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Bitter melon (Momordica charantia): a review of the bioactive components and their anti-diabetic properties

Alexia M. Harris

SRI Inc. Introduction One of the major chronic illnesses associated with the development of cardiovascular disease is diabetes mellitus. This disease has become a pandemic in many developed countries and is causing the Canadian health care system up to $9 billion dollars per year (Simpson et al., 2003). Diabetes is a metabolic disease characterized by an excess of glucose in the blood. Glucose can accumulate in the blood for various reasons, leading to two types of diabetes. Type-1, also known as juvenile diabetes, is less common and often develops during childhood in individuals with a malfunctioning pancreas that produces little or no insulin. The most common type of diabetes is type-2, which used to be called adult-onset diabetes since the disease usually develops in adults. In type-2 diabetes, the pancreas can produce insulin, but the body's cells do not respond to it (Yibchok-Anun et al., 2006). The number of individuals diagnosed with type-2 diabetes is continuing to rise worldwide, and the incidence in children and adolescents is also increasing (Sacks et al., 2002). Treatment of diabetes Although many individuals with type-2 diabetes can control their blood glucose levels by proper nutrition and exercise, these healthy lifestyle changes alone are often not enough (Collazo-Clavell, 2009). Type-1 diabetics rely on daily insulin injections to maintain blood glucose levels within a normal range. However, synthetic insulin has no stimulatory effect on the pancreas therefore the symptoms are only suppressed while the insulinsecreting beta cells of the pancreas continue to malfunction (Srivastava et al., 1993). Along with insulin therapy, doctors commonly prescribe oral anti-diabetic medications to lower blood glucose levels, such as sulfonylureas, biguanides, alphaglucoside inhibitors, thiazolidinediones and meglititinides, however these often cause adverse side effects and drug to drug interactions (CollazoClavell, 2009).

Use of bitter melon in diabetes An alternative to using synthetic antidiabetics to help control blood glucose is the use of herbal plants. There are many traditional herbal remedies that have been used to treat diabetes in Asia and other developing countries (Yibchok-Anun et al., 2006). One plant that has received the most attention for its anti-diabetic properties is bitter melon, Momordica charantia, commonly referred to as bitter gourd, karela and balsam pear (Yibchok-Anun et al., 2006, Cousens, 2008). Bitter melon is a tropical plant that is widely cultivated in Asia, India, East Africa, and South America for its intensely bitter fruits that are commonly used in cooking and as a natural remedy for treating diabetes (Abascal and Yarnell, 2005).

Appearance Bitter melon is a member of the Cucurbitaceae family and bears a resemblance to the cucumber plant due to its yellow flowers and elongated fruit. However, bitter melon has a unique appearance since the fruit is covered in bumpy lobes that form deep ridges along the length of the fruit. The fruit is harvested during its unripe stage when the skin appears light to dark green in color with a white central flesh containing the seeds. When the fruit ripens, the skin and flesh turn bright orange and the seeds become coated in bright red arils. At this stage, the fruits eventually split open revealing the red arils as a mechanism to attract birds for seed dispersal (Rodriguez et al. 1976). Unlike most fruits however, bitter melon is eaten unripe since the orange flesh has an unpleasant taste and texture, and some studies report that the red arils can be toxic to children (Morton, 2008). It is also the unripe fruit that has been studied most extensively for its therapeutic contents (Bitter Melon "monograph", 2007). Nutrient profile Bitter melon is a powerful nutrient-dense plant composed of a complex array of beneficial compounds. These include, bioactive chemicals, vitamins, minerals and antioxidants which all contribute to its remarkable versatility in treating a wide range of illnesses. The fruits contain high amounts of vitamin C, vitamin A, vitamin E, vitamins B1, B2 and B3, as well as vitamin B9 (folate). The fruit is also rich in minerals including potassium, calcium, zinc, magnesium, phosphorus and iron, and is a good source of dietary fiber (Bitter Melon "monograph", 2007). Researchers have found that bitter melon is full of antioxidants such as carotenoids, including alpha and beta-carotene, lycopene and zeaxanthin (Rodriguez et al. 1976). Beneficial effects The fruit, stems, leaves and roots of bitter melon have all been used in traditional medicine to help treat ailments such as hyperlipidemia, digestive disorders, microbial infections and menstrual problems (Yibchok-Anun et al., 2006; Bitter Melon "monograph", 2007). Bitter melon has been shown to possess powerful antiviral properties that can stimulate the immune system and activate the body's natural killer cells (Grover and Yadav, 2004) to help fight off viruses such as herpes simplex virus 1 and human immunodeficiency virus 1(Raman and Lau, 1996). Studies have also shown that bitter melon has anti-carcinogenic properties and can be used as a

cytotoxic agent against many types of cancer (Grover and Yadav, 2004). Bitter melon extract can also be used as a broad-spectrum antibacterial agent to fight off infections caused by E.coli, Salmonella, S. aureus, Staphylococcus, Pseudomonas, and Streptobaccilus (Saeed and Tariq, 2005). In addition, the plant possesses anti-helmintic properties, which are effective in the treatment of malaria. Traditionally, bitter melon has also been used as an abortifacient agent used to induce abortions and therefore pregnant women are advised to avoid consumption of the plant (Grover and Yadav, 2004). Based on the multitude of medical conditions that bitter melon can treat, scientists are more and more interested in studying its bioactive compounds and their actions on the body. However, as many studies report, there has been substantial emphasis on the anti-diabetic compounds and their hypoglycemic properties (Harinantenaina et al., 2006). Bioactive Compounds A number of reported clinical studies have shown that bitter melon extract from the fruit, seeds, and leaves contain several bioactive compounds that have hypoglycemic activity in both diabetic animals and humans (Yibchok-Anun et al., 2006). The major compounds that have been isolated from bitter melon and identified as hypoglycemic agents include charantin, polypeptide-p and vicine. Charantin Charantin is a steroidal glycoside that has been isolated from the seeds, leaves and fruit, and shown to possess powerful hypoglycemic properties (Raman and Lau, 1996). When administered orally and intravenously, charantin was found to significantly reduce blood glucose levels in both normal and diabetic rabbits (Raman and Lau, 1996). Studies have reported that the compound is more effective than the oral hypoglycemic agent tolbutamide (Cousens, 2008). In one study, two aglycones of charantin were isolated and identified as sitosterol and stigmastadienol glycosides, however, when tested separately for their hypoglycemic effects in vivo, these two constituents did not produce any notable changes in blood glucose levels (Harinantenaina et al., 2006). This is an indication that charantin may contain other specific components, yet to be identified, that are responsible for the hypoglycemic activity observed in diabetics.

Polypeptide-p An insulin-like hypoglycemic protein known as polypeptide-p or p-insulin was isolated from the fruits, seeds and leaves of bitter melon and shown to lower blood glucose levels in gerbils, langurs and humans when injected subcutaneously (Khanna et al., 1981). One study reported that subcutaneous injection of p-insulin significantly lowered blood glucose levels in type-1 diabetics (Welihinda et al., 1982). This indicates that p-insulin works by mimicking the action of human insulin in the body and thus may be used as plant-based insulin replacement in patients with type-1 diabetes. In addition, one study reported that type-1 diabetics on p-insulin therapy for 5 months showed no complaints or adverse side effects (Raman and Lau, 1996). Some studies show that oral administration of bitter melon extract may not be as beneficial for type-1 diabetics as the subcutaneous injection of isolated p-insulin. This is because proteins are generally inactivated in the gut due to digestion by proteolytic enzymes (Raman and Lau, 1996). However, one study reported, without any supporting evidence, that pinsulin is effective when administered orally (Raman and Lau, 1996). In addition, other studies have confirmed that oral intake of the extract from bitter melon seeds does produce hypoglycemic effects in streptozotocin (STZ) induced type-1 diabetic rats (Sathishsekar and Subramanian, 2005). This indicates that compounds in bitter melon seeds other than pinsulin may also be effective in the treatment of type1 diabetes. Vicine The other major compound that has been isolated from the seeds of bitter melon is a glycoalkaloid known as vicine. This pyrimidine nucleoside has been shown to induce hypoglycemia in non-diabetic fasting rats by intraperitoneal administration (Raman and Lau, 1996). However, vicine found in fava bean has been shown to induce favism, an acute disease characterized by hemolytic anemia (Raman and Lau, 1996), in individuals with a hereditary loss of the enzyme glucose-6-phosphatedehydrogenase (Basch et al., 2003). Although there have been no reports on favism induced by bitter melon, individuals susceptible to the disease should avoid eating the fruit. Further studies are required to ensure the safety and efficacy of using vicine to treat hyperglycemia (Dutta et al, 1981).

Other components Many other bitter melon constituents have been identified and isolated by various extraction techniques. The first study to show the in vivo hypoglycemic activity of the major compounds of bitter melon was done by a group of Japanese scientists. They isolated eleven compounds by fractionation of a methanol extract from dried bitter melon fruits. The structure of three cucurbitane triterpenoids were determined, as well as two other major compounds that were tested and shown to significantly lower blood glucose levels in diabetic mice. Four compounds that may be responsible for the bitter taste of the plant were isolated and identified as momordicosides K and L, and momordicines I and II. The last two compounds isolated were identified as sitosterol and stigmastadienol, the aglycones of charantin (Harinantenaina et al., 2006). Antioxidant activities There has been a lot of focus on the direct hypoglycemic action of bitter melon. However, some compounds have been reported to treat and prevent diabetic symptoms by mechanisms other than lowering blood glucose. For instance, many of the antioxidants found in bitter melon work by protecting the body's cells from oxidative damage. A common complication associated with diabetes is the development of atherosclerosis. This condition is caused by the build-up of reactive oxygen species (ROS) that cause lipids to be oxidized and accumulate on arterial walls, a process also known as peroxidation. These ROS are often involved in the pathogenesis of type-1 diabetes, which may account for the pancreatic damaged typically observed. One major antioxidant involved in preventing type-2 diabetes is conjugated linolenic acid (CLnA). One study discovered that CLnA occurs abundantly (57.7%) in the seed oil of bitter melon, and therefore its antioxidant activity was tested in diabetic rats. CLnA was found to significantly reduce plasma lipid peroxidation, as well as LDL-cholesterol in erythrocyte and liver tissue membranes. In addition CLnA indirectly lowers blood glucose levels since glucose auto-oxidation and protein glycation are often associated with hyperglycemia in diabetics (Dhar et al., 2007). Use of bitter melon for weight-loss Another mechanism whereby bitter melon's bioactive compounds indirectly work to lower blood glucose is by reducing adiposity and normalizing

glucose tolerance (Chen et al., 2003). Obesity or excessive body fat is a major risk factor for developing type-2 diabetes. More than 80 percent of type-2 diabetics are obese or overweight. Excess fatty tissue, especially around the abdomen, causes the body's cells to become resistant to ones own insulin and leads to hyperglycemia. Therefore, many overweight diabetics can improve their blood glucose levels by losing weight through proper nutrition and regular exercise (Collazo-Clavell, 2009). Another way for diabetics to lose weight is by using herbal supplements such as bitter melon. Researchers have discovered that the bioactive compounds in bitter melon have hypolipidemic actions that can lower serum and liver cholesterol, which improves glucose tolerance. One study tested these effects on normal and STZ-induced diabetic rats fed high fat diets. Results clearly showed that bitter melon supplementation accompanied by a high fat diet reduced weight gain in the rats by preventing visceral fat accumulation. In addition, bitter melon showed marked improvements in insulin resistance and therefore glucose tolerance was normalized in the rats fed a high fat diet (Chen et al., 2003). Dosage and precautions It is apparent that bitter melon's ability to cure diabetes and fight off such a wide range of illnesses, without causing adverse side effects, would make it the ideal herbal supplement. However, despite the abundance of scientific studies on the benefits of bitter melon, there is still a lack of evidence on the long-term safety of bitter melon consumption. Therefore, being cautious of the dosage and route of administration is important. The normal adult dose, administered orally, is about 50-100mL of juice daily. There have been no reported cases of serious toxicity in adults at this dose (Raman and Lau, 1996). However, toxicity caused by overdose has been observed in some animal models, and two reports have documented near-fatal reactions due to hypoglycemic coma in children (Raman and Lau, 1996). Further study is required to ensure that bitter melon is a safe and effective remedy for long term use. Doctors supervising diabetics should be aware of any bitter melon supplementation by their patients, and should be informed of the potential hypoglycemic risks associated with improper dosing (Leatherdale et al. 1981). Based on the current state of the diabetes pandemic, and the lack of safe and effective conventional drugs, the use of bitter melon as a herbal medicine, is a promising solution to the serious health threat that diabetes mellitus is posing on the general population.

References

Abascal, K., Yarnell, E. 2005. Using bitter melon to treat diabetes. Altern. Complement Ther. Med. 11:179-184. Basch, W.E., Gabardi, S., and Ulbricht, C. 2003. Bitter melon (Momordica charantia): A review of efficacy and safety. Am. J. Health-Syst. Pharm. 60:356-359. Chen, Q., Chan, L.L.Y., and Li, E.T.S. 2003. Bitter melon (Momordica charantia) reduces adiposity, lowers serum insulin and normalizes glucose tolerance in rats fed a high fat diet. J. Nutr. 133:1088-1093. Cousens, G. There is a cure for diabetes: The Tree of Life 21 day program. California: North Atlantic Books, 2008. 191-192. Dhar, P., Chattopadhyay, K., Bhattacharyya, D. Roychoudhury, A., Biswas, A., and Ghosh, S. 2007. Antioxidative effect of conjugated linolenic acid in diabetic and non-diabetic blood: an in vito study. J. Oleo Sci. 56:19-24. Dutta, P.K., Chakravarty, A.K., Chowdhury, U.S., and Pakrashi, S.C. 1981. Vicine, a favism-inducing toxin from Momordica charantia Linn. seeds. Indian J. Chem. 20:669-671. Grover, J.K., and Yadav, S.P. 2004. Pharmacological actions and potential uses of Momordica charantia: a review. J. Ethnopharmacol. 93:123-132. Harinantenaina, L., Tanaka, M., Takaoaka, S., Oda, M., Mogami, O., Uchida, M., and Asakawa, Y. 2006. Momordica charantia constituents and antidiabetic screening of the isolated major compounds. Chem. Pharm. Bull. 54:1017-1021. Khanna, P., Jain, S.C., Panagariya A., and Dixit, V.P. 1981. Hypoglycemic activity of polypeptide-p from a plant source. J. Nat. Prod. 44:648-655. Leatherdale, B.A., Panesar, R.K., Atkins, T.W., Bailey, C.J. and Bignell, A.H.C. 1981. Improvement in glucose tolerance due to Momordica charantia (Karela). Brit. Med. J. 282:1823-1824. Maria, Collazo-Clavell, Ed. M. Mayo Clinic: The essential diabetes book. New York: Time Inc. Home Entertainment Books, 2009. 7-133. Momordica Charantia (Bitter Melon): Monograph. 2007. Altern. Med. Rev. 12:360-363. Morton, J.F. 2008. The balsam pear ­ an edible, medicinal and toxic plant. Econ. Bot. 21:57-68.

Raman, A., and Lau, C. 1996. Anti-diabetic properties and phytochemistry Momordica charantia L. (Curcurbitaceae). Phytomedicine. 2:349-662. Rodriguez, D.B., Raymundo, L. C., Lee, T.C., Simpson K.L., and Chichester, C.O. 1976. Carotenoid pigment changes in ripening Momordica charantia fruits. Ann. Bot-London. 40:615-624. Sacks, D.B., Bruns, D.E., Goldstein D.E., Maclaren, N.K., McDonald, J.M., and Parrott, M. 2002. Guidelines and recommendations for laboratory analysis in the diagnosis and management of diabetes mellitus. Clin. Chem. 48:436-472. Saeed, S., and Tariq, P. 2005. Antibacterial activities of Mentha piperita, Pisum sativum and Momordica charantia. Pak. J. Bot. 37:997-1001.

Sathishsekar, D., and Subramanian, S. 2005. Antioxidant properties of Momordica Charantia (bitter gourd) seeds on Streptozotocin induced diabetic rats. Asia Pac. J. Clin. Nutr.14:153-158 Simpson, S.H., Corabian, P., and Johnson, J.A. 2003. The cost of major morbidity in people with diabetes mellitus. CMAJ. 168:1661-1667. Srivastava, Y., Venkatakrishna-Bhatt, H., Verma, Y., and Venkaiah, K. 1993. Antidiabetic and adaptogenic properties of Momordica charantia extract: An experimental and clinical evaluation. Phytother. Res. 7:285-289.

Welihinda, J., Arvidson G., Gyfle, E., Hellman, B. and Karlsson, E. 1982. The insulin-releasing activity of the tropical plant Momordica charantia. Acta. Bio. Med. Germ. 41:1229-1240. Yibchok-Anun, S., Adisakwattana, S., Yao, C.Y., Sangvanich, P., Roengsumran, S., and Haw Hsu, W. 2006. Slow acting protein extract from fruit pulp of Momordica charantia with insulin secretagogue and insulinomimetic activities. Biol. Pharm. Bull. 29:1126-1131.

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