Phytomedicine for Diabetes Mellitus: an Overview

Research in Pharmacy 1(4) : 28-37, 2011 ISSN : 2231-539X www.researchinpharmacy.com

Review Article Phytomedicine for Diabetes mellitus: An overview

Uma Makheswari M and Sudarsanam D*

Department of advanced Zoology & Bio Technology, Medical Lab Technology & Bio-medical Instrumentation Science, Loyola College – 600 034, India *Corresponding author email: [email protected]

Diabetes mellitus is a complex metabolic disorder resulting from either insulin insufficiency or insulin dysfunction. Diabetes mellitus affect most of the people of both developed and developing countries. The treatment of diabetes with synthetic drugs is costly and chances of side effects are high. Phytomedicine has been used since ancient time in many parts of the world where access to modern medicine is limited. Low-fat vegan diet has improved glycemic control in type II diabetic patients. Photochemical identified from medicinal plants presents an exciting opportunity for the development of new types of therapeutics for diabetes mellitus. Most prevalent of photochemical groups are the alkaloids, terpenes, and phenolics. Several formulations like herbal teas, extracts, decoctions, infusions, tinctures, etc are prepared from medicinal plants. Despite considerable progress in the development of synthetic drugs, the search for the invention of phytomedicine as alternative therapy is progressing.

Keywords: Diabetes mellitus, phytomedicine, vegan diet, synthetic drugs.

India is the largest producer of Diabetes mellitus medicinal herbs and is called as botanical Diabetes mellitus is a complex garden of the world. Ayurveda, Unani, metabolic disorder resulting from either Siddha and Folk (also called tribal) medicines insulin insufficiency or insulin dysfunction. are the major systems of Indian medicines. Type I diabetes (insulin dependent) is caused Among these systems, Ayurveda is most due to insulin insufficiency. Type II diabetes developed and widely practiced in India. A (insulin independent) is due to number of plants have been described in immunological destruction of pancreatic β Ayurveda and other traditional medicine for cells leading to insulin deficiency. Type II the treatment of diabetes. Isolation of the diabetes is characterized with insulin main compounds from the active extract is a resistance. It is the more common form of crucial step in all research activities for diabetes constituting 90% of the diabetic developing a novel phytomedicine for population. Symptoms for both diabetic diabetes mellitus. conditions may include: (i) high levels of sugar in the blood; (ii) unusual thirst; (iii) Uma Makheswari M & Sudarsanam / Research in Pharmacy 1(4) : 28-37, 2011 frequent urination; (iv) extreme hunger; (v) possess pancreatic beta cells regenerating, loss of weight; (vi) nausea and vomiting; (vii) insulin releasing and fighting the problem of blurred vision; (viii) Excessive tiredness, insulin resistance (Welihinda et al., 1982). irritability etc. Anti diabetic plants also possess strong antioxidant/free-radical scavenging Glycemic control properties. Glycemic control is a medical term referring to the typical levels of blood sugar Phytochemicals (glucose) in a person with diabetes mellitus. Plants have evolved secondary "Perfect glycemic control" would mean that biochemical pathways allowing them to glucose levels were always normal (70– synthesize a raft of chemicals, often in 130 mg/dl, or 3.9-7.2 mmol/L) and response to specific environmental stimuli, indistinguishable from a person without such as herbivore-induced damage, pathogen diabetes. Control and outcomes of both types attacks, or nutrient depravation (Raymond et I and II diabetes may be improved by al., 2000; Hermsmeier et al., 2001). These patients. Home glucose meters can be used secondary metabolites increase their overall to regularly measure their glucose levels ability to survive and overcome local (Gray et al., 2000). The American Diabetes challenges by allowing them to interact with Association in 1994 recommended that 60- their environment. These chemicals also help 70% of caloric intake should be in the form of humans to protect themselves against carbohydrates. But some researchers claim diseases and are called Photochemical. Thus that 40% is better, (Garg et al., 1994) while there is a need to know about the health others claim benefits for a high-fiber, 75% benefits and possible risks to ensure the carbohydrate diet (Kiehm et al., 1976). efficacy and safety of dietary supplements.

Importance of phytomedicine Photochemical are chemical Traditional herbal medicine has been compounds that occur naturally in plants that used since ancient time in many parts of the have protective or disease preventive world. The many side effects of insulin properties. Each type of fruit or vegetable therapy and other oral hypoglycemic agents may contain hundreds of photochemical. necessitate the use of more effective and safer Selenium, for example, is involved with antidiabetic drugs. For example, long-term major metabolic pathways, including thyroid use of Metformin (Bolen et al., 2007) causes hormone metabolism and immune function diarrhea, nausea, gas, weakness, indigestion, (Brown and Arthur, 2001). These abdominal discomfort and headache. Plant photochemical show multiple beneficial based drug are considered to be less toxic effects in combating diabetes and diabetes- and free from side effects than synthetic one. related complications. Hence, they play an important role as alternative medicine. Phytomedicines are The herbal drug preparation mainly whole, fragmented or cut, plants parts (phytomedicine) is obtained subjecting herbal of plants, algae, fungi, lichen in an drugs to treatments such as extraction, unprocessed state, usually in a dried form, distillation, fractionation, purification, but sometimes fresh. Herbal drugs are concentration and fermentation. These defined by their botanical (scientific) include cut or powered herbal drugs, binomial. The active principles present in tinctures, extracts, essential oils, fatty oils, medicinal plants have been reported to expressed juices and processed exudates. 29

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Getting enough phytochemicals disease (Liu and Manson, 2001; Bazzano et Food provides not only essential al., 2003) and diabetes (Colditz et al., 1992; nutrients needed for life but also other Feskens et al., 1995). Fruit and vegetable biologically active compounds for health consumption was inversely related to promotion and disease prevention. The incident type II diabetes (Ford and Mokdad, easiest way to get more photochemical is to 2001). More than 5000 photochemical have eat more fruit (blueberries, cherries, apple…) been identified, but a large percentage still and vegetables (cauliflower, cabbage, remains unknown. Largest and most carrots...). Fruits and vegetables contain many prevalent of photochemical groups are the beneficial nutrients and photochemical that is alkaloids, terpenes, and phenolics. thought to protect against cardiovascular

Table I: Medicinal plants used for the treatment of Diabetes mellitus

Medicinal Family Common Distribution Part Active Reference Plant Names Used Ingredient Aloe vera Asphodelaceae Goddess, North Africa, Leaf, gel Polysaccharid Eshun and Kumari, Canary extract es, Mannans, He, 2004 Guarpatha Islands, Lophenol, Spain, India Lectins Azadirachta Meliaceae Neem, Myanmar, fruit, Nimbin, Pillai and indica Nimtree India, leaf, Nimbidin, Santhakuma Sri Lanka, flower, Nimbinin, ri, 1981 Pakistan seed Azadirachtin Momordica Cucurbitaceae Karela, United Fruit, Charantin Lolitkar and charantia Bittermelon, States, India seed Rajarama Bittergourd. Rao, 1962 Gymnema Asclepiadaceae Gudmar, Tropical Leaf Gymnemic Sugihara et sylvestre Periploca of regions of callus, acids, al., 2000 the woods Africa, Asia stem Gymnema saponin Holostemma Asclepiadaceae Holostemma Sri Lanka, Root Flavonoids, Iwu, 1980 ada-kodien creeper, India, Tannins, Charivel Myanmar, Terpenoids China

Alkaloids their names often contain suffixes "idine", The name "alkaloids" was introduced "anine", "aline", "inine", etc. There are also at in 1819 by the German chemist Carl F.W. least 86 alkaloids containing the root "vin" Meissner. Alkaloids are a structurally diverse (extracted from the Vinca plant). group of over 12,000 cyclic nitrogen- Most plants contain several alkaloids. containing compounds that are found in over Their mixture is extracted first and then 20% of plant species (Zulak et al., 2006). individual alkaloids are separated. Biological Alkaloids are most common in flowering precursors of most alkaloids areamino acids, plants, especially in Fabaceae, Ranunculaceae such as ornithine, lysine, phenylalanine, and Solanaceae (Filho et al., 2006). If several tyrosine, tryptophan, histidine, aspartic acid alkaloids are extracted from one plant then and anthranilic acid. Alkaloids such as

Uma Makheswari M & Sudarsanam / Research in Pharmacy 1(4) : 28-37, 2011 aconitine, anisodamine, charantine, leurosine Terpenes can be used for the prevention show antidiabetic effects (Li et al., 2004). and/or treatment of diabetes type II, obesity and neuropathy. Berberine a quaternary ammonium salt from the protoberberine group of isoquinoline Phenolics alkaloids is used successfully in experimental In organic chemistry, phenols, (Wang et al., 2010) and human diabetes sometimes called phenolics, are a class of mellitus (Gu et al., 2010). It is found in such chemical compounds consisting of a hydroxyl plants as Berberis e.g. Berberis aquifolium group (-OH) bonded directly to an aromatic (Oregon grape), Berberis vulgaris (Barberry). hydrocarbon group. The simplest of the class Berberine has been shown to lower elevated is phenol also called as carbolic acid C6H5OH. blood glucose as effectively as metformin They have higher acidities due to the (Yin et al., 2008). The mechanisms of action aromatic ring's tight coupling with the include inhibition of aldose reductase, oxygen and a relatively loose bond between inducing glycolysis, preventing insulin the oxygen and hydrogen. Phenols are found resistance through increasing insulin receptor in the natural world, especially in the plant expression. kingdom. Whole grain cereals are a good source of phenolics. Terpenes Gallic acid is a trihydroxybenzoic Terpenes are a large and varied class acid, a type of phenolic acid, a type of organic of organic compounds, produced primarily acid, also known as 3,4,5-trihydroxybenzoic by a wide variety of plants, particularly acid, found in gallnuts, sumac, witch hazel, conifers. Vitamin A is an example of a tea leaves, oak bark, and other plants terpene. When terpenes are modified (Reynolds and Wilson, 1991). It is used to chemically, such as by oxidation or treat albuminuria and diabetes. rearrangement of the carbon skeleton, the resulting compounds are generally referred Is Phythochemicals Dangerous to as terpenoids. Terpenes are derived Many plants that humans consume biosynthetically from units of isoprene, which become toxic when attacked by pathogens. has the molecular formula C5H8. The basic The plants produce very dangerous molecular formulae of terpenes are multiples phytochemicals, phytoalexins, in response to of (C5H8) n where n is the number of linked being attacked by bacterial or fungal isoprene units. This is called the isoprene rule pathogens. Certain phytochemicals have been or the C5 rule. Terpenes may be classified by found to contribute to cancer cell growth. the number of terpene units in the molecule; a Beta-carotene, (it can be beneficial when prefix in the name indicates the number of taken naturally), has been found to increase terpene units needed to assemble the the risk of lung cancer in male smokers when molecule. It is classified into Hemiterpenes, taken in high-doses. Some flavonoids can Monoterpenes, Sesquiterpenes, Diterpenes, cause serious gastrointestinal or allergic Sesterterpenes and Polyterpenes. These are problems. extracted from green vegetables, soy products and grains, and represent one of the largest Vegan vs. Diabetes mellitus classes of phytochemicals. They are The incidence of diabetes has found to synthesized through two potential pathways, be lower in vegetarians. Vegan diets also the mevalonate and, more recently identified, lower advanced glycation end products deoxy-d-xylulose pathways (Rohmer, 1999). (McCarty, 2005). Several studies have shown 31

Uma Makheswari M & Sudarsanam / Research in Pharmacy 1(4) : 28-37, 2011 that a vegan diet may be effective in of populations are using traditional medicine managing type II diabetes (Barnard et al., in primary medical problems (Grover and 2006). Clinical trials using low fat vegan diets Yadav, 2004). Drug Metformin (a biguanide) have shown improvements in glycemic is a derivate of an active natural product, control and cardiovascular health (Jenkins et galegine a guanidine isolated from the plant al, 2003; Fraser, 2003). Plant-based diet diets Galega officinalis L., which was used to relieve are low in fat and high in fiber, they typically the intense urination in diabetic people cause associated reductions in dietary energy (Witters, 2001). Even the root juice of density and energy intake, which are not Helicteres isora Linn. (Family – Sterculiaceae) fully compensated for by increased food is claimed to be useful in diabetes, empyema, intake (Kendall et al., 1991; Howarth et al., and a favorite cure for snakebite (Singh et al., 2001). Whole-grain consumption also reduces 1984). the risk of type II diabetes. The vegetarian Despite considerable progress in the diet forms of benefit for both the management of diabetes by conventional carbohydrate and lipid abnormalities in drugs, the search for natural antidiabetic diabetes. Vegan diets have been associated plant products as alternative therapy is with very low LDL cholesterol levels (Sacks et progressing. al., 1985). The weight loss may be one of the Many medicinal plants have shown advantages of vegetarian diets. Diet and experimental or clinical antidiabetic activity lifestyle changes can prevent the and that have been used in traditional development of diabetes in susceptible systems of medicine. Plants such as M. individuals (Knowler et al., 2002). charantia, Eugenia jambolana, Mucuna pruriens, Murraya koeingii and Brassica juncea have Animal studies found to have anti diabetic property (Grover Proper animal model have to be used et al 2002). All plants have shown varying for testing the anti diabetic activity (Versphol, degree of hypoglycemic and anti- 2002). The only model with supporting data hyperglycemic activity. In the recent years for type II diabetes is the streptozotocin more than 500 herbal medicines have been diabetic rat (Islas-Andrade et al., 2000). But reported to possess antidiabetic property according to Versphol, the only way to get (Handa et al., 1989; Jia et al., 2003). An ethno type II diabetic animals by chemical botanical survey of semi-structured induction is by the proper use of questionnaire of medicinal plants in five streptozotocin in neonatal rats (n-STZ), or use districts of Lagos State of Nigeria reputed for genetically models like fa/fa zucker diabetic the treatment of diabetes have been reported fatty rat. Anti diabetic plants have been (Gbolade, 2009). The principal antidiabetic observed to possess potent antioxidant plants included Vernonia amygdalina, Bidens activity, which may contribute to anti- pilosa, Carica papaya, Citrus aurantiifolia, diabetic property in streptozotocin/alloxan, Ocimum gratissimum, Momordica charantia and induced animal model (Grover et al., 2002). Morinda lucida. The database maintaining the record Anti-diabetic activity and Phytomedicine of medicinal plants having anti- A number of plants have been hyperglycemic or anti-diabetic activity has described in Ayurveda and other traditional been reported on 2009 (Singh et al., 2009). The medicine for the treatment of diabetes. In herbal drugs with antidiabetic activity are yet Ayurveda, diabetes is described as to be commercially formulated as modern ‘Madhumeha’. In developing countries 80% medicines, even though they have been 32

Uma Makheswari M & Sudarsanam / Research in Pharmacy 1(4) : 28-37, 2011 acclaimed for their therapeutic properties in application to parasitic diseases. The neem the traditional systems of medicine. tree offers an opportunity to reduce insulin The market for herbal medicines is requirements with a safe and proven herb. booming (Brevoort, 1998) and evidence for Many scientists have done clinical trial effectiveness is revealed to all at a faster rate. supporting the hypothesis that leaf extracts, Some of the most promising plants for seed oil and nimbidin exert hypo- diabetes mellitus were Aloe vera, Azadirachta glycaemic/anti-hyperglycaemic effects. indica, Momordica charantia, Gymnema sylvestre, Holostemma ada-kodien., etc. Table I depicts the Momordica charantia characteristics of these anti diabetic plants. Momordica charantia, called bitter melon or bitter gourd in English, is a tropical Aloe vera and subtropical vine of the family Aloe vera is a stemless/short-stemmed Cucurbitaceae, widely grown in Asia and succulent plant growing to 60–100 cm tall, Africa. There are many varieties that differ spreading by offsets. Aloe vera has been substantially in the shape and bitterness of widely grown as an ornamental plant. Aloe the fruit. Bitter melon has been used in vera gel is better known as a home remedy for various Asian and African traditional minor burns and other skin conditions. Aloe medicine systems for a long time (Beloin et vera extracts may be useful in the treatment of al., 2005). wound and burn healing, minor skin The plant contains biologically active infections, diabetes, and elevated blood lipids compounds, chiefly momordicin I and II, and in humans. These positive effects are thought cucurbitacin B. (Fatope et al., 1990) The to be due to the presence of compounds such plants contain also bioactive glycosides as polysaccharides, mannans, anthra - (including momordin, charantin, quinones, and lectins (Eshun and He, 2004). charantosides, and momordicosides) and Intake of Aloe vera has been reported to other terpenoid compounds (including improve blood glucose levels in diabetics momordicin-28, momordicin, momordenol (Yongchaiyudha et al., 1996) and lowered and momordol) (Begum et al., 1997; Kimura blood lipids in hyperlipidaemic patients et al., 2005). (Nassiff et al., 1993). Use of Momordica charantia by diabetic patients for its hypoglycemic potential is a Azadirachta indica common practice in India (Sastri, 1962). Effect Azadirachta indica is commonly known of Momordica charantia fruit powder on serum as neem, margosa or Indian lilac. Azadirachta glucose level and body weight in Alloxan- indica is a tree in the mahogany family induced diabetic rats has been studied (Jafri Meliaceae. It was introduced to Africa by et al., 2009). It was found that Momordica Indian immigrants and has since been charantia fruit powder is helpful in treating naturalized in many African countries and hyper glycemic rats in diabetes mellitus type cultivated in several others. The seeds contain II. Charantin has been extracted from the a complex secondary metabolite azadirachtin. plant, which had hypoglycaemic effect on Three bitter compounds were extracted from normal and diabetic rabbits (Lolitkar and neem oil, which were named nimbin, Rajarama Rao, 1962). Momordica charantia has nimbinin, and nimbidin (Pillai and been found to increase insulin Santhakumari, 1981). The efficacy of neem as sensitivity.(Sridhar et al 2008). Momordica a broad spectrum pesticide, non-toxic to charantia also contains a substance lectin that humans has important implications for its has insulin-like activity due to its non- 33

Uma Makheswari M & Sudarsanam / Research in Pharmacy 1(4) : 28-37, 2011 protein-specific linking together to insulin Asclepiadaceae is used to control diabetes receptors. This lectin lowers blood glucose (Moming, 1987). Plant has various types of concentrations by acting on peripheral tissues phytochemicals like alkaloids, flavonoids, and act as a major contributor to the flavanones, tannins, terpenoids, amino acids hypoglycemic effect. Tablets of bitter melon and carbohydrates. Presence of flavonoids extract are also produced as a food and tannins are responsible for the observed supplement in many countries. anti diabetic activity (Iwu, 1980) Anti diabetic activity of Holosstemma Gymnema sylvestre ada-kodien Schults in alloxan induced Gymnema sylvestre is an herb native to diabetic rats have been studied. Extracts of the tropical forests of southern and central this plant possess a variety of actions related India where it has been used as a natural to the antidiabetic properties such as treatment for diabetes for nearly two reducing insulin requirements by possibly millennia. The common name of the plant enhancing endogenous insulin availability, species is miracle fruit (Wiersema and Blanca, improving vitiated blood glucose 1999). It is also known as gymnema, cowplant homeostasis, better controlling of and Australan cowplant.The major bioactive hyperlipidemia associated with diabetes, and constituents of Gymnema sylvestre are a group reducing amylase activity. of oleanane type triterpenoid saponins known as gymnemic acids. Conclusion Gymneme syvestre leaves contain Prevention is a more effective strategy triterpene saponins belonging to oleanane than treatment. Natural products formed by and dammarene classes. It also contains living systems, especially from plant origin, flavones, anthraquinones, hentri-acontane, have found to be beneficial in treating human pentatriacontane, α and β- chlorophylls, diseases such as cancer, diabetes and phytin, resins, tartaric acid, formic acid, infectious diseases. Plant-based foods, such as butyric acid, lupeol, β-amyrin related fruit, vegetables, and whole grains, which glycosides and stigmasterol. contain significant amounts of bioactive Gymneme syvestre found to have an photochemical, may provide desirable health antidiabetic and hypolipidemic activity on benefits beyond basic nutrition to reduce the both alloxan induced diabetic rats and risk of chronic diseases. Analysis of the normal rats. From extract of the leaves were pharmacological activities of plant extracts isolated gymnemic acids, which exhibit anti- may enable the design of less expensive sweet activity (Kinghorn and Compadre, therapies. Despite considerable progress in 2001). Gymnema sylvestre may be useful as the treatment of diabetes by oral therapeutic agents for the stimulation of hypoglycemic agents, search for newer drugs insulin secretion in individuals with type II continues because the existing synthetic diabetes (Asare-Anane et al., 2005). It can drugs have several limitations. Thus also help prevent adrenal hormones from phytomedicine have retained functional stimulating the liver to produce glucose, strength compared to other medical system thereby reducing blood sugar levels (Gholap because of its safe and easy accessibility. and Kar, 2003). References Holostemma ada-kodien Asare-Anane, H., Huang, G.C., Amiel, S.A., Holostemma ada-kodian, an important Jones, P.M., and Persaud, S.J. 2005. medicinal plant belonging to family Stimulation of insulin secretion by an 34

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