Review

Paper
AND PLANTS AS

A REVIEW OF NATURAL PRODUCTS POTENTIAL ANTIDIABETIC DRUGS

Summary

The present paper reviews the active, natural principles and crude extracts of plants which have been ~Kper~rneuta~~y studied for hypogly~om~~ activity in the last ten years. Phyto~o~stituents with known structures have been classified in appropriate chemical groups and the active crude extracts have been listed alphabetically according to genus. Data are reported on their pharmacological activity, mechanism of action, toxicity and other properties.

Introduction

Diabetes mellitus is a metabolic disease as old as mankind and its incidence is considered to be high 44- StloLTreatment of this disorder takes three main forms: i4 diet and exercise, 66;)insulin replacement therapy and G4 the use of oral hypoglycemic agents ~sulfonylureas and biguanidesl. However, since time immemorial, patients with non-insulin requiring diabetes have been treated orally in folk medicine with a variety of plant extracts. The evaluation of these plants and, especially, of their active natural principles is a logical way of searching for new drugs to treat this disease. We have reviewed the relevant literature on the plants which have been used in folk medicine and for which hypoglycemic activity has been scientifically documented in clinics or by the use of experimental methods.

0 1939 Elsevier ~~8~~~~~39~~1.~ Published and Printed in Ireland

Scientific Publishers

Ireland Ltd.

TABLE 1 ISOLATED FROM PLANTS Part used Data on structure and action of principle :

ACTIVE ANTIDIABETIC

PRINCIPLES

Active principle

Plant species

Polysaccharides

and proteins

Aconitum

carmichaelii

Debx.

Roots
These mice. duced action

Aconitans A, B, C and and D

(Ranunculaceael

glycans exhibited pronounced hypoglycemic effects in normal The main glycan, aconitan A, administered i.p. to aIloxan-prohyperglycemic mice, also exhibited a blood sugar lowering (Konno et al., 1985d).

Arborans A and B

Aloe arborescens Mill. var. natalensis Wood. et Ev.

Leaves

These glycans elicited marked hypoglycemic effects in normal and alloxan-induced hyperglycemic mice (Hikino et al., 1986c).

(Liliaceael
asphodeloides

Anemarans and D

A, B, C

Anemarrhena

Rhizomes

Bunge (Liliaceae)

These constituents displayed hypoglycemic effects in normal mice and the main glycan, anemaran C, administered i.p. to alloxaninduced hyperglycemic mice reduced plasma glucose level (Takahashi et al., 19851

Atractans

A, B and C

Atractyloides

japonica Koidz.

Rhizomes

(Compositael

Hypoglycemic effects were seen in normal mice and the main glycan, atractan A, also reduced blood glucose when injected i.p. to alloxaninduced hyperglycemic mice (Konno et al., 1985e). These components elicited hypoglycemic effects in normal mice and coixan A showed a hypoglycemic effect when administered to alloxan-induced hyperglycemic mice (Takahashi et al., 1986)

Coixans A, B and C L. var. maSeeds

Coix lachryma-jobi

yuen Stapf. (Gramineae) Tubers

Dioscorea

japonica Thunb.

Dioscorans A, B, C, D, E and F

(Dioscoreaceae)

All the dioscorans had a hypoglycemic effect when injected i.p. to normal mice and the main glycan, dioscoran C, also exhibited a hypoglycemic effect in alloxan-induced hyperglycemic mice (Hikino et al., 1986a).

Eleutherococcus senticosus

senticosus

Roots

Eleutherans A, B, C, D, E, F and G

Maxim; synonym:

Acanthopanax

Harms. (Araliaceae)

When eleutherans A-G were injected i.p. to normal mice, hypoglycemic activity was observed with all the glycans except eleutheran E. 1.~. administration of eleutheran C to alloxan-treated mice also lowered blood glucose level (Hikino et al., 1986d3.

TABLE Part used Data on structure and action of principle

1 (continued)

Active

principle

Plant

species

Panaxans A, B, C, D and E

Panax ginseng Mey. (Araliaceael Roots

These glycans had a hypoglycemic action in normal mice and the i.p. administration of panaxan A and B in alloxan-induced hyperglycemic mice also reduced the blood glucose levels (Konno et al., 19841. Panaxan A has a molecular weight of 14,000 and is composed mainly of a-1-6 linked D-g~UCOpyranOSC residues with branching at the C-3 position; the ratio of terminals, branching positions and intermediate units is 1:1:2 (Tomoda et al., 19841. Panaxan B was shown to be a peptidoglycan with molecular weight of about 1,800,OOO and is composed mainly of a-l-% linked D-glUCOpyranOSe residues with branching at the C-3 position; the ratio of terminals, branching positions and intermediate units is about 1: 1:1.8 (Tomoda et al., 19851. Other glycans, panaxans F, G and H (Hikino et al., 1985c1, I, J, K and L (Oshima et al., 19851, Q, R, S, T and U (Konno et al., 1985c1, M, N, 0 and P (Konno and Hikino, 19871 with hypoglycemic effects were isolated from the roots of P. ginseng. The quinquefolans showed hypoglycemic effects in normal mice and of quinquefolan A to alloxan-induced hyper i.p. administration glycemic mice also produced a hypoglycemic effect (Oshima et al., 19871. parts These products had hypoglycemic and anti-atherosclerotic activity in mice and rats, respectively (Takagi, 19861. The accumulation of lipid peroxides induced by a high sugar diet was inhibited by combined feeding with a polysaccharide fraction of S. officinarum (Hikino et al., 1985dl.

Quinquefolans and C

A, B

Panax quinquefolium (Araliaceael

L.

Roots

Saccharans A, B, C D, E and F

,
Aerial

Saccharum officinarum L. (Gramineael

Flavonoids

and related products

( - l-Epicatechin
Roxb.

Pterocarpus marsupium (Leguminosael

Bark

t - l-Epicatechin was reported to protect rats from alloxaninduced diabetes when the compound was administered (30 mgikgl twice daily for 2 days prior to alloxan and 1 day after alloxan administration

(Chakravarthy et al., 1981al. Moreover, this compound could reverse ~lloxan-induced hyperglycemia when it was administered for 2-3 days (30 mg/kg twice daily) canning 24 h after alloxan adm~nistration ~~hakrsva~h~ et al., 1981b, 1981c and 19821. However, other authors failed to confirm the antidiabetic effect of 4- ~epicateehi~ in different experimenta diabetic models, e.g. streptozotoc~n-treated C57BL/65 mice Kolb et al., 19821, alloxan-treated Wistar rats (Kolb et al., 1982; Sheehan et al,, 1983a,bl, streptozotocin-diabetic or spontaneously diabetic BB/E rats (Bone et al., 19851. (- l-Epicatechin had direct effects on islets of Langerbaus function. This compound (1 m&II increased insulin secretion from isolated rat islets in the presence of either 2 or 20 mlU glucose in static incubations or in perfosion. Iajeetion of epiestechin (30 m&kg twice daily for 4 days) into normal rats brought about an increase in insulin secretion from isolated islets when exposed to 20 mM glucose and in islet content in treated rats. Furthermore, adult rat islets cultured with 5.5 mhI giueose for 4 days showed a significant increase in DNA synthesis in the presence of 0.05 m&I epi~techin &Iii and Wowell, 1984al. The effect of epicatechin on insulin release coufd have been brought about, at least in part, by changes in cyclic AMP metabolism (epicatechin at 1 mmol~ increased cyclic AMP concentrations in islets, Hii and Ifowell, 1984b3 or by changes in Ca2+metabolism (epicatechin at 0.8 mmolll inhibited Y?az efflux and increased the uptake of 45Caz+ the presin ence of 20 m&I glucose, Nii and Howe& 19851. Bark These flavonoids are present in equal proportions in a fraction isolated from 2. rz~gosa. This fraction produced hy~giyce~a in rabbits Khosa et al., 19831.

Kaempferol-~~rhamnoside Quercitin-3.~rhamnoside ~~i~tin~~rham~oside Leaves

Quer~etjn

~uu~~n~ ~~reo

L. &R&iGo variegata L, vsr, candti Roxb. Ileguminosael

Oral administration of this compound (100 mgkgl lowered the blood glucose level in normal rats 2 h after glucose injection (Abd-ElWahab et al., 19871. On the other hand, quercetin fO.OI--0.1 mmol/ll enhanced insulin release in isolated rat islets of Langerhans; this compound (0.01 mmol/lf also inhibited sea** efflux and increased the uptake of q5Caz+ isolated rat islets @Iii and Howell, 19851. in

2 rJ

TABLE

(continued)

itima lge. (Compositae)

levels at a dose of 20 mg/kg when given orally to glucose-induced hyperglycemic rats &War and Pay& 19851. It has been demonstrated that with an oral dose of 30 mg/kg this compound increased the fasting plasma insulin levels in normoglycemic rats and improved the oral glucose tolerance test with a corresponding increase in glueoseinduced insulin secretion (Ivorra et al., 1988al. However, f3-sitosterol 36-u-glucoside did not change insulin and glucose levels in rats with streptozotocin-induced severe diabetes. The glyeoside (0.1 - 0.5 mM1 stimulated insulin release from isolated rat islets of Langerhans in the presence of 1.66 mM glucose but did not increase the insulinreleasing capacity of 16.6 mM glucose. These data suggest that 6sitosterol 3++glucoside exerts its action on intact pancreatic /3-cells by stimulating insulin secretion. A high dose of those compound (600 mg/kg i.p. to mice) did not produce any symptoms of toxicity and none of the mice died during the I-day observation period (Ivorra, M.D. et al., unpublished observations). Green beans This substance given orally ta mice decreased levels (Sampaio et al., 19791. their blood glucose

fi-Sitosterol

Coffeu arabica L. (Rubiaceael

G~nsenoside Rb, Roth single i.p. administrat~vn (Yvkosawa et al., 19841 or repeated administration of gi~senvside Rb, (IO mg/rat~day for 8 days) (Yvkvzawa et al., 1985ct to streptozot~in.diabetie rats decreased the elevated serum levels vf glucose, triglycerides non-shafted fatty acids and total chv~esterv~ forthermo~e, the IipoIyt~e activity of lipoprotein Iipase was stimulated with a co~co~~nt decrease in the levels of triglyceride and very low density lipoprotein in the serum after ginsenvside-Rb, treatment for 6 days (Yvkozawa et al., 198%). In addition to the hypoglycemic and hypvlipemic effect, single i.p. ~m~n~strat~on (Yv~osawa et al., 19841 or repeated administration (Yvkozawa et al., 198Sc, 198%) of ginsenodde Rb, lowered the serum levels of ~~ydroxybuty~~te and ace~acetate in strep~~toci~induced diabetic rats. This indicates au ~m~rvvement of diabetic ketoacidosis. Moreover, successive i.p. administration of gitwenosideRb, remarkably improved diabetic symptoms such as overeating, polyuria and glyeosuria; on the other hand, body weight increased in ginsenos~de-Rb~-trea~d diabetic rats Qokozawa et al., 1985a, 1987aL ~nrthermore, administration of ~~senos~de Rb, in strepto~ta~ndiabetic rats iodu~ed a decrease in blood usea N level and an increase in total protein and several amino acids in serum, but no significant change in serum albumin was observed. The urea content of liver decreased with a concomitant increase in RNA content (Yokozawa et al., 1987aL The hypoglycemic action of ~~senoside-Rb* may be due to its effects on glucose meta~iism. The ~~~noside~ Rb,-treated group showed a decrease in the activity of he~atie glucose~-phosphate after 6 days of treatment. In contrast, the hepatic g~ucv~nase was significantly increased and the liver glycvgen content tended to increase after 6 days of ginsenvside-Rb2 treatment fYokvsawa et al., 1985b). G~nsenosid~Rb~ decreased ghxose in the hepatic tissue of diabetic rats while the g~ucose~~hos~~te level was unchanged and tke lactate fevel tended to decrease (Yokosawa et al., 1981b). The blood insulin levels remained unchanged throughout the Qday treatment, which indica~s tbat the ~nse~osid~Rb~induced decrease in bfood sugar and the improvement in sugar and lipid metabolism in streptozotoc~~ diabetes are not associated with an increase in insulin (Kobayashi et al., 1985).

Roots

txJ %

TABLE Part L. Leaves This principle, a novel diterpene, showed hypoglycemic activity it was administered to alloxanized mice (40 mglkg i.p.1 (Mossa 19851. parts when et al., used Data on structure and action of principle

1 (continued)

Active

principle

Plant

species

Saudin

Cluytiu &hard&a (Euphorbiaceae)

Tormentic

acid

Poterium ancistroides (Rosaceael

Desf.

Aerial

This principle (10 mglkgl had a hypoglycemic effect in normal rats (Villar et al., 19861. It was been demonstrated that tormentic acid (30 mglkgl had a hypoglycemic effect in normoglycemic and glucoseinduced hyperglycemic rats with a corresponding increase in circulating insulin levels. However, the compound (30 mglkg) did not change the glucose and insulin levels in streptozotocin-induced diabetic rats (Ivorra et al., 1988b). On the other hand, tormentic acid (0.05-0.5 mM) initiated insulin secretion by isolated rat islets of Langerhans in a dose-dependent fashion. The compound has no effect on the insulinreleasing capacity of 16.6 mM glucose. These results suggest that tormentic acid rats, at least in part, by increasing insulin secretion from intact pancreatic islets of Langerhans (Ivorra et al., 1989al. Tormentic acid was not toxic in mice in that i.p. administration of a high dose (600 mglkgl did not produce any symptoms of toxicity (Ivorra, M.D. et al., unpublished observations). Hypoglycemic streptozotocin activity was shown in rats (Yamahara et al., 1981). with diabetes induced by

Ursolic

acid

Cornus off%nalis Sieb. et Zuec. Seeds synonym: Macrocarpium officinale Nakai (Cornaceael

Oleanolic

acid

Cornus officinalis Sieb. et Zucc. Seeds (Cornaceael

Isolated together with decreased the amount diabetic rats (Yamahara

ursolic acid from C. officinalis, this compound of water consumption and urine volume in et al., 19811. Two glycosides were isolated, one contained glucose and the other contained glucose and arabinose. Both glycosides contained oleanolic acid as aglycone and showed hypoglycemic action in streptozotocininduced diabetic rats at a dose of 25 mg/kg; i.p. administration showed better activity than oral administation (Reza-Ul Jab1 et al., 19861.

Momordica cochinchinensis Sprengel Seeds (Cucurbitaceae)

Berberine Aerial parts

Co@ chinensis Fancb. synonym: C. tecta Walt var. cirinens& Fran&. (~nun~n~aEe~~

~y~giycern~c effects in normal, afloxan diabetic and spontaneously dia~tic KK mice. Antagonized the hyperglycemic effect induced by i.p. ~admin~stration of glucose or adrenaline in normal mice and improved the glucose tolerance of KK mice after 15 days of ~eatment. furthermore, be~~rine decreased serum ~hoIestero1 lev els of mice fed a high cholesterol diet and inhibited the platetet aggregation of rabbits in vitro Chen and Xie, 1986). Capsaicin (14 mg%t) inhibited the intestinal glucose transport in both rat and the hamster in vitro (~onseree~nsor~, 1979; ~onsereenusoro and G~insokoo, 1978, 1979a). This effect may be due in part to a greater metabolic breakdown of glucose into lactic acid ~~onsereennnusorn, 19791 or may be doe to a secondary inbibi~ry effect on the ATP~e-dependeat sodium pump (~onsereenusorn and G~insukon, 1979bj. Hypog~yce~e activity seen at an oral dose of 10 mg&g, in gb~coseinduced hyperglycemic rabbits. It was a more potent antidiabetic agent than to~b~tamide 6% rng~g~ ~Karawya et al., 19841.

~~psaicin Fruits

Bulbs

Thea sinends (~~ea~eae) L, Leaves Seeds

Galegin

This principle is cited in the review of Gfiver (1979). More recently, the bypo~ly~emic effect of in al~oxan~a~ti~ rats has been remonstrated. galegin sulfate in mice was 0.122 g/kg ~Petrieic and

Bever and Zahnd galegin 636 rn~~g~ The oral LD, of Kalodera, 1962). Lathyrine and y-L-gIu~myl-L-lathyrine showed hypoglycemic activity in mice. Latbyrine (66 m&g i.v.1 had a bypo~lyeemic effect on al~oxon-indn~ed diabetic mice t~itsubishi Ghem, Ind., 1982).

Lathpus

japmkus sic ~~~minosae)

Seeds

TABLE Part Data on structure and action of principle used

1 (continued)

Active

principle

Plant

species

Lepidine

Lepidium

ruderale

L.

Aerial

parts

(Cruciferae)

Hypoglycemic effects in mice and rabbits (Paskov and Boyadzhieva, 1981) in alloxan-induced mild chronic diabetes (Boyadzhieva, 1981, 1982a) and in adrenaline-induced hyperglycemic rats (Paskov and Boyadzhieva, 1982). However, this principle failed to affect carbohydrate metabolism in diabetic rats made absolutely insulininsufficient by surgical pancreatectomy (Boyadzhieva, 1982b3). Furthermore, this compound decreased glucosuria, polydipsia and increased glycogen in liver in alloxan-induced mild chronic diabetes (Boyadzhieva, 1982a). Hypoglycemic and central nervous rabbits (Manhajan and Jolly, 1985). system depressant activity in

1,2 Substituted dines

pirroli-

Tinospora cordifoliu Miers. (Menispermaceae) Whole plant

253

TABLE II (continoledl Data on action of extract

Plant species (Family)

Part used (country)

Bride&u ferruginea

Leaves (Africa)

Benth. (~uphorbiaceae)

The fasting blood sugar levels of maturity-onset diabetic patients were lowered to normal by daily doses of aqueous extracts; glycosuria was eliminated after 2 weeks of therapy. The aqueous and methanol extracts (200 mg/kgl lowered the fasting blood sugar in normal rats but not in alloxan-treated rats: however they lowered the hyperglycemia in alloxan-treated rats when they were administered 1 h prior to alloxan injection (Iwu, 19831. Flavonoids quercetin and kaempferol and their glycosides were isolated from the methanol extract of this plant (Iwu, 1983).

Bryonia alba sic

(Cucurbitaceael

Methanol extracts (5 mglkg) and the fraction containing trihydroxyoctadecadienoic acids (0.5 mg/kgl decreased blood sugar in rats with alloxan diabetes after 20 days i.m. treatment (Panosyan et al., 19811. An ethanol extract (250 and 500 mglkgl elicited a hypoglycemic effect in normal rats and rabbits. In alloxan-induced mild diabetic rats, the daily administration of the ethanol extract (500 mg/kg per day p.o.1 for 12 days lowered the blood glucose levels from the 8th day of treatment. Moreover, the extract improved glucose tolerance in alloxan-induced diabetic rats. In addition, the extract enhanced glucose uptake in skeletal muscle and inhibited glyeogenolysis in the liver. Besides hypoglycemic activity, the ethanol extract also elicited antiinflammatory activity but did not show any significant effects on blood pressure and respiration. LD,, by the p.o. route in mice was 2580 mglkg and in rats 8670 mglkg, and by the i.p. route in mice was 127 mglkg and in rats 187 mglkg (No. brega et al., 1985). Bassic acid, triterpenic acid, was isolated from the ethanol extract but it was not established whether bassic acid is responsible for the observed hypoglycemic activity of the ethanol extract (Nobrega et al., 1985).

Bumelia sartorum (Sapotaceael

Mart.

Root bark (Brazil)

Capsicum annuum L.

Fruits (Tropical regions)

(Solanaceael

The aqueous extract caused a dose-dependent decrease in fasting blood glucose levels in rats either by p.o. or i.p. route. Pretreatment with 500 mglkg of the extract p.o. or i.p. improved the oral glucose curves, and the p.o. administration of extract reduced the intracardiac glucose tolerance curve. The hypoglycemic effect of Copsicum may involve both the inhibition of intestinal glucose transport and its action upon the systemic glucose metabolism (Monsereenusorn, 19801.

Cecropiu obtusifolia Bert. (Mora~eae~ Hypoglycemic effect of an aqueous extract in alloxan-diabetic mice was seen when administered by p.0. or i.p. routes (Perez et al,, 19841. An aqueous extract (15 mg/ml iv.1 exhibited hypoglycemic effects in normal and pancreatectomized dogs; in both groups of animals, an increase in the concentration of triglycerides was observed. In intact normal animals there was no corresponding increase in insulin plasma levels. These results suggest that the effect of the piant extract may not be related to stimuli of the p-pancreatic cells (Mellado and Loxoya, 19841. Aqueous extracts (20 g/kg p.o.1 of these species elicited hypoglycemic effects in normal mice. LD, values (g dried plant/kg) of aqueous extracts fi.v.1 of these species were 4.6 for C. aspera, 14.6 for C. ca~~trup~ 8.2 for C. s~~t~t~l~ and 4.1 for C. meliteneis (Mass0 et al., 19791. Tbe aqueous extract of C. asperu produced hypoglycemia in rats and mice while showing no central and autonomic nervous system or local anesthetic activity in rats; the extract caused transitory bypotension in the anesthetized rat and cat and induced contractions in the iso lated guinea pig ileum. It showed no cholinergic OF fi-adrenergie activity &lasso, 19801. Infusions (5 g/kg orally) decreased blood glucose levels in normoglycemic and glucose-induced hyperglycemic rats, but had no effect on alloxan-diabetic animals. There was an increase in circulating insulin levels in normoglycemic rats. Moreover, a heavy release of insulin from isolated rat islets was induced by doses of 25, 50 and 160 mglml. These results suggest that the effect of C. COTCUbionensis may be due to stimulation of insulin release by the pancreas (Chuela et al., 19881. Administration of hexanie extract (106 mg/kg i.pl to normal reduction in the blood glucose (Tilmisany and Ajabnoor, 19861. rabbits caused

Leaves (Mexico1

Centaurea aspera L. C, culcitrapa L. C. meliten&s L. C. ~a~t~t~~~ L.

Aerial parts (Spain)

Centaurea c~c~b~onens~e Lain2 (Compositael

Leaves and flowers (Spain)

Cluytiu richardha (~uphorb~ceae~

sic

Whole plant (Saudi AraArabia1

Coccinia indica Wight et Am.; synomym: C. cordifobia Cogn. (Cucurbi~~eae~

Leaves and roots (India1

A hypoglycemic effect and an improvement on oral glucose tolerance were observed in patients with maturity-onset diabetes mellitus treated with the leaves of this plant. The maximum effect was obtained after three weeks of of a treatment (Azad Khan et al., 19861, In animals, the administration suspension of dried powdered leaves of C. in&a with milk caused a reduction in blood glucose levels in alloxan diabetic dogs but did not induce hypoglycemia in a normal group of animals. Moreover, the drug reduced blood glucose during glucose tolerance test conducted in both normal and diabetic dogs (Singb et al., 19851.

TABLE (country) Data on action of extract

II (continued)

Plant

species

(Family)

Part

used

Cuminum nigrum L. (Umbelliferae)

Seeds

(Asia)

Oral administration of C. nigrum seeds (l-4 g/kg) as well as the water and methanol extracts (4-8 g/kg) decreased blood glucose levels in normal and alloxan-diabetic rabbits. Total blood lipids were not influenced by this substance in either normal or diabetic rabbits. Acute toxicity studies carried out in rabbits revealed no adverse side effects of this folk medicine at the dosages used (2-8 g/kg p.o.1 (Akthar and Ali, 1985). Plasma glucose was somewhat lower 10 h after intragastric dried C. coma&s (3.6 g/kg). Chronic treatment of normal mice dried C. comatus in the diet resulted in a reduction in plasma days and an improvement in i.p. glucose tolerance. However, was interrupted although energy intake was not substantially al., 19841. administration of with 33.3% (w/w) glucose after 11 body weight gain reduced (Bailey et

Coprinus comatus Fr. (Coprinaceae)

Fruits

(Europe)

Cyamopsis tetragonolobus L. (Leguminosae) gum) of seeds

Fibre (guar (India)

Urinary glucose excretion decreased in 9 diabetic patients when their diets were supplemented with the dietary fibre (guar gum, 25 g daily for 5 or 7 days) (Jenkins et al., 1977). Moreover, administration of 20 g of guar gum to 6 healthy volunteers improved tolerance to glucose by decreasing oral glucose absorption (Trinick et al., 1986). Treatment of 8 type 2 diabetic patients with guar gum improved plasma cholesterol and triglyceride values (Briani et al., 1985). The whole fruit extract (20 g/kg) showed significant hypoglycemic activity in normal rabbits and the seeds (20 kg/kg) had a hypoglycemic effect in glucose-fed fasting rabbits. In alloxan diabetic animals, the decoction was effective at 40 gi kg (Pillai et al., 1980).

Fruits

and seeds

(India)

Dioscorea Pax. (Nigeria)

dumetorum

Tubers

(Dioscoreaceae)

A hydroalcoholic extract administered to fasting normal rabbits induced a hypoglycemic effect accompanied by some serious toxic reactions (Akubue and Mittal, 1982). More recently it was demonstrated that the toxic reactions could be separated from hypoglycemic activity through fractionation of the extract by solvent partition. Whereas the alkaloid-containing fraction was hyperglycemic in fasting normal mice, the whole extract and the fractions containing steroidal derivatives evidenced significant hypoglycemic activities in fasting normal mice or rabbits and in severely alloxan diabetic rabbits (Undie and Akubue, 1986).

Eriobotrya japonica Lind. (Rosae~ae~

Leaves &dial

An alcoholic extract (100-200 mglkg, orally) exerted a significant hypoglycemic effect in normal rabbits but had no effect on alloxan-treated rabbits. Tbis suggests that the extract acts by initiating the release of insulin from pancreatic fi* cells of normal rabbits. The dose used did not produce acute toxicity (Noreen et al., 19881. It was demonstrated that oral administration of the seeds to rats for 15 days caused a lowering of blood glucose accompanied by a significant increase in pancreatic cathepsin B activity. These effects were comparable to those of chloropropamide (Bansal et al., 1981).

Eugenda j~rnbo~~~ Lamk.; synonym: E. cumini Skeels, Syty g&m jambo~~um DC. (Myrtaeeae~

Seeds (India1

Aerial parts (India)

Oral administration of powdered plant (l-2 g/kg1 or the methanol extract (5 gl kg1 decreased the blood glucose level of normal rabbits but had no effect on alloxan.treated rabbits. This suggests that this plant acts probably by initiating the release of insulin from the pancreatic @ells of normal rabbits. Acute toxicity studies and records of behavioral patterns carried out in rabbits and rats respectively showed no adverse effects at the dosages tested (3-6 g/kg1 (Akhtar et al., 19841, A hypoglycemic effect was seen for the powdered plant (l-3 g/kg, p.o.1 in nor. ma1 rabbits. In alloxan-diabetic rabbits, the plant did not produce this effect, which suggests that it may act by stimulating pancreatic /l-cells in normal animals. The acute toxicity studies and behavioral pattern records indicate that the plant was quite safe at the dosages employed (3-6 g/kg1 since no visible signs of toxicity or adverse effects were observed 1Akhtar et al,, 19841. An aqueous extract (50 mgirat weighing 200-250 gl reduced blood glucose and insulin levels 10 min after oral glucose infusion and increased blood insulin without affecting blood glucose 30 and 60 min after oral giucose infusion. Glucose absorption from the small intestine was not inhibited by the water extract (200 Kg/ml). In addition, the water extract 150 m&at) inbibited the elevation of blood glucose indueed by intravenous infusion of adrenaline without elevating the blood insulin level. This extract inhibited adrenaline-induced lipolysis in rat adipoeytes while it failed to affect lipogenesis from glucose (Kimura et al., 19881.

Fumaria purvifolia Lamk. (Fumariaceael

Aerial parts (India)

Ganoderma lddum &en (Polyporaceae)

Kar-

Fungus (China, Japan1

Plant species (Family) Oral administration of the powdered leaves decreased blood glucose and increased the circulating insulin levels in alloxan diabetic rabbits and in a single maturity-onset diabetic patient. This effect was associated with a reduction in the serum lipid levels (Shanmugasundaram et al., 1981). Moreover, oral treatment of alloxan-diabetic rats for a period of two weeks with an aqueous extract corrected the hyperglycemia in moderately diabetic animals but did not reduce blood sugar levels in severe and toxic groups of diabetic rats; however, in these groups the drug prolonged their survival time (Srivastava et al., 1985, 19861. Rathi et al. (19811 demonstrated that the levels of some protein-bound polysaeeharides (hexuronic acid, hexoses, hexosam~nes, non~aminopolysaecharides and sialie acid) and some glyeosamino~lycans (hyaluronic acid and heparin sulfate) are increased in alloxan-induced diabetic rats. The deposition and accumulation of these macromolecules in tissues is related to the vascular complications of diabetes mellitus. These authors also showed that treatment of diabetic animals with a hydroalcoholic extra& of G. syluestre (200 mg/kg daily for a month) brought these elevated levels back to near normal values, Moreover, the levels of the 3ehondroitin sulfates and the sulfated to non-sulfated glycosaminoglycan ratio, which showed a decrease in diabetic animals, were restored to normal or near normal by Gymnema treatment (Rathi et al., 19811. When dried leaf powder of G. sylvestre (250 mg/kg for 12 or 24 weeks) was administered to alloxan diabetic rabbits, it not only produced a decrease in blood glucose levels, but also corrected certain metabolic disorders in liver, kidney and muscle of diabetic animals. In this way, the glyeogen and protein depletion and lipid accumulation in the diabetic animal were reversed by G. sylwestre treatment. The uptake and incorporation of f%]glucose into glycogen and protein were increased in the liver, kidney and muscle in diabetic animals given G. sylwestre and pathological changes initiated in the liver during the hyperglycemic phase appeared to be reversed when G. sylvestre was used to control hyperglycemia. Moreover, the activities of the insulin-dependent enzymes (hexokinase, glycogen synthetase, glyceraldehyde~3~phosphate dehydrogenase and glucose-g-phosphate dehydrogenasel that are lowered in the diabetic tissues, were increased by G. sylvestre administration while there was a decrease in the elevated activities of enzymes catalysing insulin-independent pathways (glycogen phosphorylase, gluconeogenic enzymes, glucose-@phosphatase, fructose 1-6 diphosphatase and sorbitol dehydrogenase) during the administration of the herb (Shanmugasundaram et al.,

Part used (country)

Data on action of extract

Gynmema sylvestre R. Br. (Asclepiadaceael

Leaves (India1

19831. More recently, it has been demonstrated that gymnemie acid, isolated from the leaves of G. s~lve~tTe (0.2 g/kg p.o.1 inhibited the sucrose-induced etevation of the blood glucose level in rats (Yoshioka et al., 19851. Gymnemie acid was found to be a complex mixture of at least nine closely-related acidic glyeosides (Sinsheimer et al., 1970; Sinsheimer and Rao, 19701. An ethanol extract (ZOO-400 mg/kgl produced a decrease in blood sugar levels in alloxan-treated mice but had no effect on normal animals. The extract had no apparent adverse toxic effects. Phytochemical analysis showed the presence of alkaloids, cardiac glycosides, flavonoids, sterols, volatile oil and bases, tannins, eoumarins and saponins (Ajabnoor et al., 1984al.

Hammado salicornica R, Br. Khenopodiaceae)

Whole plant (Saudi AraArabia)

Hedyotk biflora Roth. synonym: GIdenlandio

Whole plant (India1

corgmbosa

L.

(R~bia~eae~

A water extract showed a hypoglycemic effect in alloxan-dia~tic rabbits. On column chromatography, this extract gave a hypoglycemic fraction composed of 13 free amino acids, peptides or proteins, K, Na+ and Cl- (Dechatiwongse et al., 19831. Powdered seeds have hypoglycemic and hypocholesterolemic effects in diabetic and hypercholesterolemie rats. The seeds contain mimosine, a toxic amino acid (Singhal et al., 19821. An active fraction (4 mglkg p.o.1 exhibited a hypoglycemic effect on normal rabbits Kabo et al., 19831 and in glucose- or diazoxide-induced hyperglycemic rabbits but had no effect in alloxan- or streptozotoein-hyperglycemic rats, which suggests that the presenee of @pancreatic cells is required for activity (Cab0 et al., 19841.

Leucaena

leucocephulu

Seeds (India1

sic (Le~mino~e~

Lupine: albus L. (Leguminosael

Seeds (India)

Lythrum

oa&ati

L.

(Lythraeeael

Flowers, leaves and stems (Spain1

Several extracts of flowers, leaves and stem (10 g/kg p.o.1 possessed hypoglycemic activity in normal and in glucose-induced hyperglycemic rabbits; there was an increase in circulating insulin in normoglycemic rabbits. The root was inactive (Cadavid and Calleja, 19801. The ether extract was the most active extract and it caused a significant reductian in blood glucose in normal rats and a corresponding increase of circulating insulin; moreover, the ether extract (50 mglmll increased insulin secretion in isolated rat isfets of Langerhans (Lamela et al., 19851. Ether extract (10 g/kg, p.o.1 also exhibited hypoglycemic activity in rats with glucose- and epinephrine-induced hyperglycemia and in alloxan-diabetic mice. In alloxan- and streptozotocin-diabetic rats, the daily administration of this extract (10 g/kg/day for 8 days) induced a partial reversal of the diabetic-like

Plant species (Family) state. Moreover, both stem and flower extracts reduced the elevated r-glutamyl transpeptidase activity induced by streptozotocin in rats while the stem extracts reduced the elevated lactic dehydrogenase activity. The flower extract clearly accentuated the elevated levels of aspartate aminotransferase induced by streptozotocin (Lamela et al., 19861. On the other hand, the ether extract (10 g/kg, p.o.1 induced an enhancement of glycogen content in the liver but had no effect on muscular glycogen content and, in addition, the extract lowered serum levels of triglycerides while increasing free fatty acids levels. No effect on serum cholesterol levels was observed (Lamela et al., 19851.

Part used (country)

Data on action of extract

Momordica ~haran~~ L.

(Cucurbitaeeael

Fruits (Asia, Central and South America1

Aqueous extracts of M. charant& fruit reduced blood glucose levels in normal rats and improved glucose tolerance in rats (Leatherdale et al., 1981; Karunanayake et al., 19841. Powdered fruit (0.5-1,5 g/kg) produced a hypoglycemic effect in normal and alloxan-induced diabetic rabbits (Akhtar et al., 19811. An aqueous extract of cerasee, a wild variety of M. charuntia, improved glucose tolerance in normal mice and reduced hyperglycemia in streptozotoein-diabetic mice. This effect was not associated with increased circulating insulin, which suggests that cerasee may exert an extrapancreatic effect (Bailey et al., 19851. Moreover, oral administration of M. charantiu juice improved glucose tolerance in noninsulin dependent diabetics (Leatherdale et al., 1981; Welihinda et al., 19861. It was hypothesized that M. charuntia fruit contains more than one type of hypog lycemic component. These may include a principle called charantin, a homogeneous mixture of p-sitosterol fl+glueoside and 5,25-stigmatadien-3.~-ol-glucoside (Suerow, 19651 that can produce a hypoglycemic effect in normal rabbits (Lotlikar and Bajarama-Rao, 19663. There is evidence for the existence of insulin-like compounds. A peptide, polypeptide-p, has been isolated from fruit, seeds and tissue of M. ckaruntia and caused hypoglycemic effects when it was administered subcutaneously in patients with juvenile diabetes (Khanna et al., 19811. Other polypeptides decreasing blood sugar levels in normal and diabetic mice were also isolated from the fruit of M. churuntio (Lei et al., 19851. Moreover, different fractions (Ng et al., 1986bl and a galactose-binding lectin with a molecular weight of 124,000 (Ng et al., 1986al capable of antilipolytic and lipogenic aetivities in isolated rat adipocytes have been isolated from M. charantiu seeds. Although some authors have indicated that the effect of M. charantia is not associated with an increase in circulating insulin (Leatherdale et al., 1981; Bailey

et al., 19851, Welihinda et al. (19821 demonstrated that an aqueous extract from the fruit of M. c~uru~~~ was a potent stiiulator of insulin release from @-cellrich pancreatic islets isolated from obese-hyperglycemic mice. This action may involve interaction with the membrane lipids in a way which differs from the physiological activation of secretion. The insulin-releasing effect of M. chmantiu can not be attributed to eharantin. M, chaTant& seeds (l-3 glday per rabbit) induced a hypoglycemic effect and improved glucose tolerance in mildly streptozotocin-diabetic rabbits. This effect was associated with an increase in liver gly cogen and a decrease in elevated levels of serum cholesterol, free fatty acids and triglycerides. However, the seeds did not improve impaired renal function caused by streptozotocin, nor did they decrease the elevated levels of urea and serum ereatinine (Kedar and ~bakrabarti, 19821. M. c~a~a~~~ juice (1 ml/l00 gf stimulated glucose uptake by diaphragm tissue in vitro. Oral treatment with the juice prior to a glucose load was found to increase the glycogen content of liver and musde while it bad no effect on the triglyceride content of adipose tissue (Welihinda and ~runanayake, 19861. A hydroalcobolic extract (2 g/kg) inhibited the acute phase of hyperglycemia induced by streptozotocin when a single dose was given intragastrically to mice 30 min before streptozot~in. When Myrtus extract was given 48 h after streptozotocin, it reduced the hyperglycemia and this effect could be maintained by repeated administration. The extract had no effect on the blood glucose level of normal mice (Elfellah et al., 19841. An ethanolic extract (500 mg/kgl possessed hypoglycemic and alioxa~hy~ergly~emie mice (Gupta et al., 19841, activity both in normal

Myrtus commvnis L. (Myrtaceael

Leaves and branchlets (Libya1

N~u~~~ b&ata R. Br. (Composite)

Leaves (Central America)

Opuntia streptacantha Lemaire (~a~ceae~

Stems iMexico

Oral administration of sap (5 ml/kg) obtained from Opuntia stems produced hypoglycemic effects in normal dogs, in glucose-induced hyperglycemic rats and rabbits and in pan~eatec~mized rabbits (Ibaflez~~amacho and Oman-Ramos, 1979; Iba~ez-Camacho et al., 19831, but there was no effect in panereateetomized rabbits treated with alloxan. This indicates that in order to obtain the Opmtia hypoglycemic effect the presence of intact pancreatic tissue is required (IbanezCamacho et al., 19831. Moreover, complementary daily administration of Opuntiu sap to diabetic volunteers under chlorpropamide treatment improved the general symptomatology of the patients as well as their insulin and glucose blood levels (Meckes-Lozoya and Roman-Ramos, 19861. The hyperglycemic hormones, glucagon, cortisol and growth hormone appeared not to be involved in the

TABLE Data hypoglycemic effect of Opuntio. In an oral glucose tolerance test run on healthy volunteers, the levels of these hormones were not modified by Opuntia administration (Fernandez et al., 19841. More recently, it has been suggested that Opuntia probably acts by interfering with intestinal dextrose absorption because Opuntia intake in healthy volunteers (100 gl diminished blood glucose in an oral glucose tolerance test but had no effect in an intravenous glucose tolerance test and no effect on basal glucose levels (Frati-Murani et al., 1987). Japan and on action of extract

II (continued)

Plant

species

(Family)

Part

used (country)

Panax ginseng Mey.

(Araliaceael

Roots (China, Korea)

Different hypoglycemic and insulin-like principles have been isolated from the roots and include various glycans, designated panaxans A to P and ginsenoside Rb, (see Table 11. Some compounds are reported with antilipolytic activity: adenosine, a carboxilic acid and a peptide with a molecular weight of 1400 that can inhibit catecholamine-induced lipolysis in rat epididymal fat pads (Ng and Yeung, 19851. Finally, two fractions from water and methanolic extracts have been isolated from P. panax, DPG-3-2 and EPG-3-2, respectively, for which the chemical structures have yet to be determined but which possess hypoglycemic activity. A hypoglycemic component was partially purified from ginseng roots by various methods of fractionation based on an assay system to evaluate hypoglycemic effects in alloxan diabetic mice. Some ginseng fractions inhibited epinephrineinduced transient hyperglycemia in mice, increased glycogen content in rat liver, decreased the blood levels of acetone bodies in alloxan diabetic mice and inhibited the release of free fatty acids from rat epididymal fat pads (Kimura et al., 1981al. Kimura et al. (1981b) isolated two hypoglycemic fractions, DPG-3-2 and EPG-3-2, from P. ginseng and demonstrated that the hypoglycemic effect of EPG-3-2 on alloxan diabetic mice was abolished by i.v. injection of antisera against bovine insulin. This indicated a stimulatory action of the fraction on blood insulin levels. Moreover, the same dose of EPG-3-2 (lo-50 mglkgl increased blood insulin levels in alloxan diabetic mice and in normal mice loaded i.p. with glucose but had no effect in normal mice. On the other hand, DPG-3-2 (0.2 mglmll stimulated insulin release from perfused rat pancreas and enhanced glucose-stimulated insulin release from the pancreas of both normal and diabetic rats. This effect was also observed in the presence of cyclohexamide, which suggests that the insulin release from the pancreas induced by DPG-3-2 was independent of insulin biosynthesis. Waki et al. (1982) demonstrated that DPG-3-2

(0.2 mgimll increased incorporation of 14C-Ieucine into a protein fraction obtained by perfusing the pancreas of diabetic and normal rats. Glucose increased incorporation of 13HJleueine into insulin in islets from normoglycemic mice fKK1 and hyperglycemic mice &K-CAY) whereas DPG-3-2 had this effect ony in KK-CAY mice. In addition, long-term treatment with RPG-3-2 10.5 mg/mll stimulated insulin biosynthesis in islets from KK-CAY mice (Waki et al., 19821. Kimura and Suzuki 419811 analyzed the glucose tolerance curves of KK-CAY mice pharmacokinetically by the use of a mathematical model (Compartment-H model). The curves were classified into several patterns by analysis of the humping effect (the transient rise in blood glucose level after a precipitous fall). The humping effect was enhanced by those hypogIycemics which promote insulin secretion from pancreatic islets (sulfonylureas~ and was decreased by those hypoglycemics which promote glucose utilization in peripheral tissues Cbiguanides). It has been demonstrated that DPG3-2 inhibited the humping effect in a dose-dependent manner; this effect was clearly distin~ishabIe from that of tolbutamide. However, both DPG-3-2 and tolbutamide have an insulin-releasing effect in pancreatic islets. An aqueous extract lowered blood sugar leveis in normal and alloxan-diabetic rabbits (~amakrishnan et al., 19821. More reeently, two flavonoids isolated from the water-soluble fraction of the ethanol extract showed hypoglycemic activity in alloxan-treated albino rats when they were administered at a dose of 100 mg/ kg p.o., but had no effect in normal rats (Hukeri et al., 19881.

Phyllantus nkuri L.; synonym: P. xnk2a~ia Wall, (Euphorbiaceae}

Leaves (India)

P~~tago

~syllium L.

Mucilage (Mexico)

(~la~ta~na~eae~

Carranza et al. (19851 indicated that this plant can be useful trol of diabetic patients. Frati-Munari et al. (19851 suggested interferred with intestinal glucose absorption since mucilage gl mixed with glueose in healthy volunteers lowered glucose not OCCUF when the mucilage was given prior to glucose.

for metabolic eonthat the mucilage administration (10 levels, and this did

Poupartia birrea Aubr.;

Leaves (Africa1

synonym: Sc~Toear~o birrea Hoehst. (Ana~ardiaceae~

Oral administration of an aqueous or ethyl acetate extract ~250-1000 mg/kgl decreased the glucose levels in glucose-iudu~ed bypergly~emic rats; the aqueous extract was also effective in alloxan-diabetic rats but not in normoglycemie rats. The LD,, of aqueous extract was found to be 1.9 g/kg (i.p. in mice1 (Laurens et al., 19841. Moreover, in vitro studies with purified aldose-reductase (enzyme that converts glucose into sorbitoll showed that the aqueous and ethyl acetate extract exhibited enzyme- inhibiting activity with an IC,, (50% inhibitory concentration) of 1.35 rgiml and 0.81 pgiml, respectively. These results indicate that

TABLE II (continued1 Data on action of extract this plant has a possible antidiabetic effect in respect to cataract and post-diabetic neuropathies, since the accumulation of sorbitol is responsible, at least in part, for these diabetes complications (Laufens et al., 19851. Aeute i.p. treatment with I g/kg fruit juice produced a hypoglycemic effect in normal and alloxan-treated diabetic mice. Oral administration in maturity-onset diabetic and healthy volunteers also lowered blood glucose (Cheng and Yang, 19831. An ethanolic extract from leaves (200 mglkg, p.o.1 and a n-BuOH soluble extract prepared from an ethanolic extract 125 or 100 mglkgl were found to inhibit the increase in plasma glucose level in alloxan-induced diabetic rats and also improve glucose tolerance in diabetic rats. The ethanbolic extract, the n-BuOHsoluble fraction and water-soluble fraction were found to suppress adrenalineinduced lipolysis in fat cells from rat epididymal adipose tissues (Maruyama et al., 19851. Oral administration of an infusion and an ethyl ether fraction (5 g/kg! exhibited kypogly~emic activity in n~~o~ly~ernie and in glucose-indu&ed kyper~ly~emic rabbits. In alloxan-diabetic rabbits, the daily administration of 5 g/kg of the infusion resulted in a decrease in the blood glucose levels, Administration of the ethyl ether fraction produced an increase in circulating insulin in normoglycem~c animals. This suggests that the hypoglycemic activity may be due to in part to stimulation of insulin secretion from islets of Langerhans (Alonso et al., 19801. An infusion and a suspension (0.25 g/kg p.o.1 showed hypoglycemic effects in nor moglycemic rabbits whereas no change was seen in insulin levels. In alloxan-diabetic rabbits, daily administration of 0.25 g/kg of infusion decreased blood glucose levels. Absorption of glucose by the intestine may be a significant factor since there was an hypoglycemic effect in glucose-induced hyperglycemic rabbits when the plant infusion was administered simultaneously with glucose but this effect was not observed wken tke plant infusion was administered 60 min before glucose (Jimenez et al., 19361. E

Plant species (Family1

Part used (country)

Psidhn gaajava L. (~yrta~eae~

Fruits (China1

Leaves (Japan1

Leaves (Spain1

Salvia lavandulifolia Vahl. (Labiataef

Aerial parts (Spain)

TABLE II (continued1 Data on action of extract

Plant species (Family)

Part used (country)

Trigosellu foenum cum IA.

grae-

Seeds (Israel)

(Leguminosael

Hypoglycemic activity has been reported in the review of Oliver Bever and Zahnd (19791. Sham et al. (19741 reported that ~~~go~e~~ seeds and the major alkaloid component, trigonelline, exerted a mild hypoglycemic effect; other eomponents, nicotinie acid and eoumarin, displayed a more profound but shorter hypoglycemic activity in alloxan-diabetic rats. More recently it has been demonstrated that the antidiabetic action of Xrigonella can be associated with the defatted seed material which contains fibers, saponins, and proteins (Ribes et al., 1984; Valette et al., 19841 and more specifically with subfraction a which contains the testa and endosperm and is rich in fibers (Ribes et al., 19861. The defatted fraction caused a decrease in hyperglycemia and hypoeholesterolemia in alloxan-diabetic dogs while the lipid extract proved to be ineffective (Ribes et al., 1984); Valette et al., 19841. Chronic administration of subfraction a (mixed with two daily meals, in addition to insulin treatment for a period of 21 days) in alloxan-diabetic dogs resulted in a decrease of hyperglycemia and glyeosuria accompanied by a reduction of the high plasma glucagon and somatostatin levels in diabetic dogs; there was also a decrease in the hyperglycemic response to oral glucose tolerance. In contrast, chronic administration of subfraction b, which contains the cotyledons and axes and is rich in saponins and proteins, had no effect on hyperglycemia or on the levels of pancreatic hormones in diabetic dogs (Ribes et al., 1986). Amin Riyad et al. (19881 demonstrated that treatment of streptozotocin diabetic rats with diets containing 20% fenugreek seeds for a period of 10 weeks did not improve the diabetic state: on the other hand, diabetic animals pretreated for 5 weeks with fenugreek and followed by 6 weeks of feeding with the same diet, showed a general improvement in their clinical status in that hyperglycemia, free fatty acids, cholesterol and triglyceride levels were reduced.

267

Our report covers the literature published during the last ten-year period (1979-19881 because there is an earlier review that Covers the literature up to 1978 (Oliver Bever and Zahnd, 19791. The present information has been organized in two different ways. The first classifies according to general chemical structure those hypoglycemic natural products which have been isolated from plants (Table 11. The second approach is devoted to those plants whose hypoglycemic action has been studied experimentally but whose active principles have not yet been isolated. We have listed these different plants alphabetically according to their botanical genus (Table 21. In both instances we give information about the pharmacological data, mechanisms of action, toxicity and other properties. Discussion Since ancient times, plants have been used in the treatment of diabetes mellitus. In the present work we describe the plants whose activities have been studied in the 1979-1988 decade. In general, we can say that there are a great many hypoglycemic plants and the chemical structure of their active principles varies widely. Therefore, there must also be considerable diversity in the mechanisms of action. Some act by in&easing the release of insulin and require a minimum of fi-cells to exert their action. Other plant extracts or constituents act by modifying glucose metabolism and finally there are some that appear to correct the complications of diabetes. All are important since they potentially can be used to treat the different aspects of diabetes mellitus. They are a fertile source for new hypoglycemic agents. For the study of antidiabetic plants, we consider glucose-induced hyperglycemic rats and streptozotocin-induced diabetic rats as good preliminary models for hypoglycemic screening. It is important to do a toxicity study because, as is known, hepatotoxic agents can influence the activity of certain hepatie enzymes involved in gluconeogenesis. This can lead to a reduction in the amount of glucose that reaches the blood resulting in false-positive results. As is the case with any ethnopharma~ologi~ study, careful collection of plant material and proper identification/verification is of primary importance. References
Abd-EbWahab, SM., Wassel, G.M., Ammar, N.M. and Hanna. T. (19871 Flavonoid constituents in the different organs of selected Bauhiniu species and their effect on blood glucose. Herba Hungatica 26, 27 - 40. Ajabnoor, M.A., Al-Yahya, M.A., Tariq, M. and Jayyab, A.A. (1984a) Antidiabetic activity of Hammada salicomia Fitoterapda 55, 107 - 109. Ajabnoor, M.A., Al-Yahaya, M.A., Tariq, M. and Jayyab, A.A. (1984b) Antidiabetic activity of Teuc~~rn ol~~e~~~rn. F~to~era~~ 55, 227 - 230. Akhtar, M.S. and Ali, M.R. (1985) Study of hypo~l~caemic activity of ~~rn~~urn n~gr~rn seeds in normal and alloxan diabetic rabbits. Planta Medica 51, 81-85.

268 Akhtar, M.S., Athar, M.A. and Yaqub, M. (19811 Effect of ~orno~d~ca cha~unt~u on blood glucose levef of normal and alloxan~iabetic rabbits. Pfanta Medica 42, 205-212. Akhtar, M.S., Khan, Q.M. and Khaliq, T. (1984) Effects of ~~~~orb~ ~0s~~~~~ and &mar&z mzruiforu in normogiycaemic and alloxan-treated hyperglycaemic rabbits. Planta Medicu 50, 138- 142. Akubue, P.I. and Mittal, G.C. (1982) Clinical evaluation of a traditional herbal practice in Nigeria. Journal of Ethnopharmacology 6.355-359. Al-Awadi, P.M., Khattar, M.A. and Gumaa, K.A. (19851 On the mechanism of the hypoglycaemie effect of a plant extract. Diobetologiu 28, 432-434. Alonso, R., Cadavid, I. and Calleja, J.M. (19801 A preliminary study of hypoglycemic activity of
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Al-Waili N.S.D. (19861 Treatment of diabetes mellitus by Artemisia herba-ulba extract: Preliminary study. C&&al and Experimental Pharmacology and Physiology 13,569-573. Ambike, S.H. and Rajarama-Rao, M.R. 09671 Studies on a phytosterolin from the bark of Ficus religiosa The Indian Journal of Pharmacy 29,91-94. Amin Riyad, M., AbduI~Ghani, Abdui-Salam, S. and Suleiman ~ohammad, S. 11988) Effeet of fenugreek and Lupine seeds on the development of experimental diabetes in rats. Planta Medica 54,286 - 290. Azad Khan, A.K., Akhtar, S. and Mahtab, H. (1980) Treatment of diabetes mellitus with Coccidiu
indict British Medical Journal 280, 1044.

Bailey, C.J., Turner, S.L., Jakeman, K.J. and Hayes, W.A. (1984) Effect of Coprinus corn&us on plasma glucose concentrations in mice. Planta Medica 50, 525- 526. Bailey, C.J., Day, C., Turner, S.L. and Leatherdale, B.A. (19851 Cerasee, a traditional treatment for diabetes studies in normal and streptozotocin diabetic mice. Diabetes Research 2,81-84. Bansal, R., Ahmad, N. and Kidwai, J.R. (19811 Effects of oral administration of Eugenio jumbolana seeds and chlorpropamide on blood glucose level of pancreatic cathepsin B in rat. Zndmn
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Boyadzhieva, N. (19811 Study of the effect of lepidine on the course of a mild chronic form of alloxan-diabetes. Part II. Problemi na VTreshtnata Meditsina 9, 130-139. Chemical Abstracts 98, 83431~ (19831. Boyadzhieva, N. (1982al Study of the effect of lepidine on the chronic form of experimental alloxan diabetes in rats. Fcwmatsiyu (Sofia) 32, 43-49. Chemical Abstracts 98, 191565~ (1983). Boyadzhieva, N. (1982bl Study on the influence of the plant Lepidium ruderale L. on the course of experimental sugar diabetes with absolute insulin insufficiency. Problemi na %Treshtnatu ~ed~ts~na 10, 125-130. Chemical Abstracts 98, 209841t (19831. Briani, G., Bruttomesso, D., Bilardo, G., Vitale, E., Zolli, M., Crecca, R., Valerio, A., Duner, E., Marescotti, C., Tiengo, A, and Crepaldi, G. (19851 Mediterranean diet and guar gum: Advantages for diabetic patients?. Giornali della Arteriosclerosi 10, 187- 196. Cabo, J., Jimenez, J., Miro, M., Riseo, S. and Zarzuelo, A. (19831 Etudes sur Iaction hypogly~~m. iante des graines du lupin ~~~~n~s albus L.1. VIII: Stabilite de laetion hy~glyc~miante de la fraction active. Plantes rn~d~~ina~s et phytoth~rupie 17, 182- 188. Cabo, J., Jimenez, J., Miro, M., Riseo, S. and Zarzuelo, A. (19831 Etudes sur laction hypoglycemgraines du lupin cl;upinus albus L.1. IX: Action hypoglyckmiante de la fraction active. Plantes medicinales et phytothkrapie 23, 237-242. Cadavid, I. and Calleja, J. (19801 A preliminary study of hypoglycemic acivity of Lythrum salicaria Journal of Natural Products 43,559563.

Carranza, M.A., Guillen, M.A. and Rodriguez, J. (1985) Psyllium plantago in diabetic patient management. Compendium de Zn~est~g~iones Clinicas Latinoamerica~s 5,20-32. Chakravarthy, B.K., Gupta, S., Gambhir, S.S. and Gode, K.D. (1981al The prophylactic action of
( - f-epicatechin against alloxan-induced diabetes in rats .I@ Sciences 29, 2043 - 2047. Chakravarthy, ELK., Gupta, S., Gambhir, S.S. and Gode, K.D. (198ib) Pancreatic beta-cell eration in rats by ( - t-epicatechin. The Lancet 2, 759-760. regen-

269

Chakravarthy, B.K., Gupta, S., Gambhir, SS. and Gode, K.D. (1981c) Epicatechin, a novel antidiabetic drug. Iadian Drugs 18,184- 185. Chemical Abstracts 95,90973h (1981). Chakravarthy, B.K., Gupta, S. and Gode, K.D. (19821 Functiou~ beta ceil regeneration in the islets of pancreas in alloxan induced diabetic rats by ( - I-epieateehin. Life Stiences 31,2693-2697. Chen, Q.M. and Xie M.-Z. (1986) Studies on the hypoglycemic effect of Coptis chinensis and berberine. Acta Pharmaceutics Sinica 21, 401-406. Biological Abstracts 33, 68309 (1987). Cheng, J.T. and Yang, R.S. (19831 Hypoglycemic effect of guava juice in mice and human subjects. American Journal of Chinese Medicine 11, 74-76. 3iolog~al Abstracts 77, 94056
09841.

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of Ga~o~e~a

~~c~~urn on

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