Summary

In addition to their pharmacological or counseling treatment regimen, 41 diabetes patients took one capsulecontaining 500 mg Momordica charantia extract beforetwo larger meals daily. The literature reports a blood glucose-lowering effect and action for M. charantia (bitter melon). After a 6-month observation period, itwas demonstrated in 21/41 patients that their fastingblood glucose levels, which were as high as 200 mg/dlbefore they started taking the bitter melon, dropped by upto 25% from baseline, and that during this period HbA1cwas lowered by an average of 0.5 percentage points. Thisresult is consistent with the findings of a UK ProspectiveDiabetes Study indicating a risk reduction for the latesequelae of diabetes by another 10% down to

M. charantia is a lanky, green climbing plant with yellow flowers, their leaves are reminiscent ofgrapevine leaves. The warty vegetables look likecucumbers, the young fruit is green turning to orange-yellow when ripe which then splits. The soft fruit contains a scarlet red placenta with brown and whiteseeds (Fig. 1). It may be confused with M. balsamina(balsam apple).

Extracts of the fruit are manufactured with both polarand apolar solvents and tested for their efficacy.

Phytochemistry

As early as in the Forties of the lastcentury (23) and then again in theEighties (11), chemical analysiswere conducted on the constituentsof M. charantia. Alongside thenutritive, protective constituentslike calcium (20 mg/100 g edible

fruit), carotene (0.13 mg/100 g), riboflavin (0.09mg/100 g), and vitamin C (88 mg/100 g), it has a highcontent of protein (1.6 g/100 g), minerals (0.8 g/100 g),and carbohydrates (4.2 g/100 g) as well as low fat content (0.2 g/100 g). A phytosterolin (charantin) (23)has also been isolated, a mixture of equal parts ofB-sitosterol-B-D-glucoside and a-5, 25-stigmastadein-3B-1-ol, reputed to have hypoglycemic effects (21). Apolypeptide with 166 amino acids and a molecularweight of 11,000 daltons has been isolated from thefruit and the seeds (P-insulin), which has proved veryhomologous with bovine insulin in terms of its aminoacid composition (13), although it is not immunologicallycross-reactive (27).

Phytotoxicology

Ethanolic extracts of the fruit which are administeredeither by the oral or subcutaneous route to adult malegerbils (Meriones hurrianae) in amounts rangingbetween 200 and 400 mg/kg of body weight daily fortwo weeks reduced spermatogenesis and gonadal atrophy. Feeding 1.75 g/kg of body weight of M.charantia fruit to male dogs for 60 days similarly led toan interruption in spermatogenesis as well as gonadalatrophy. The prostate conversely was not affected (8,9).

The bitter melon is a very common vegetable in Asia,and in general, can be regarded as a safe food. When

consumed in excess, however, it can lead to diarrheaand stomachache. However, the relevant side effect,while at the same time constituting its physiologicalcarbohydrate metabolism regulating action, is frequently described as the property that considerablyreduces blood sugar after ingestion (4, 14). This kind ofefficacy plays a particular role in non-insulin depend-ent diabetics and determines drug interactions withoral anti-diabetics (sulfonyl ureas, phenformin/ met-formin, thiazolidine) and also insulin. The concomitant use of M. charantia extracts and therequired blood-sugar lowering therapy may not lead tohypoglycemia and must therefore take place undermedical supervision.

Pharmacological actions

One working group in Hong Kong discovered two proteins (a and B-momorcharin) in the seeds of M.charantia that modulate the activity of T- and B-lym-phocytes and suppress the macrophage activity (17)but are not cytotoxic. Furthermore, a pure protein(MAP30) was isolated from bitter melon which, on itsown or as recombinant protein (re-MAP30), caninhibit virus expressions during the various life cyclesof the HIV virus, both during the acute infectiousphase as well as during the replicative phase chronical-ly infected cells. At the same time, anti-tumoral activi-ty has been described for re-MAP30 (16). An 80%ethanolic extract of bitter melon exhibits both anti-mutagenic activity in the bacterial (Salmonella)B-glucuronidase test and chemopreventive action withregard to colon carcinogenesis in male F344-rats (6).The preventative action specifically influences the promotion phase and not the initiation phase. A hotwater extract of bitter melon significantly inhibits thespontaneous development of breast tumors in nulliparous SHN mice (20). Various momordins in bitter melon inhibit the binding of the transcriptionfactors jun/fos on DNA, which led the authors to presume that they act cytotoxically on jun/fos overexpressing cells (15).

In addition to the anti-viral action (5, 10), the anti-carcinogenic action of bitter melon has not yet attractedthe full interest of researchers, although the many,often anecdotic reports about the blood-sugar loweringaction of bitter melon, combined with the positivereports from clinical trials (1, 14) provide justificationfor a field study, where bitter melon extract was given

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Figure 1

to non-insulin dependent diabetics as a balanced dietaryfood supplement to determine whether critical laboratoryparameters (hBA1c, fasting glucose levels) would changesignificantly. More recently, and especially in the past sixyears, various working groups and authors have focusedincreasing attention on the blood sugar-lowering actionof bitter melon.

Rationale

The remarkable evidence gained in the various pharma-cological studies on animal species and on humans, butalso the available reports on the clinical relevance (1, 14)of the properties of bitter melon provides justification fora field study to determine whether laboratory parameterssuch as fasting glucose levels and HbA1c are significantlychanged when a standardized extract is taken. To test thehypothesis, non-insulin dependent diabetics with WHOclassification of NIDDM type 2 were given the extract asa balanced dietary food supplement.

Study Design

The study was conducted according to an open-label andprospective design (protocol and original study data onfile/KSZ) in a general medical practice (G.G.) and a practice specializing in nephrology (S.H.). Nine maleand 11 female (G.G.) and 10 male and 11 female (S.H.)patients with an age distribution between 40 and 90 yearsthat was relevant to the practices were observed in a controlled setting. The patients were instructed that, inAsia, America, and now to an increasing extent inEurope, a vegetable from the squash family has been onthe market, and that the scientific literature reports thatIt may be able to lower blood sugar levels. They gavetheir written consent to take one capsule containing 500mg M. charantia extract before each of two of their dailylarger meals. They additionally agreed that the necessarymedical glucose test of the fasting serum levels as well asthe HBA1c measurements conducted five times throughoutthe 24 weeks of the daily consumption of the capsulesmay be used not only to allow the physician to test theoutcome of therapy, but also be evaluated in anonymizedform for scientific purposes.

The therapy prescribed by the physician (pharmacological)as well as the doctors recommendations on nutritionand exercise (non-pharmacological) should not be affectedby the consumption of the capsules or quantitativelycorrected. The patients understood that they were not

involved in a drug trial as defined in the terms of the(German) Drug Law on the licensing of new drugs,rather that a balanced dietary food supplements wasinvolved in combination with oral antidiabetics that cancontribute to having a positive effect on carbohydratemetabolism. Insulin-dependent patients were excluded.Depending on the physicians diagnosis, all licensed oralantidiabetics were used.

The statistical analysis included the patients own monitoring of the clinical course (comparison of the pairof baseline values [glucose fasting in the serum andHbA1c]) before ingestion with the subsequent four pairsof values, recorded after 6, 12, 18, and 24 weeks duringthe period of daily consumption of two bitter melonextract capsules.

Bitter Melon Extract Capsules

An aqueous bitter melon extract with a minimum con-tent of 10% charantin was derived from pesticide-freecrop from China (cultivated in the Jiang Su territory)that held a certificate concerning heavy metal and bacterialburden. After repeated analytical testing of the certifiedextract in a German laboratory and its release, ARCO-Chemie (Herdecke) manufactured capsules containing500 mg of bitter melon according to GoodManufacturing Practices (GMP). The capsule size wasconducive to unhindered ingestion. The recommendationwas given [that the patients always take the capsules]with the amount of drink that they individually required.

Tolerability Results

None of the patients complained to the responsiblephysician about any adverse concomitant phenomenaduring the supplemental consumption of bitter melonextract for 24 weeks. The physicians were not able toascertain any causal connection between the consumptionof the extract and general well-being or any worsening ofdiabetogenic metabolism. The results were reaffirmedthat bitter melon extract is a foodstuff with healthpromoting constituents in Europe too and can be regardedas a good and tolerable food supplement.

Results on efficacy

Regarding the fasting values for blood glucose and thelong-term parameter HbA1c, the patients in the presentstudy were divided into two groups*:

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*In patients with well-adjusted diabetes, the values forfasting glucose range between 80 and 100 mg/dl, thosefor HbA1c< 6.5%.

Group A: values fasting < 200 mg/dl glucose in the serum(25/41) with corresponding HbA1c < 8.0% (29/41):

Group B: fasting values > 200 mg/dl glucose in the serum(16/41) with corresponding HbA1c > 8.0% (12/41).

Fig. 2-4 show the ideally typical curves for glucosereduction in the fasting serum parallel to the reductionin the HBA1c in two patients from group A (Fig. 2 and3) and one patient from group B (Fig. 4). The timeconcentration curves during the observation periodclearly demonstrate that the bitter melon extract exertsa glucose lowering, and consequently, an HBA1c lowering action not only as a supplement to drugtherapy (Fig. 2 and 4) but also in addition to nutritionaland exercise counseling therapy, i.e. according to await and watch strategy. The significant reduction inthe HBA1c levels also provides evidence that the meanglucose levels must have constantly fallen during theobservation period on 24 weeks, since less substrate(glucose) must have been available for Amadori productsand the Mallard reaction for fucosylation and therebyled to an increased production of advanced glucosylationend products (AGE).

In 21 patients in group A, the fasting values for glucosein the serum over 24 weeks of observation were signif-icantly reduced form a mean of 162 mg/dl glucose to a

mean of 120 mg/dl glucose (p< 0.01)(Fig, 5). Duringthis process, glycosylated HBA1c was significantly lowered by 0.5 percentage points from 6.8 to 6.3 %(P

In group B, the pattern with regard to changes in themain parameters was very heterogeneous: increases(11/41), consistently stable (6/41) or falling values(3/41) were observed in this population to an equalextent. In this group, it was particularly noticeable thatthe fluctuations in HBA1c and the fasting glucose values in the serum frequently drifted apart considerably,i.e. brief, sequential measurements of blood sugar leveldid not adequately reflect long-term changes inHBA1c. Nevertheless, 9/41 patients in this group experienced an improvement and/or stability of theirdisease when the main parameters were taken intoconsideration.

As a result for both groups, it can be concluded that, bytaking a daily supplement of bitter melon extractbefore two larger meals, non-insulin-dependentpatients can be reclassified into the group of impairedglucose tolerance patients (up to 126 mg/dl fastingglucose) assuming proper patient compliance. Thiscan be considered a remarkable success for an easy-to-handle, supplemental dietary intervention.

Discussion

In the first European field observation on the safetyand efficiency of an extract of Momordica charantia,its blood sugar-lowering action could be confirmed innon-insulin-dependent patients. This was particularlytrue when their diabetogenic metabolism was determinedby the limits for the two main parameters: fasting glucose not greater than 200 mg/dl and HbA1c up to8.0%. This sort of diabetic subgroup could then beclassified into the prognostically more favorable groupwith the status impaired glucose tolerance (= fastingglucose

Using a KK-Ay mouse model, one group of Japaneseresearchers demonstrated that the mechanism ofaction of M. charantia, at least in part, is based on areduction in insulin resistance in the plasma membraneof the muscles, since the GLUT4 protein was elevatedin the treated animals (19).

Another working group in Birmingham arrived aslightly differing opinion. They suggested that thehypoglycemic action is due to an extra pancreatic effectthat is independent of glucose absorption in the smallintestine (7). Another working group in Bangladeshconcluded from their STZ rat model that the bloodsugar lowering action was attributable to the inhibitionof gluconeogenesis and increased glucose oxidation(26); a mechanism of action, which could also bedemonstrated by an Indian working group with theresults that their STZ rat model showed increase glucose utilization in the liver (25).

The experimental data clearly indicated that the constituents of bitter melon have hypoglycemic activity.The data strengthen the clinical field observations thatthe supplemental intake of a bitter melon extract canlower main parameters such as HbA1c and fasting glucose and thereby reduce by up to 42% the relativerisk in this patient population for developing latesequelae. The authors Platel and Srinivasan recommendedback in 1997 (22) that potentially blood sugar-0loweringvegetables should be included as food on the dailymenu. Their recommendation has now been compellinglyconfirmed on the specified extract of Momordica charantia in a field observation.

Prof. Kurt S. Zaenker, M.D.University Witten/ HerdeckeInstitute for ImmunologyStockumerstrasse 1058448 Witten

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