Antidiabetic effect of compounds isolated from plants

Phytomedicine, Vol. 5(1), pp . 55 -75 © Gustav Fischer Verlag 1998

_

REVIEW

Antidiabetic effect of compounds isolated from plants R. M . Perez

c.', M.

A. Zavala 5.2 , S. Perez G. 2 , C. Perez G.2

lLab oratorio de Invesrigacion de Productos N atura les. Escuela Superior de Ingenieria Qu imica e Ind ustr ias Extractivas lPN . Punt o Fijo 16 Col. Torre s Lindavista CP 07050. Mexic o D.E 2Departamento de Sistemas Biologicos Universidad Autonoma Metrop olitana-Xochimilco. A.P. 23181 Mex ico D.E

Summary This review shows some of the compounds isolated and identified from the plants that previously demostrated a hypoglycemic effect. These compounds have been classified in appropiate chemical groups and data are reported on their pharmacological activity, mechanism of action, and other properties. This paper reviews mucilages, glycans, proteins, pectins , flavonoids, steroids and triterpenoids, alkaloids, other nitrogen compounds and miscellaneous sub stance s with hypoglycemic effect. Key words: Hypoglycemic compounds, plants, chemical structures, mucilages, glycans, proteins, pectins, f1 avonoids, stero ids, tr iterp enoids, alkaloid s and other nitr ogen compounds.

Introduction The term diabetes mellitu s (DM) comes from Greek words for "flo w" and " honey" and refers to the excess urinar y flow that occur s when diab etes is untreated and to the sugar in that urine; the disease can be defined as a syndrome characterized by a state of chronic hypergl ycemia. DM and its complications (myocardial infarct, cardiovascular disord ers and terminal nephritis) are the fourth most imp ort ant causes of mortality an d the principal cau se of irreversi ble blindnes s. The incidence of this disease is found in 6% of world popupulation (De la Fuente, 1995 ). Diabet es treatm ent has been restr icted to diets, the use of insulin or oral hypoglycemic dru gs (sulfonyl ureas an d biguanides). Treatm ent with these agents is successful in some cases, but the mortality index due to this sickness keeps increasing. Th e lack of effective drug s and tre atments for DM makes this disease a major health problem around the worl d. The plants used in folk medicine to tr eat diabetes represent a viable altern ati ve for the control of this disease. Plants have been used to treat non insulin depend ent diabete s since ancient times. Th e Ebers pap yrus in Egypt in 1550 B.c. recommended a high fiber diet and th e plant M omordica cbarantia (Akhtar, 1982). Nu-

merous investigato rs have take n great interest in plants as possible sources for new hypoglycemic agents and many plants have already been screened. Today, mor e than 800 plants ha ve been identified as potential tre atments for DM but only a few of them have been evaluated medically and scientifically to determine their effectiveness (Bailey et al., 1989; Ivorra et al., 1989; Alarcon et al., 1993; Perez et al., 1984 ). The plants that have been studied can be arr anged int o 2 categories accord ing to th e type of study performed. One is plants whose hypoglycemic effect has been demonstrated in different animal models but whose active principles have not been isolated and identified and the oth er is antidia betic plants (aproxi mately 100) from wh ich a potential hypoglycemic agent has been determined witho ut clinical evaluati on. Th e prin cipal chemical compounds that ha ve been isolated and identified are mainly glycans, proteins and mucilages. Other compounds identified ar e flavonoids, steroi ds, triterpenoids and alkaloids with hypoglycemic activity (see also recent review articles of Ma rles and Farns worth (1995) and Ramon and Lau (1996).

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R. M. Perez G. et al.

Table 1. Mucilages with hypoglycemic activity. Hypoglycemic Agent

Source

Plant part

Abelmoschus-mucilage G

Abelmoschus glutinotextilis Kagawa (Malvaceae)

Root

Abelmoschus-mucilage M

Abelmoschus manihot Medic (Malvaceae)

Root

Althaea-mucilage 0

Althaea officinalis L. (Malvaceae)

Root

Althaea-mucilage OL

Althaea officinalis L. (Malvaceae)

Leaf

Althaea-mucilage R

Althaea rosea Cavailles (Malvaceae)

Root

Bletilla-glucomannan

Bletilla striata Reich. (Archidaceae)

Tuber

Dioscorea-mucilage B

Dioscorea batatas Decaisne (Dioscoreaceae)

Rhizophor

Glucomannan-mucilage

Amorphophallus konjac (Araceae)

Tuber

Hibiscus-mucilage Mo

Hibiscus moscheuto L. (Malvaceae)

Root

Hibiscus-mucilage SL

Hibiscus syriacus L. (Malvaceae)

Leaf

Lilium-A-Glucomannan

Lilium auratum Lind\. (Liliaceae)

Bulb

Lilium-S-Glucomannan

Lilium speciosum Thunb (Liliaceae)

Bulb

Lilium-S-Glucomannan

Lilium maculatum Thunb. (Liliaceae)

Bulb

Lilium-J-Glucomannan

Lilium japonicum Thunb. (Liliaceae)

Bulb

Lycoris-R-Glucomannan

Lycoris radiata Herbert (Amarylidaceae)

Bulb

Lycoris-S-Glucomannan

Lycoris squamigera Maxim. (Amarilidaceae)

Bulb

N arcissus-T-Glucomannan

Narcissus tazettaL. (Amarantaceae)

Bulb

Okra-mucilage F and Okramucilage R

Abelmoschus esculentus Moench (Malvaceae)

Immature fruit and root

Paniculatan

Hydrangea paniculata Sieb. (Saxifragaceae)

Inner-bark

Plantago-mucilage A

Plantago asiatica L. (Plantaginaceae)

Seed

Properties

Twenty water-soluble mucilages obtained from plants in the Liliacea, Amaryllidaceae, Dioscoreaceae, Orchidaceae, Saxifragaceae, Malvaceae and Plantaginaceae families were tested for the hypoglycemic activity after administration to normal mice. Considerable activity was observed for most of the mucilages isolated from plants in the Malvaceae family. They have the repeating structure (1 ~ 4)-[O-~-(D-glucopy­ ranosyl uronic acid)-(l ~ 3)-O-a-(D-galactopyranosyluronic acid)-(l ~ 2)-O-a-L-rhamnopyranose in their main parts. The deacerylated product of Plantago-mucilages A, the main mucilage present in the seed of Plantago asiatica, also showed remarkable hypoglycemic activity (Tornoda et al., 1987).

Review : An ti diabetic effec t o f co m po unds iso la te d from plants

57

Table 2. Glycans and proteins with hypoglycemic activity. Hypoglycemic Agent

Source

Plant pa rt

Properties

Anemaran A, B, C, and 0

An emarrbena aspho deloides Bunge (Liliaceae)

Rhi zome

Th ese glycans have been assayed for hypo glycemic activity in normoglycemic and hyperglycemic mice. Anemara n A, B, C, and D induc ed significant decreases in glycemia levels in mice (Taka hashi et aI., 1985a).

Aconita n A, B, C, and 0

Aconitu m carmichaeli Deabux (Ranunculaceae)

Root

Th ese glycans aco nita ns A, B, C, and D exh ibited pronounced hypoglycemic effect in norm al mice. Th e main glycan, aconitan A, also exh ibited a blood sugar lowering actio n when administered i.p. to hyperglycemic mice with allox an-d iabetes (Konno et al.,1985a).

Arborans A and B

Aloe arborescens Mill. (Liliaceae )

Leaf

Aloe arborescens Mill leaf has been considered an effective antidiabetic agent for many years. A marked hypoglycemic effect was observed when blood glucose levels were measur ed in norm al and alloxan-diabetic mice treated with these glycans (Hikino et al., 1986a ).

Atractans A, B and C

Atractylo des japonica Koidzum i (Co mpositae)

Rhizome

Blood glucose levels of normal and alloxan -treated diabetic mice were determ ined after i.p. administration of various doses of the atractans A, Band C. From the data obta ined, it was concluded that th ese glycans produce a significant hypoglycemic effect in normal as well as in diabetic mice (Konno et aI., 1985b ).

Coixan s A, B, and C

Coix lachryma-jobi L. (Poaceae)

Seed

A water extract of the or ienta l crude dru g "y okuinin". (Coix lachrym a jobi) disclosed a marked hypoglycemic action when administered to mice. fractionati on activity led to isolatio n of three glycan s: coixan s A, B, and C. The se components elicited remarkable hypoglycemic effects in normal and hyperglycemic mice treated with alloxan. (Takahashi et al., 1986)

Dioscorans A, B, C, 0, E, and F

Di oscorea [aponica Thumb. (Dioscoreaceae)

Rhizophor

Aqueous methanol/wate r extracts of the oriental cru de drug "sanyaku" (D. japonica and D. batatas rhizophors) notably lowered blood glucose concentrations in mice. Activity-guided fractionation of the extract from D. japonica a fforded six glycans dioscora ns - A, B, C, D, E and F - which exhibited remark able hypoglycemic effects in norm al and alloxan -induced hyperglycemic mice (Hikino et al., 1986b).

Di oscorea batatas Dec. (Diosco reaceae)

Eleuth erans A, B, C, 0 , E, F and G

Eleuther ococcus senticosus M axim. (Araliaceae)

Fru it

Hypoglycemic activ ity was observed when the glycans eleurherans A, B, C, D and F were injected i.p. into normal mice. No activity was ob served with eleuthera n E (H ikino et aI., 1986c).

Ephedr an s A, B, C, D and E

Ephedra distachya L. (Ephedraceae)

Bark

Admin istration o f a aqueous meth anol/water extract of the orienta l crude dru g " mao" (Ep hedra distachya herbs ) ca used tran sient hyperglycemia followed by long last ing hypoglycemia in mice. Activity-guided fractio nation of th e extract led to isolation of five glycans-ephedrans, A, B, C, D and E which exh ibited significant hypoglycemic effect in normal and alloxan-induced hyperglycemic mice (Konno et aI., 1985c).

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Table 2. Glycans and proteins with hypoglycemic activity (continued) Hypoglycemic Agent

Source

Plant part

Properties

Ganoderan A, Band C

Ganaderma lucidum Karst. (Polyporaceae)

Fruit

The peptidoglycans ganoderan A, Band C with molecular weights of 2,300, 7,400 and 5,800, respectively elicited hypoglycemic effects in normo- and hyperglycemic mice (Hikino et al., 1985a). Ganoderan B contains D-glucopyranosyl ~-1 ~ 3 and ~­ 1 -4 6 linkages. Ganoderan C contains D-glucopyranosyl ~-1 ~ 3 and ~-1 ~ 6 linkages and a D-galactopyranosyl o-I ~ 6 linkage (Tomoda et al., 1986).

Heteroglycan-complexes

Chlorella vulgaris Chlorococcales (Chlorophyta)

Leaf

Peptidoglycans and RNA-peptidoglycans complexes isolated from C. vulgaris by column chromatography injected i.p. into mice lowered blood glucose levels. Alloxan induced diabetes by 25% 3 h after the administration of 100 mg/kg (Takahashi et al., 1989).

Moran A glycoprotein

Marus alba L. (Moraceae)

Root bark

An aqueous methanol extract of the oriental crude drug "sohakuhi", (the root barks of Morus alba) markedly reduced the plasma sugar level in mice. Activity-guided fractionation of the extract furnished a glycoprotein, moran A, which elicited remarkable hypoglycemic effects in normal and alloxan-induced hyperglycemic mice (Hikino et al., 1985b).

Lithospermans A, B, and C Lithospermum erytbrorhizon Sieb. (Boraginaceae)

Roots

A water extract of the oriental crude dru "shikon" Lithaspermum erythrorhizon roots, remarkably diminished the plasma sugar level in mice. Fractionation of the extract by monitoring the activity yielded three glycans: Lithospermans A, B, and C. These glycans exerted hypoglycemic effects in normal and alloxan-induced hyperglycemic mice (Konno et al., 1985d).

Oryzarans A, B, C, and D

Oryza sativa Bran. (Poaceae)

Seed

The crude drug "beithiko" (rice brain), the external seed coat of Oryza sativa L. has been used for the treatment of beriberi in oriental medicine. It is the famous source from which vitamin B] was first isolated. A water extract of rice bran prominently decreased the plasma level in mice. Fractionation of the extract by monitoring the activity furnished four glycans: oryzabrans, A, B, C, and D. These polysaccharides exerted marked hypoglycemic effects in normal and alloxan-induced hyperglycemic mice (Hikino et al., 1988).

Peptides

Centaurea aspera L. (Compositae)

Flower

The peptides were precipitated from aqueous extract of Centaurea aspera with an aqueous solution of (NH4hS04.Various fractions of peptides injected into rabbits showed blood sugar-lowering properties (Viguera and Casanueva 1965).

Review: Antidiabetic effect of compounds isolated from plants

59

Table 2. Glycans and proteins with hypoglycemic activity (continued) Hypoglycemic Agent

Source

Plant part

Properties

Pectin

Coccinia indica Wight. (Cucurbitaceae)

Fruit

The hypoglycemic effect of orally administered extracts of the fruit of Coccinia indica has been reported earlier. The oral administration of the pectin isolated from the fruit of this plant at doses of 200 mg/day produced significant hypoglycemic action in normal rats with a significant reduction in blood glucose and an increase in liver glycogen. The reduction may be due to decreased absorption of glucose from the intestine, higher rate of glycolysis as envisaged by the higher activity of hexokinase, one of the key enzymes of glycolysis, and enhanced rate of glycogenesis as evidenced by the higher amount of liver glycogen present in the pectin-administered groups. The increased activity of glycogen synthetase and higher incorporation of labelled glucose into liver glycogen in the pectin-administered group corroborate the enhanced rate of glycogen synthesis. A decreased activity of glycogen phosphorylase in the pectin-fed group revealed a decreased rate of glycogenolysis (Kumar et aI., 1993).

Pectin

Musa sapientum L. (Musaceae)

Flowers

The pectin isolated from the juice of the inflorescens talk of M. sapientum has been found to show hypoglycemic effects both in normoglycemic and alloxan diabetic. A dose of 20 mg increased the concentration of hepatic glycogen and glycogenesis as evidencea from the increased activity of glycogen synthetase and increased incorporation of labeled glucose into hepatic glycogen in normoglycemic rats (Gomathy et aI., 1990)

Peptidoglycans

Malva verticillata L. Emblic (Malvaceae)

Seeds

The peptidoglycan MVS-1 and MVS-IIA obtained from the seed of M. verticillata are composed of ~­ 1,3-linked-D-glucan and of a-1,5-linked L-arabino~-3,6-branched D-galactan; MYS-IIA is essentially a-1,5-linked Larabino-BvLc-branched D-galactan. Both glycans possess arabino-3,6-galactan moieties accompanying a-1,5-linked L-arabinopyranosyl ~­ 1,4-1inked-D-xylosyl, and a-1,4-linked D-galacturonic acid units. These compounds exhibited significant hypoglycemic effect in normal and alloxan-induced hyperglycemic mice (Masashi et aI., 1990).

Polypeptide

Panax ginseng Meyer (Araliaceae)

Root

Different hypoglycemic and insulin-like principles have been isolated from the roots including various glycans, designated as panaxans A to P and ginsenoside Rb 1 . Some compounds are reported with antilipolytic activity: adenosine, a carboxylic acid, a peptide with a molecular weight of 1,400 that can inhibit catecholamine-induced lipolysis in rat epididymal fat pads (Ng and Yeung 1985). Kimura et al. 1981 isolated two hypoglycemic fractions, DPG-3-2 and EPG-3-2, from P. ginseng and demonstrated an hypoglycemic effect of EPG-3-2 on alloxan diabetic mice (Wan et aI., 1991, Tomoda et aI., 1984).

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Table 2. Glycans and proteins with hypoglycemic activity (continued) Hypoglycemic Agent

Source

Plant part

Properties

Polypeptide

Cystoseira barbata P Cystoseiroceae (Rhodophyta)

Leaf

Two polypeptide fractions were isolated from C. barbata by gel filtration. One of these fractions had lipolytic effect, the other hypoglycemic effects. (Gueven et al., 1974).

Polypeptide p-insuline

Momordica charantia L. (Cucurbitaceae)

Fruit, seeds

A polypeptide p-insuline was isolated from the fruit, seeds and tissue of Momordica charantia (bitter gourd). Amino acid analysis indicated 166 residues composed of 17 amino acids with a molecular weight of 11,000. Methionine was the only additional amino acid of p-insuline not found in bovine insulin. However, inmunoassays did not indicate any cross-reaction between p-insuline and bovine insulin. In gerbils, langurs and humans with diabetes, pinsulin exhibited hypoglycemic activity after s.c. administration. In juvenile diabetic patients, the peak effect was observed within 4 - 8 h as compared with 2 h for bovine insulin (Pushpa et al., 1981) (see also review article of Raman and Lau (1996).

Proteins

Acacia milanoxylon Willd (Leguminosae) Bauhinia retusa L. (Leguminosae)

Seeds

The effect of protein, isolated from seeds A. milanoxylon and B. retusa was studied in normoglycemic and hyperglycemic rats. This principle lowered the fasting plasma glucose level in normoglycemic and hyperglycemic rats (Singh and Chandra, 1977).

Roots

The i.p. administration of quinquefolan A, B, and C to alloxan-induced hyperglycemic mice produced hypoglycemic effects (Oshima et al. 1987).

Quinquefolans A, B, and C Panax quinquefolium L. (Araliaceae) Saccharans A, B, C, D, E, and F

Saccharum officinarum L. (Poaceae)

Leaf

These compounds showed hypoglycemic and antiatherosclerotic activity in mice and rats (Takahashi et al., 1985b).

Trichosans A, B, C, D, and E

Trichosanthes kirilowii

Roots

The nondialyzable portion of the water extract of the oriental crude drug "Karokon" (the roots of Trichosanthes kirilowii) reduced the plasma glucose levels in mice. Activity-guided fractionation of this nondialyzable portion led to the isolation of 5 glycans: trichosans A, B, C, D and E that showed hypoglycemic activity in normal mice. Trichosan A, the main glycan also exhibited activity in alloxan-induced hyperglycemic mice (Hiroshi et aI., 1989).

Uncharacterized glycoside

Ficus bengalensis L. (Moraceae)

Leaf

This glycoside exhibited significant hypoglycemic activity in normoglycemic and hyperglycemic mice. (Brahmachari et al., 1964).

Review: Ant idiabetic effect of compounds isolated from plants

61

Tabl e 3. Plant flavonoids with hypoglycemic activity. Hypoglycemic Agent

Source

Plant part

Properti es

Pterocarpus

Bark

H°'rAfr'rt)r'''"

marsupium Roxb .

Extr acts of P. m arsup iu m have been reported to be pot entially useful as hypoglycemic agents in the tr eatment of OM. Recentl y it has been reported th at the active hypoglycemic principal o f the brk is (-)epicatechin (Sheeha n and Zemaitis 1983). Furthermore it has been reported that the hypoglycemic effect of th is compo und is due to regener at ion of f3 cells in the pancreat ic islets of alloxan diab etic rats (Hii and Howell 1984, Cha krav art hy et al., 1981, Kolbet et al., 198 2 ).

Leaf

The effects of some f1 avon oides, one of which has been claimed to po ssess antidia betic activities on insuline release and 45Ca 2• handl ing, have been studied in isolated rat islets of Langerh ans. Insulin release was enhanced by approximat ely 44 - 4 7% when islets were exposed to q uercetin, na ringenin and chrysin. Th e qu ercet in inhibited 45Ca2• efflux in the presence an d a bsence of extrace llular Ca >2. The se results suggest th at stimulatory co mpounds such as quercetin may, at least in part, exert their effects on insulin release via changes in Ca· 2 metabolism (Hi i and Howell 1985 ).

Bark

Th e f1a vonoids kaemp ferol-3-0-rhamnoside, quercetin-3-0-rhamnoside and myricetin-3-0-rhamn oside isolat ed from Z, rugosa prod uced hypoglycemia in rabbits (Khosa et aI., 1983).

~~OH

(Leguminosa e)

OH

(-)-Epicatechin

HOVXfYOH o )VJ OH OH

Baubinia purpurea L. (Leguminosae)

o

Quercet in

HW~~H OH

?=t~ Me

HO

Kaempferol-J-o-rharnnoside

HO~~,.&H ~>--<:

HO

O~OH

Me

Q uercetin-S-o-rh amnoside

Zizipbus rugosa Lam . (Ramnaceae)

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R. M. Perez G. et al.

Table 3. Plants flavonoids with hypoglycemic activity (continued) Hypoglycemic Agent

©' OH

OH

,0

.'

Source

Plant part

Properties

Garcinia kola Hook F. (Gutiferae)

Leaf

Blood glucose level in normal and alloxan-treated diabetic mice were measured after oral administration of various doses of the kolaflavonone. From the data obtained, it is concluded that this compound produces a significant hypoglycemic effect in normal and alloxan-induced diabetes mice (Coterill et al., 1976).

Swertia chirayita Roxb. (Gentianaceae)

Leaf

A xanthone was isolated from the hexane fraction of S. chirayita and identified as 1,8-dihydroxy-3,Sdimethoxyxanthone (swerchirin). It has a very significant blood sugar lowering effect in fasted, fed, glucose loaded, and tolbutamide pretreated albino rat models (Mukherjee and Mukherjee, 1987).

Swertia

Leaf

Hypogycemic activity-guided fractionation led to the isolation of known xanthones bellidifolin, methylbellidifolin, swertianin and methylswertianin of S. [aponica; and their identification was based on spectroscopic methods. Bellidifolin and methylbellidifolin showed a potent and dose-dependent hypoglycemic activity in streptozotocin (STZ) induced diabetic rats after both i.p. and p.o. administration but methylswertianin and swertianin did not show any activity (Basnet et al. 1994).

Leaf

The leaf of F. bengalensis is used in traditional medicine for the management of diabetes mellitus. Leucocyanidin has been shown to have a hypoglycemic effect in fasted normal rats, it has also been shown to check hyperglycemia induced by the effects of alloxan (Brahmachari et al., 1964).

Kolaflavanone OCH3

Swerchirin OCH3

japonica Makino (Gentianaceae)

Bellidifolin

OH

HO

OH Leucocyanidin

OH

OH

Ficus bengalensis L. (Moraceae)

Review: Antidiabetic effect of compounds isolated from plants

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Table 4. Steroids and triterpenoids. Hypoglycemic Agent

Source

Plant part

Properties

Phyllanthus emblica H. B. K. (Euphorbiaceae)

leaf

Hypoglycemic effects were seen in normal mice. A reduced blood glucose level was also observed when fagasterol was injected i.p. to alloxan-induced hyperglycemic mice (Cuellar et al., 1980).

Gymnema sylvestre R. Br. (Asclepiadaceae)

Leaf

A mixture of triterpenoid saponins extracted from the leaves of Gymnema sylvestre has been known not only to suppress selectively the sweet taste sensation in man, but also to inhibit the glucose absorption in the rat small intestine, leading to a reduction in plasma glucose in the oral glucose tolerance test (Shigemasa, 1992). Serum enzymes and histological observations suggested reduced tissue damage in diabetic animals. Glycogenesis and protein anabolism were improved and the activity of insulin-dependent enzymes such as hexokinase and glycogen synthase was increased (Shanmugasundaram et aI., 1983).

Coffea arabica L. (Rubiaceae)

Green beans

The ~-sitosterol exhibited significant hypoglycemic activity in normal and hyperglycemic mich (Sampaio et aI., 1979).

Phoenix dactylifera L. (Palmaceae)

leaf

Lupeol acetate showed hypoglycemic activity in rabbits (Harborne and Baxter, 1993).

Momordica cochinchinensis Sprengel (Cucurbitaceae)

Seeds

Oleanolic acid and ursolic acid, isolated together from C. officinalis, decreased the amount of water consumption and urine volume in diabetic rats (Reza-ul-jalil et aI., 1986).

HO

Fagasterol

Gymnemic acid

~-Sitosterol

O~

c-o

cHI

.

HO ·CH3

Lupeol acetate

HO

Oleanolic acid

Comus officinalis Sieb. (Cornaceae)

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R. M. Perez G. et al.

Table 4. Steroids and triterpenoids (continued) Hypoglycemic Agent

Source

Plant part

Properties

Bumelia sartorum L. (Sapotaceae)

Root Bark

Sapogenol elicited a hypoglycemic effect in normal and alloxan induced hyperglycemic mice (Nobrega et aI., 1985).

Poterium ancistroides Desf. (Rosaceae)

Leaf

The hypoglycemic activity of torementic acid was determined in norrnoglycemic (Villar et aI., 1986), hyperglycemic and streptozotocin diabetic rats. This principle lowered the fasting plasma glucose level with a corresponding increase in circulating insulin levels. Mereover, it improved the glucose tolerance test by increasing insulin secretory response to glucose. However, tormentic acid did not change the insulin and glucose levels in streptozotocin induced diabetic rats. All effects have been compared with that of glibenclamide. These results suggest that tormentic acid, like glibenclamide, may act by increasing insulin secretion from islets of Langerhans (Ivorra et aI., 1988.

Stevia rebaudiana L. (Compositae)

Leaf

A new sweetening glucoside saccharol isolated from S. rebaudiana and having sweetness exceeding sucrose sweetness by 300-fold was evaluated in experiments on rats. When given at the level adequate to equal sucrose for ~ 10 mo, saccharol did not significantly affect the metabolic indexes and morphological features of internal organs. At the level of 50-fold sucrose sweetness, saccharolinhibited oxidative phosphorylation in hepatic tissues. (Smolyar et aI., 1992)

Eriobotrya japonica Linde (Rosaceae)

Leaf

The effect of the polyhydroxylated triterpenoids isolated from Eriobotrya [aponica by MeOH extraction were studied in genetically diabetic mice and norrnoglycemic rats. They produced a marked inhibition of glycosuria and reduced blood glucose levels in normogycemic rats (Tommasi et aI., 1991).

Tormentic acid

Saccharol

,

~H,

HO CH,

HO

'oH

~H,

Polyhydroxylated triterpenoids

Review: Antidiabetic effect of compounds isolated from plants

65

Table 4. Steroids and triterpenoids (continued) Hypoglycemic Agent

Source

Plant part

Properties

Xanthium strumarium L. (Compositae)

Leaf

Glycoside

A glycoside from Xanthium strumarium had hypoglycemic activity at a dose of 1- 5 mg/kg i.v. in laboratory animals (Ogzewalla et al., 1974).

Panax Ginseng Meyer (Araliaceae)

Leaf

Ginseng saponins had a hypoglycemic action in rats with streptozotocin-induced diabetes. Studies on some enzymes in vitro could not explain this effect (Chung and Joo et al., 1992).

Comus officinalis Sieb, (Cornaceae)

Seeds

Ursolic acid produced hypoglycemic activity in rats with diabetes induced by STZ (Yamahara et al., 1981).

Momordica charantia L. (Cucurbitaceae)

Fruit

A wide range of compounds have been isolated from M. charantia (karela) fruit, seeds and vines: saponins (sitosterol and stigmastadienol glucosides), proteins (p-insulin), steroidal glycosides (momordicines and momordicosides) and pyrimidine nucleoside (vicine) (Raman and Lau, 1996). Sitosterol and stigmastadienol glucosides when administered i.p. to normal rabbits produced a gradual but significant fall in blood sugar. Pancreatectomy was found to reduce but not abolish the hypoglycemic effect of charantin (mixture of sitosterol and stigmastadienol glucosides) (Lotlikar and Rajarama, 1966).

HO

A-0r:~,>-

OHCH,? H6)-Y CH,OH OH OH Ginsenoside Rg2

HO

Ursolic acid

Sitosterol- D-glucoside

5,25 -Stigmastadienol-glucoside

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R. M. Perez G. et al.

Table 5. Alkaloids and other nitrogen compounds. Hypoglycemic Agent

Source

Plant part

Properties

HO~OH

Momordica charantia Linn (Cucurbitaceae)

Fruit

The pyrimidine nucleoside vicine has been isolated from the seeds of kare1a. l.p, administration caused a hypoglycemic response in normal fasting albino rats. Note: M. charantia shows toxicity in animals to the liver and reproductive system (Raman and Lau, 1996).

Tecoma stans H.B.K. (Bignonaceae)

Leaf

A decoction has been thoroughly used to treat DM since pre-Colombian times in Mexico. Administration of tecomine to normal and alloxan-induced hyperglycemic mice caused reduction in the blood glucose. The traditional use of leaves from T. stans for the treatment of diabetes has been supported by the isolation of two hypoglycemic substances: tecomanine and tecostanine. Tecomine showed hypoglycemic activity in fasting rabbits at 20 mg/kg i.p. and 50 mg/kg oral administration. Tecomine showed poor stability and was required in sufficiently large doses to question their clinical potential. (Hammouda and Amer,1966).

HO

0

HO

H

~"' NH2

Vicine

Tecomine

HO~20H

HO

HO

Tecostanine

O~NH2

a--y NH,

Catbarantbus roseus [L.] G. Don.

(Apocynaceae)

Catharantbus roseus is a wild shrub know for its antidiabetic activity and a source of indole alkaloids used in the treatment of cancer and hypertension (Ban et al., 1988). Hypoglycemic activity was observed for catharanthine, leurosine, lochnerine, tetrahydroalstonine, vindoline and vindolinine. Administered orally in a dose of 100 mg/kg, leurosine sulfate and vindolinine hydrochloride were more hypoglycemic than tolbutamide (Maries and Farnsworth, 1995).

OlgO

Vindoline

Catharanthine

Lochnerine

Leurosine

CH2CH 3

Tetrahydroalstonine

Vindolinine

"'11

a-J3 00c

Vincamine

(-) Eburnamonine

Review: Antidiabetic effect of compounds isolated from plants

67

Table 5. Alkaloids and other nitrogen compounds (continued) Hypoglycemic Agent

Source

Plant part

Properties

Papaver somnirerum L. (Papaveraceae)

Fruit

The hypoglycemic effect of morphine (40 mg) injected intrathecally was studied and compared with the effects of other hypoglycemic agents. The hypoglycemic effects of both morphine and insulin appear to be due largely to an increased glucose uptake by muscle (White et aI., 1993). The papaverine is an phosphodiesterase inhibitor which increases intracellular cAMP by preventing its breakdown (Hill et al., 1987).

Morphine CH,O

CH,O OCH,

Papaverine

OCH,

OH Me

~COOH

Dioscorea dumetorum Tubers Pax (Dioscoreaceae)

Dioscoretine

OH

Dioscoretine, the hypoglycemic principle of D. dumetorum, was isolated by bioassay-guided fractionation of the methanolic extract of the tuber of D. dumetorum when administered intra-peritoneally to normal and alloxan diabetic rabbits. Dioscoretine produces hypoglycemic effects at a dose of 20 mg/kg (lwu et aI., 1990).

Decodon verticillatus L. Elliot (Erytraceae)

Leaf

Administration of cryogenine to normal and alloxan-induced hyperglycemic mice caused a reduction in the blood glucose. This compound also has antiinflammatory, sedative and hypotensive activities (Ferris, 1962).

Galega officinalis L. (Leguminosae)

Seeds

The hypoglycemic effect of galegine (30 mg/kg) in alloxan-diabetic rats has been demonstrated. The oral LDso of galegine sulfate in mice was 0.122 g/kg (Petricic and Kolodzera, 1982).

Lepidius ruderale L. (Cruciferae)

Leaf

Lepidine showed hypoglycemic effects in mice and rabbits with mild alloxan-induced chronic diabetes. It decreased glucosuria, polydipsia and increased glycogen in the liver (Boyadzhiera, 1982).

OCH 3

Cryogenine

Galegine

©Q

Lepidine

CH 3

N00~

HN 2

Lathyrine

t-1-12

Lathyrus [aponica Sic. Seeds (Leguminosae)

Lathyrus japonica seeds have been considered an effective antidiabetic agent for many years. Blood glucose levels in normal and alloxan-diabetic mice treated with Larhyrine and y-L-glutamyl-L-lathyrine showed marked hypoglycemic activity (Mitsubishi 1982).

68

R. M. Perez G. et al.

Table 5. Alkaloids and other nitrogen com pounds (continued) Hypoglycemic Agent

Source

Plant part

Properties

r0'~

Capsicum annuum L. (Solanaceae)

Fruit

Capsaicin inhibited intestinal glucose transport in both rats and the hamsters. Thi s effect may be due in part to a greater metab olic breakd own of glucose into lactic acid or to a seconda ry inhibitory effect on th e ATPase-dependent sodium pump (Monsereenusorn, 1980 ).

Coptis chinensis Fanch Leaf (Ran unculaceae)

Berberine, the major component of th is plant, had a hypoglycemic effect in norm al, alloxa n-diabetic and spo ntaneously diabetic KK mice. Berberin also antagonized the hypoglycemic effect induced by i.p. injection of glucose or adrenaline in normal mice. It decreased the serum cholestero l level of mice fed a high-cholesterol diet and inhibited the aggregat ion of rabbit platelets in vitro (Q irning an M ingzhi, 1986, Berberine Chen and Xie, 1986).

Kitasatoa griseophaeus P

Leaf

Two constituents have been isolated fro m the new species of Kitasatoa griseophaeus and ident ified as quin oline-2-m ethanol and qu inoline-2-methanol aceta te. Th e first exhibits hypoglycemic activity in rat s (Satoshi et aI., 1976).

Allium cepa L. (Liliaceae)

Bulb

Onions bulbs have long been used as dietary supple ment s for the trad itional treatment of diabetes in Asia, Europe, and the Middle East (Day 1984). Onion has been reported to lower free fatty acid co ncentrations in health y subjects (Augusti and Benaim 1975 ). Diph enylamine showed hypoglycemic effect at a dose of 10 mg/kg in hyperglycemic rabb its. It was a more potent hypoglycemic agent than tolbutamide (Karawya et aI., 1984). In an in vitro study Smethylmeth ionine (SMC S) showe d an insulin secretagogue effect on the ~-cells of the pancreas in modera tely diabeti c rats. In addition, the antioxidant properties of a sulphoxide group and a possible lipotropic effect of a lab ile meth yl gro up present in SMCS might also be involved in the antidiabetic effect (Kumari and Augusti 1995). Allyl propyl disulfide and diallyl oxide (Allicin) active in normal and alloxa n-diabetic ani mals and patient s with N IDDM, are believed to act by competing with insulin (Ma ries and Farnsworth, 1995 ).

Tinospora cordifolia Mier s (Menispermaceae)

Leaf

Th e 1,2-sub stituted pyrrolidines isolated from T. cordifolia Miers showed hypo glycemic and centra l nervous system depressant activity in rabbits (Man. hayan and Jolly, 1985 ).

Ganoderma lucidum Karst. (Polyporaceae)

Fruit

Blood glucose levels of normal and alloxan-diabetic mice treated with these compounds showed mark ed hypoglycemic effect (Sterne, 196 9).

¥'OCH3 OH

Capsaicin

OCH 3

Berberine

roCH'OH Quinoline-2-methanol

Diphen ylamine

R

I

LJ

R'

1, 2-substituted pyrrol idines

Guanidine derivati ves

Review: Antidiabetic effect of compounds isolated from plants

69

Table 5. Alkaloids and other nitrogen compounds (continued) Hypoglycemic Agent

,

»:

l~. <:»: yOH

Hypoglycin A

Source

Plant part

Properties

Camellia sinensis L. Kuntze (Theaceae)

Leaf

Theophylline increases extracellular Ca+2 enhances calcium-stimulated ATPases and reduces glycogenolysis (Hill et aI., 1987).

Blighia sapida Fruit Koening (Sapindaceae)

The hypoglycis, contained in the seeds and unripe fruits of the ackee tree, which are responsible for the jamaic vomiting sickness. In alloxan-diabetic rats showed that the hypoglycemic effect was not mediated by an increased insulin secretion (Jeliffe and Stuart, 1954, Bresler et aI., 1969, Mackerns et al., 1960).

Castanospermum australe A. Cunn (Fabaceae)

Leaf

Castanospermine, an alkaloid isolated from Castanospermum australe, is an intestinal enzyme inhibitor with hypoglycemic activity (Rhinehart et aI., 1987).

Litchi sinensis Sons (Sapindaceae)

Seed

Methylenecyclopropyl glycine showed hypoglycemic activity when it was administered to alloxan-diabetic mice (Bresler et aI., 1969, Senior and Sherratt 1967).

o

~C02H ,

H~~CO~

o Hypoglycin B

OH

Castanospermine

HH o

Methylene cyclopropyl glycine

70

R. M. Perez G. et a!.

Table 5. Alkaloids and other nitrogen compounds (continued) Hypoglycemic Agent

Source

Plant part

Properties

Trigonella foenum graecum L. (Leguminosae)

Seed

Seeds of two Leguminosae plants, Trigonella foenum graecum and Lupinus termis are known in local medical folklore to exhibit hypogl ycemic activity when taken orally. The effect on diabetes in rats wa s investigated. Blood glucose and lipid levels of normal and streptozotocin diabetes rats were deter mined after treatment with trigon elline (their major alkaloid), nicotinic acid, lup inid ine, lupanine, coumarin and scopoletin. Th e ra ts showed a general improvement in their clinical status as reflected by blood parameters and body weight gain; hyperglycemia was significantly reduced and free fatty acids, cholesterol and trig lycerides were significantly reduced and returned to normal levels. The only alkaloids active in non-diabeti c rat s were nicotinic acid which behaved as a sho rt-acting drug, and coumarin, wh ich exerted a prol onged effect. Some borderline hypoglycemic activity was noticed in normal rats with high doses of scopoletin . (M ishkinsky et aI., 1974).

Lup inus termis L. (Leguminosae) Catharanthine

a

COO H

N::?'

N icotin ic acid

c~mo0 Lupinidine

y~ o

Lupanine

H

~I bScopoletin

c~mo0 H

Ib-

Scopoletin

~0'10

Vv Coumarin

Review: Antidiabetic effect of compounds isolated from plants

71

Table 6. Micellaneous. H ypoglycemic Agent

~H

Source

Plant part

Properties

Acrocomia mexicana Karw (Palmae)

Root

The compound showed a significa nt blood sugar loweri ng effect on diabetes induced mice in a dosedependent (Perez et al., 1997).

Eriobotrya [aponica Linde (Rosa ceae)

Leaf

Th e effects of the sesquiterpene glycosides and polyhydroxylated triterpenoids isolated by Me OH extraction from Eriobotrya japonica were studied in genetica lly diabetic mice (C57 BLlKS-db/db/Ola) and normoglycemic rats. T hey pro duced a mar ked inhibition of glycosuria and reduc ed blood glucose levels in nor mog lycemic rats (Tommasi et al., 199 1).

. Gossypium herbaceum Fruit (Ma lvaceae )

Administra tion of gossypo l to normal and alloxa ninduced hyperglycemic mice redu ced blood glucose levels (Harborne and Baxter, 1993 ).

Ho~o1H_O_CH 2

o----G- 0 H

hJH

OH

Coyolose

Sesquiterpene glycosides 2

1

4

1

R= Glu .-. Rha-" Rha R= Glu6_

~ha~Rha

R= Glu 6--.1R ra

Glu = B-D-Glucopyran ose Rha = a-L-rhamnopyranose

Gossypol Myrtillin

Eucalyp tus citriodora H ook (Min aceae)

Leaf

Myrtillin isolated from the leaves of E. citriodora pro duced in rabbits a temporary hypoglycemia after ora l ad ministra tio n. Th e reduct ion in blood sugar in alloxa n-dia betic rab bits was more mark ed but did not lead to nor mal values (Revorero, 1958 ).

Chrom ium, manganeso an d magnesium salts

Atriplex halimus L. (Chenopodiaceae)

Leaf

Studies of the leaf ash and chromium in vitro showe d a po tentatio n of insulin-stimu lated glucose utilization by epidymal fat cell of chro mium deficient rats. Chronic administration of magnesium salts has also been show n to be beneficial in the treatm ent of NlD DM (Ma rIes and Farn sworth 1995).

Saud in

Cluytia richardiana L. Leaf (Euphorbiaceae)

Th is principl e, a novel diterpene, showe d hypoglycemic activity when was administered (40 mg/kg) to alloxan -induced diabetic mice (Mossa, 1985).

72

R. M. Perez G. et al.

Table 6. Micellaneous. Hypoglycemic Agent

Source

Plant part

Coleus forskolii (Poir.) Leaf Briquet (Lamiaceae)

Properties Forskolin is an adenylate cyclase activator which increases intracellular cAMP by stimulating its biosynthesis (Maries and Farnsworth, 1995).

Forskolin S-allylcysteinesulfoxide

Allium sativum L. (Liliaceae)

Fruit

S-methylcysteine sulfoxide

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Address R.M. Perez Guttierez, Laboratorio de lnvestigacion de Produtos Naturales. Escuela Superior de lngeneria, Quimica e lndustrias Extractivas IPN. Punto Fijo 16 Cal. Torres Linda vista CP 07050, Mexico D.E