Botanical Products in Diabetes

199Diabetes Spectrum Volume 14, Number 4, 2001

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Biological Complementary Therapies: AFocus on Botanical Products in Diabetes

No one has thoroughly determinedhow many patients with diabetes usecomplementary therapies. A recentsurvey of diabetes educators in thewestern half of the United States1 eval-uated the most frequently recom-mended and used alternative thera-pies. These included physical activity,self-help groups, lifestyle diets, laugh-ter and humor, relaxation therapy,prayer, imagery/visualization, medita-tion, massage, and music therapy.Although botanical products wereincluded in the survey, they were notfrequently recommended or used.

Another survey of alternative treat-ments used by patients with diabetes2

did indicate that herbal treatments areused along with other modalities. Insome cases, patients used these treat-ments instead of conventional medica-tions, and severe complications,including increased hospitalizations,ketoacidosis, and acute hyperglycemia,occurred.

Technically, an herbal product ismade from the leaves and roots of aplant, whereas a botanical productincludes parts or pieces from thewhole plant. However, these terms areoften used interchangeably in discus-sions of complementary therapies.

CONCERNS ABOUT BIOLOGICALOR BOTANICAL THERAPIES

As with conventional medicines, theuse of complementary therapies raises

concerns about possible side effects3

and drug interactions.4 Patients usingcomplementary therapies have experi-enced many serious side effects; insome cases, they may attribute theseeffects to another medication. Becausepatients often take medications totreat their diabetes, concomitant useof complementary therapies may alsoresult in toxicity secondary to exag-gerated effects or sub-therapeuticeffects of their conventional medica-tions.

Another concern relates to the vari-ability of products. Botanical productsare available in capsules and tablets,as well as in other forms, such aswater extracts (also called decoctionsor infusions), tinctures (hydroalco-holic extracts), and glycerites (glyc-erin-extracted preparations that arealcohol-free). All vary in potency. Inaddition, product quality may dependon what part of the plant was used,how it was stored, how long it wasstored, the processing technique, andhow the extract was prepared.3

Some products are available in aform standardized for pharmacologi-cal activity. This should guaranteethat there is consistency from batch tobatch and that the active ingredientsare stable.5 However, standardizationis not simple because, for manybotanicals, the active constituents areunknown. A product may be stan-dardized for one or more biologicallyactive compounds, but that com-

Laura Shane-McWhorter, PharmD,BCPS, FASCP, CDE, BC-ADM

Several botanical and biological products claim to lower blood glucose ordecrease complications of diabetes, and some of these are being used by peo-ple with diabetes. Products thought to lower blood glucose include gymnema,fenugreek, bitter melon, ginseng, and nopal. Claims have also been made foraloe, bilberry, and milk thistle, but there is less evidence in support of these.Botanical products thought to decrease diabetes complications include �-linolenic acid, ginkgo biloba, and garlic. A vitamin-like substance, �-lipoicacid, has been used to treat neuropathic complications.

In Brief


pound may not be the active ingredi-ent. Pharmacological action maycome from the additive or synergisticeffects of several ingredients, none ofwhich separately has the same activityas the whole plant.6 Furthermore,active constituents in extracts or driedbotanicals may vary secondary to geo-graphical or soil differences, differ-ences in exposure to sunlight or rain-fall, differences in the time of harvest,and differences in the methods of dry-ing, storing, and processing. All ofthese variables may affect pharmaco-logical activity.7

Other factors involve potentialmisidentification, mislabeling, andpossible addition of unnatural toxicsubstances, such as adulteration withheavy metals or steroids and contami-nation with microbes, pesticides,fumigants, and radioactive products.7

BOTANICAL PRODUCTS THATMAY LOWER BLOOD GLUCOSELEVELS

GymnemaA member of the milkweed family,gymnema (Gymnema sylvestra) is awoody plant found in tropical forestsof India and Africa.8–10 For more than2,000 years, people have chewed itsleaves to treat “madhu meha” (“honeyurine”).9 Used in Ayurvedic medicine,it is thought to destroy a person’s abil-ity to discriminate sweet taste; hence,it is often called “gurmar” or “sugardestroyer.”8

Chemical constituents of the plantinclude the gymnemic acids (gym-nemosides), saponins, stigmasterol,quercitol, and the amino acid deriva-tives betaine, choline, and trimethy-lamine.8 Gymnema has been used forcenturies to treat diabetes.10

Proposed mechanism of action.Although the exact mechanism isunknown, there are a variety of theo-rized mechanisms. Besides impairingthe ability to discriminate sweet taste,gymnema increases the enzyme activi-ty responsible for glucose uptake andutilization.11 It may stimulate �-cellfunction, increase �-cell number,and/or increase insulin release byincreasing cell permeability toinsulin.8,12 In pancreatectomized ani-mals, it has no hypoglycemic effect,indicating that its effect may requiresome residual �-cell function.13

Side effects and drug interactions.No side effects have been reported sec-ondary to gymnema use. Hypoglycemiais a potential side effect;10 drug interac-

tions may occur from the additiveeffects when used concomitantly withhypoglycemic agents.

Clinical studies. There are only afew human studies, and these do notreport important design details, suchas blinding or randomization.

One study14 was conducted in type1 diabetic patients on insulin, 27 ofwhom took 200-mg gymnema cap-sules after breakfast and supper and37 of whom took insulin only for aperiod of 6–30 months. After 6–8months, mean HbA1c decreased in thegymnema group from a baseline of12.8 to 9.5% (P < 0.001). After16–18 months, 22 patients remainingon gymnema had a mean HbA1c of9% (P values not given). At the end of26–30 months, six patients remainingon gymnema had a mean HbA1c of8.2% (P values not given).

Mean fasting blood glucose (FBG)also decreased from a baseline of 232to 177 mg/dl after 6–8 months 150mg/dl after 16–18 months, and 152mg/dl after 20–24 months (P valuesnot given). The mean insulin dosedecreased from a baseline of 60 to 45units/day after 6–8 months and to 30units/day at 26–30 months (P valuesnot given). Patients on placebo had nosignificant changes from baseline.

Another study15 was conducted inpatients with type 2 diabetes on sul-fonylureas; 22 took 400 mg/day ofgymnema capsules in addition to sul-fonylurea treatment, and 25 took aplacebo and sulfonylureas for a peri-od of 18–20 months. Mean HbA1cdecreased from a baseline of 11.9 to8.48% (P < 0.001). Mean FBGdecreased from 174 to 124 mg/dlafter 18–20 months (P < 0.001). Fivepatients were able to discontinue sul-fonylureas. In this study, lipids alsodecreased significantly. Patients onplacebo had no significant changes inHbA1c, FBG, or lipids.

Clinical notes. Because of the pos-sibility of hypoglycemia when gymne-ma is used with insulin or other dia-betes agents, doses for existing dia-betes therapies may have to be adjust-ed with the addition of gymnema.This product should not be used with-out medical supervision. A typicaldose is 400 mg/day standardized tocontain 24% gymnemic acids.8,10

FenugreekFenugreek (Trigonella foenum-grae-cum) has been used as a cooking spiceand flavoring agent for centuries.9 It isa member of the Leguminosae family,

along with other legumes.9,10 Theplant grows in India, Egypt, and theMiddle East.9

Fenugreek has also been used as amedicinal agent to treat diabetes, con-stipation, and hyperlipidemia.10 It hasbeen used topically to treat inflamma-tion, and it has been used postpartumwith a substance called jaggery to pro-mote lactation. Because its taste andodor resemble maple syrup, it hasbeen used to mask the taste of medi-cines.9

Chemical constituents of the plantinclude saponins, many of which areglycosides of diosgenin.9 The seedsalso contain the alkaloids trigonelline,gentianine, and carpaine compounds.Other components of the seedsinclude several C-glycosides. Theseeds contain up to 50% mucilagi-nous fiber.9 Other seed constituentsinclude 4-hydroxyisoleucine, anamino acid, and fenugreekine.

Proposed mechanism of action.Fenugreek is thought to delay gastricemptying, slow carbohydrate absorp-tion, and inhibit glucose transport.16 Ithas been shown to increase erythro-cyte insulin receptors and improveperipheral glucose utilization, thusshowing potential pancreatic as wellas extrapancreatic effects.17

Various components of the seedshave varying activities. For example,the component called fenugreekine, asteroidal sapogenin peptide ester, mayhave hypoglycemic properties.10

Trigonelline, another component, mayexert hypoglycemic effects in healthypatients without diabetes,10 but otherstudies have shown that fenugreek hasno effect on fasting or postprandialblood glucose levels in nondiabeticsubjects.18

Side effects and drug interactions.The main side effects are flatulence anddiarrhea, which subside after a fewdays. However, fenugreek also hasuterotonic properties.10 Hypersensitivityreactions have also been reported,10

including rhinorrhea, wheezing, andfainting after inhalation of the fenu-greek-seed powder. Wheezing andfacial angioedema after application of atopical fenugreek paste for dandruffwas reported in a patient with chronicasthma.19

Because fenugreek is a member ofthe Leguminosae family, which in-cludes peanuts,9 it is theoretically pos-sible for someone with a peanut allergyto react to fenugreek. However, thisreaction has never been reported.

All of fenugreek’s side effects may


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occur in infants of nursing motherswho use this substance.

Because of the coumarin con-stituents, fenugreek may potentiallyenhance anticoagulant activity ofdrugs or herbs that have antiplateletactivity.10 It may inhibit corticosteroiddrug activity, interfere with hormonetherapy, and potentiate monoamineoxidase (MAO) inhibitor activity. Atheoretical interaction is decreased ordelayed absorption of concomitantmedications because of the highmucilage content. Additionally, theremay be additive hypoglycemic activitywhen combined with diabetes medica-tions.10

Clinical studies. There are fewhuman studies, and most of these areshort-term, involve few patients, anddo not adequately report study designdetails.

In one study,20 10 patients withtype 1 diabetes on insulin underwenta 10-day metabolic trial. Patients wereblinded, but it was unclear whetherthe investigators were blinded.Patients were randomized to eitherplacebo or 50 g fenugreek defattedseed powder twice a day in chapati(unleavened bread). Mean FBGdecreased from a baseline of 272 to196 mg/dl (P < 0.01). Patients alsodemonstrated a statistically significantdecline in serum total cholesterol (P <0.001), triglycerides, and LDL choles-terol (P < 0.01 vs. placebo for triglyc-erides and LDL), but no change inHDL cholesterol.

The largest fenugreek study21 wasa 6-month trial in 60 patients withinadequately controlled type 2 dia-betes. The authors did not provideinformation on randomization orblinding. Patients were administered a75-g oral glucose tolerance test(OGTT) to determine mean baselineparameters. Fenugreek seed powder,25 g/day, was administered in twoequal doses with lunch and dinner for6 months. Mean FBG decreased froma baseline of 151 to 112 mg/dl after24 weeks. The mean 1-h OGTT base-line was 284 mg/dl, compared to 196mg/dl after 24 weeks. Mean 2-h val-ues decreased from a baseline of 257to 171 mg/dl after 24 weeks (P <0.001 vs. baseline for both). MeanHbA1c decreased from a baseline of9.6 to 8.4% after 8 weeks (P <0.001). Although 40 patients were onoral diabetes medications, the authorsdid not report on whether they wereable to decrease their doses or discon-tinue their diabetes drugs.

Clinical notes. Fenugreek has beencategorized as “generally recognizedas safe” in the United States.10 Doserecommendations vary depending onthe source. However, all recommend-ed doses are much lower than thoseused in the clinical studies, whichranged from 15 g mixed in water to50 g twice daily. One source recom-mended 1–2 g of the seed or its equiv-alent three times daily or 1 cup of thetea, made by steeping 500 mg seed in150 ml cold water several times aday.10

Bitter Melon Bitter melon (Momordica charantia),also known as bitter gourd, bitterapple, bitter cucumber, karolla, andkarela, is a vegetable cultivated intropical areas, including India, Asia,South America, and Africa. It is yel-low-orange with a bumpy exteriorresembling a gherkin and is bitter butedible.9

Bitter melon has been used to treatdiabetes and psoriasis and for HIVsupportive therapy, and it has beenstudied as a potential contraceptiveagent.9,10 It has been taken for cen-turies as a dietary treatment and morerecently has been used as an injectableextract for research.22

Bitter melon contains several chemi-cal constituents, including the glyco-sides mormordin and charantin.Charantin contains mixed steroidswith hypoglycemic activity. Anothercomponent is the peptide polypeptide-P.9 Bitter melon also contains the alka-loid mormordicine. Its seeds containthe abortifacients �-mormorcharinand �-mormorcharin, as well as thepyrimidine nucleoside vicine.9

Proposed mechanism of action.The fruit and seeds of bitter melon arethought to exert hypoglycemic effectsin normal and diabetic animalmodels.10 The specific componentsthought to contribute to its hypo-glycemic activity include charantin,polypeptide P, and vicine. Other theo-retical actions include extrapancreaticactivity, such as increased tissue glu-cose uptake, liver/muscle glycogensynthesis, and decreased blood glu-cose synthesis through depression ofthe enzymes glucose-6-phosphatase,fructose-1, and 6 bisphosphatase, andenhanced glucose oxidation byenzyme G6PDH pathway.9

Side effects and drug interactions.Bitter melon may produce digestivetract discomfort.9 Hypoglycemiccoma from a tea containing bitter

melon10 has been reported. Favism(acute hemolytic anemia character-ized by headache, fever, abdominalpain, and coma) has also beenreported from one of the seed con-stituents of bitter melon, vicine.10

The red arils around bitter melonseeds have produced toxicity; in onechild, vomiting, diarrhea, and deathoccurred.9 Bitter melon has abortifa-cient effects9,10 and in animals hasproduced hepatotoxicity.10

Concomitant use with stimulantlaxatives or other agents that decreasepotassium may increase the risk ofpotassium depletion.10 If combinedwith secretagogues, additive hypo-glycemia may occur. This was report-ed when a patient used both bittermelon and chlorpropamide.23

Clinical studies. Most studies inhumans involve very small numbers,are of very short duration, and havebeen reported with only sketchy infor-mation about details of study design,including blinding and randomization.Although there are several studiesusing bitter melon, only studies inwhich glucose values were reportedwill be discussed.

An early study of 19 patients (11with type 1 and 8 with type 2 dia-betes)22 used polypeptide-P zinc chlo-ride, a momordica extract, preparedin the same manner as bovine insulin.This “plant insulin” was injected sub-cutaneously in five patients with type1 diabetes and six patients with type 2diabetes. No details of randomizationor blinding were provided. FBG wasmeasured at the time of injection, aswell as 4, 6, 8, and 12 h after injec-tion. The control group, consisting ofsix patients with type 1 and twopatients with type 2 diabetes, did notreceive any treatment.

In the patients with type 1 diabetes,mean FBG decreased from 304 to 169mg/dl 4 h after injection (P < 0.05),and this effect was maintained at 6and 8 h after injection (FBG 176 and174 mg/dl, respectively, P < 0.05 com-pared to baseline). At 12 h, FBG hadstarted to increase (208 mg/dl).

In the patients with type 2 diabetes,changes were significantly differentbetween the experimental and controlgroups at 1 and 6 h (P < 0.05).However, there were no significantdifferences from baseline in the exper-imental group. In the control groupsof both the type 1 and type 2 diabetesinterventions, blood glucose valueswere not significantly changed frombaseline.


The largest study using bittermelon24 was done in 100 type 2 dia-betic patients but was conducted foronly 2 days using an aqueous suspen-sion of the vegetable pulp. Day 1mean FBG was 152 mg/dl, and after a75-g OGTT, the mean 2-h postpran-dial glucose level was 257 mg/dl. Onday 2, momordica extract was given,and blood glucose was measured 1 hlater. This mean value was 131 mg/dland was significantly different fromthe FBG of 160 mg/dl (P < 0.001).Patients then received a 75-g oral glu-cose load, and blood glucose wassampled 2 h later. The mean 2-hblood glucose was 222 mg/dl. Onehour after momordica was given, 86patients had decreased values and anattenuated blood glucose response tothe 75-g glucose load, in comparisonto the previous day (222 vs. 257mg/dl, P value not significant).

Clinical notes. There is insufficientinformation to recommend a reliabledose.10 Various forms of bitter melonhave been used in research, includingpowder, extract, juice, as well as thecooked vegetable. Some sources havestated that 50 ml fresh juice takendaily with food may be used.10

Tinctures are becoming available.Medical supervision is always neces-sary when using bitter melon.

GinsengA variety of products are called “gin-seng.” The most commonly used arethree different botanicals: Asian orKorean ginseng (Panax ginseng C.A.Meyer), American ginseng (Panaxquinquefolius L.), or Russian orSiberian ginseng (Eleutherococcus sen-ticosus Maximum). The part used isthe root.25

Ginseng has been described as an“adaptogen”—a drug that mayincrease resistance to adverse influ-ences such as infection and stress.25

Individuals use ginseng in an attemptto enhance physical performance, psy-chomotor performance, and cognitivefunction; for immunomodulation; andas treatment for infections and dia-betes.26 Generally, length of use is upto 3 months, with possible repeatedcourses.27 In diabetes, only Koreanand American ginseng have been stud-ied, so this discussion will be limitedto these two substances.

Ginseng contains a family ofsteroid-like compounds called gin-senosides. Although there are manysubtypes, ginsenosides are tetracyclictriterpenoid saponin glycosides

thought to have various hormonaland central nervous system (CNS)effects. Some ginseng compoundsshow contradictory effects; for exam-ple, ginsenoside Rg1 has hypertensiveand CNS-stimulant effects, whereasginsenoside Rb1 has hypotensive andCNS-depressant effects.9,25

Proposed mechanism of action. Indiabetes, the mechanism of beneficialeffect is unknown. Animal researchhas indicated that ginseng may lowerblood glucose by possibly decreasingthe rate of carbohydrate absorptioninto the portal hepatic circulation28

and possibly increasing glucose trans-port and uptake.29 Another potentialmechanism is modulation of insulinsecretion.30 Some ginseng fractionshave increased serum insulin levelsand glucose-stimulated insulin secre-tion in mice.

Side effects and drug interactions.The most commonly reported sideeffects include nervousness and excita-tion.9 Other effects include headache,hypertension, insomnia,9,10 estrogeniceffects including mastalgia,31 vaginalbleeding,32 and cerebral arteritis.33

“Ginseng abuse syndrome” is acontroversial adverse effect that wasreported in 14 of 133 long-term usersof high daily doses.34 This syndromeconsisted of hypertension, nervousness,sleeplessness, skin eruptions, increasedlibido, and morning diarrhea.

Several drug interactions have beenreported. Diuretic resistance canoccur when ginseng is used in con-junction with a diuretic.35 Tremors36

and hypomania37 can occur when it isgiven with phenelzine, an MAOinhibitor. Insomnia, headache, anddecreased warfarin effect have alsobeen reported.38 Concomitant usewith diabetes agents may cause hypo-glycemia. If combined with stimu-lants, ginseng may potentiate stimu-lant effects.10

Clinical studies. Ginseng has beenevaluated in many studies of varyingquality. A recent meta-analysis thatevaluated its effects on physical orpsychomotor performance, cognitivefunction, immunomodulation, andother outcomes26 drawing on onlyrandomized, placebo-controlled stud-ies showed that ginseng has subopti-mal efficacy.

Ginseng has only been studied intype 2 diabetes. In a randomized, dou-ble-blind study of ginseng in 36 newlydiagnosed type 2 diabetic patients,39

12 people each were assigned toplacebo, 100 mg/day, or 200 mg/day

of ginseng tablets for 8 weeks. At theend of the study, mean FBG values forthe three groups were 149, 139, and133 mg/dl, respectively. (Results wereonly statistically significant for the100-mg/day group, P < 0.05.) Baselinevalues were not reported, and averageHbA1c levels at the end of the studywere 6.5, 6.5, and 6.0%, respectively(P < 0.05 for 200-mg group).

Another study compared the effectsof American ginseng and placebo inpatients with and without type 2 dia-betes.40 Ten patients without diabetesand nine patients with type 2 diabeteswere given a 25-g OGTT, with andwithout 3 g of ginseng capsules.Patients were given ginseng 40 minbefore or with the glucose challenge.Patients were blinded, but the authorsdid not state whether the investigatorswere blinded.

No significant difference in post-prandial glucose was reported whenginseng was taken with the glucosechallenge in patients without diabetes.Taking ginseng 40 min before theOGTT resulted in a significant reduc-tion in postprandial glucose (P <0.05vs. placebo). In patients with diabetes,ginseng given either concomitantly or40 min before the OGTT significantlylowered postprandial glucose (P <0.05vs. placebo).

Clinical notes. Ginseng productshave been found to be adulteratedwith other substances including man-drake root or phenylbutazone,9 and inone case even led to positive results ona “doping” test for an athlete.41

Typical doses are 200–600 mg/day.10 These doses are lower than inthe study using American ginseng cap-sules but a bit higher than the tabletsused in the study of newly diagnosedtype 2 diabetic patients. Besides cap-sules and tablets, ginseng comes in avariety of forms ranging from freshand dried roots to extracts, solutions,sodas, teas, and cosmetics.9 The rootcontains at least 1.5% ginsenosides.27

Some people use ginseng on a con-tinual basis, but others use ginseng fora period of 3 weeks to 3 months.10,27

Evidence for efficacy of ginseng is lim-ited, at best.

NopalNopal (Opuntia streptacantha Le-maire), also known as prickly pear, isa member of the cactus family.9

Multiple species are known asOpuntia, including Opuntia megacan-tha, Opuntia ficus indica, and Opuntiafuliginosa. Research has focused on


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Opuntia streptacantha Lemaire tolower blood glucose.

Nopal stems are used as a foodsource in Mexico.10 The leaves con-tain mucopolysaccharide solublefibers and phytochemicals. Leaves andstems are also used for other reasons,such as for diabetes control and treat-ment of hyperlipidemia.10

Proposed mechanism of action.Studies in pancreatectomized animalshave shown that the hypoglycemicactivity does not depend on the pres-ence of insulin.42 However, the mech-anism of action is unknown. The fiberand pectin components are thought tohave hypoglycemic activity. Becauseinsulin concentrations decrease withnopal administration, enhancedinsulin sensitivity is another theorizedmechanism of action.43

Nopal’s hypoglycemic activity hasbeen reported to reach maximumeffects 3–4 h posptrandially and tolast up to 6 h.10 The fiber content mayaffect intestinal uptake of glucose.Animal research indicates that thepectin component may alter hepaticcholesterol metabolism.10

Side effects and drug interactions.Reported adverse effects includeincreased stool volume and frequencyand abdominal fullness.44 Dermatitishas also been reported.10 In a casereport of 8-week coadministrationwith chlorpropamide, additive effectson blood glucose and insulin levelswere found.43 Additive hypoglycemiawith secretagogues is a theoreticalconcern, although there have been noreports of this.

Clinical studies. Most trials aresmall and have been published inSpanish, although English abstractsare available. Two small trials havebeen published in English.

One trial involved three groups ofpatients with type 2 diabetes treatedwith diet alone or in combination withsulfonylureas.45 Details of blinding orrandomization were not provided.After a 12-h fast, 16 patients received500 g broiled nopal (Group 1); 10people received 400 ml water (Group2); and 6 people received 500 gbroiled zucchini (Group 3).

In Group 1, mean blood glucosedeclined from 222 mg/dl fasting to203, 198, and 183 mg/dl after 60,120, and 180 min, respectively (P <0.001 compared to baseline). Therewas no significant drop in glucose inGroup 2. In Group 3, broiled zucchinicaused a drop from a mean baselineof 246 mg/dl fasting to 226, 219, and

206 mg/dl at 60, 120, and 180 min,respectively (P < 0.05 vs. baseline for60 and 120 min; P < 0.01 vs. baselineat 180 min).

Another trial compared 14 patientswith type 2 diabetes on sulfonylureas(Group 1) to individuals without dia-betes (Group 2).46 Details of blindingor randomization were not provided.Both groups received 500 g broilednopal or 400 ml water.

In patients with diabetes, meandecreases in glucose concentrationswere 21, 28, and 41 mg/dl at 60, 120,and 180 min, respectively, after nopaladministration (P < 0.005 for 60 and120 min vs. baseline; P < 0.001 for180 min vs. baseline). There were nosignificant differences after wateradministration. Insulin concentrationsalso declined significantly with nopal.In patients without diabetes, therewere no significant differences.

Clinical notes. Nopal is given withmeals in doses of 500 g broiled orfresh nopal stems.10 However, idealdoses and optimal preparation meth-ods have not been established. Thereare no known risks with nopal use,but there have been no well-designedor long-term studies. Evidence infavor of nopal is limited at this time.

AloeAloe is a desert plant with a cactus-like appearance. It belongs to the fam-ily Liliaceae.9 There are more than500 species, but the most familiarform is aloe vera. It has been usedsince prehistoric times for burns andwound healing.

There are two forms of aloe vera:dried juice from the leaf and aloe gel.Latex from pericyclic cells obtainedbeneath the skin of leaves may beevaporated to form a sticky substanceknown as “drug aloes” or “aloe.”This aloe juice contains the catharticanthraquinone, barbaloin, a glucosideof aloe-emodin, as well as other sub-stances.9

Aloe gel is obtained from the innerportion of the leaves. It does not con-tain anthraquinones but does containa polysaccharide, glucomannan, thatis similar to guar gum.9 Aloe gel isused topically, but it has also beenused orally for diabetes.

Proposed mechanism of action.Aloe gel taken internally may producea mild reduction in mean glucose lev-els, but the mechanism has not beenelucidated.

Side effects and drug interactions.The laxative form of aloe may cause

abdominal cramps, pain, and severediarrhea, with subsequent fluid andelectrolyte disturbances. This formmay deplete potassium, predisposingpeople who use it to cardiac abnor-malities. It may also potentially inter-act with glycosides because of thehypokalemic effects.10 Additivehypokalemia may also occur when itis coadministered with other drugsthat deplete potassium, such as diuret-ics or corticosteroids.10 Additivecathartic effects may occur when com-bined with other laxatives. Topicaluse has not been reported to produceany problems.

Aloe gel taken internally may exac-erbate Crohn’s disease and ulcerativecolitis. It may also produce additivehypoglycemia when taken concomi-tantly with secretagogues.10

Clinical studies. A very small,uncontrolled study was conducted inpatients with type 2 diabetes.47 Fivepatients were administered one-halfteaspoonful, twice daily, of dried aloesap for 4–14 weeks. Details were verysketchy, and information regardingblinding was not provided. FBG fellfrom a mean of 273 to 151 mg/dl (P <0.001). Mean HbA1c decreased from10.6 to 8.2% (significance not report-ed).

Clinical notes. Aloe has been usedtopically and as a cathartic. It has alsobeen used orally to boost the immunesystem and for treatment of asthma,ulcers, and diabetes.

Doses are variable and include50–200 mg/day of aloe leaf gel.10 Thereis insufficient evidence for the use ofaloe in diabetes. Supplementation isnot recommended.

BilberryBilberry is a plant closely related tothe American blueberry, cranberry,and huckleberry.10 Two forms of bil-berry are used: the dried fruit and theleaf. The dried fruit is used to treatdiarrhea27 and to improve visual acu-ity and night vision.10,48 The leaf isused for diabetes, arthritis, circulatorydisorders,9,27 cataracts,49 and varicoseveins.10 In folk medicine, it is used as a“blood sugar–reducing” drug, and istherefore a common constituent in“antidiabetic” teas.50

Proposed mechanism of action.Anthocyanosides are bioflavonoids,chemical constituents in bilberry fruitthought to be responsible for some ofits vascular effects.9 Anthocyanosidesare thought to decrease vascular per-meability and redistribute microvascu-


lar blood flow.10 They are similar tosome of the agents in grape seed.

The mechanism in diabetes may berelated to the high chromium contentin bilberry leaf (9 parts per million),but further research is needed todetermine this.50

Side effects and drug interactions.Reported adverse effects have beenmostly benign, including mild diges-tive distress, skin rashes, and drowsi-ness.50 There are no known druginteractions. Because it may affectblood glucose, additive hypoglycemiamay occur with secretagogues. If analcoholic extract is used, there couldbe a disulfiram reaction (cramping,diaphoresis, and nausea if alcohol isingested).10 In animals, prolonged useand very high doses have resulted intoxicity, including initial cachexia andexcitation and eventual death.27

Clinical studies. Despite enthusi-asm during World War II about usingbilberry preserves for improving nightvision in Royal Air Force pilots,9 bil-berry has not had demonstrated effi-cacy in controlled trials.48 Although itsuse has been suggested for lowering ofblood glucose, there have been nohuman trials. In streptozotocin-induced diabetic rats, 4 days of bilber-ry leaf administration caused plasmaglucose levels to consistently decreaseby 26%.51

Clinical notes. There is potentialbenefit but very limited evidence thatbilberry may improve conditionsrelated to blood vessel function, suchas varicose veins, cataracts, and otherocular diseases.

For the fruit, standard doses of thedried ripe berries are 20–60 g/day.Decoctions have also been preparedby placing 5–10 g mashed berries incold water, simmering for 10 min,then straining. The form used in stud-ies has been standardized to contain25% anthocyanosides.10 A tea is pre-pared using 1 g finely chopped driedleaf in 150 ml boiling water andsteeping for 5–10 min.10

Milk ThistleMilk thistle (Silybum marianum) is amember of the aster family (Asteraceaeor Compositae), which also includesdaisies and thistles.52,53 Milk thistle hasbeen used extensively for varioushepatic disorders, including hepato-toxicity secondary to acute and chron-ic viral hepatitis, mushroom poison-ing, and alcoholic cirrhosis. It has alsobeen used to attenuate hepatotoxiceffects of certain medications.52

Recently, its use has been proposed indiabetes to diminish insulin resis-tance.54

Chemical constituents are found inthe fruit, seeds, and leaves. Milk this-tle contains silymarin, which is com-posed of three main constituents: sily-bin, silychristine, and silidianin.Silybin is thought to have the mostpotent biological activity.53

Proposed mechanism of action.There are several proposed mecha-nisms that may benefit patients withhepatic disease or impairment.52 Oneis inhibition of hepatotoxin binding tohepatocyte membrane receptor sites,resulting in hepatocyte stabilization.Another is reduction of glutathioneoxidation, which may deplete dimin-ished glutathione levels in the liverand intestines. Milk thistle also hasantioxidant activity to protect againsttoxic free radicals. Finally, it stimu-lates protein synthesis, which maylead to enhanced hepatocyte regenera-tion.

Milk thistle may benefit patientswho have insulin resistance secondaryto hepatic damage. One theory is thatlipoperoxidation may affect patientswith diabetes, and restoration of nor-mal malondialdehyde concentrationsmay improve diabetes.54

Side effects and drug interactions.Reported dose-related (>1,500 mg/day) adverse effects include loosestools as a result of increased bile flowand secretion.55 Patients with allergiesto the Asteraceae or Compositae fami-ly may exhibit cross-allergenicity withmilk thistle administration.10 Noadverse drug interactions have beenreported with milk thistle. Beneficialinteractions, however, have includedreduction of hepatotoxicity associatedwith acetaminophen, antipsychotics,halothane, and alcohol.52

Clinical studies. Several studieshave evaluated the impact of milkthistle on hepatic disease. These stud-ies include acute viral hepatitis, mush-room poisoning, drug-induced hepati-tis, chronic liver disease, and alcoholicliver disease.53 However, these studieshave been fraught with shortcomings.Many were open-label, involved smallnumbers of patients, used differentdoses, involved different severities ofliver disease, lacked control groups,and lacked well-defined study end-points.

Milk thistle was evaluated in a 12-month, randomized, open-label trialin 60 type 2 diabetic patients with cir-rhosis.54 All subjects used insulin. One

group of 30 received 600 mg/day ofsilymarin, and the other group of 30received a placebo for 12 months.

Mean FBG declined from 190mg/dl at baseline to 165 mg/dl at 12months (P < 0.01 vs. baseline). HbA1cdeclined from 7.9% at baseline to7.2% at 12 months (P < 0.01 vs. base-line). Mean daily insulin requirementdecreased significantly from 55units/day at baseline to 42 units/dayat 12 months (P < 0.01 vs. baseline).Results were significant in the groupof patients on silymarin, but not inthe control group.

Clinical notes. Milk thistle mayprotect against hepatotoxicity by suchagents as acetaminophen, antipsy-chotics, alcohol, and halothane. Thetypical dose for liver disease is 200 mgthree times/day. Milk thistle extractshould be standardized to contain70% silymarin, which then contains140 mg silymarin. Because phos-phatidylcholine enhances oral absorp-tion, preparations containing thisingredient may be dosed at 100mg/day.52 These doses differ fromdoses used in clinical studies, whichhave ranged from 280 to 800 mg/day.

Milk thistle’s potential use for dia-betes is very preliminary.

BIOLOGICAL PRODUCTS THATMAY ADDRESS COMPLICATIONSOF DIABETES

� Linolenic Acid � linolenic acid (GLA) is an �-6 fattyacid. Although other sources of GLAinclude black currant and borage oil,the main source used in nutritionalsupplements is evening primrose oil.9

GLA has been used to treat diabeticneuropathy, hyperlipidemia, mastitis,premenstrual syndrome, eczema,rheumatoid arthritis, and multiplesclerosis.9

Proposed mechanism of action. Inthe body, linoleic acid (LA) is convert-ed to GLA via regulation by theenzyme �-6-desaturase (D6D).56 Twometabolites of GLA, dihomogammali-nolenic acid (DGLA) and arachidonicacid (AA) are prostaglandin precursorsthat regulate the balance of plateletaggregation and maintain blood flowin small blood vessels.56

In diabetes, conversion of LA toGLA is thought to be impaired sec-ondary to problems with D6D.Subsequent problems may occur, suchas difficulty maintaining nerve mem-brane structure, nerve blood flow, andnerve conduction.57 An exogenous


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source of GLA bypasses the need forconversion of LA to GLA.

Side effects and drug interactions.Most adverse effects are mild andinclude headache and mild gastroin-testinal (GI) complaints, such as bloat-ing and loose stools.10 There arereports of prolonged bleeding timeand one case report of seizures.9

Seizures may potentially occur if GLAis combined with phenothiazinesbecause these drugs may lower theseizure threshold.10

Clinical studies. Two main clinicaltrials have evaluated GLA. One was a6-month randomized, double-blind,placebo-controlled trial evaluating itseffects on peripheral neuropathy in 22patients with type 1 or type 2 dia-betes.58 Twelve patients received 360mg/day GLA, and 10 patients receiveda placebo. At the end of 6 months,there was improvement in neuropathysymptom scores (P < 0.001) as well asother parameters of neuropathy in theGLA group. There was no significantchange in HbA1c.

Another trial was a year-long, mul-ticenter, randomized, double-blind,placebo-controlled trial involving 111patients with type 1 or type 2 dia-betes.59 Patients were given 480mg/day GLA. The investigatorsreported significant improvement in13 of 16 parameters of neuropathy.HbA1c did not improve, but GLAresponse was better in those patientswhose initial baseline HbA1c was<10%.

Clinical notes. GLA derived fromEPO may improve problems withnerve membrane structure, impulseconduction, and nerve blood flow.Since HbA1c does not improve, benefitis not secondary to blood glucose con-trol. Doses used to treat neuropathyare 360–480 mg/day. Some expertshave stated that it may take severalmonths to see results with GLA andthat, for maximal absorption, itshould be taken with food.

Although the initial data seempromising and GLA is relativelybenign, its role in treating neuropathiccomplications requires more investiga-tion.

Ginkgo BilobaGinkgo biloba is one of the world’soldest living tree species, dating backmore than 200 million years.9 Extractsfrom dried leaves of younger trees areused in complementary therapies.Active ingredients include flavonoids(ginkgo-flavone glycosides) and ter-

penoids, consisting of ginkgolides andbilobalides.60

Ginkgo biloba is one of the mostwidely used drugs in Germany. It isused for “cerebrovascular insufficien-cy” and dementia. In diabetes, ginkgobiloba may be of use in amelioratingperipheral circulatory problems, suchas intermittent claudication.61 There isalso some evidence that it may benefitsexual dysfunction.62

Proposed mechanism of action.The flavone glycosides, includingquercetin, kaempferol, and isorham-netin, are thought to have antioxidantactivity and inhibit platelet aggrega-tion. The ginkgolides are thought toimprove circulation and inhibit theplatelet-activating factor. The bilob-alides are thought to have neuropro-tective properties.9,10,60

Side effects and drug interactions.Patients may experience transientheadaches for the first 2–3 days of use.GI upset occurs in <1% of patients.Exposure to the fruit pulp may pro-duce cross allergenicity with poisonivy. Eating the seeds may produce lossof consciousness and tonic-clonicseizures.9 There have been case reportsof subdural hematoma,63 subarach-noid hemorrhage,64 and bleeding fromthe margin of the iris.65

The main drug interaction is thepotential for additive antiplatelet activ-ity when combined with antiplateletdrugs, such as warfarin or aspirin orwith herbs that also have antiplateletactivity, such as ginger, garlic, andfeverfew.10

Clinical studies. Clinical studieshave been done with products contain-ing 24% flavone glycosides and 6%terpene lactones.10 For intermittentclaudication, different trials have foundthat ginkgo increases maximum walk-ing distance and pain-free walking dis-tance. A recent meta analysis revealeda significant effect on increased pain-free walking distance.61 The weightedmean difference was 34 m.

Ginkgo was found to improve anti-depressant-induced sexual dysfunctionin an open-label trial.62 Ginkgo hasbeen reported to have a beneficialeffect on erectile dysfunction byimproving penile arterial blood flow.66

Clinical notes. Doses used rangefrom 120 to 160 mg/day for peripher-al vascular disease.10 Ginkgo is admin-istered in divided doses, usually twoto three times/day. Administration for6–8 weeks is required to determinebenefit. The role for ginkgo in dia-betes care is still preliminary.

GarlicGarlic, a member of the lily family,9

has been used in cooking for thousandsof years. Garlic contains the sulfur-con-taining chemical constituent, alliin,which must be converted to allicin (theactive form) by the enzyme allinase.When the garlic bulb is chewed orcrushed, this reaction occurs.9 Ajoeneis formed by the acid-catalyzed reac-tion of two allicin molecules.

Commercial preparations usuallycontain allin, not allicin. Conversionrequires allinase, which is unstable instomach acids. Dried garlic prepara-tions may be effective only if they areenteric-coated to prevent gastric acidbreakdown and permit release in thesmall intestine. Fresh garlic is effec-tive.9,10

Garlic is used to treat hyperlipi-demia and hypertension, for cancerprevention, and for other antibacterialactivity. Although evidence is prelimi-nary, garlic may be useful in dia-betes.67

Proposed mechanism of action.Allicin has antibacterial and antioxi-dant activity. It may possibly increaseblood levels of catylase and glu-tathione peroxidase activity. Ajoenedecreases the activity of factors need-ed for lipid synthesis by reducing thethiol group in coenzyme A and HMGCoA reductase and also by oxidizingNADPH. Ajoene has antiplateletactivity and interferes with thrombox-ane synthesis and decreases plateletaggregation.9

Researchers have noted that garlicuse may be associated with increasedserum insulin and improved liverglycogen storage.67 A constituent ofgarlic, allylpropyl disulfide, mayreduce blood glucose and increaseinsulin.10

Side effects and drug interactions.Side effects include breath odor,mouth and GI burning or irritation,heartburn, flatulence, and rare topicalreactions. There are cases of sponta-neous spinal epidural hematoma68 andexcessive bleeding.69

Potential drug interactions mayoccur if a patient is taking antiplateletagents, such as warfarin or aspirin.10

Additive anticoagulant effects mayoccur when combined with herbalproducts that have antiplatelet activity,such as ginkgo, ginger, and feverfew.

Clinical studies. A recently pub-lished meta-analysis included trialsfrom previously published meta analy-ses and newer trials.70 The resultsrevealed that garlic reduced total cho-


lesterol more than did placebo (P <0.01). The result was more modestthan in previous studies. Mean totalcholesterol decrease was 15.7 mg/dl.

In mild hypertension, a 1994 meta-analysis indicated that mean systolicblood pressure was 7.7 mmHg lowerthan with placebo, and diastolic bloodpressure was 5 mmHg lower.71

However, only three of the trials wereconducted in hypertensive subjects.Seven of the eight trials in the meta-analysis compared garlic to placebo.Three of the trials found a significantreduction in systolic blood pressure,and four trials showed a significantreduction in diastolic blood pressure.

Clinical notes. Although lipid low-ering has been shown with garlic use,the results are less impressive thanwith traditional agents. Althoughtotal cholesterol is lowered, there isless evidence for benefit to LDL,triglycerides, or HDL cholesterol.Garlic may not provide the aggressivelipid lowering that is recommendedfor patients with diabetes. Likewise,patients with diabetes need moreaggressive antihypertensive effectsthan garlic may provide.

The dose to treat hyperlipidemiaand hypertension is 600–900 mg/dayin divided doses.10 For fresh garlic, thedose is one clove (4 g) takenonce/day.10 Dried garlic powderpreparations standardized to 1.3%allicin content have been used in stud-ies. These preparations should beenteric-coated to prevent breakdownby stomach acids.10

�-Lipoic Acid�-lipoic acid (ALA), also known asthioctic acid, is a disulfide compoundsynthesized in the liver.72 It functionsas a cofactor in enzyme complexessuch as pyruvate dehydrogenase,where it assists in the conversion ofpyruvic acid to acetyl-coenzyme A inthe oxidative metabolism of glucose.72

In vitro and animal research indi-cates that elevated glucose levels mayincrease free radical-mediated oxida-tion, which in turn is strongly impli-cated in the pathogenesis of diabetes-related neuropathy.73 Because ALAmay decrease oxidative stress (in partcaused by increased blood glucose lev-els), it may help minimize diabetescomplications. ALA has been used inGermany for decades to treat periph-eral neuropathy.

Proposed mechanism of action.ALA is readily converted to itsreduced form, dihydrolipoic acid

(DHLA).18 ALA and DHLA are bothpotent antioxidants and have threedistinct actions: 1) free radical scav-enging activity; 2) regeneration ofendogenous antioxidants such as vita-min C, vitamin E, and glutathione;and 3) metal chelating activity.73

Side effects and drug interactions.Serious side effects have not beenreported. ALA may produce GI sideeffects and possible allergic skin con-ditions.74 ALA may potentially resultin additive hypoglycemia when com-bined with hypoglycemic agents.75

Clinical studies. ALA was studiedin the ALADIN (Alpha Lipoic Acid inDiabetic Neuropathy) trials. The firsttrial74 was a randomized, double-blind, placebo-controlled trial in 260type 2 diabetic patients with sympto-matic peripheral neuropathy. For 3weeks, patients were administeredplacebo or intravenous (IV) ALA(100, 600, or 1,200 mg) daily. Totalsymptom scores of neuropathydecreased significantly for all threeALA doses versus placebo (P < 0.05).Burning, paresthesia, and numbnessdecreased significantly in patients on600 and 1,200 mg/day versus placebo(P < 0.05). Pain scores decreased sig-nificantly only in the 600 mg/day ver-sus placebo group (P < 0.05).However, both the 600- and 1,200-mg doses decreased Hamburg PainAdjective List scores (P < 0.01 vs.placebo). The Neuropathy DisabilityScore decreased but was significantonly for the 1,200-mg group versusthe placebo group (P = 0.030).

The second ALADIN trial (ALADINII) was a randomized, double-blind,placebo-controlled 2-year trial in 65patients with type 1 or type 2 diabetesand polyneuropathy symptoms.76

Following administration of placebo,600 mg, or 1,200 mg/day IV for 5days, patients were then randomized tooral placebo, 600 mg, or 1,200 mg/dayfor 2 years. Mean sural nerve conduc-tion velocity changes were significantonly for 600 and 1,200 mg versusplacebo (P < 0.05). Sural sensory nerveaction potential scores decreased signif-icantly only for 600 mg versus placebo(P < 0.05). Tibial motor nerve conduc-tion velocity changes were significantonly for 1,200 mg versus placebo (P <0.05).

ALADIN III77 was a randomized,double-blind, placebo-controlled trialin 503 patients with type 2 diabetes.One group was given 600 mg IV/dayof ALA for 3 weeks, and then subjectswere randomized to oral ALA, 600

mg three times daily, or placebo for 6months. The other group was givendaily IV placebo for 3 weeks followedby oral placebo for 6 months. Meanbaseline neuropathic impairmentscores decreased after 19 days in thetwo ALA groups versus placebo (P =0.02). After 7 months, however, dif-ferences were not significant betweenthe groups. The authors suggestedthat lack of effect in this trial, asopposed to the earlier trials, mighthave been due to intercenter variabili-ty in symptom scoring.

Clinical notes. There is no infor-mation on the prevention of neuropa-thy with ALA. The clinical signifi-cance of the reported improvement indifferent parameters of neuropathy inthe ALADIN studies74,76,77 may beenhanced quality of life for patientswho experience neuropathy.

Long-term trials are necessary todetermine whether ALA slows progres-sion of neuropathy or merely improvesneuropathy symptoms. The Neurolog-ical Assessment of Thioctic Acid inNeuropathy Study (NATHAN) is anongoing multicenter trial in Europeand North America to evaluate theability of oral ALA to slow progressionof neuropathy in diabetes.78

Typical oral doses of ALA are600–800 mg/day.10 Although intra-venously administered ALA has beenshown to be effective when used inshort-term clinical trials,74 it is not apractical form for supplementation.

The American Diabetes Associationdoes not sanction use of ALA.

ConclusionsAlthough biological complementarytherapies have been studied in humanclinical trials, there are many problemswith study design, study endpoints,numbers of patients, and study dura-tion. There is insufficient evidence torecommend generalized use forpatients with diabetes. Furthermore,these products have many side effectsand may potentially interact with tra-ditional diabetes medications.

References1Sabo CE, Rush MS, Temple LL: The use ofalternative therapies by diabetes educators.Diabetes Educ 25:945–946;949–950;952–954,956, 1999

2Gill GV, Redmond S, Garratt F, Paisey R:Diabetes and alternative medicine: cause for con-cern. Diabet Med 11:210–213, 1994

3Huxtable RJ: The harmful potential of herbaland other plant products. Drug Safety 5 (Suppl.1):126–136, 1990


Fro

m R

esearch to

Practice

/Co

mp

lemen

tary &In

tegrative M

edicin

e

4Fugh-Berman A: Herb-drug interactions. Lancet355:134–138, 2000

5Hamburger M, Hostettmann K: Analyticalaspects of drugs of natural origin. J PharmBiomed Anal 7:1337–1349, 1989

6Bonati A: How and why should we standardizephytopharmaceutical drugs for clinical valida-tion? J Ethnopharmacol 32:195–197, 1991

7Grant KL: Patient education and herbal dietarysupplements. Am J Health Syst Pharm57:1997–2003, 2000

8Anonymous: Gymnema sylvestre. Altern MedRev 4:46–47, 1999

9Facts and Comparisons: The Review of NaturalProducts. St Louis, Mo., Wolters Kluwer, 1999

10Jellin JM, Batz F, Hitchens K: Pharmacist’sLetter/Prescribers Letter Natural MedicinesComprehensive Database. Stockton, Calif.,Therapeutic Research Faculty, 1999. Availablefrom www.NaturalDatabase.com

11Shanmugasundaram ER, Panneerselvam C,Samudram P, Shanmugasundaram ERB: Enzymechanges and glucose utilisation in diabetic rab-bits: the effect of gymnema sylvestre. JEthnopharmacol 7:205–234, 1983

12Persaud SJ, Al-Majed H, Raman A, Jones PM:Gymnema sylvestre stimulates insulin release invitro by increased membrane permeability. JEndocrinol 163:207–212, 1999

13Shanmugasundaram ERB, Gopinath KL,Radha Shanmugasundaram KR, Rajendran VM:Possible regeneration of the islets of Langerhansin streptozotocin-diabetic rats given Gymnemasylvestre leaf extracts. J Ethnopharmacol30:265–279, 1990

14Shanmugasundaram ERB, Rajeswari G,Baskaran K, Rajesh Kumar BR, RadhaShanmugasundaram K, Kizar Ahmath B: Use ofGymnema sylvestre leaf extract in the control ofblood glucose in insulin-dependent diabetes mel-litus. J Ethnopharmacol 30:281–294, 1990

15Baskaran K, Kizar B, Ahamath K, RadmaShanmugasundaram K, ShanmugasundaramERB: Antidiabetic effect of a leaf extract fromGymnema sylvestre in non-insulin-dependentdiabetes mellitus patients. J Ethnopharmacol30:295–306, 1990

16Madar Z: Fenugreek (trigonella foenum-graceum) as a means of reducing postprandialglucose levels in diabetic rats. Nutr Rep Int29:1267–1273, 1984

17Raghuram TC, Sharma RD, Sivakumar, SahayBK: Effect of fenugreek seeds on intravenous glu-cose disposition in non-insulin dependent diabet-ic patients. Phytother Res 8:83–86, 1994

18Bordia A, Verma SK, Srivastava KC: Effect ofginger (zingiber officinale rosc.) and fenugreek(trigonella foenumgraecum l) on blood lipids,blood sugar and platelet aggregation with coro-nary artery disease. Prostaglandins LeukotEssent Fatty Acids 56:379–384, 1997

19Patil SP, Niphadkar PV, Bapat MM: Allergy tofenugreek (trigonella foenum graecum). AnnAllergy Asthma Immunol 78:297–300, 1997

20Sharma RD, Raghuram TC, Sudhakar Rao N:Effect of fenugreek seeds on blood glucose andserum lipids in type 1 diabetes. Eur J Clin Nutr44:301–306, 1990

21Sharma RD, Sarkar A, Hazra DK, Miehra B,Singh JB, Sharma SK, Maheshwari BB,Maheshwari PK: Use of fenugreek seed powderin the management of non-insulin-dependent dia-betes mellitus. Nutr Res 16:1331–1339, 1996

22Khanna P, Jain SC, Panagariya A, Dixit VP:Hypoglycemic activity of polypeptide-p from aplant source. J Nat Prod 44:648–655, 1981

23Aslam M, Stockley IH: Interaction betweencurry ingredient (karela) and drug (chlor-propamide). Lancet 1:607, 1979

24Ahmad N, Hassan MR, Halder H, BennoorKS: Effect of momordica charantia (karolla)extracts on fasting and postprandial serum glu-cose levels in NIDDM patients. Bangladesh MedRes Counc Bull 25:11–13, 1999

25Raman A, Houston P: Herbal products: gin-seng. Pharm J 255:150–152, 1995

26Vogler BK, Pittler MH, Ernst E: The efficacy ofginseng, a systematic review of randomized clini-cal trials. Eur J Clin Pharmacol 55:567–575,1999

27Blumenthal M, Busse WR, Goldberg A,Gruenwald J, Hall T, Riggins CW, Rister RS(Eds.): The Complete German Commission EMonographs: Therapeutic Guide to HerbalMedicines. Klein S., translator. Boston, Mass.American Botanical Council, 1998

28Yuan CS, Wu JA, Lowell T, Gu M: Gut andbrain effects of American ginseng root on brain-stem neuronal activities in rats. Am J Chin Med26:47–55, 1998

29Ohnishi Y, Takagi S, Miura T, Usami M, KakoM, Ishihara E, Yano H, Tanigana K, Suno Y:Effect of ginseng radix on GLUT2 protein con-tent in mouse liver in normal and epinephrine-induced hyperglycemic mice. Biol Pharm Bull19:1238–1240, 1996

30Kimura M, Waki I, Chujo T, Kikuchi T,Hiyama C, Yamazaki K, Tanaka O: Effects ofhypoglycemic components in ginseng radix onblood insulin level in alloxan diabetic mice andon insulin release from perfused rat pancreas. JPharmacobiodyn 4:410–417, 1981

31Palmer BV, Montgomery AC, Monteiro JC:Ginseng and mastalgia (Letter). Br Med J1:1284, 1978

32Hopkins M, Androff I, Benninghoff AS:Ginseng face cream and unexplained vaginalbleeding. Am J Obstet Gynecol 159:1121–1122,1988

33Ryu S-J, Chien Y-Y: Ginseng-associated cere-bral arteritis. Neurology 45:829–830, 1995

34Siegel RK: Ginseng abuse syndrome: problemswith the panacea. JAMA 241:1614–1615, 1979

35Becker BN, Greene J, Evansan J, Chidsey G,Stone WJ: Ginseng-induced diuretic resistance.JAMA 276:606–607, 1996

36Shader RI, Greenblatt DJ: Phenylzine and thedream machine: ramblings and reflections. J ClinPsychopharmacol 5:65, 1985

37Jones BD, Runikis AM: Interaction of ginsengwith phenelzine. J Clin Psychopharmacol7:201–202, 1987

38Janetzky K, Morreale AP: Probable interactionbetween warfarin and ginseng. Am J Health SystPharm 54:692–693, 1997

39Sotaniemi EA, Haapakoski E, Rautio A:Ginseng therapy in non-insulin dependent diabet-ic patients. Diabetes Care 18:1373–1375, 1995

40Vuksan V, Sievenpiper JL, Vernon YY, KooMSC, Francis T, Beljan-Zdravkovic U, Xu Z,Vidgen E: American ginseng (Panax quinque-folius L) reduces postprandial glycemia in nondi-abetic subjects and subjects with type 2 diabetesmellitus. Arch Intern Med 160:1009–1013, 2000

41Cui J, Garle M, Eneroth P, Bjorkhem I: Whatdo commercial ginseng preparations contain?(Letter). Lancet 344:134, 1994

42Ibanez-Camacho R, Roman-Ramos R:Hypoglycemic effect of opuntia cactus. ArchInvest Med 10:223–230, 1979

43Meckes-Lozyoa M, Roman-Ramos R: Opuntiastreptacantha: a coajutor in the treatment of dia-betes mellitus. Am J Chin Med 14:116–118,1986

44Frati A: 2000 medical implications of pricklypear cactus. http//www.tamuk.edu/webuser/cac-tus/cac_med.html (accessed 14 February 2001).

45Frati-Munari AC, Gordillo BE, Altamirano P,Ariza CR: Hypoglycemic effect of opuntia strep-tacantha lemaire in NIDDM. Diabetes Care11:63–66, 1988

46Frati AC, Gordillo BE, Altamirano P, ArizaCR, Cortes-Franco R, Chavez-Negrete A: Acutehypoglycemic effect of opuntia streptacanthalemaire in NIDDM (Letter). Diabetes Care13:455–456, 1990

47Ghannam N: The antidiabetic activity of aloes:preliminary clinical and experimental observa-tions. Horm Res 24:288–294, 1986

48Muth ER, Laurent JM, Jasper P: The effect ofbilberry nutritional supplementation on nightvisual acuity and contrast sensitivity. Altern MedRev 5:164-173, 2000

49Head K: Natural therapies for ocular disorders,part two: cataracts and glaucoma. Altern MedRev 6:141–166, 2001

50Wichtl MW: Herbal Drugs andPhytopharmaceuticals. Bisset NG, Ed. Stuttgart,Germany, Medpharm Scientific Publishers, 1994

51Cignarella A, Nastasi M, Cavalli E, Puglisi L:Novel lipid-lowering properties of vacciniummyrtillus L. leaves, a traditional antidiabetictreatment, in several models of rat dyslipidaemia:a comparison with ciprofibrate. Thromb Res84:311–322, 1996

52Pepping J: Alternative therapies: milk thistle:silybum marianum. Am J Health Syst Pharm56:1195–1197, 1999

53Flora K, Hahn M, Rosen H, Benner K: Milkthistle (silybum marinum) for the therapy of liverdisease. Am J Gastroenterol 93:139–143, 1998

54Velussi M, Cernigoi AM, De Monte A, DapasF, Caffau C, Zilli M: Long-term (12 months)treatment with an anti-oxidant drug (silymarin)is effective on hyperinsulinemia, exogenousinsulin need and malondialdehyde levels in cir-rhotic diabetic patients. J Hepatol 26:871–879,1997

55Luper S: A review of plants used in the treat-ment of liver disease: part 1. Altern Med Rev3:410–421, 1998

56Jamal GA: The use of gamma linolenic acid inthe prevention and treatment of diabetic neu-


ropathy. Diabet Med 11:145–149, 1994

57Horrobin DF: Essential fatty acids in the man-agement of impaired nerve function in diabetes.Diabetes 46 (Suppl. 2):S90–S93, 1997

58Jamal GA, Carmichael H: The effect of �-linolenic acid on human diabetic peripheral neu-ropathy: a double-blind placebo-controlled trial.Diabet Med 7:319–323, 1990

59The Alpha-Linolenic Acid Multicenter TrialGroup, Keen H, Payan J, Allawi J, Walker J,Jamal GA, Weir AI, Bissessar EA, Watkins PJ,Sampson M: Treatment of diabetic neuropathywith alpha-linolenic acid. Diabetes Care16:8–15, 1993

60Kleijnen J, Knipschild P: Ginkgo biloba. Lancet340:1136–1139, 1992

61Pittler MH, Ernst E: Ginkgo biloba extract forthe treatment of intermittent claudication: a metaanalysis of randomized trials. Am J Med108:276–281, 2000

62Cohen AJ, Bartlik B: Ginkgo biloba for antide-pressant-induced sexual dysfunction. J SexMarital Ther 24:139–143, 1998

63Rowin J, Lewis SL: Spontaneous bilateral sub-dural hematomas with chronic ginkgo bilobaingestion. Neurology 46:1775–1776, 1996

64Vale S: Subarachnoid haemorrhage associatedwith ginkgo biloba (Letter). Lancet 352:36, 1998

65Rosenblatt M, Mindel T: Spontaneous hyphe-ma associated with ingestion of ginkgo bilobaextract (Letter). N Engl J Med 336:1108, 1997

66Shon M, Sikora R: Ginkgo biloba extract in thetherapy of erectile dysfunction. J Sex Ed Ther17:53–61, 1991

67Pareddy SR, Rosenberg JM: Does garlic haveuseful medicinal purposes? Hosp Pharmacist Rep8:27, 1993

68Rose KD, Croissant PD, Parliament CF, LevinMB: Spontaneous spinal epidural hematoma

with associated platelet dysfunction from exces-sive garlic ingestion: a case report. Neurosurgery2:880–882, 1990

69Burnham BE: Garlic as a possible risk for post-operative bleeding (Letter). Plast Reconstr Surg95:213, 1995

70Stevinson C, Pittler MH, Ernst E: Garlic fortreating hypercholesterolemia, a meta-analysis ofrandomized clinical trials. Ann Intern Med133:420–429, 2000

71Silagy CA, Neil HA: A meta-analysis of theeffect of garlic on blood pressure. J Hypertens12:463–468, 1994

72Evans JL, Goldfine ID: Alpha-lipoic acid: amulti-functional antioxidant that improvesinsulin sensitivity in patients with type 2 dia-betes. Diabetes Technol Ther 2:401–413, 2000

73Giugliano D, Ceriello A, Paolisso G: Oxidativestress and diabetic vascular complications.Diabetes Care 19:257–267, 1996

74Ziegler D, Hanefeld M, Ruhnau K-J, MeibnerHP, Lobisch M, Schutte K, Gries FA, TheALADIN Study Group: Treatment of sympto-matic diabetic peripheral neuropathy with theanti-oxidant �-lipoic acid: a 3-week multicentrerandomized controlled trial (ALADIN Study).Diabetologia 38:1425–1433, 1995

75Jacob S, Ruus P, Hermann R, Trittschler HJ,Maerker E, Renn W, Augustin HJ, Dietze GJ,Rett K: Oral administration of RAC-�-lipoic acidmodulates insulin sensitivity in patients withtype-2 diabetes mellitus: a placebo-controlledpilot trial. Free Radic Biol Med 27:309–314,1999

76Reljanovic M, Reichel G, Rett K, Lobisch M,Schuette K, Moller W, Tritschler HJ, Mehnert H,The ALADIN II Study Group: Treatment of dia-betic polyneuropathy with the antioxidant thioc-tic acid (alpha-lipoic acid): a two year multicen-ter randomized double-blind placebo controlledtrial (ALADIN II). Free Radic Biol Med31:171–179, 1999

77Ziegler D, Hanefeld M, Ruhnau K-J, HascheH, Lobisch M, Schutte K, Kerum G, Malessa R,The ALADIN III Study Group: Treatment ofsymptomatic diabetic polyneuropathy with theantioxidant �-lipoic acid: a 7-month multicenterrandomized controlled trial (ALADIN III Study).Diabetes Care 22:1296–1301, 1999

78Ziegler D, Reljanovic M, Mehnert H, Greis FA:Alpha-lipoic acid in the treatment of diabeticpolyneuropathy in Germany: current evidencefrom clinical trials. Exp Clin EndocrinolDiabetes 107:421–430, 1999

Suggested Readings/WebsitesTyler VE: Herbs of Choice: The Therapeutic Useof Phytomedicinals. Binghamton, N.Y.,Pharmacaeutical Products Press, 1994

Gruenwald S, Brenoller T, Jaenicke L (Eds.):PDR for Herbal Medicine. Montvale, N.J.,Medical Economics, 1999

Leung AY, Foster S: Encyclopedia of CommonNatural Ingredients Used in Foods, Drugs, andCosmetics. 2nd ed. New York, Wiley, 1995

Newall CA, Anderson LA, Phillipson JD: HerbalMedicines: A Guide for Health-CareProfessionals. London, Pharmaceutical Press,1996

Bisset NG (Ed.): A Handbook for Practice on aScientific Basis. Boca Raton, Fla., MedpharmScientific Publications CRC, 1996

www.nal.usda.gov/fnic/IBIDS

Laura Shane-McWhorter, PharmD,BCPS, FASCP, CDE, BC-ADM, is anassociate clinical professor in theDepartment of Pharmacy Practice atthe University of Utah in Salt LakeCity.

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Botanical Products in Diabetes