REVIEW ARTICLE

Hypoglycaemic plant compounds Caroline Day PhD, Research Fellow, Diabetes Research Group, Department of Pharmaceutical Sciences,

Aston University, Aston Triangle, Birmingham 64 7ET, UK

The attributes of insulin and oral blood glucose-lowering drugs are well recog- nised. Yet even the most judicious use of these agents does not reinstate normal glucose homeostasis in diabetic patients. Hence the search continues to discover new molecules to improve glycaemic control and combat complications.

Plants provide a vast resource of novel compounds with potential for the de- velopment of new antidiabetic drugs, and worldwide more than 700 different plants have been described as traditional treat- ments for diabetes’. Most of these have not been evaluated under controlled conditions, and it is not clear how they may act. Some n ~ a y only be effective against very specific presentations, eg malnutrition diabetes due to local mineral deficiencies2s3. Others appear to influ- ence associated rnaladies without neces- sarily improving glycaemic control. Nevertheless, it is the traditional plant treatments for diabetes that would appear to be our most likely source o f new hypoglycaemic chemicals, and it is these plants which are attracting thc attention of both the pharmaceutical industry and enthusiasts of alternative medicines.

Hypoglycaemic constituents in the diet Many of the plant components o f a healthy diet have been used as traditional treatments for diabetes in the UK ( Tuble I ) . Some of these may owe their‘repu- tation to a high fibre, mineral or vitamin content, and few have been scrutinised thoroughly. However, several have yiel- ded hypoglycaemic principles such as the propyl disulphides from haricot bean pods, onion bulbs and the leaves of Brussica species. Guandidine is a known hypoglycacniic component of goat’s me, and uncharacterised hypoglycaemic fractions have been obtained from sweet corn, coriander and agrimony2-’. A diet rich in the cdible mushroom (Agur icz~~ hz.sponrs) improves glycaemic control in streptozotocin-diahetic animals, and fractions of the fruiting bodies have been shown t o stimulate insulin secretion and exert an insulin-like effect in isolated adipocytesi.

Among the dietary adjuncts used iixiinly by immigrants t o the UK ( TubLZ), cerasee and karela (wild and cultivated

Table 1 (based on reference 5). Some traditional plant treatments for diabetes used as dietary adjuncts in the UK

Herbs and spices

Agrimony Burdock Chile pepper Coriander Dandelion Ginger Liquorice Nettle Sage Tarragon Thyme

Vegetables

Cabbage Celery Garlic Haricot bean Leek Lettuce Mushroom Onion Pea Potato Sweetcorn Turnip

Fruits

Apple Blackberry Elder

Juniper Lemon Lime Raspberry

HOP

Agrimonia eupatoria Arctium lappa Capsicum fructescens Coriandrom sativum Taraxacum officinale Zingiber o fficinale Glycyrrhiza glabra Urtica dioica Salvia officinale Artemisia dranunculus Thymus vulgaris

Brassica oleracea Apium graveolens Allium sativum Phaseolus vulgaris Allium porrum Lectuca sativa Agaricus bisporus Allium cepa Pisum sativum Solanum tuberosum Zea mays Brassica rapa

Pyrus malus Rubus fructicosus Sarnbucus nigra Humulus lupulus Juniperus communis Citrus limonum Tilia europa Rubus idoeus

Leaf Leaf Seed Seed Root and leaf Root Root Aerial parts Leaf Leaf Leaf

Leaf Aerial parts Bulb Pod Aerial parts Leaf Fruiting body Bulb Seed Tuber Style Root

Fruit Leaf Leaf Leaf Berry Fruit Fruit Aerial parts

Table 2. Dietaryadjuncts used mainly by immigrants to the UK

r Cerasee Momordica charanfia (wild) Aerial parts Guava Psidium guajava Fruit & leaf Karela Momordica charantia (cu Itivated) Fruit Lychee Lycium chinense Fruit & seed Indian cluster bean Cyamopsis tetragonolobus Seed Mistletoe Viscum album Leaf Pawpaw Carica papaya Fruit

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REVIEW ARTICLE Hypoglycaemic plant compounds

varieties of Momordica charuntiu) have substantial evidence of hypoglycaemic activity. This is achieved without increas- ing insulin concentrations6p7 and appears to involve suppression of hepatic glucose production' and a reduced rate of in- testinal glucose absorptions. Most of the activity resides within the alkaloid fract- ions, and it is noteworthy that the hypo- glycaemic effect of karela is additive to that of sulphonylureas, increasing the risk of hypoglycaemialo in patients already taking sulphonylurea as treatment.

Hypoglycaemic compounds Several detailed listings of known hypo- glycaemic compounds from plants have been publishedll-13 although some of the studies conducted with these compounds are difficult to interpret. Animal models are often poorly characterised, experi- ments are ill-designed or inappropriately analysed, and the purity of some pre- parations or extractions is unconfirmed. Hence a rather selective, critical and questioning approach has been adopted here, with a view simply to illustrating the

diversity of chemical types with hypo- glycaemic activity (Figure I ) .

Polysaccharides Plant polysaccharides provide a valuable source of novel fibre molecules such as the galactomannan guar from the Indian cluster bean, (Cyamopsis tetragoviolo- bus), and glucomannan from the konjac plant (Amorphophallus konjac). Consu- mption of these and many other 'fibrous' polysaccharides from plants have been shown to have an antihyperglycaemic effect by slowing the rate of digestion and absorption. Interestingly, several plant polysaccharides exert a hypoglycaemic effect when administered intraperito- neally'. The effect is evident in alloxan- diabetic animals but the mechanism has not been established. Examples include the series of D-glucopyranoses extracted from the roots of ginseng (Panax ginseng) and the peptidoglycans from the fruits of Ganodemza luciduml2.

Flavonoids Epicatechin from Pterocarpus manupiurn

(bjsar, false teak) and some other flavo- noids have been reported to stimulate insulin release by isolated islets but they generally exert little or no hypoglycaemic activity after enteral administration. Ex- travagant claims for the antidiabetic properties of some flavonoids have not been ~ubstantiated~~-~3.

Alkaloids Alkaloid fractions with hypoglycaemic activity have been isolated from many plants, and those which have been fully characterised provide a variety of struc- tures and effectd. Some are alpha- glucosidase inhibitors, slowing the rate of carbohydrate digestion, eg castanosper- mine from the seeds of Castanospemzum australe and derivatives of moranoline from the roots of mulberry (Morusalba)15. Others appear to inhibit intenstinal glu- cose transport (eg alkaloids of capsicum, Capsicum annum) or suppress hepatic glucose production (eg karela alkaloids), while alkaloid5 from the periwinkle (Catheranthus roseus) reputedly exert some weak insulin-like effects. Trigo-

Figure 1. Examples of compounds from plants with known or reputed bloodglucose-lowering activity.

A. Guanidine D. Castanospermine (alkaloid) 6. Guar (galactomannan polysaccharide) C. Epicatechin (flavonoid)

E. Neomyrtillin (glucoside) F. Hypoglycin A (aminopropylpropionic acid derivative)

HO-

H H

H H

CHzOH O I n

OH C.

OH '0 CHzOH /

E. "OW _ _

OH

CI-

F.

NH2 cH2 = C- /c\Hz CH - cHZ- CH- I COOH

2 70 PracticalDiabetes International Nou/Dec 1995 Vol. 12 No. G

REVIEW ARTICLE Hypoglycaemicplant compounds

nelline, a nictonic acid derivative from fenugreek (Trigonella finum-graecum) may act like nicotinic acid through an antilipolytic effect. Further alkaloids such as tecomine and tecostanine from the leaves of Tecoma stuns show hypogly- caemic activity in the presence of a functional pancreas, but their mode of action is unestablished113.

Glucosides Glucosides are common plant constitu- ents. and several are reputed to be hypo- glycaemic. Neomyrtillin from the leaves of bilberry (Vaccinium myrtillus) reduced insulin requirements in IDDM patients and appeared to improve insulin action'. Beta-sitosterol-D-glucoside has been iso- lated from various plants including Ficus and Centaurea species and it is claimed to lower blood glucose concentrations through an insulinotropic effect16. The hypoglycaemic activity of Gymnema syl- vestre (gunnar) leaves, an established traditional treatment for diabetes in India, is attributed at least in part to uncharac- terised glucosides which may suppress hepatic gluconeogenesis13. Ethoxyphenyl- glucosides which act without increasing insulin concentrations have been isolated from sugar cane (Saccbarum ofBcin- arum)12.

Propionic acids Aminopropylpropionic acids known as 'hypoglycins' have been isolated from the unripe fruits of the ackee apple (Bligbia sapida). Their hypoglycaemic potency appears to result from the inhibition of fatty acid oxidation which depletes hepatic glycogen stores and prevents hepatic glucose production17.

Other hypoglycaemic chemicals Of the various mineral deficiencies which are deemed to be corrected by plants, manganese (from Medicago sativa), chro- mium (from yeast) and zinc (from Atriplex halimus) are recognised as important requirements for normal insulin secretion and action3. Plants rich in vanadium are reportedly used as traditional treatments for diabetes in South America (Prof. Schecter, personal communication) and many animal studies have substantiated the insulin-like effects of vanadium saltsls. Xantbium strumarium contains carboxyatractylate as its reputedly hypo- glycaemic constituent19. Several plant chemicals used in other branches of medicine are known to have hypogly- caemic properties, for example quinine

Figure 2. The Serandi blanco story I

In her autobiography21, the late Barbara Woodhouse suggested that as a young woman she was cured of insulin-requiring diabetes by a South American plant which she believed to be Serandi blanco (Phyllanthus sellowianus). While the identity of the plant and the exact nature of the diabetic condition remain questionable, it is well recognised that P. sellowianus is a traditional treatment for diabetes in parts of Argentina. However, experimental studies have not consistently shown any acute or chronic benefits of P. sellowianus in diabetic animals, and studies with other Phyllanthus species have also been inconclusive. Whether the Barbara Woodhouse experience was a fortunate coincidence or a case of mistaken botanical identity, her account has raised unrealistic expectations in others.

I

(from Cincboma species) and ouabain (from Akocanthera species) stimulate insulin secretion, whilst the hypogly- caemic mechanism of salicylates (from Salix species) is unestablishedzo.

Conclusion Despite many anecdotal claims (eg Figure 2) there is no 'controlled' evidence of an effective botanical substitute for insulin in patients with C-peptide negative IDDM. However, several plant chemicals un- doubtedly increase insulin secretion, improve insulin action or exert insulin- like effects which can benefit glycaemic control in diabetic patients. Although some natural hypoglycaemic chemicals are either too weakly active or too toxic for clinical use, this does not preclude the development of more appropriate ana- logues. Indeed a precedent already exists for this approach in diabetes, since guanidine from Galega qfiicinalis pro- vided a template for the development of biguanides such as nietformin22.

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