REVIEW : POTENTIAL OF MEDICINAL IN AS ANTIDIABETIC ACTIVITY

Nur Annisa*, Rini Hendriani*, Ahmad Muhtadi* Departement of Pharmacology and Clinical Pharmacy, Universitas Padjajaran Jl. Raya Bandung-Sumedang km.21 Jatinangor, West Java, Indonesia. Email : [email protected]

ABSTRACT

Diabetes mellitus is one of the leading causes of world death. This disease has the highest prevalence of death in Indonesia in . Diabetes mellitus is mostly found in men patients as much as 60%. Currently, there are various kinds of antidiabetic drugs that have been circulating in the market and consumed by humans. Unfortunately, the drugs that have been circulating it still has a considerable shortage of side effects. Thus, researchers are still looking for and developing new drugs. In addition, many people turn to alternative medicine. In addition, traditional medicine also has advantages such as side effects that are so small that many people turn to traditional medicine. One of the that can play a role in antidiabetic is Amaryllidaceae. In the last 10 years there are known to be 9 in the Amaryllidaceae that have potential in antidiabetic activity with secondary metabolite compounds in the form of alkaloid and flavonoid that play a role in decreasing blood sugar levels in the body. The 3 best candidates are on the Galanthus reginae-olgae subsp plant. vernalis, Allium cepa L., and candida (Lindl.) Herb. All of the genera belonging to this Amaryllidaceae whose existence of habitat in Asia is the genera of Allium and these genera belong to category 3 of the best candidate. So that other species contained within this genera can be studied and developed in Indonesia.

Keywords: Diabetes Mellitus, Anti-diabetic, Medicine plant, Amaryllidaceae

Introduction Ipheion Raf. Diabetes mellitus is one of the leading Leucojum L. causes of death in the world. By 2015 DM Herb. affects about 8.5% of the world population Muilla S. Watson ex with most male patients as much as 60% Benth. (IDF,2018). Until now, the great public Narcissus L. interest in traditional medicine causes Nerine Herb. researchers to search and develop new Nothoscordum Kunth. drugs. There are 800 plants that have a Kunth. potential antidiabetic activity or 1,200 Herb. species such as the Scadoxus Raf. Amaryllidaceae(Kitukale, et al., 2014). The Sprekelia Heist. Amaryllidaceae is known to have 9 species Herb. potentially in antidiabetic activity with Sternbergia Waldst. & secondary metabolite compounds such as Kit. alkaloid and flavonoids compounds. Tristagma Poeep. Tulbaghia L. The study of literature review carried out by Zephyranthes Herb. searching on electronic diabetes including Google Scholar, Pubmed, Science Direct Distribution and Habitat and Research Gate. They Keyword The existence of the “Antidiabetic”, “Amaryllidaceae”, Amaryllidaceae in the world is widespread. “Phytochemical”, and each genera name The is located in the tropics and is from Amaryllidaceae obtained from The generally located in the center of South Plant List and was used to find all of the and sometimes in Andrean South article research about an antidiabetic activity America. In addition, there is also in the of Amaryllidaceae plants from 2009 until Mediterranean (Dahlgren, et al., 1985). 2018. The list of references in the relevant There are genera groups related to articles also studied to find another article phylogenetics with certain geographic relevant to the topic. conditions(Dahlgren, et al., 1982). In this family, there is a monophyletic group Amaryllidaceae consisting of 25 recognized genera. They Classification for Kingdom Plantae Down usually grow in grasslands, savannahs and to Amaryllidaceae (ITIS, 2018). tropical forests in sub-Saharan Africa, but Kingdom : Plantae are most typical in southern Africa where Subkingdom : Viridiplantae habitats include semiarid dwarf shrubs found Infrakingdom : Streptophyta in winter-rainfall climates(Snijman & Superdivision : Embryophyta Linder, 1996). Of the 25 genera in this Division : Tracheophyta family, there are 8 genera with 9 species that Subdivision : Spermatohytina are known to have potential antidiabetic Class : Magnoliopsida activity isAllium sativum L., Allium cepa L., Superorder : Lilianae Crinum jagus (Thomps.) Dandy, Galanthus : reginae-olgae subsp. vernalist, Lycoris Family : Amaryllidaceae radiata (L'Hér.) Herb., Pancatrium : Agapanthus L’Hér. maritimum L., Sternbergia lutea (L.) Ker Allium L. Gawl. ex Spreng., Tulbaghia violacea Harv., L. and Zephyranthes candida (Lindl.) Herb. Ammocharis Herb. with the presence of the habitat attached in Clivia Lindl. table 1. Crinum L. Eucharis Planch. & Linden. Galanthus L. Habranthus Herb. Hippeastrum Herb.

Table 1: Distribution and Habitat 9 species in Amaryllidaceae Genera Species Distribution and Habitat References Name Allium sativum L. In mountainous regions in Central (Brewster, Allium L. Allium cepa L. Asia 2018) On the banks of rivers and lakes in Crinum jagus (Vrijsen,et the tropics and subtropics around (Thomps.) Dandy al., 1986) Crinum L. the world, including . In Sicily and the western and (World north-western Balkans (parts of Checklist of Galanthus reginae- Greece and the former Selected Galanthus L. olgae subsp. vernalis Yugoslavia) Plant Families, 2017) Lycoris In , Korea and Nepal (Li,et al., Lycoris Herb. radiata (L'Hér.) Herb. 2004) Pancatrium In southern California, Bermuda (Ali,et al., Pancratium L. maritimum L. and the 1990) (World Checklist of Sternbergia Waldst. Sternbergia lutea (L.) On the Balearic Islands in the Selected & Kit. Ker Gawl. ex Spreng. Western Mediterranean to Plant Tajikistan in Central Asia Families, 2017) World (Checklist In Southern Africa (KwaZulu- Tulbaghia violacea of Selected Tulbaghia L. Natal and Cape Province) Harv. Plant Families, 2017) In (South Africa, , Zimbabwe, (World , central and southern Checklist of China, Korea, Nansei-shoto Selected Zephyranthescandida (Ryukyu Islands), Bhutan, Plant Zephyranthes Herb. (Lindl.) Herb. , , Families, , Tonga, Society Islands , 2017) Mariana Islands, southeastern United States to North Carolina), Little Antilles, and )

Diagnostic Characters look that looks obsolete. Otherwise Amaryllidaceae has characteristics of form terminated by 2 or more spathaceous, bulbous (rarely rhizomatous), mostly obvolute or equitant, usually also a brass geophytic, perennials, terrestrial, marcescent that attaches flowers in the bud occasionally aquatic or epiphytic, rich in or can be said are rarely absent, and family-specific alkaloids. Then this family than inner bracteoles usually present, but it has tunicate, annual or persistent also has a shorter and narrower (Meerow & leaves, sessile and linear, lorate, or petiolate Snijman, 1998). and lanceolate to usually elliptic, distichous or spirally decided and sometimes on the The flowers are I-many, perfect, often large basal sheathing can form an aerial and conspicuous, sessile or pedicellate, each pseudostem, generally glabrous and rarely of which is usually punctuated by bracteole, with trichomes. Inflorescence scapose, actinomorphic or zygomorphic, usually pseudo-umbellate or can also reduce protandrous. In perigone crateriform, helicoid cymes, sometimes scape is salverform, funnelform, tubular or completely on the subterranean and has a ventricose have 3 + 3 segments (tepals) connoted below which act as short or long elaiosome located at the end of the chalazal, tubes or are also rarely free to the base, but endosperm with hemicellulose and lipids. In the strips are generally shorter than the addition, in the richer genera with water or outside. Sometimes perigone growth is starch (Meerow & Snijman, 1998). present in the form of a striking or paraperigone-like corona, relatively Phytoconstituent inconspicuous and consisting of a short In Amaryllidaceae, there are secondary callose cord or scales ring (fimbriae in the metabolite compounds that play a role in the throat). In flowers there are 3 + 3 stamens, activity of antidiabetes namely alkaloids and rarely 5 or 18 can also be more than 18, flavonoids. It is known that at present there subequal or vary in length, inserted in the are 110 alkaloid compounds that have been perigone throat or below, sometimes found in Amaryllidaceae which include a filaments are diverse or attached, rarely role in antidiabetic activity such as S-allyl attached to the force, sari is usually cysteine sulphoxide isolated (Eidi, et al., dorsifixed, rarely centrifuged or in basifiks, 2006), lycorane (Conforti, et al., 2010; distorted, dehiscing longitudinally or can be Gbolade, 2009), Galanthamine (Conforti, et said also rarely from terminal pores. There is al., 2010; Preethi, 2013), Lycorenan also a style of filiform, hollow, sometimes (Conforti, et al., 2010), Tazettine (Conforti, twisting, rarely tripartite; stigma capitate, 3 - et al., 2010), Crinine (Conforti, et al., 2010), lobed or very trifid, usually papillate. There Neronine (Conforti, et al., 2010), β-1,5-O- is a synarposal, tricarpellate, inferior, tri- Dibenzoyl- ribofuranose; 4- (rarely uni) ovary locally, with an anterior Methoxybenzaldehide; Oley Alcohol, septal; ovulus axile or basal in placentation, trifluoroacetate; Disulfide, bis (2- anatropous, crassinucellate, (bi- / uni / sulfhydrylethyl) -; Benzene, 1-methyl-4- ategmic)(Meerow & Snijman, 1998). (methylthio) -; 2,4-Dithiapentane; n-propyl 9, 12-octadecadienoate; methyl 5.13- In Amaryllidaceae, there is a ripe fruit with Docosadienoate Moodley, et al., 2015), and the characteristics of a suddenly chapped, crinane (Pingili, et al., 2014). While the sometimesindehiscent capsules, rarely form flavonoid compound that plays a role is 4'- baccate. On the seeds are globose Hydroxy-5,7-dimethoxy-8-methylflavan or (subglobose), fleshy (hard/flat) and winged. can we know by the name of flavan Usually, the testa phytomelanous is black or (Makinde, et al., 2015). brown, sometimes with a caruncular

Anti-diabetic Activity

Table 2 :Various Species of The Amaryllidaceae Family That Have Antidiabetic Activity Secondary Mechanism IC References Genus Species Metabolite 50 of Action (µg/mL) Name Compound alkaloids (S- decreased allyl cysteine (Eidi,et al., Allium sativum L. blood sugar 14.073 sulphoxide 2006) levels Allium L. isolated) decreased 33.6 & (Kelkar, et al., Allium cepa L. alkaloids blood sugar 30.7 2001) levels decreased Crinum jagus alkaloids (Gbolade, blood sugar 2 (Thomps.) Dandy (Lycorane) 2009) Crinum L. levels alkaloids (Galanthamine, decreased Galanthus reginae- Lycorenan, (Conforti,et al., Galanthus L. blood sugar 38.5 olgae subsp. vernalis Tazettine, 2010) levels Crinine, Neronine) Lycoris alkaloids decreased Lycoris Herb. 4 (Preethi, 2013) radiata (L'Hér.) (Galanthamine) blood sugar Herb. levels

Flavonoids (4'- decreased Pancatrium Hydroxy-5,7- (Makinde,et Pancratium L. blood sugar 5 maritimum L. dimethoxy-8- al., 2015) levels methylflavan) Sternbergia decreased Sternbergia W (Iscan, et al., lutea (L.) Ker Gawl. alkaloids blood sugar 12.85 aldst. & Kit. 2017) ex Spreng. levels β-1,5-O- Dibenzoyl- ribofuranose; 4- Methoxybenzalde hide; oley Alcohol, trifluoroacetat; Disulfide, bis(2- decreased Tulbaghia violacea sulfhydrylethyl)-; (Moodley,et Tulbaghia L. blood sugar 0.30 & 0.32 Harv. Benzene, 1- al., 2015) levels methyl-4- (methylthio)-; 2,4- Dithiapentane; n- propyl 9, 12- octadecadienoate; methyl 5,13- Docosadienoate decreased Zephyranthes Zephyranthescandid alkaloids (crinane 29.6, 15.5, (Pingili et al., blood sugar Herb. a (Lindl.) Herb. and lycorane) 26.5 2014) levels

Discussion and Conclusion reducing the sucrase activity after preincubation with Caco-2 cells for 72 Diabetes mellitus is also one of the hours. in this alkaloids there is no significant degenerative diseases that need to be effect on gluconeogenesis and glucose watched by the people. Diabetes mellitus consumption of Caco-2 cells so that the can be said to be a chronic metabolic antihyperglycemic activity that occurs is by disorder characterized by hyperglycemia, inhibiting alpha-glucosidase and reducing changes in lipid metabolism, carbohydrates, the transport of glucose through the and proteins that affect the human body in intestinal epithelium. While the role of terms of physical, psychological, and social flavonoids in antidiabetic activity is health (Patel, et al., 2011; Warjeet, 2011). synergistic inhibition of the gut-glucosidase based on the classification of diabetes is (maltase and sucrase) by inhibiting divided into four types, namely type 1 intestinal-glucosidase and pancreatic-oylase, diabetes mellitus (diabetes insulin dependent which is one of the therapeutic approaches diabetes mellitus, diabetes childhood), type to the treatment of diabetes mellitus 2 diabetes mellitus (Adult-onset diabetes, (Gaikwad, et al., 2014; Gruenwald, et al., Maturity-onset diabetes), type 3 diabetes 2000; Pan, et al., 2003; Singh, et al., 2003). mellitus, and type 4 diabetes mellitus or gestational(Kitukale & Chandewar, 2014). Of the nine species, the only research But the type of diabetes is common in the conducted in vivo research and no clinical community that is type 1 & 2 diabetes. research. In some species, there is a similar alkaloid compound that is lyrocane The role of alkaloid compounds in contained in Galanthus reginae-olgae subsp. antidiabetic activity is as an vernalist and Zephyranthes candida (Lindl.) antihyperglycemic agent by inhibiting Herb. as well as galantamine compounds in disaccharide activity in CaCo-2 cells by Galanthus reginae-olgae subsp vernalist and Zephyranthes candida (Lindl.) Herb. and from the habitat of nine species, the plants Lycoris radiata (L'Hér.) Herb. when viewed that can be developed in Indonesia are from from IC50 values in species containing the genera Allium. Excess genera Allium lyrocane, Galanthus reginae-olgae has a other than genera is widely found in the area higher IC50 value than Zephyranthes of Indonesia, this plant is also commonly candida. as well as in species that contain used as a food herb. galantamine. Lycoris radiata has a lower IC50 value compared to Galanthus reginae- References olgae. This is possible because the content of compounds is different in number in each 1. Adisakwattana, S., Charoenlertkul, P., species or because the Galanthus reginae- Yibchok-Anun, S. 2009. Glucosidase olgae has several compounds that have inhibitory activity of cyanidin-3- potential in antidiabetic activity so that it galactoside and synergistic effect with gives a synergistic effect. Seen from the acarbose. J. Enzyme. Inhib. Med. value of IC50 of 9 species on Amaryllidaceae Chem., 24, 65-69. then got 3 best candidate that is Galanthus 2. Akkarachiyasit, S., Piyawan, C., reginae-olgae subsp plant. vernalist, Allium Sirintorn, Y., Sirichai, A. Inhibitory cepa L., and Zephyranthes candida (Lindl.) activities of cyanidin and its glycosides Herb with IC50 values of 38.5, 33.6 and 30.7, and synergistic effect with acarbose and 29.6, 15.5 and 26.5. There are now a lot against intestinal -glucosidase and of medicinal plants developed in Indonesia. pancreatic - amylase. 2011. Int. J. Mol. 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