the defects glaucoma, ischemic heart disease, nephropathy, and ke- in insulin action, or secretion, or both. It is a chronic, toacidosis [1]. non-communicable disease that can result in blindness, The two major types of diabetes are categorized as renal failure, and limb amputations [1]. The latest esti- type 1 and type 2. Type 1 diabetes, commonly known as mates show that in 2017, the total global prevalence of insulin-dependent diabetic mellitus (IDDM), is a pancre- diabetes is 425 million. Incidence rates are expected to atic islet autoimmune disorder resulting in absolute in- rise to 629 million by year 2045 as the prevalence of sulin secretion deficiency by β cells. In contrast, type 2 unhealthy behaviors, physical inactivity, and obesity in- diabetes, also known as non-insulin-independent diabetic creases [2]. Diabetes can occur due to genetic disorders, mellitus (NIDDM), is caused by inadequate insulin se- *To whom all correspondence should be addressed: Rhunyian Koh, Division of Applied Biomedical Science and Biotechnology, School of Health Sciences, International Medical University, No. 126, Jalan Jalil Perkasa 19, Bukit Jalil, 57000 Kuala Lumpur, Malaysia; Tel: +60327317207, Fax: +60386567229, Email: [email protected]. Abbreviations: IDDM, insulin-dependent diabetic mellitus; NIDDM, insulin-independent diabetic mellitus; GLUT, glucose transporter; OGTT, oral glucose tolerance test; HbA1c, hemoglobin A1c; STZ, streptozotocin; COB, Cleistocalyx operculatus flower buds; LD50, median lethal dose; OA, oleanolic acid; MA, maslinic acid; SGLT, sodium-glucose linked transporter. Keywords: Diabetes, Syzygium sp. Author Contributions: ASZ drafted the manuscript; CL, APL, SC, and RK critically reviewed the manuscript. Copyright © 2020 307 308 Zulcafli et al.: Antidiabetic potential of Syzygium sp. cretion and also insulin resistance action of various target peptide-1 homeostasis [46]. Accessibility is one of the tissues or cells [3,4]. IDDM is due to chronic autoimmune main reasons herbal medicines are widely used in the destruction of the insulin-producing pancreatic β-cells. In treatment of diabetes, especially in rural communities patients with IDDM, uncontrolled lipolysis that leads to [47]. Hence, the antidiabetic potential of a wide reper- increasing levels of free fatty acids in the plasma occur toire of medicinal plants has been widely reviewed in the as a result from the insulin deficiency. This will suppress last few decades [48]. glucose metabolism that takes place in the peripheral tis- Recently, some highly effective biomolecules with sues. In type 2 diabetes, pathological defects leading to potential antidiabetic effects have been isolated from impairment in insulin secretion and resistance manifests plants [49]. Medicinal plants with mild-to-potent an- as hyperglycemia in patients. The genetic association of tidiabetic activity include those from the families Cu- disease in type 2 diabetes is greater than in type 1 [4]. curbitaceae, Apocynaceae, Asclepiadaceae, Malvaceae, The most clinically significant complication from ei- Acanthaceae, Anacardiaceae, Meliaceae, Amaranthace- ther types of diabetes is diabetic ketoacidosis, which is a ae, Rutaceae, Poaceae, Menispermacea, and Myrtaceae major cause of morbidity and mortality among diabetic (Table 1) [50-139]. Several species from the family Myrt- patients. Long-term complications of diabetes include aceae have shown potential antidiabetic effects, for exam- retinopathy, nephropathy, and neuropathy [1]. Diabetes ple, Psidium guajava, of which its leaf aqueous extract can be diagnosed through fasting plasma glucose assess- has proven to be able to lower blood glucose. The extract ment or oral glucose tolerance test (OGTT). Besides, the contains flavonoid glycosides which have been used in use of hemoglobin A1c (HbA1c) has been recommended the treatment of diabetes to improve insulin sensitivity. by American Diabetes Association to diagnose diabetes Other active antidiabetic components such as glycopro- [5]. teins were identified in the leaf extract [51]. The aqueous Conventional treatments of diabetes include insulin extract of Eucalyptus globulus leaves was found to con- injections, oral glucose-lowering drugs, and nutritional tain a high level of manganese which is highly efficient in therapy [6]. For patients who fail to achieve an acceptable diabetes management. In a study by Pinto et al. (2007), level of glycemic control, oral therapy is usually indicat- the extract reduced blood glucose levels more drastically ed. However, oral hypoglycemic drugs have the poten- than the reference drug, glibenclamide [52]. Several stud- tial to lose their efficacy despite providing a good initial ies focused on the antidiabetic activity of Campomanesia response. Administration of drugs such as sulfonylurea, xanthocarpa leaf decoction. In one study, streptozotocin thiazolidinedione, and biguanide gives rise to various un- (STZ)–induced diabetic rats which were treated with a desirable side effects which include weight gain, fatigue, leaf decoction of C. xanthocarpa experienced reduced and increased low-density lipoprotein cholesterol levels blood glucose levels, reduced loss of liver glycogen and [7,8]. Additionally, the use of oral drugs usually leads to minimal pancreas and kidney histopathological alter- hypoglycemia [9-11]. Nonetheless, supplementation of ations [53-56]. Another study evaluated the efficacy of chromium may improve glucose control in diabetic pa- aqueous extract of Cleistocalyx operculatus flower buds tients [12-27]. Supplementation of vitamin D and vana- (COB) in diabetic patient management. In the trial, pa- dium treatment was also presumed to be beneficial for tients drank 150 mL of COB tea before and while having alleviating diabetes, however, no randomized controlled a meal of 170 g cooked rice. Results showed suppression trials had demonstrated their benefit on glycemic control of postprandial blood glucose, overall blood glucose and [28-42]. HbA1c levels in the COB tea group [57]. Schumacher et Currently, the use of modern medicines for glycemic al. (2015) studied the effect of Eugenia uniflora aqueous control has caused numerous adverse side effects, result- leaf extract in type 1 diabetic mice, and concluded that ing in an increasing demand for safe and cost-effective the extract had antioxidant activity due to its high phenol measures [43,44]. Medicinal plants contain phytoconstit- content and may even reduce the risk of diabetes [58]. uents, some showing mild-to-potent antihyperglycemic Another study on alloxan-induced diabetic rats showed a activity. As an example, alkaloids are known to interact decrease in blood glucose levels after 500 mg/kg of Euca- with proteins involved in glucose homeostasis, hence lyptus citriodora aqueous extract was administered orally exhibiting excellent antidiabetic effect. Recent evidence [59]. The findings are summarized in Table 2 [51-59]. showed that alkaloids might act as potent α-glucosidase The antidiabetic potential of Syzygium, another genus inhibitors and could be alternatively used in the treatment of the family Myrtaceae, has also been widely researched of diabetes, although further evaluation is necessary to with promising findings. This article aims to review the validate their efficacy [45]. Bioactive compounds isolated antidiabetic potential of various Syzygium species based from plants may lower blood glucose levels by improv- on current in vivo and in vitro evidence. ing beta cell function, promoting glucose reabsorption, reducing insulin resistance, or regulating glucagon-like Zulcafli et al.: Antidiabetic potential of Syzygium sp. 309 Table 1. Families of medicinal plant with antidiabetic activity. Family Active compounds Reference Acanthaceae Tannins,