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Food Reviews International

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Bitter melon (Momordica charantia L.) bioactivecomposition and health benefits: A review

Sing P. Tan, Tuyen C. Kha, Sophie E. Parks & Paul D. Roach

To cite this article: Sing P. Tan, Tuyen C. Kha, Sophie E. Parks & Paul D. Roach (2016) Bittermelon (Momordica charantia L.) bioactive composition and health benefits: A review, Food ReviewsInternational, 32:2, 181-202, DOI: 10.1080/87559129.2015.1057843

To link to this article: http://dx.doi.org/10.1080/87559129.2015.1057843

Accepted author version posted online: 09Jun 2015.Published online: 09 Jun 2015.

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Bitter melon (Momordica charantia L.) bioactive compositionand health benefits: A reviewSing P. Tana, Tuyen C. Khab, Sophie E. Parksa,c, and Paul D. Roacha

aSchool of Environmental and Life Sciences, University of Newcastle, Ourimbah, New South Wales, Australia;bFaculty of Food Science and Technology, Nong Lam University, Ho Chi Minh City, Vietnam; cCentral CoastPrimary Industries Centre, New South Wales Department of Primary Industries, Gosford, New South Wales,Australia

ABSTRACTBitter melon (Momordica charantia L.) has traditionally been used as amedicinal food in many developing countries. It is a tropical fruitclaimed to have therapeutic effects due to its content of bioactivecompounds. The present review is an attempt to highlight the bittermelon varieties, bioactive composition that is linked to its therapeuticeffects, especially antidiabetic effect, in vitro and in vivo models, andunderstanding of the mechanisms of actions of bitter melon that areassociated with epidemiological evidences. This paper also outlines aproposed processing scheme aiming to fully utilize bitter melon andadd further value to this fruit.

KEYWORDSAntidiabetic effects;bioactive compounds; bittermelon; mechanism ofactions

Introduction

Momordica charantia L. is a member of the Cucurbitaceae family.(1,2) The two mostcommon names of M. charantia are bitter melon and bitter gourd, as every part of theplant is bitter.(2,3) It is also referred to by different names around the world, such asbalsam pear (English), Karella (Hindi or Urdu), Nigauri or Goya (Japanese), Ku gua(Mandarin), Ko guai (Taiwanese), Kho qua (Vietnamese), Ampalaya (Filipino), andAssorossie (French). Momordica means “to bite,” which refers to the leaf of the bittermelon plants; the leaf has jagged edges and looks as if it has been bitten.(2)

The health and pharmacological properties of bitter melon have been widely investi-gated in the past decade and will be described in detail in this paper. More than 100studies(2,4–7) have revealed that bitter melon is associated with a wide range of beneficialeffects on health: anticancer,(8–14) antiviral,(2,16) anti-inflammatory, analgesic,(17–20) hypo-lipidemic, and hypocholesterolemic effects.(21–25) Furthermore, numerous studies havebeen conducted on the effectiveness of fresh, juiced, or dried bitter melon in diabeticanimals and in type 2 diabetic human subjects.(2,26–33)

Bitter melon is a promising plant for human health. As such, it is desirable to under-stand the bioactive composition of bitter melon that is linked to its medicinal properties aswell as its mechanisms of actions. The present review is an attempt to highlight the bittermelon varieties, bioactive composition of bitter melon that is linked to its pharmacological

CONTACT Sing P. Tan sing.p.tan@uon.edu.au School of Environmental and Life Sciences, University of Newcastle,10 Chittaway Road, NSW 2258, Australia.Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lfri.

FOOD REVIEWS INTERNATIONAL2016, VOL. 32, NO. 2, 181–202http://dx.doi.org/10.1080/87559129.2015.1057843

© 2016 Taylor & Francis

effects, especially antidiabetic effect, cell culture, animal, and human studies, and under-standing of the mechanisms of actions of bitter melon that are associated with theepidemiological evidences.

Bitter melon varieties

Bitter melon is popular medicinal foods in many developing countries, especially in Asiaand Africa. It can be found growing in most countries with a tropical or subtropical climate,such as China, Taiwan, Malaysia, Thailand, Vietnam, Indonesia, India, and Africa.(4) Thereare many different varieties grown worldwide. The origins of the different varieties andcultivars are unknown; therefore, they are not classified in the Linnaean taxonomy system.

Growing bitter melon requires a good irrigation system, a well-drained sandy loam soil,and an appropriate fertilizer, but it has been argued that production could be moreefficient if guidelines were created.(34) The crop production requires warm conditions, asit is a tropical fruit. Therefore, summer is the best season for germination and productionunder temperate field conditions. However, it can also be grown in greenhouses duringthe cooler months. It is a climbing perennial that usually grows up to 5 m, and bearselongated fruit with a range of 9–60 cm long and a warty-looking exterior.(5) An exampleof a cross-sectional photo of commercial bitter melon is shown in Fig. 1. This variety iseasy to pack and is not damaged during transportation. It has a smooth shiny and brightskin with fewer bumps than other varieties.(34)

Cultivars of Chinese bitter melon are commonly categorized into three types dependingon their shape, color, size, and bitterness (Table 1).(35) The maturity of the bitter melon canbe defined based on the hardness or firmness of the fruit, the color of the skin, and the colorof the seed aril.(3) The color of the seed aril changes from white-yellowish to yellowish-orange, and it turns red when the bitter melon is ripe or overripe.(2,36) The commercialbitter melon comes in three main skin colors: green, pale green, and dark green. The green-colored-skin melon is immature, whereas the ripe bitter melon is orange.(2)

Immature bitter melon is the most common type consumed worldwide. Generally, thebitterness of immature bitter melon is stronger and more intense in those with the darkergreen skins (Table 1), lighter skin color melon tends to be less bitter.(3) Furthermore, thebitterness of the fruit is less intense as it ripens, and this may be due to their high contentof carotenoids.(37) This is similar to the Momordica cochinchinensis (Gac fruit), a fruit ofthe Cucurbitaceae family, which is also known as sweet gourd due to its extraordinarilyhigh content of carotenoids.(38) Generally, the bitterness of bitter melon is attributed totheir saponins, mainly four cucurbitane glycosides: momordicines I and II and momordi-cosides K and L.(2,40) A recent study has reported that the lightest green skin color bittermelon contained lower amounts of saponins than the darker green skin ones.(1)

As mentioned previously, varieties of bitter melon differ in color, shape, and size andmay also differ in their content of bioactive compounds. Two studies demonstrated thatvarieties had a significant impact on the bioactive compounds, such as phenolics andantioxidant capacity, in four bitter melon varieties(41) and 58 underutilized Malaysianfruits of 32 different species from 21 genera.(42) However, for both studies, the growingconditions for the varieties of fruit production were not provided. A recent studydemonstrated that bitter melon varieties grown under controlled conditions differed inthe production and quality characteristics.(43) These bitter melons were grown in a

182 S. P. TAN ET AL.

Figure 1. A cross-sectional photo of commercial bitter melon.

Table 1. Different types of bitter melon.(35)

Shape Bitterness Color Length (cm) Width (cm)Pericarp (the edible part)

thickness (cm) Weight (g)

Small Extreme Dark green 10–20 5.0–8.0 0.4–0.8 100–300Long Slight Light green 30–60 3.5–6.0 0.5–0.8 200–600Triangular Moderate to

strongLight todark green

15–25 9.0–12.0 1.0–1.5 300–600

FOOD REVIEWS INTERNATIONAL 183

greenhouse under a standard hydroponic condition, in which the nutrients and climateswere regulated. Therefore, it is also important to be aware that bioactive compoundsmeasured in bitter melon can be affected by environmental conditions.(44)

The variability of bioactive content could be also due to other parameters, such asharvest time,(45) environmental factors (e.g., light and temperature),(2,47) agriculturalpractices (e.g., compound fertilizers),(48) pest management,(47) degree of maturity,(49)

and postharvest storage.(50) Thus, further tests are required to determine whether theseabove-mentioned parameters affect the bioactive content of bitter melon.

Traditional uses of bitter melon

Bitter melon is sold cheaply in markets throughout the year, especially in Asia and tropicalareas of Africa. Therefore, consumers are able to easily buy them from year-roundmarkets.(51) People in Asia commonly consume bitter melon by preparing them indifferent ways, including stir-frying, boiling, steaming, pickling, or even canning.(2,52)

People also drink bitter melon preparations as herbal teas.(3) However, as their nameimplies, the melons and their preparations are very bitter and they are not tolerated byeveryone.(2) Therefore, salt or vinegar is traditionally used to extract the bitter compoundsfrom the bitter melon before it is eaten, in order to reduce its bitter taste.

Recently, one study reported on a variety of cooking techniques that make the bittermelon more palatable, thereby encouraging their consumption.(53) The results showed thatthe bitterness of bitter melon could be masked by cooking them with chilli, curry,minestrone soup containing tomato base, and tomato sauce, and the latter was acceptedby most participants. Even so, the bitterness of bitter melon is still a major concern forconsumers, and preparation and cooking techniques to remove the bitter compounds mayalso remove the bioactive compounds and therefore the health benefits of the bitter melon.

As a result, regardless of the many traditional preparations or the variety of new recipes,which can be used to remove the bitter taste of bitter melon, new taste-masking food-processing techniques, such as encapsulation, remain important to develop in order to achievethe full potential of the health benefits of bitter melon preparations.(2,55) This technique willfurther improve the acceptability of the bitter melon preparations and could expand its use ina range of foods, such as yogurt and ice cream. Moreover, the stability of the bioactivecompounds of the encapsulated bitter melon product will be increased, since the vulnerablecompounds are coated with at least one layer of neutral- or better-tasting agents.(56)

Bioactive composition of bitter melon

Bitter melon has long been used as food and medicine in Asia and Africa. It containsvitamins, minerals, and flavonoids.(5) It is a good source of phenolic compounds,particularly gallic acid.(2) Bitter melon also contains a variety of other bioactive com-pounds, especially saponins, peptides, and alkaloids.(52) These bioactive compoundspotentially impart a wide range of health benefits. Every part of the bitter melon,including the roots, vines, stems, leaves, seeds, unripe, and ripe flesh, is claimed tohave potential medicinal value, especially as antidiabetic products. To take advantage ofthis, knowledge of the various bioactive components of bitter melon and anunderstanding of their pharmacological activities will be essential for optimizing the

184 S. P. TAN ET AL.

bitter melon preparations. Table 2 shows the total contents of phenolics, flavonoids, andsaponins of bitter melon obtained from the recent publication data.

Phenolic compounds

Bitter melon contains phenolic compounds with potent antioxidant properties.Whole bitter melon (flesh, aril, and seed) has been shown to be a good source ofphenolic compounds,(41) and one study demonstrated that the flesh, the aril, andseeds all had very high antioxidant activity.(41) Another study suggested that theantioxidant and free radical–scavenging properties in the extracts of bitter melonscould be attributed to flavonoids and other phenolic compounds.(60) The results alsodemonstrated that the bitter melon had better antioxidant capacity, measured by 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging, and iron-chelating activitiesthan vitamin E.(60)

However, other studies have shown that the antioxidant activity varies in the differentparts of the bitter melon and at their different maturity stages,(49,62) with the latter mostlikely affected by the increasing content of the carotenoids as the melons ripen. Also, thehighest amounts of total phenolic compounds in the bitter melon did not always result inthe highest total antioxidant activities.(49)

Extracted phenolic compounds have been applied in foods as natural antioxidants.They provide an alternative to synthetic antioxidants for extending the shelf life of foodproducts by reducing oxidation in the foods and may also provide health benefits forconsumers. Therefore, the extraction of these compounds from bitter melon may proveuseful in this fashion as well. The following section describes the major phenolic com-pounds present in bitter melon.

Table 2. Total phenolic, flavonoid, and saponin contents of whole fruit of bitter melon.Component Extraction type Range References

Total phenoliccontent

Water extraction 5.1–10.6 mg gallic acid equivalents (GAE)/g of dried bitter melon

(43, 57)

Methanol extraction 5–6 mg GAE/g dried bitter melon (58)Soxhlet water extraction 5–7 mg GAE/g dried bitter melon (58)Subcritical water extraction (SWE) 52.6 mg GAE/g of dried bitter melon (58)Ethanol extraction 7.3–15.7 mg gentisic acid equivalents

(GE)/g of extract(49)

Total flavonoidcontent

Freeze-dried juice 0.15 mg quercetin equivalents (QE)/gfresh weight

(59)

Water extraction 18.2 mg rutin equivalents (RE)/g of driedbitter melon

(60)

(100 g of bitter melon powder with 1 Lof boiling water for 1 hour)Water extraction 3.9–16.9 mg RE/g of dried bitter melon (61)(two extractions at 40 °C for 15 minutesat a ratio of 100:1 mL/g of bitter melonpowder)Solvent extraction 1.81–23.2 mg RE/g of dried bitter melon (61)

Total saponincontent

Solvent extraction 2.9–2.1% haemolytic saponins (1)Water extraction 46.8–93.2 mg aecsin equivalents (AE)/g of

dried bitter melon(43)

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Gallic acidGallic acid is one of the major phenolic compounds in bitter melon.(41) Gallic acid can befound in free form or as a part of tannin molecules. Tannic acid is a type of polyphenol,which contains several polymerized gallic acids and therefore has many phenolic rings inits structure. Tannic acid can be found in the leaf and stem, in unripe and ripe bittermelons.(62) However, the amount of tannic acid in bitter melons was found to be very lowcompared with gallic acid; its concentrations were at least 80% less than for gallic acid.(62)

The range of gallic acid of four varieties of freeze-dried flesh of bitter melon was 8.04–13.74 mg/100 g dry basis.(41) However, the concentration of gallic acid in the freeze-driedseed was almost 50% less than that of the flesh.(41)

Gentisic acidGentisic acid is a phenolic compound found in bitter melon.(41) Gentisic acid is abiosynthetic derivative of salicylic acid,(63) the well-known analgesic drug in humans.However, in plants, salicylic acid and gentisic acid play essential roles as pathogen-inducible signals for the activation of plant defenses.(2,64) The concentration of gentisicacid in the oven-dried bitter melon was determined to be 0.90–5.91 mg/g dry weight.(58)

Catechin and epicatechinCatechin and epicatechin are the two most common flavonoids in plants. The flavonoidshave important roles in protecting plant tissues from ultraviolet (UV) radiation,(65)

microbial invasion, and attacks from insects and herbivores.(65) Budrat and Shotipruk(66)

reported that the concentrations of catechin in the dried bitter melon extracted bysubcritical water extraction (SWE), methanol extraction, and soxhlet water extractionwere 46.16, 1.61, and 1.77 mg/g, respectively.

Caffeic acid and chlorogenic acidCaffeic acid and chlorogenic acid are classified as phenylpropanoids. In plants, both caffeicacid and chlorogenic acid play an important role in the biosynthesis of lignin and, as forthe flavonoids, they also play a protective role against pathogens and herbivores.(67) Theconcentration of caffeic acid in bitter melon was found to be 3.55 mg/L in the methanolfraction.(62) The range of chlorogenic acid in the freeze-dried and oven-dried flesh of fourvarieties of bitter melon were 6.42–14.15 mg/100 g dry basis and 4.55–16.37 mg/100 g drybasis, respectively.(41) However, the concentrations of chlorogenic acid in freeze-dried andoven-dried seed and inner tissues were lower than that of the flesh ones.

Saponins

Saponins are found in a wide range of plants, but only some, such as soybeans, spinach,and bitter melons, are eaten as foods.(68) They are composed of one or more sugar chains(glycosides), which is the hydrophilic part, and a nonsugar aglycone (steroid/triterpenoid),which is the hydrophobic part of these amphiphilic molecules.(69) The aglycone (glycoside-free part) is also named sapogenin. The difference between the steroid and triterpenoidsapogenins is in their number of carbon atoms. The steroid sapogenins are made up of 27carbon atoms, whereas the triterpenoids have 30 carbon atoms.(70,71)

186 S. P. TAN ET AL.

Saponins are good foaming and emulsifying agents due to their amphipathic properties.They are used in herbal medicines as active ingredients but also for food and industrialapplications.(2,73) Notably, they are prescribed as antihyperglycemic herbal medicinalagents for controlling blood glucose levels.(2,52)

Bitter melon contains various saponins, both steroids and triterpenoids, in their fleshand seeds. The most well-known steroidal glycosides from bitter melons are β-sitosterylglucoside and 5,25-stigmasteryl glucoside, and both together (1:1) are often referred to ascharantin, a name based on the taxonomic classification of the fruit species.(74)

Many triterpenoids have been identified to be in bitter melon, including momordico-sides A and B,(74) momordicosides C, D, and E,(74) momordicosides F and I,(74) momor-dicosides G and F2,

(74) momordicosides K and L,(74) momordicosides Q and R,(75)

momordicosides S and T,(75) goyaglycoside-a, -b, -c, -d, -e, -f, -g, and -h(76) and goyasa-ponins I, II, and III (oleanane types).(76)

Polypeptide-pAlthough in low amounts like in other fruits, bitter melon contains proteins. The totalprotein content of four varieties of bitter melon was shown to range from 1.2 to 2.4 mg/100g.(77) A study established that they contained eight of the nine essential amino acids:histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, and valine, inthe pericarp and seeds.(78) These findings were in agreement with other studies.(2,80)

Similar to other plant proteins, bitter melon appears to be lack of one essential aminoacid, tryptophan.

A particular polypeptide, named polypeptide-p or p-insulin, has been isolated from thewhole bitter melon fruit, the flesh, and the seeds.(81) The p-insulin polypeptide has beenreported to have a minimum molecular weight of 11,000 daltons (166 residues) and bemade up of 17 of the 20 usual amino acids, as determined using an automated amino acidanalyzer.(81) As the name p-insulin implies, polypeptide-p has been ascribed potentialblood glucose–lowering properties.(82)

AlkaloidsAlkaloids are found throughout the plant kingdom, and most of the alkaloid structurescontain nitrogen atoms. However, the nitrogen atoms are located differently in the carbonring depending on the types of alkaloids. Vicine is one of the alkaloids found in the seedsof bitter melon.(74)

Health benefits

Bitter melon has been hypothesized as having significantly health-promoting properties. Itis a well-known therapeutic agent in herbal medicine, which is particularly prescribed forregulating blood glucose levels and lipid metabolism. The first study showing in vivohypoglycemic effects of bitter melon is often cited as being a study from India in 1960,done in the alloxan-induced diabetic rabbit model using bitter melon juice.(83)

Since then, especially over the last two decades, numerous bitter melon extracts havebeen extensively investigated in cell culture, animal model, and human studies. Althoughthe available scientific data are still not sufficient to fully support the use of bitter melonfor the treatment of type 2 diabetes in evidence-based Western medicine, it has been

FOOD REVIEWS INTERNATIONAL 187

extensively used in traditional Indian and in Western herbal therapy as a treatment forreducing blood glucose.(84) Bitter melon preparations have also been prescribed as herbaltherapy for hyperlipidemia and hypercholesterolemia. The melons are also thought tohave anticancer, antiviral, anti-inflammatory, and many other effects. Some of thehypothesized therapeutic effects of bitter melon, their postulated bioactive constituents,and their mechanisms of action will be discussed in the following sections.

Blood glucose control

Bitter melon extracts have been widely studied in animal models and cell cultures in thepast decades. The rabbit, rat, and mouse are the three main animal species that have beenused for investigating the pharmacological effects of whole bitter melon, its juice, orextracts. However, because most of the animals and cells used do not normally havediabetes to start with, diabetogenic chemicals such as alloxan or streptozotocin (stz) arecommonly used for rendering the laboratory animals type 1 diabetic for in vivo studiesand for treating pancreatic β-cells in culture for in vitro studies. The drugs are used toinduce diabetes mellitus conditions by damaging the β-cells, resulting in a loss of insulinproduction capacity.

For studies more relevant to type 2 diabetes mellitus (DM), animals are renderedhyperglycemic using a high-fat diet or either the oral or intraperitoneal administrationof glucose or fructose. Some small-scale studies have also been conducted on human type2 diabetic subjects. The findings relating to the effects of bitter melon on blood glucosewill be covered in the following sections.

The hypoglycemic effects of bitter melon in animal studies

In the realms of therapeutic ethnobotanical practices and Asian traditional remedies, bittermelon is considered to be very useful plants, especially for the treatment of diabetes. Forexample, a recent review by Paul and Raychaudhuri has documented the many proposedmedicinal properties of various extracts of the different parts of bitter melon that are usedin India.(84) Even more recently, another review evaluated the possible use of bitter melonin a supportive diet in the complementary therapeutic care in diabetic patients.(85)

The hypoglycemic effects of bitter melon have mainly been studied in animal studies.Table 3 presents five of the publications from 2006 to 2011 on the glucose-lowering effectsof bitter melon in animal models of hyperglycemia. All studies have shown that the bloodglucose levels of the treatment groups fed bitter melon or its juice, extracts, and fractionswere significantly reduced compared with controls.

Antidiabetic mechanisms of action of bitter melon

It has been suggested that bitter melon may be able to protect the pancreatic β-cells. In onestudy in rats, the effect of bitter melons was investigated by looking at the number of β-cellsin the pancreas of stz-diabetic untreated rats compared with stz-diabetic rats treated withfresh bitter melon, and normal nondiabetic rats were used as controls.(90) The resultsshowed that the number of β-cells in the treated diabetic rats was significantly increased

188 S. P. TAN ET AL.

Table 3. Studies on the hypoglycemic effect of bitter melon (BM) in animals.

Animal (Treatment groups)Component and study

duration Results

Study 1(86)

Male C57BL/6J miceTreatment groups:(1) Low-fat diet (LFD) (n = 6)(2) High-fat diet (HFD) (n = 7)(3) BM extract–treated HDF group (n = 7)

Powdered water extractfrom BM fed in high-fatdiet at 1.2% (w/w)Duration:12 weeks

● Fasting plasma glucose and insulinlevels were significantly lower in BMextract–treated HFD group comparedwith the HFD group.

● Glucose tolerance was significantlyimproved by BM extract.

● Insulin sensitivity was significantlyimproved in the treatment group com-pared with the HFD group.

Study 2(87)

Male C57BL/6J miceTreatment group (n = 6/group):(1) Group N (normal control)(2) Group D (streptozotocin [stz]-diabetic

mice)(3) Group 16 (stz-diabetic mice + fraction

16 [50 mg/kg body weight]—adminis-tered by gavage everyday)

(4) Groups 21 and 23 (stz-mice + dailygavage of fraction 21 or 23 at 100 mg/kg)

BM fractions 16, 21, and 23from a wild variant WB24Duration:7 days

● Fraction 16 significantly reduced theblood glucose levels at 8 hours aftergavage in diabetic mice on each day.

● High-dose fractions 21 and 23 signifi-cantly reduced blood glucose levels at 2and 4 hours after gavage from day 2 today 6.

Study 3(88)

Adult male stz-Sprague-Dawley rats andneonatal rats given treatments as oraldoses per kg of body weight by gavage

Treatment groups (n = 5/group):(1) Control(2) BM (500 mg/kg)(3) Rosiglitazone (R) (2 mg/kg)(4) R (5 mg/kg)(5) R (2 mg/kg) + BM (500 mg/kg)(6) R (5 mg/kg) + BM (500 mg/kg)

Powdered methanolextract of BM containing0.51% charantinDuration:2-Hour glucose tolerancetestSerum glucose levels (28days)

● Reduction of serum glucose levels in allthe treatment groups compared withcontrol.

● The combination of R and BM exhibited ahigher reduction in serum glucose levelsthan the individual treatments.

● The effectiveness in reducing glucoselevels of high and low R dose in combi-nation with BM was similar.

● The high R dose combination had thehighest effect compared with the indivi-dual treatments.

● The volume of islet cells was significantlyincreased in the combination treatmentgroups.

Study 4(89)

Male C57BL/6J mice fed 60% fructose (FRU)diet and given treatments as oral dosesper kg of body weight by gavage

Treatment groups:(1) Control group (FRU) + distilled water(2) FRU + P1 (0.2 g/kg/day)(3) FRU + P2 (1.0 g/kg/day)(4) FRU + G1 (0.2 g/kg/day)(5) FRU + G2 (1.0 g/kg/day)(6) FRU + Rosiglitazone (R) (0.01 g/kg/day)

Different extractionmethods yielding fourfractions: P1, P2, G1, andG2Duration:8 weeks

● Reduction in the levels of blood glucose(P < 0.001) and insulin (P < 0.05) in P1,P2, and R treated groups comparedwith control.

● Increase in the expression of PPARγ butreduction in the expression of leptin inwhite adipose tissue in P1, P2, and Rtreatment groups compared with control(P < 0.05).

● Increase in the expression of PPARγ butreduction in the expression of leptin inwhite adipose tissue in P1, P2, and Rtreatment groups compared with control(P < 0.05).

● The mRNA expression and GLUT4 in ske-letal muscle were significantly increasedin the P1, P2, and R treatment groups(P < 0.05).

(Continued )

FOOD REVIEWS INTERNATIONAL 189

as compared with the untreated diabetic rats. However, the number of β-cells in thepancreas of the treated diabetic rats was still significantly lower than in the control rats.

Another study reported that the n-butanol-soluble fraction of bitter melon significantlyreduced the blood glucose levels in stz-diabetic rats.(91) The authors suggested that theextract had properties similar to sulfonylurea (a synthetic drug) in that it appeared toincrease the secretion of insulin from the β-cells of the stz-diabetic rats.

Other studies have suggested that bitter melon may also increase the insulin sensitivityof the target tissues and the uptake of glucose from the blood via glucose transporters.One study reported that an ethanol extract of the fruit had extrapancreatic effects(92); theextract stimulated the uptake of glucose by the liver and increased the storage of it asglycogen rather than acting as an insulin secretagogue. Another study reported that thehypoglycemic effects of a water extract of bitter melon involved an increase in the activityof the facilitative glucose transporter isoform 4 (GLUT4) in the plasma membrane of thetype 2 diabetic mice muscles.(93) Similarly, a study showed that a protein extract of bittermelon significantly reduced the blood glucose level by stimulating glucose uptake in thestz-diabetic rat muscle tissues (myocytes) and fat tissues (adipocytes).(82) The resultsalso revealed that the extract increased insulin secretion in both the stz-diabetic andnormal rats.(82)

Bitter melon also could inhibit the intestinal absorption of glucose at the brush-borderlevel. Matsuda and coworkers reported that the level of serum glucose in glucose-loadedtype 2 diabetic rats was significantly reduced by bitter melons extracts enriched inoleanolic acid 3-O-glucuronide and momordin Ic.(94) The gastric emptying in these ratswas suppressed and the glucose uptake was inhibited in the small intestines. However,there were nonsignificant effects on the serum glucose levels in normal rats and in alloxan-induced type 1 diabetic mice.(94) Therefore, the authors surmised that the bitter melonextract did not act as an insulin secretagogue but rather as an inhibitor of glucosetransport at the brush border of the small intestine.

In support of this hypothesis, an in vitro study with inverted rat gut sacs suggested thatthe Na+/K pump could be involved in the hypoglycemic effects of a water extract of bittermelon capable of reducing the glucose uptake by the small intestines.(95) The resultsshowed that the amount of glucose taken up from the intestinal lumen containing the

Table 3. (Continued).

Animal (Treatment groups)Component and study

duration Results

Study 5(82)

Male Wistar rats given treatments assubcutaneous injections in mg doses perkg of body weight

Treatment groups (n = 8/group):Normal rats(1) Control (0.2 mL of 0.9% NaCl)(2) Extract (1 mg/kg)(3) Extract (5 mg/kg)(4) Extract (10 mg/kg)stz-Diabetic rats(1) Control (0.2 mL of 0.9% NaCl)(2) Extract (1 mg/kg)(3) Extract (5 mg/kg)(4) Extract (10 mg/kg)

Protein extracts from BMDuration:8 hours

● Protein extract (5 and 10 mg/kg) sig-nificantly reduced the plasma glucoseconcentration in both normal and dia-betic rats.

● 10 mg/kg of protein extract showed themaximal reduction in plasma glucoseconcentration.

● No significant reduction in plasma glu-cose concentration was observed withextract at 1 mg/kg.

● Concentration of plasma insulin signifi-cantly increased at 4 and 6 hours in bothnormal and diabetic groups by proteinextract at 10 mg/kg.

190 S. P. TAN ET AL.

added plant extract and appearing in the serosal solution (simulating intestinal absorp-tion) was significantly lower compared with control without the bitter melon extract.Furthermore, the amount of Na+ absorbed into the serosal solution and the volume ofserosal solution were significantly lower with than without the extract.

Inhibition of hepatic gluconeogenesis is another postulated explanation for the hypogly-cemic effect of bitter melon.(6) In a study investigating the hypoglycemic effect of an ethanolextract of bitter melon in normal and stz-diabetic rats,(96) the extract (200 mg of extract/kgbody weight) significantly reduced blood glucose by 22% compared with control and thehepatic gluconeogenesis enzymes, glucose-6-phosphate, and fructose-1,6-bisphosphatasewere decreased by 27% and 29%, respectively. However, glucose-6-phoshate dehydrogenase,a pentose phosphate pathway enzyme, was increased by 29%. Therefore, the authorssurmised that the hypoglycemic effect of the extract was linked to suppression of themain gluconeogenesis enzymes and to an increased rate of glucose metabolism via thepentose phosphate pathway. However, the exact mechanism by which the bitter melonextracts depressed the hepatic gluconeogenesis enzymes has still not been established.

Another interesting possibility is inhibition of the enzyme 11β-hydroxysteroid dehy-drogenase type 1 (11β-HSD1). Generally, 11β-HSD1 is responsible for stimulating theconversion of cortisone to cortisol (an active hormone) and thereby activating theglucocorticoid receptors. One study has reported that an excess in the production of theglucocorticoid hormone, cortisol, can result from the overexpression of 11β-HSD1 andcan lead to visceral obesity and insulin resistance.(97) As a result of such findings,inhibition of 11β-HSD1 has been suggested as a novel therapeutic target for the treatmentof obesity and type 2 diabetes.

Only recently, Blum and coworkers have reported that bitter melon contains at leastone constituent that has inhibitory effects on 11β-HSD1, as shown in in vitro studies withpurified human 11β-HSD1 enzyme and human liver and placental cells.(98) The authorssuggested that such a selective inhibitor could contribute to the mechanism of action bywhich bitter melon lowers blood glucose.

Other in vitro cell culture studies have also proposed mechanisms of action for particularbitter melon constituents. For example, a study demonstrated that an ethanol saponin-richextract fraction of bitter melons and two cucurbitane triterpenoids (momordicine II andkuguaglycoside G) significantly stimulated insulin secretion in mouse insulinoma (MIN6) β-cells.(99) Chang and coworkers also reported that a 5β,19-epoxy-25-methoxy-cucurbita-6,23-diene-3b,19 diol, a constituent purified from a fraction 16 of bitter melon, could activate theadenosine monophosphate kinase (AMPK), and no cytotoxicity was observed.(87) Theauthors also indicated that this active compound was more effective at activating AMPKthan troglitazone, a currently prescribed an antidiabetic drug.

Several studies have suggested that the glucose-lowering effect may be attributable toconstituents such as its saponins (i.e., charantin), polypeptide-p (p-insulin), and itsantioxidant phenolic compounds.(2,81,100) However, one study has reported that theaglycones of charantin, sitosterol, and stigmastadienol did not have any significant effecton the blood glucose level.(33) Therefore, the authors concluded that the hypoglycemiceffect may be due to the glycosides of the steroids and not their aglycones.

In summary, several mechanisms of action regarding the hypoglycemic effects of theaqueous and organic solvent (e.g., ethanol and n-butanol) extracts of bitter melon havebeen proposed. However, although several candidate bioactive compounds found in bitter

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melon have been suggested, the exact compounds responsible for the hypoglycemia effectsare not yet well established. Therefore, it is desirable to carry out further investigations toclarify antidiabetic mechanism of actions for specific bioactive compound(s) in bittermelon.

The hypoglycemic effects of bitter melon in human clinical trials

In contrast to the many studies in animal models, only a few studies have been done inhumans. Table 4 shows the three recent studies on the hypoglycemic effect of bitter melonin human clinical trials.

The first study in Table 4 was a 4-week, multicenter, randomized, and double-blind active-controlled trials in Thailand.(101) The 120 subjects who completed the trial were randomlyassigned to three groups given 500, 1000, or 2000mg of a hot air–dried bitter melon fruit pulppowder in capsule form (500 mg powder/capsule). The seeds were removed before the pulpwas dried. The active control group received the drug metformin, which is commonlyprescribed for lowering blood glucose in type 2 diabetes mellitus (DM). Although there wasno effect of the bitter melon powder on fasting glucose, there was an encouraging significantlowering of fructosamine with the 2000 mg dose. This gave an indication that the averageblood glucose levels were most likely lowered over the 4-week trial period.

However, in a longer 3-month study (Study 2 in Table 4) in the Philippines with abitter melon food supplement commercially available in capsule form, there were non-significant changes observed in fasting plasma glucose or hemoglobin HbA1c, which is amarker of long-term blood glucose concentrations.(26) Similarly, a study in Pakistan

Table 4. Studies of hypoglycemic effect of bitter melon (BM) in humans.Human (Treatment groups) Component fed and study duration Results

Study 1(101)

Newly diagnosed with type 2diabetics (n = 30/group)

Treatment groups:(1) 500 mg/day BM(2) 1000 mg/day BM(3) 2000 mg/day BM(4) 1000 mg/day metformin

(active control)

Dried powder of whole bitter melon(BM) without seeds, containing0.04–0.05% charantinDuration:4 weeks

● Significant reduction in fructosamine in2000 mg/day treatment group.

● The hypoglycemic effects of BM were lowerthan for metformin.

● No significant effects on fasting plasmaglucose levels and 2-hour plasma glucoseafter oral glucose tolerance test in any ofthe BM treatment groups.

Study 2(26)

Newly diagnosed or poorlycontrolled type 2 diabetics(n = 20/group)

Treatment groups:(1) Placebo(2) BM treatment

Two capsules of BM (3 times/day)—local commercial complementarymedicine preparationDuration:3 months

● Only 0.22% difference in glycosylatedhemoglobin levels (HbA1c) when com-pared BM treatment groups with placebo.

● No effects on fasting blood sugar, serumcholesterol, weight, and other experimentalparameters in BM treatment groups.

Study 3(102)

Type 2 diabetic subjects(n = 25/group)

Treatment groups:(1) Normal control(2) R treatment (4 mg/24 h)(3) BM treatment (55 mL/24 h)

Fresh BM juice and rosiglitazone (R)Duration:6 months

● In BM treatment groups, the concentra-tions of serum sialic acid and serum glu-cose were not significantly differentcompared with control, but total choles-terol increased within the normal range.

● In R treatment groups, the concentrationsof serum sialic acid, serum glucose, andtotal cholesterol were significantlyincreased.

192 S. P. TAN ET AL.

(Study 3 in Table 4), which went for 6 months, showed nonsignificant beneficial effects ofbitter melon juice on hyperglycemia.(102)

These three clinical trial studies were based on positive results of various extracts ofbitter melon previously observed largely in case studies.(2,81,103–107) However, clearly, morehuman randomized control trials need to be done in order to determine whether bittermelon has hypoglycemic effects in humans. Furthermore, for such trials, well-character-ized and stable bitter melon preparations will be needed.

Hypolipidemic and hypocholesterolemic effects

Besides their proposed hypoglycemic activity, bitter melon has also been linked with otherbeneficial health effects. One such study in rats indicated that the levels of hepatic andserum total cholesterol and triglycerides were significantly reduced and the concentrationof serum high-density lipoprotein (HDL)-cholesterol (the so-called good cholesterol frac-tion) was elevated as the amount of a freeze-dried bitter melon preparation was increasedin the diet.(108) These findings were in agreement with another study, which demonstratedthat an ethanol bitter melon extract significantly reduced the serum cholesterol andtriglycerides and increased the HDL-cholesterol levels in stz-diabetic Wistar rats.(24)

Increased production of very-low-density lipoprotein (VLDL) and increased secretionof apolipoprotein (apo) B-100 from the liver have been associated with low insulinsensitivity and increased blood glucose levels.(109) An in vivo study in human hepatoma(HepG2) cells indicated that the secretion of apo B-100 and of newly synthesized trigly-cerides were significantly reduced by bitter melon juice.(110) Similarly, bitter melon juicewas observed to normalize to control levels the levels of apo B-100 and apo B-48 (secretedfrom the intestines) in mice fed with a high-fat diet.(111)

One recent double-blind study in humans showed that both total and VLDL cholesterolwere significantly reduced in the treatment group taking a combination of several extracts(0.37 g red yeast rice, 40 g fresh bitter melons, 1.5 g chlorella, 1.1 g soybean, and 2.2 glicorice) once daily for 12 weeks.(112) In the treatment group, the level of fasting triglycer-ides was significantly reduced and blood pressure was normalized compared with theplacebo group. The authors concluded that these plant extracts had synergistic effects onthe symptoms of the metabolic syndrome.

Wound-healing, antimicrobial, and immunomodulatory effects

Similarly, studies have suggested that bitter melons possess wound-healing properties.Prasad and coworkers determined that a bitter melon ointment had beneficial effects onthe excision, incision, and dead space in a wound model in rats.(113) Another studyreported that a bitter melon pulp extract significantly stimulated the production ofhepatocyte growth factor (HGF) in different cell types and the proliferation of humandermal fibroblasts.(114) The authors suggested that bitter melon is a potential planttherapeutic agent for tissue regeneration. However, further investigations are needed todetermine the exact mechanisms by which bitter melon could enhance wound-healing.

An in vitro study suggested that a bitter melon seed extract had antimicrobialproperties.(115) The antimicrobial effects of four different bitter melon extracts onStaphylococcus aureus, Bacillus subtilis, Psuedomonas aeruginosa, and Esherichia coli

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were tested. Among the extracts prepared using four solvents (petroleum ether, methanol,ethanol, and water), the aqueous extract was the most effective against all the microorgan-isms, especially Staphylococcus aureus, which is known to aggravate psoriasis. Similarly,another study demonstrated that the essential oils of bitter melon seeds effectivelyinhibited the growth of microorganisms.(116) Another in vitro study showed that methanoland ethanol bitter melon extracts had antimicrobial properties and that their antioxidantactivity was higher than ascorbic acid.(117)

Finally, Meng and coworkers reported that α-momorcharin, a bioactive compoundisolated and purified from bitter melon seeds, exhibited immunomodulatoryproperties.(118) However, their results showed that high doses or long-term consumptionof α-momorcharin could lead to toxicity.

Anticancer effects

The potential effects of bitter melon on cancer have also been investigated. Yasui andcoworkers investigated the antineoplastic effects of 9c,11t,13t-conjugated linolenic acids(CLN), free fatty acids purified from bitter melon seeds, on colon cancer Caco-2 cells.(14)

The results showed that the growth of Caco-2 cells was significantly inhibited by9c,11t,13t-CLN through the induction of programmed cell death (apoptosis). The induc-tion of apoptosis was also significantly increased by 9c,11t,13t-CLN and its dihydroxyderivatives in HL-60 human leukemia cells.(119) Another study in Wistar rats showed thatan hexane extract of bitter melons not only had protective activities against cancer but alsopossessed antioxidant properties.(120)

The P-glycoprotein, known to be involved in multidrug resistance, is expressed in theintestinal epithelial cells and functions as a defense against harmful substances. The effectsof P-glycoprotein are a common problem likely to be found in patients who receivedtherapeutic drugs long term, and overexpression of p-glycoprotein can lead to drugresistance in cancer cells.(13) A clinical study on cervical cancer patients undergoingradiotherapy was conducted, and the effects of bitter melons on their natural killer(NK) cells (lymphocytes) and P-glycoprotein levels were investigated.(11) The resultsshowed that the P-glycoprotein level was significantly reduced in NK cell membranes,suggesting that bitter melon may be beneficial for patients who received radiotherapy.

Finally, a ribonuclease (RNase MC) was isolated from bitter melon seeds and its effectson MCF-7 breast cancer cells were investigated.(121) The results indicated that apoptosiswas significantly induced by RNase MC2. Similarly, apoptosis was significantly induced byRNase MC2 in both mice and HepG2 cells.(122)

Proposed processing scheme of bitter melon

To fully utilize this fruit, a summary of the proposed processing scheme for bitter melon isshown in Fig. 2. Research on understanding how the growing production system mightaffect bioactive contents of bitter melon is highly recommended. Several assisted greentechnologies, such as microwave-assisted extraction, ultrasound-assisted extraction, andsupercritical fluid and/or carbon dioxide extraction, need to be investigated and optimizedin order to improve the efficiency of extraction for bioactive compounds from bitter melon.

194 S. P. TAN ET AL.

Future work on identification and purification of bioactive compounds of bitter melon,followed by the tests in vitro and in vivo models, is desirable. Further investigations onidentifying and purifying the bioactive compounds are also recommended for a better under-standing of the profile of bioactive compounds in bitter melon extracts. Evaluating the biologyactivity of isolated bioactive compounds of bitter melon singularly or/and in combinationwith others in vitro and in vivo models will then further offer new insights into the exactmechanisms of action of bitter melon on health benefits. The bioactivity test will then revealthe characteristics of bioactive compounds and/or synergy effects of these compounds.

Evaluation of safety and toxicity tests in vivo and human studies is needed prior tocommercializing the products. A stable final product, such as encapsulation of the crudeand/or purified bioactive compounds, is also highly recommended to be fortified in foodproducts as functional foods and/or used as therapeutic agents in the pharmaceuticalindustry.

Conclusions

Bitter melon has been reported to be associated with a wide range of health benefits, especiallyfor the treatment of diabetes, due to its content of bioactive compounds and its antioxidant

Figure 2. A summary of the proposed processing scheme for bitter melon.

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capacity. Future studies on the exact compounds of bitter melon responsible for the ther-apeutic effects and more human randomized control trials need to be done in order tounderstand the exact mechanism of actions of bitter melon in humans. Further investigationson the bioactive compounds of bitter melon varieties and utilization of bitter melon in foodand/or as a therapeutic agent are also important for further adding value to this fruit.

Funding

The authors acknowledge the University of Newcastle, Australia, for financial supportthrough a PhD scholarship for S. P. Tan.

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