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Phytomedicine Vol. 2 (2), pp.

137-189, 1995
1995 by Gustav Fischer Verlag, Stuttgart [ena . New York Review article

Antidiabetic plants and their active constituents 1

R. J. MARLEsa and N. R. FARNSWORTHb

a Department of Botany, Brandon University, Brandon, MB R7A 6A9, CANADA


b Program for Collaborative Research in the Pharmaceutical Sciences, College of Pharmacy, University of
Illinois at Chicago, Chicago, Illinois 60612, U.S.A.

Summary

Diabetes mellitus is a debilitating and often life-threatening disease with increasing incidence in
rural populations throughout the world. A scientific investigation of traditional herbal remedies
for diabetes may provide valuable leads for the development of alternative drugs and therapeutic
strategies. Alternatives are clearly needed because of the inability of current therapies to control
all of the pathological aspects of diabetes, and the high cost and poor availability of current ther-
apies for many rural populations, particularly in developing countries. This review provides in-
formation on more than 1200 species of plants reported to have been used to treat diabetes
and/or investigated for antidiabetic activity, with a detailed review of representative plants and
some of great diversity of plant constituents with hypoglycemic activity, their mechanisms
of action, methods for the bioassay of hypoglycemic agents, potential toxicity problems, and
promising directions for future research on antidiabetic plants. The objective of this work is to
provide a starting point for programs leading to the development of indigenous botanical re-
sources as inexpensive sources for standardized crude or purified antidiabetic drugs, and for the
discovery of lead compounds for novel hypoglycemic drug development.

Key words: antidiabetic plants, botany, chemistry, mechanism of action, bioassays for hypogly-
cemic agents.

Introduction pact of the disease is enormous. In 1987 an estimated 5.7


million hospital days were attributed to the treatment of di-
At least 30 million people throughout the world suffer abetic complications, with an additional 2 million labor
from diabetes mellitus. Life expectancy may be halved by days lost to out-patient physician visits and work loss. Di-
this disease, especially in developing countries where its rect medical costs due to diabetes are estimated to have
prevalence is increasing and adequate treatment is often un- been $9.6 billion, and indirect costs for short-term morbid-
available. Even in developed countries such as the USA, ity, long-term disability, and mortality (more than 80,000
where sophisticated therapy is widely available, more deaths) are estimated to have been $10.6 billion (Center for
deaths are attributed to diabetes than to lung cancer, breast Economic Studies in Medicine 1988).
cancer, or motor vehicle accidents (World Health Organiza- There has been a striking emergence of non-insulin-de-
tion 1985). pendent diabetes mellitus as a major health problem in
Diabetes not only kills, but is a major cause of adult populations undergoing modernization of life-style, both in
blindness, kidney failure, gangrene, neuropathy, heart at- developing nations and in rural areas of developed coun-
tacks, and strokes. In the USA, where there are an estimat- tries (Bennett 1983, Bransome 1992, World Health Organ-
ed 14 million diabetics (Bransome 1992), the economic im- ization 1985, Gohdes 1986, Schraer et al. 1988). The enor-
1 Reprinted, with revisions and additions, from Economic and
mous costs of modern treatment indicate that alternate
Medicinal Plant Research Volume 6, Academic Press Ltd., 1994, strategies for the prevention and treatment of diabetes must
with permission. be developed. Since almost 90 % of the people in rural are-
138 R. J. Marles and N . R. Farnsworth

as of developing countries still rely on traditional medicines responsiveness to glucose, and increased glucagon secretion
for their primary health care , and scientific investigations through a reduced ability of glucose to suppress glucagon.
of traditional medicines have led to the discovery of at least The efficiency of glucose upt ake by the peripheral tissues is
88 drugs now in professional use worldwide (Soejarto and also impaired due to a combination of decreased insulin se-
Farnsworth 1989), a synthesis of local traditional and mod- cretion and defective cellular insulin action (insulin resis-
ern knowledge and techniques for the management of dia- tance) (Porte and Kahn 1991). Receptor mediated insulin
betes should be feasible. A rationally designed interdiscipli- resistance may be a consequence of various factors includ-
nar y research program could lead to the development of in- ing increa sed serinelthreonine phosphorylation of the re-
digenous, renewable, medicinal plant resources as practical ceptor with decreased tyrosine phosphorylation, receptor
and cost-efficient alternatives. The purpose of this review is desensitization, auto-antibodies to the receptor and inherit-
to prov ide the information needed for the design of such a ed structural defects in the insulin receptor. Defects in insu-
project. lin action could also arise at post-receptor events particu-
larly glucose transport. Other circulating hormones such as
islet amyloid polypeptide (amylin) may also cause insulin
Background: Diabetes Classification resistance (Pillay and Makgoba 1991).
and Modern Therapy Malnutrition-related diabetes mellitus (MRDM) refers to
the condition of young diabetics in tropical developing
Diabetes mellitus comprises a group of etiologically and countries with a history of nutritional deficiency and a set
clinically heterogeneous disorders with a common set of of symptoms which fail to meet the criteria used to classify
symptoms: excessive thirst and hunger, muscular weakness IDDM and NIDDM. The subclass, "fibrocalculous pan-
and weight loss, excessive urination, and elevation of the creatic diabetes " (FCPD), is believed to be associated with
blood glucose level which , when it exceeds the renal thresh- the consumption of foods containing cyanogenic glyco-
old, results in the excretion of glucose in the urine. These sides, such as cassava (Manihot esculenta Crantz, Euphor-
sympto ms were described by the ancient Egyptians in the biaceae). The other main subclass , "protein-deficient pan-
Ebers Papyrus about 3500 years ago (H engesh and Hol- creatic diabetes" (PDPD), is believed to be associated with
comb 1981 ), and by the Greek physicians Aretaeus the early childhood malnutrition conditions such as kwashior-
Cappadocian (A.D. 30-90) and Galen (A.D. 130-200) kor in which ~-cell damage occurs (World Health Organ-
(Farnsworth and Segelman 1971). ization 1985, McMillan and Geevarghese 1979). Both
There are three main types of diabetes mellitus recog- FCPD and PDPD may be forms of NIDDM complicated by
nized by the World Health Organization (1985). Insulin-de- dietary factors , and thus not necessaril y associated with liv-
pendent diabetes mellitus (IDDM) requires daily inject ions ing in a tropical developing country (Alberti 1988).
of insulin to prevent a catabolic cascade culminating in di- Although this classification of diabetes mellitus is actual-
abetic ketoacidosis, coma, and death. It is characterized by ly too simplistic to properly explain the etiology of the dis-
the virtual absence of ~-cells from the islets of Langerhans ease in most individuals, since a wide range of factors may
in the pancreas, and a level of insulin secretion insufficient determine the expression of diabetic symptoms (Rossini et
to restrain excessive secretion of glucagon or to counter its al. 1988), it is still a clinically useful scheme for determin-
enhancement of hepatic glucose and ketone production. ing the appropriate therapeutic method.
The loss of ~-cells may be due to exogenous chemicals from Modern therapy of IDDM began with the discovery of
the environment or diet, viral infection, or immunological the involvement of the pancreas in diabetes by von Mering
factors such as an autoimmune disorder in genetically vul- and Minkowski in 1889, and the demonstration by Banting
nerable individuals (Unger and Foster 1985). and Best in 1921 that an extract of beef pancreata could
Non-insulin-dependent diabetes mellitus (NIDDM, also successfully lower blood glucose levels in pancreatecto-
known as Type II or maturity-onset) occurs predominantly mized dogs. Their use of a pancreatic extract in a human di-
in older people, e.g. 16.8 % of persons over 65 years of age abetic in 1922 marked the first use of the pancreatic antidi-
in the United States have NIDDM, and it is often associat- abetic principle, insulin, in the treatment of diabetes mellit-
ed with obesity (Ilarde and Tuck, 1994). NIDDM repre- us. Several different preparations of bovine, porcine, and
sents a variety of diabetic states in which the ~-cells are usu- human insulin (1, in Fig. 1) are now available, including
ally low in number relative to a-cells and insulin secretion lente or long-acting forms, and a regimen of daily injections
is usually sufficient to oppose the ketogenic actions of glu- represents the current standard of therapy for IDDM (Hen-
cagon but not to prevent hyperglycemia. The basal rate of gesh and Holcomb 1981).
hepatic glucose production is elevated in subjects with Insulin acts by bind ing to a cell membrane tetrameric
NIDDM and this is positively correlated with the degree of protein receptor which consists of two extracellular a- and
fasting hyperglycemia. This increased rate of glucose re- two transmembrane ~-subunits. Binding of insulin to the a-
lease by the liver results from impaired hepatic sensitivity to subunit causes autophosphorylation of ~-subunit intracel-
insulin, reduced insulin secretion through impaired ~-cell lular tyrosine residues. The activated insulin receptor then
Antidiabetic plants and thei r active constituents 139

r---S - S~
gLy - i t e-vat -a t u- a tn -cvs -cvs - thr - s e r - i le - cys ser - leu - t yr -gl n- leu -glu -asn - tyr - cys -asn
~ 8 9 10 s---'
I I
s S
I I
phe-va l-asn-g ln-hi s - l eu- cys -gl y-s er -h i s -leu- va l -g l u-a la - l eu- t yr- l eu-val -cys-g l y- g lu- ar g- gl y-phe-ph e- t yr-thr

,-------J
pr o- tys - r hr
30
8 9 10 30
Bov ine i ns ul i n: a ta -se r - va t ala
Porci ne i ns uLi n: thr -ser - f Ie a la

2 3

E
N~S02NHC(=O)NH-o
"<::: OCH 3
I~
CI
4 5

NH ~
HN-< ~
NHCNH 2
II
NH

6 7
Fig. 1. Insulin and some synthetic oral hypoglycemic drugs.

couples to cytosolic receptor substrates which can affect ever, the oral route is the most pra ctical for patients. This
different signalling cascades eliciting the pleiotropic hor- has been achieved by encap sulation of insulin in liposomes,
mone response on cell metab olism and growth. Most of the imperviou s polymer films, or in polyalkylcyanoacrylate
proteins involved in the signal transduction pathway of in- nanocapsules which can pass through the intestinal epithe-
sulin are not known yet, but each of them may playa role lium (Damge et al. 198 8, Saffran et al. 1986).
in the various forms of insulin resistance (M uller-Wieland Unfortunately, although adm inistration of insulin orall y
et al. 1993 ). or by injection reverses the main sympto ms of diabetes,
Insulin is a polypeptide drug which would be subject to with a return to a near-norm al life expectanc y, it does not
digestion in the stomach and small intestine if taken orally. prevent all of the metabolic defects of diabetes, nor does it
Preparations for nasal and rectal adm inistration have been prevent all the diab etic compl icat ions from developing . It is
developed. Low biological efficacy restricts their use but believed that the problem lies in the fluctuation of blood
absorption-promoting mechani sms are being developed glucose levels caused by injection of insulin, and several
and easier administration and acceptance by patients is en- methods are being developed to achieve a more constant
couraging the development of new intranasal insulin prep- state of normoglycemia, including portable insulin pumps
arations (Gizurarson and Bechgaard 1991). Insulin can be with blood glucose monitors for feedback regulation (Pfeif-
combined with protease inhibitors for administration in the fer 1987), allotransplantation of pancreatic islet endocrine
ileum and the ascending colon (Darnge et al. 1988). How- aggregates (Kakizaki et al. 1987), and fetal or dispersed
140 R.]. Maries and N . R. Farnsworth

adult pancreas transplantation (Hellerstrom et al. 1988 ). effects of gliclazide beneficial for the prevention of diabeti c
Treatment with an insulin pump or multiple daily injections microangiopathic complications include reduction of plate-
still differs fro m the natural situation because exogenou s let adhes ion, aggregation and hyperactivity, and increa sed
insulin is entering the periph eral circulation first rather fibrinolysis (Campbell et al. 1991, Alberti et al. 1994). Pos-
than the liver and these methods do not perfectl y imitate sible detrimental side effects of sulfonylureas include hypo-
the pulsatile character of insulin secretion nor the rapid natremia, dermatological reactions, hepatitis, and hemato-
post-prandial rise of insulin levels and subsequent rapid logic effects (Ferner 1988 ).
drop. Microencapsu lation of pancre atic islets has been at- None of the currently available sulfonylureas compl etely
tempted in spontaneously diabetic models, but variable re- normalize insulin secretion and action (Beck-Nielsen et al.
sults were obtained due to fibrosis of the capsules . This can 1988). Failure to respond to sulfonylurea drugs may be pri-
be minimized by purification of the capsule material (sodi- mar y (25 % to 30 % of initially treated patients) or secon-
um alginate-poly-L-lysine) and decreasing the size of the dar y, occurring in 5 % to 10 % of pat ients per year (Ilarde
microcapsules (Clayton et al. 1993) . Hybri d artificial pan- and Tuck 1994 ), e.g. when NIDDM is a transitional state
creas consist of insulin-secreting pancreatic tissue sur- preceding IDDM. Combinati on therapy with insulin and a
rounded by a memb rane that protects the tissue fro m rejec- sulfonylurea agent only slightly improve d glycemic control
tion by the immune system following implantation. Unre- in NID DM patients - less exogenous insulin was needed
solved problems with this mode of therapy includ e biocom - but fasting serum insulin levels showe d no difference
patibility, oxygen supply limitations, and prevention of im- between treatment groups. This therapy did not produce
mune rejection (Colto n and Avgoustiniatos 1991 ). near-normal blood glucose levels and so it is not recom -
Due to the immunological nature of some cases of mended for poorl y controlled NIDDM patients receiving
IDDM , treatment with immune suppressants has been at- insulin (Peters and Davidson 1991 ).
tempted. Cyclosporin is only temporarily effective in Another class of drug s, the biguanides, was also shown to
IDDM and its use is not recommended (Faulds et al. 1993 ). be effective, and phenformin (6) wa s approved in 1959, but
Therapy of NIDDM involves modifications of lifestyle due to its association with fatal lactic acidosis it was re-
and diet, an exercise regimen, and use of oral hypog lycemic called in 1977. Metformin (7) is a less toxic biguanide
agents (Fig. 1). Dietary modifications include limiting total which can be a useful adjunct in NIDDM therapy, since it
caloric intake, increas ing the percentage of calories from impro ves perip hera l sensitivity to insulin through a stimu-
comp lex carbohydrates and reducing the intake of fats and lated tissue glucose uptake by a transporter-linked system
cholesterol (Ilarde and Tuck, 1994). To be effective, thera - (Sirtori and Pasik 1994).
peutic inter ventions for NIDDM must reduce heptic glu- Other therapeutic options for NIDDM include the use of
cose production either by improving islet dysfunction and insulin-sparing antihyperglycemic agents such as a -glucosi-
raising plasma insulin levels, or improving the effectiveness dase inhibitors, thiazolidinediones, chloroquine or hy-
of insulin on the liver (Porte and Kahn 199 1). The use of droxychloroquine, or fibric acid derivativ es such as clofi-
oral hypoglycemic drugs may be effective in controlling brate. Other experimental agents include fatt y acid oxid a-
blood glucose levels, but may not prevent all the complica- tion inhibitors and dichloroacetate . To prevent th e compli -
tions of diabetes (Unger and Foster 1985) . cations arising from the spectrum of clinical and metabolic
Observations in the 1940's that certain sulfonamide anti - abnormalities which arise from insulin resistance other spe-
biotics, used to treat typhoid fever and pneumonia, caused cific agents may be used including antihypertensives, lipid
the side-effect of hypogl ycemia led to the development of lowering agents and sorbitol inhibitors (Iiarde and Tuck
the sulfonylurea hypogl ycemic agent s. Tolbutamide (2) was 1994). Insulin-like growth factor-I (IGF-l ) produced by re-
the first, approved for use in the United States in 1957. Al- combinant DNA technology is being used in NIDDM pa-
though the "first generation " drug chlorpropamide (3) tient s to stimul ate glucose upt ake, improve glucose toler-
causes side effects more often, the incidence of severe hypo- ance, decrease hyperinsulinemia and decrease hypertrigly-
glycemia, the major lethal side effect, is at least as high with ceridemia. Since it improve s metabolic control in pat ients
the " second generation" glyburide (4). To lower the inci- with extreme insulin resistance it is a useful therapeutic ad-
dence of this problem gliclazide (5) was developed. Its junct (Kolaczynski and Caro 1994 ).
mechanisms of action involve stimulation of insulin secre- From this brief overview of diabetes classification and
tion through the ~-cell sulfon ylurea receptor, involving clo- modern therapy, it can be seen that current methods of
sure of K+ ATP channels, and possibly through a direct ef- treatment for all types of diabetes mellitus fail to achieve
fect on intracellular calcium transport, and also reducti on the ideals of normogl ycemia and the prevention of diabetic
of hepatic glucose production and improvement in glucose complications. Promising fields of research such as pan-
clearance. This is accomplished without changes in insulin creatic transplants offer little hope to the majority of the
receptors, suggesting a post-recepto r effect on insulin ac- world's diabetics, for whom such procedures will be too ex-
tion perhaps by stimulation of hepa tic fructose-2,6-bis- pensive and difficult to obtain. Most developin g countries
phosphata se and muscle glycogen synthetase. Additional cannot even afford adequate conven tional therapy at the
Antidiabetic plants and their active constituents 141

1987 average U.S. price of $14.28 per oral hypoglycemic Table 1. Plant Families Most Often Cited for Antidiabetic Activi-
prescription, or $14.23 per insulin prescription (Center for ty.
Economic Studies in Medicine 1988). Family Species cited Total species'
Further problems with conventional therapy in develop-
Fabaceae 127 18,000
ing countries include insulin supply, storage, and injection, Asteraceae 98 21,300
dietary control and complications from malnutrition, a Lamiaceae 36 3,500
lack of trained health care workers, and a lack of education Liliaceae 35 6,460
for the patients (Gill 1988). In such situations the incidence Poaceae 30 10,000
of diabetes-related mortality is far greater than in well- Euphorbiaceae 30 7,000
served urban areas. There is, therefore, a clear need for al- "According to Thorne (1981).
ternate sources of both oral and parenteral antidiabetic
drugs and alternate strategies for diabetes therapy. often useful in the discovery of new plants with biological-
ly active constituents, it will be necessary to learn more
about particular groups of hypoglycemic natural products
Plants and the Treatment of Diabetes Mellitus and their mechanisms of action before this method of drug
discovery can be successfully employed.
Traditional medicines for the treatment of diabetes mel- Half of the species found in our literature review have
litus are probably based mainly on treatment of its obvious been used in traditional medicine to treat symptoms of dia-
symptoms of pronounced thirst and polyuria. Even glyco- betes. Half of these traditional remedies have had some ex-
suria was recognized as a symptom of diabetes in ancient perimental testing for hypoglycemic activity, e.g., in nor-
Ayurvedic medical texts such as the Sushruta Samhita and mal, glucose-loaded, alloxan- or streptozotocin-induced di-
Charaka Samhita (Nagaraj an et al. 1982). The Greek phy- abetic, or naturally diabetic subjects. Distinctions of the ex-
sician Aretaeus recommended treatment of diabetes by perimental model used are clearly important for gaining an
treatment of the profound thirst. For this he recommended understanding of the mechanism of action of these botani-
starting with a purgative to strengthen the stomach, fol- cal drugs. Further details of the bioassay methods common-
lowed by consuming water boiled with autumn fruit (a ly used and their significance for the discovery of new anti-
good source of soluble fibre and complex carbohydrates diabetic agents will be provided below.
like pectin), milk, gruels of a variety of whole grains (an ex- A summary of the results of screens for blood glucose
cellent source of soluble and insoluble fibre and glycans), lowering activity, presented in Table 2, shows that 81 % of
and astringent wines (alcohol is hypoglycemic according to those traditional antidiabetic plants tested gave positive re-
Hengesh and Holcomb 1981, Lomeo et al. 1988). He also sults. Even for those plants for which no traditional use was
recommended a crude drug of animal origin: venom of the mentioned, 47 % of those species screened were active.
"dipsas" viper, which in bite victims causes a severe thirst. This rate of positive results is higher than one would expect
Aretaeus suggested it could be used as a mithridate, i.e., a by random chance - perhaps 10 % would be reasonable,
poison which is deliberately administered in small, gradual- based on the number of active species obtained by the U.S.
ly increasing doses in order to develop an immunity to the National Cancer Institute's random screening of more than
effect of the poison (Adams 1856). In fact, the venom of the 35,000 species for antitumor activity (Spjut and Perdue
Middle Eastern viper Piscivorus piscivorus (Crotalidae) 1976). The high percentage of active plants probably re-
was found to be hypoglycemic when administered i.v. at a flects, at least in part, the great variety of possible active
dose of Iflug/kg in normal rats and rabbits, but was inac- constituents and mechanisms of action, the possibility that
tive against alloxan-induced hyperglycemia in rats (Taha not all negative results were reported, and for the non-tra-
1982). ditional plants, other considerations made in selecting them
More than 1200 species of organisms have been used eth- for study (e.g. chemotaxonomic). Nevertheless, it is clear
nopharmacologically or experimentally to treat symptoms from the above results that the study of traditional reme-
of diabetes mellitus (see the Appendix). They represent dies for diabetes mellitus yields an excellent return in po-
more than 725 genera in 183 families, extending phyloge- tential new sources of antidiabetic drugs.
netically all the way from marine algae and fungi to ad- If the same or a closely related plant is used traditionally
vanced plants such as the composites. The most frequently for the same purpose in more than one country, it suggests
cited families are shown in Table 1. These are very large
and widely distributed families, so the large number of spe- Table 2. Activity of Traditional Antidiabetics vs. Other Plants.
cies reported to have been used traditionally or experimen-
Traditionals Others
tally for the treatment of diabetes may be coincidental. The
phylogenetic distance between even this select group of Total no. tested 295" 541
families is a strong indication of the varied nature of the ac- Total active 238 (81 %) 254 (47%)
tive constituents. Thus, while chemotaxonomic studies are a Out of a total of 582 known traditionally used plants
142 R. J. Maries and N. R. Farnsworth

Table 3. Most Widely Used Traditional Antidiabetic Plants.


Scientific name Countries where used traditionally
CUCURBITACEAE
Momordica charantia Saudi Arabia, West Africa, Pakistan, India, Sri Lanka, Thailand, Fiji, Bimini, Panama, Puerto Rico,
Belize, Jamaica, Trinidad, Virgin Islands, England
APOCYNACEAE
Catharanthus roseus Australia, England, Thailand, Natal, Mozambique, India, Philippines, Vietnam, Dominican Republic,
Jamaica
ANACARDIACEAE
Anacardium occidentale Ecuador, Colombia, Mexico, Venezuela, Jamaica, Madagascar, India, Thailand, England
MYRTACEAE
Syzygium cumini India, Pakistan, Thailand, West Indies, USA, Portugal
Eucalyptus globulus West Indies, Mexico, Guatemala, China
FABACEAE
Lupinus albus Canary Islands, India, Israel, Portugal, Morocco
Trigonella [oenum-graecum Israel, Egypt, France, India
LILIACEAE
Aloe vera Haiti, India, Tunisia, Kuwait, Saudi Arabia
Allium cepa India, Saudi Arabia, North Africa, Peru
Allium sativum India, Saudi Arabia, Mexico, Venezuela
BIGNONIACEAE
Tecoma stans India, Mexico, Guatemala, Virgin Islands, Cuba
URTICACEAE
Urtica dioica England, USA, Guatemala, Nepal, India
ASTERACEAE
Taraxacum officinale Europe, Costa Rica, Mexico, USA
CYPERACEAE
Kyllinga monocephala India, Ethiopia, Indonesia, South America (country not specified)
EUPHORBIACEAE
Phyllanthus emblica India, Nepal, Tibet, Pakistan
Pbyllantbus niruri Indonesia, India, West Indies, Brazil
MELIACEAE
Azadirachta indica India, Fiji, Saudi Arabia, Trinidad
MORACEAE
Morusalba India, USSR, China, Peru
ROSACEAE
Poterium ancistroides Spain, Greece, Syria, Israel
APIACEAE
Daucus carota India, China, England, USA

either cultural contact between the countries or indepen- such useful drugs as reserpine, from Rauvolfia serpentina,
dent discovery. In either case, the conservation of that tra- which is used as an antihypertensive and tranquilizer (Tyler
ditional use indicates a higher probability that the tradi- et al. 1981). Reserpine is also reported to be hypoglycemic
tional practitioners found the remedy to be effective. Table in normal animals and animals made hyperglycemic by pre-
3 lists the twenty most widely used traditional antidiabetic treatment with epinephrine (Ricci and Ricordati 1955). In-
plants. With the notable exception of Kyllinga, all of these dian traditional medicines may very well supply the world
species have already been studied and shown to be active or with some new antidiabetic drugs.
have active constituents, and for most of them the identity Several reviews of plants with known antidiabetic activ-
of the probable active constituents is known. Several of ity or traditional use as antidiabetic remedies, prepared on
these plants will be discussed in detail below. a more limited scale than the current work, have been pub-
Seventeen of the twenty most widely used traditional lished (Farnsworth and Segelman 1971, Ajgaonkar 1979,
antidiabetic plants, and many others too, are used in India. Oliver-Bever and Zahnd 1979, Oliver-Bever 1980, Nagara-
The Indian subcontinent has an extensive indigenous phar- jan et al. 1982, Mossa 1985, Oliver-Bever 1986, Day and
macopoeia, including the Ayurvedic, Unani, and folkloric Bailey 1988, Bailey and Day 1989, Handa et al. 1989, Rah-
medical systems, which has already supplied the world with
Antidia betic plants and their active constituents 143

o1
COOO COOO
~O'-./COOH

oi
I '-':::
~
~
NH
I '-':::
~
~
NH
NH2

CI
I ~

8 9 10

U
I h
C0 2H ( XCOOH
~ I
U
I h
N+
C0 2
-
( XC0 2H
~ l
N NH2 I
CH
3 OH

11 12 13 14
Fig. 2. Plant growt h regulators with hypoglycemic activity.

man and Zaman 1989, Ivorra et al. 1989, Winkelman in their metabolic processes. Glucose is the metabolic ener-
1989). gy source and most important biosynthetic precur sor in
The object of this review is to present a comprehensive plants, so glucose undergoes storage and mobilization
literature review of plants associated with the treatment of under hormonal control in plants as it does in animals .
diabetes mellitus, and to discuss with detai led examples Plant growth regulators such as indo le-3-acetic acid (Fig. 2,
their potential as sources for new antidiabetic drugs. The 8) and natural and synthetic analogs such as indole-3-bu-
primary source of the information on antidiabetic plants tyric acid, indole-3-propionic acid, L-tryptophan (9), and
presented here was the NAPRALERT (Natural Products p-chlorophenoxyacetic acid (10) , inhibit insulinase in vitro
Alert ) comp uter database of the Program for Collaborative and arc hypoglycemic in vivo in normal rats (Mirsky et al.
Research in the Phar maceut ical Sciences, College of Phar- 1956). Nicotinic acid (11) and anthranilic acid (12) also in-
macy, University of Illinois at Chicago . hibit insulinase and potentiate simultaneously adm inistered
insulin. An inhibitor of indole-3-acetic acid oxida se from
Phaseolus vulgaris fruit exocarps also has hypoglycemic ac-
Hypoglycemic Constituents and tivity. The hypoglycemic alkaloid trigone lline (13), from
Mechanisms of Action Trigonella [oenum-graecum, is a plant growth inhibitor
and produces dormancy.
To understand how plant constituents can be hypoglyce- Salicylic acid (14) is also a plant growth inhibitor and hy-
mic in anima ls, it is worthwhile to consider the reasons why poglycemic agent (Oliver- Bever and Zahnd 1979). Thus,
compounds with hypoglycemic activity occur in plants. In plant meta bolism-regulating constituents can also be ani-
genera l, discussions of medicinal agents from plants center mal metabo lism-regulating agents. The variety of ways in
on plant secondary metabolites, i.e., non -ubiquitous con- which this may be possible will become more clear with the
stituents with no known essential role in the plant's metab - discussion of hypoglycemic mechanisms of action to follow.
olism. Possible active hypoglycemic constituents have been re-
It has been postu lated that bioact ive plant secondary me- ported for 88 (16 % ) of the plants used trad itionally as
tabol ites may playa role in chemical defense mechanisms antidiabetics and 62 (11 %) of the other plants screened.
(Ehrlich and Raven 1964, Berenbaum 1983). While the There are more than 200 pure compounds from plant
precise mechanisms that may be involved in chemically me- sources reported to show blood glucose lowering activity.
diated coevolution between plants and herbivores or path - Table 4 prov ides a summary of the chemical classes of these
ogenic organisms are controversial (Stro ng et al. 1984, compounds. The wide variety of chemical classes indicates
Spencer 1988), it has been suggested that natural selection that a variety of mechanisms must be involved in the lower-
would ensure the survival for reproduction of those indi- ing of the blood glucose level. Some of these compounds
viduals of a species having the gene coding for production may have therapeutic potential, while others may produce
of a tox in, while individuals without the toxin would be hypoglycemia as a side-effect of their toxicity, especially he-
consume d (Williams et al. 1989 ). patotoxicity.
Most hypoglycemic plant constituents, such as the Cath- Some of the compounds reported to be active in vitro or
aranthus alkaloids, might fit in this category, but there are at high doses in vivo, e.g., p-sitosterol-D-glucoside (daucos-
other rather common plant constituents for which this ex- terol, Fig. 3, 16), occur so widely in nature that therapeutic
planation is not entirely satisfact ory. At the cellular and activity seems unlikely. This could be due to their low con-
molecular levels, plants and animals are not very different centrat ion in the plant or co-occurrence with complexing
144 R. J. Maries and N. R. Farnsworth

Table 4. Hypoglycemic Natural Products

Chemical class Number active Chemical class Number active


Alkaloids 38 Peptides and amines 15
Carbohydrates 66 Phenolics (simple) 4
Coumarins 4 Phenolpropanoids 1
Cyanogenic gycosides 1 Steroids 7
Flavonoids 7 Stilbenes 1
Glycopeptides 20 Sulfur compounds 2
Inorganic salts 3 Terpenoids 17
Iridoids 4 Vitamins 2
Lipids 6 Xanthenes 1

or counteracting constituents. Some examples of plants hinda et al. 1986). Some confusion also prevails with hypo-
with known active constituents and known mechanisms of glycemic testing in normal animals (Rivera 1942, Pons and
action will be described below to show the range of active Stevenson 1943, Morrison and West 1982, Karunanayake
constituents and mechanisms of hypoglycemic action. et al. 1984, Meir and Yaniv 1985, Welihinda and Karuna-
nayake 1986).
Several active compounds have been isolated from M.
Peptides and Terpenoids from Momordica
charantia (Fig. 3), and some mechanistic studies have been
The most widely used traditional remedy for diabetes done. Khanna et al. (1981) have reported the isolation from
mellitus is Momordica charantia L. (Cucurbitaceae), com- the fruits, seeds, and tissue culture of seedlings, of "poly-
mon names for which are "bitter gourd," "balsam pear," peptide-p," a 17-amino acid, 166-residue polypeptide
"cundeamor," and "cerasee." The fruit, leaf, and stem have which did not cross-react in an immunoassay for bovine in-
been used to make an antidiabetic decoction (Rivera 1941, sulin. This peptide was shown to be "insulinomimetic"
Rivera 1942, Pons and Stevenson 1943, Ram 1956, Oakes when administered subcutaneously in rodent and primate
and Morris 1958, Khan and Burney 1962, Lotlikar and experimental assays and in a limited clinical trial with both
Rajarama Rao 1966, Jain and Sharma 1967, Morton 1967, juvenile- and maturity- onset diabetic patients. A number
Olaniyi 1975, Ayensu 1978, Halberstein and Saunders of other polypeptides from M. charantia seeds have been
1978, Aslam and Stockley 1979, Gupta et al. 1979, Ama- studied in vitro for the insulin-like activities of stimulation
son et al. 1980, Oliver-Bever 1980, Nagarajan et al. 1982, of lipogenesis and inhibition of corticotropin-induced lipol-
Morrison and West 1982, Mossa 1985, Bailey et al. 1986, ysis. The mechanism was suggested to involve interaction
Singh 1986). In anti hyperglycemic bioassays using oral, of the peptides with a-adrenergic or corticotropin receptors
subcutaneous, and intravenous dosing of mice, rats, and (Ng et al. 1986).
rabbits pretreated with anterior pituitary extract, alloxan, Another active constituent, charantin, has been isolated
or streptozotocin, and in diabetic humans, it gave different from both M. charantia and M. foetida, and identified as a
and often apparently conflicting results (Chatterjee 1964, mixture of two steroid glycosides: l3-sitosterol-D-glucoside
Khanna et al. 1981, Mossa 1985, Bailey et al. 1985, Weli- (15) and 5,25-stigmastadien-3-I3-ol-D-glucoside (16). Anti-
hinda et al. 1986). In a clinical trial with NIDDM patients, hyperglycemic activity in alloxan-treated rabbits and de-
73 % of the patients showed improved glucose tolerance pancreatized cats dosed p.o. or i.v. was equivocal, but hy-
with oral administration of M. charantia fruit juice (Weli- poglycemic activity was observed in normal rabbits, rats,

15 16
Fig. 3. Steroid glycosides of Momordica charantia reported to be hypoglycemic.
Antidiabetic plants and their active constituents 14 5

and cats dosed p. o., i.p., or i.v. (Lotlikar and Ra jarama Rao vate rati o, and an increase in AT P content s and energy
196 6). Stu dies per formed in vitro with M. charantia fruit cha rge potential (Benzi et al. 19 84 ). Tetrahydroalsto nine
extrac ts indicated a significa nt enha ncement of glucose up- (20), administered ora lly in rats wi th alloxan-induced hy-
tak e in mu scle tissue and of glycogen accumulation in mu s- perglycemia, produced a triphasic res po nse of a rapid-on set
cle and hepatic tissue, but no effect on glucose uptak e or hypoglycemia, a recovery period from 2-12 hours po st-
trigl yceride synthesis in adipose tissue (Meir and Yaniv treatment, and then a prolonged hypoglycemic effect last-
1985, Welihinda and Karunanayake 1986 ). Inhibition of ing mor e than 48 hours post-treatment (Kocialski et al.
glucose uptak e by intestina l fragment s was also observed 1972 ).
and attributed to a glycosidic consti tuent of th e frui t ex- In an in vitro study of the mechan ism of actio n of th e
tra ct (Me ir and Yaniv 1985 ). Thus, th ere appear to be con- quin oline deri vati ves, qu inolate an d 3-mercapto picolina te,
stituents of M. charantia with both pancreati c and extra - Sne ll (1979 ) rep orted th at hep ati c gluco neogenesis from
pancreat ic effects with th erapeut ic pot enti al for diabe tic lactate or alanine, and th e relea se fro m mu scle of alanine, is
pa tients. Ca ut ion is advise d, however, beca use a mildly tox - inh ibited thro ugh inhibitio n of cytosolic and mitochondrial
ic lectin has been reported from th e seeds and outer rind of ph osph oenolp yru vate carboxykin ase. Th e mechan ism in-
the fruits, which is capa ble of inte rfering with pr ot ein syn- volves a direct effect which is facilit at ed by complex forma-
the sis in the intestinal wall (Lampe and McCann 19 85). tion between the agent and Fe2+ or Mn 2 +, an inhibitory ac-
tion on the ferroactivat or-rnediated Fe2+ activation of cyto -
solie phos phoeno lpy ruva te ca rbo xy kinase, and indirec t ef-
Alkaloids from Catharanthus
fects by lowering of cytosolic oxaloac etate concentra tio ns
The M adagascar periwinkle (Catharanthus roseus IL.] G. th rou gh blocking th e tr an slocation of an ions such as 2- ox -
Don , Apocyna ceae), is ano ther widel y used tradition al rem- oglutarate from mito cho ndria, and inhibiting cytosolic
edy for diab etes, and a pr oprietar y preparation , Vinculin, asparta te aminotra nsferase.
was mar keted in England as a " treatment" for diab etes. Certai nly th e active alkaloids of Catharanthus co uld
Pharmacological studies have been conducted on periwin- serve as models for the development of new antidiabetic
kles since the 1920's, and while two studies of leaf aqueous drugs. Eleven indolizine alkaloids, synthesized as analogs
extract s administered ora lly to rabbits (Asthana and Mi sra of vincamine, vindolin e, and vind olinine, were tested for
19 79 ) and dogs (Mo rriso n and West 1982 ) reported a hy- or al hypoglycemic activity in fasted rat s, but the best was
poglycem ic respon se, man y other experiments with a varie - only one th ird as active as to lbutam ide (De and Sah a 1975).
ty of lab oratory an imals and limited clinical studies ha ve
given negative or at best equi vocal results (N oble et al.
Sulfur Compounds from Allium
195 8, Farnsworth 1961, Svobo da et al. 195 9 and 1964,
Farnsworth and Segclma n 1971 , Swanston-Flatt er al. T he hypogl ycemic pr inc iples of onio n (Allium cepa L.,
198 9 ). Liliaceae) and garlic (A. sativum L.) ar e the sulfur-contain-
Despite these disappointing results, Svoboda et al. (1964) ing compounds, allyl propyl disul fide (25 in Fig. 5) and di-
test ed for hypoglycemic activity a nu mb er of alkaloids (Fig. allyl disulfide oxide (allicin, 26). Activ e in normal and al-
4 ) isolat ed from C. roseus during an investigation of the loxan-diabetic an imals and patient s with NIDDM, but not
pl ant's onc olytic act ivity, which was discovered by No ble et pancreat ectomized ani ma ls, the y are believed to act by
al. (1958) while investigat ing th e plant's reputed antidiabet- competing with insul in, which has a disulfide link age, for
ic activity. Hypoglycemic activity was observed for catha- endoge no us sulfhydry l-rich insulin -inactivating com-
ranthine (17) , leurosine (18), lochn erine (19 ), tetr ah ydr oal- pounds (Augusti et al. 19 74 , Oliver-Bever and Zahnd
sto nine (2 0 ), vindo line (21), and vindo linine (22) . Adminis- 19 79). H owever, an ora l feeding study of garlic bul bs given
tered orally in a dose of 100 mg/kg, leuro sine sulfa te and to normal or streptozotoci n-dia betic mice showed redu ced
vindo linine hydrochloride were more hypoglycemic th an hyperph agia and polydip sia but no effect on hyperglycemia
tolbutamide, the commercial antidiab etic sulfonylur ea used or hypo insulinemia (Sw anston-Flatt et al. 1990).
as a positive control (Svoboda et al. 1964). Svoboda et al.
(1964 ) suggested th at to xicity of crude extracts an d frac-
Inorganic Ions from Atriplex
tion s (e.g., severa l of th e alka loids are potent cytotoxic
agents) may ha ve mad e th eir experimental antidiabe tic ver- Th e saltbush (Atriplex halimus L., Chenopodiaceae) was
ificat ion difficult, but tha t further stu dy of C. roseus as a investiga ted for antidia betic activity after sand rat s (Psam-
natural antidiabetic agent would be worthwhil e. momys obesus), tha t in nature feed extensively on the
Some progress has been made in th is dir ection. The Cath- leaves of this plant, developed diab etic symptoms after be-
aranthus and Vinca alkaloids, vinca mine (23) and (-)-ebur- ing captur ed and fed lab oratory rat cho w or fresh vegeta -
nam onine (24), have been shown to induce an extensive de- bles. The sand rat s have a genetic pred isposition to diabetes
crease in rat brain tissue glucose, a concomitant increase in that seems to be prevented by th e pr esence of chro mi um,
lactate and pyruvate concentrations and the lactate/pyru- manganese, and magn esium salts in the saltbush leaves.
146 R. J. Maries and N. R. Farnsworth

C0
2CH3

CH
30

17 18

CH
30

C0
2CH3

19 20

21 22

23 24

Fig. 4. Hypoglycemic alkaloids of Catharanthus roseus.

Studies of the leaf ash and chromium in vitro showed a po- able but the majority of patients showed an improved effi-
tentiati on of insulin-stimulated glucose utilization by epi- ciency of insulin. (Mertz 1993) .
didymal fat cells of chromium deficient rats. The mecha- Chronic administration of magnesium salts has also been
nism may involve Cr 2+ inactivation of an insulin-inactivat- shown to be beneficial in the treatme nt of NIDDM. Hypo-
ing enzyme (Aharonson et al. 1969, Oliver-Bever and magnesemia is a common finding in diabetic subjects. Mag-
Zahnd 1979). The reputed hypoglycemic activity of the nesium is a necessary cofactor for many enzymes and is in-
"glucose- tolerance factor" of brewer's yeast, Saccharomy- volved in protein synthesis. Treatment with magnesium
ces cerevisiae, which has been attributed to trivalent chro- salts resulted in a net increase in acute insulin response and
mium (Cr 3+), was contradicted by long-term feeding studies the rate of glucose disappearance after glucose loading
in genetically diabetic mice, in which no beneficial effect (Paolisso et al. 1989, White and Campbell 1993).
was seen (Flatt er al. 1989). Howe ver, chromium does pot- Other minerals may also playa role in diabetes pathogen-
entiate the action of insulin in vitro and in vivo. Maximal in esis and therapy. The protein tyrosine kinase associated
vitro activity requires mineral complexation, e.g. a chromi- with the insulin receptor has been shown to be Mn 2+ depen-
um-nicotinic acid complex . Clinical trial results were vari- dent (Reddy and Kahn 1988). Vanadium is another trace
Antidiabetic plants and their active constituents 147

CH2=CH-CH2-S-S-CH2CH2CH3

25

27

26
Fig. 5. Hypoglycemic sulfurcompounds from Allium spp.
~C02H

mineral whose salts have insulin-like properties in animal


- HNyJ::02H
o
models of insulinopenia or insulin resistance in vitro and in
vivo, due to stimulation of glucose metabolism. Like most 28
dietary trace mineral s vanadium is toxic in excess so its
therapeutic potential is being investigated carefully (Brich-
ard et al. 1991).
(CH3hN+CH2CH(NHCOCH3)CH2COO'

Amino Acids from B/ighia 29


Ingestion of unripe akee fruit (Blighia sapida Koenig, Sa-
pindaceae) causes the often fatal disorder "vom iting sick-
ness" in Jamaica. The emetic constituents were discovered (CH3)3N+CH2CH(NH2)CH2COO'
to be the cyc1opropanoid amino acid, hypoglycin A (27 in
Fig. 6), and its y-L-glutam yl dipeptide, hypoglycin B (28), 30
which are also potent hypoglycemics. Th ey appear to act by Fig. 6. Inhibitors fo fatty acid oxidation.
inhibiting p-oxidase enzymes, thus blocking oxidation of
long-cha in fatt y acids. Since the fatt y acids are no longer nase and cytochrome oxidase, thus increasing anaerobic
available as an energy source, hepatic glycolysis is stimulat- glycolysis and decreasing gluconeogenesis, resulting in en-
ed to provide an alternate source, and the increased utiliza- hanced glucose uptake and hypoglycemia. Biguanides are
tion of glucose brings about a fall in blood glucose levels. also known to inhib it glucose absorption from the intestine
Hypoglycin A is twice as potent a hypoglycemic as hypo- (Oliver-Bever and Zahnd 1979).
glycin B; the latter is also teratogenic, so these compounds
are too toxic to be used therapeutically, though they may
Vitamins, Coumarins, and Steroids from Trigonella
provide models for the development of new hypoglycemic
agents (Feng and Patrick 1958, von Holt et al. 1966, Tana- Fenugreek (Trigonella foenum-graecum L.), seeds con-
ka et al. 1972, Oliver-Bever and Zahnd 1979). tain a number of hypoglycemic principles , although an oral
In order to find a more specific inhibitor of free fatty acid feeding stud y performed with normal and streptozotocin-
oxidation, Kanamaru et al. (1985) screened microbial me- diabetic mice showed no significant effect of seed consump-
tabolites for substances that would inhibit the oxidation of tion on basal glucose and insulin, insulin -induced hypogl y-
long-chain fatty acids in rat liver mito chondria. This re- cemia, glycosylated hemoglobin, or pancreatic insulin con-
search led to the discovery of the ~-aminobetaines , emerice- centration (Swanston-Flatt et al. 1989 ). Trigonelline (Fig.
din (29) and its more potent synthetic derivative emeria- 2: 13), which is the N-methyl derivative and main human
mine (30), from the fungus Emericella quadrilineata IFO metabolite of the vitamin nicotinic acid (niacin, 11), has a
5859 (Trichocomaceae). Emeriamine was shown to be a po- weak and transient hypoglycemic effect when admin istered
tent and specific inhibitor of carnitine palmitoyltransferase orally to diabetic patients. It acts by slowing the metab-
I, and both compounds had dose-dependent oral hypoglyce- olism of nicotinic acid, also present in Trigonella, which is
mic and antiketogenic activities in fasted norm al, strepto- known to increase glucose uptake from the blood and its
zotocin-di abetic, and genetically obese (Zucker) rats. subsequent oxidation, if adm inistered orally. Nicotinic acid
is hyperglycemic if administered parenterally, by means of
impairment of carbohydrate utilization (Mishkinsky et al.
Guanidines from Ga/ega
196 7, Shani et al. 1974). Taken orally, nicotinic acid is con-
Seeds of the traditional antidiabetic plant, "go at's rue," verted in the body into nicotinamide, which is an inhibitor
(Ga/ega cfficinalis L., Fabac eae) contain the guanidine de- of the enzyme poly(ADP-ribose) synth etase, respon sible for
rivative, galegine (31 in Fig. 7). Like syntheti c biguanide the depletion of NAD from pancreatic p-cells, and is also a
hypoglycemics (6, 7), galegine blocks succinic dehydroge- potent hydroxyl-radical scavenger, by which mechanisms
148 R. J. Marles and N. R. Farnsworth

HN < NH
NH
2

~ <
31 7

Fig. 7. Comparison of the structures of galegine and metformin. 32

nicotinamide can prevent the ~-cell toxicity of streptozoto- ~o 0


cin and alloxan (Ledoux et al. 1988). Free-oxygen radicals
are important mediators of ~-cell destruction in IDDM, 33 34
and nicotinamide's antioxidant activity has been shown to
have some effect on preventing IDDM in high-risk individ-
uals and has a slight effect on residual insulin secretion in
newly diagnosed patients. Other antioxidants have been
tested in animal models with results suggesting prevention
of diabetes (Ludvigsson 1993).
Vitamin E (a-tocopherol, 32 in Fig. 8), which occurs in
seed oils and green leafy vegetables, has been shown at dos-
es of 600-1200 mg daily to reduce the levels of glycosylat-
ed hemoglobin in diabetic subjects independently of chang-
es in plasma glucose, which may help reduce the incidence
35
of diabetic complications (Ozden et a1. 1989, Ceriello
Fig. 8. Some antidiabetic constituents of Trigonella [oenum-grae-
1991).
cum.
Coumarin (33), another constituent of Trigonella, is pro-
foundly hypoglycemic in normal and alloxan-diabetic rats
(Shani et al. 1974). The mechanism for this observation by thickening the unstirred water layer adjacent to the in-
probably involves hepatotoxicity. Coumarin is hepatotoxic testinal villi (Leeds 1981, Karlstrom et al. 1987). Modifica-
in rats and dogs, where it is metabolized through 3-hy- tion of the physical and chemical characteristics of the in-
droxycoumarin to reactive quinone metabolites that bind testinal contents by leguminous gums might also modify
covalently to microsomal proteins. In humans and other the release of gastrointestinal hormones which influence in-
primates, however, coumarin is metabolized through 7-hy- sulin secretion and gastrointestinal motility (Forestieri et al.
droxycoumarin to a glucuronide conjugate that is rapidly 1989). Provision of purified guar fiber as tablets taken with
excreted, and no hepatotoxicity occurs (Cohen 1979). Sco- meals significantly reduced low-density lipoprotein choles-
poletin (34), another coumarin constituent of Trigonella, terollevels but did not improve excessive postprandial gly-
exerted borderline hypoglycemic effects in normal and al- cemia in NIDDM patients in whom near-normal fasting
loxan-diabetic rats at high doses (Shani et al. 1974). Fenu- plasma glucose levels had been obtained with diet, sulfo-
greekine (35), a steroidal sapogenin-peptide ester, is an- nylurea, or human ultralente insulin therapy (Holman et a1.
other hypoglycemic constituent (Ghosal et a1. 1974). 1987). Patient compliance may be a problem with pure
guar gum due to its unpalatability and tendency to cause
abdominal distension and diarrhea, but incorporation into
Complex Carbohydrates and Postprandial
high-carbohydrate foods has been shown to provide even
Blood Glucose
more effective blunting of the postprandial glycemic profile
Seeds of a number of other members of the Fabaceae are without gastric distress (Briani et a1. 1987).
used traditionally to treat diabetes. In addition to direct hy- Some legumes also contain low levels of lectins, which if
poglycemic effects of their constituents, dietary effects are incompletely destroyed by inadequate cooking, might ac-
also important. Clinical studies of high legume diets celerate intestinal motility and increase mucus secretion,
showed improvement in many of the indices of blood glu- thus modifying absorption of glucose (Leeds 1981). The
cose control, especially postprandial levels. Beans are high antidiabetic activities of a number of other plant gums were
in complex carbohydrates which are more slowly digested attributed to inhibition of gluconeogenesis and stimulation
than other types of starch. Non-cellulosic types of dietary of peripheral glucose utilization, not to interference with
fiber such as carob gum and guar gum, high-molecular- intestinal absorption of glucose (Al-Awadi and Gumaa
weight galactomannans from Ceratonia siliqua L. and Cya- 1987). Some structure-activity relationships of hypoglyce-
mopsis tetragonoloba (L.) Taub., respectively, slow intesti- mic plant mucilages have been studied (Tomoda et al.
nal absorption of glucose by slowing gastric emptying and 1987). Intestinal bacterial fermentation of leguminous olig-
Ant idiabetic plants an d their active constituen ts 149

mulb erry (Morus alba L., Moraceae) root bar k and also

~
2 0H

HO ~ leaves of ]acobinia (Acanthaceae) and cultures of Bacillus


and Streptomyces, inh ibits intestinal a -glucosidase potently
HO HO
HN
~3 but only weakly inhi bits ~-glucosi da se, glucoamylase, and
a- amylase (Yoshikuni 1988). Miglitol (39), prep ared semi-
HO HO o~20H synth etically from moranoline, is an a-glucosidase inhibi-
tor which, unlike acarb ose, is absorbable from the gastroi n-
HO
testinal tract. It may exert inhibitory effects on nonintesti-
HOo~
~HHO
nal a -glucosidase present in various cell types, and has been
clinically evaluated as a hypoglycemic agent in both 100M
HO and N IOOM (Reuser and Wisselaar 1994 ).
OH

36
H ypoglycem ic Glycans

HO~
H ikino's research group (Hikin o et al. 1985a-c, 1986a-c,
_T~~H 198 8, Konno et a!. 1985a-e, Tak ah ashi et al. 1985a,b,
OH HO~~ 1986, Tomoda et al. 1987, 1990) has isolated a variety of
HO HO OH glucans , pept idoglucans, and heteroglycans from plants
OH used in oriental tra ditional medicine. Th ese compl ex carbo-
38 hydrates, with molecular weight s ranging from approxi -
37
mately 1000 - >10,000,000 amu , were shown to have re-
mark a ble hypoglycemic activity when administered intra-
20 H / CH2CH2OH

8
peritoneally (i.p.) to normal, alloxa n-hyperglycemic, and
HO spontan eously diab etic mice.
HO OH The mechanism of action of th e glucan aconitan A, from
Aconitum carmichaeli Oebeaux (Ranunculaceae), involves
significant potenti ation of the activity of hepatic ph ospho-
39
fructok inase. Accelerat ion of glycolysis in the liver was ac-
Fig. 9. Hypoglycemic intestina l enzyme inhibitors. compa nied by some increase in hepatic total glycogen syn-
th etase, but liver glycogen content and pla sma and liver
osaccharid es and fiber, in additio n to producing a feeling of cholestero l and triglycerid e contents were unchanged, indi-
satiety that might aid in compliance with a fixed diet, pro- cating that th e conversion of glucose into glycogen or lipids
duces short-c hain fatty acids which are th en absorbed and does not contribute to th e hypoglycemic activity of aconi-
affect metabolic processes relevant to dia betic control, such tan A. Plasma insulin levels and insulin binding to isolated
as hepatic gluconeogenesis (Leeds 1981 ). adip ocytes also were unaffected. Stimulation of glucose up-
A microbial product, acarbose (36 in Fig. 9), isolated ta ke and metabolism in small intestine tissues was ob-
from strains of Actinoplanes sp. (in the or der Actinomyce- served. Thus, stimulation of glucose utiliza tion in the liver
tales) (Hi llebrand 1987), is known to inhibit the intestinal and peripheral tissues is the main mecha nism for the hypo-
a- glucosidases, y-amylase, sucrase, and maltase. Th is ac- glycemic activity of aco nitan A (Hikino er al. 1989a).
tion reduces the release of glucose from car bohydra tes, re- Gano deran B, a glycan from Ganoderma lucidum Kar-
sulting in a do se-related delay in, or reduction of, the post- sten (Polyporaceae), increases the plasma insulin level in
prand ial increase in blood glucose an d triglycerides, dimin- normal and glucose-loaded mice, increases the activi ties of
ished prevalence of dia betic nephro path y, as well as in- hepatic glucokinase, ph osphofru ctokinase, and glucose-6-
creased insulin bind ing in muscle (Hillebrand 1987, Yoshi- ph osphate dehydrogenase, decreases the activities of he-
kuni 1988, Le Marchand-Brustel et al. 1990, Hanefield et pati c glucose-e-phosphatase and glycogen synthetase, and
al. 1991). reduces hepatic glycogen content. The observ ed stimu-
Castanospermine (37), an indol izidine alkaloid isolated lation of glucose metabolism in a homogenate of the
from Castanospermum australe A. Cunn. (Fabaceae), is an- small intestine suggests that accelera tion of glucose util-
oth er example of an intestinal enzyme inhibitor with hypo- izat ion may also occur in peripheral tissues (H ikino et al.
glycemic activity. Structurally, casta no spermine shares sim- 1989b ).
ilar ities with the pyran ose form of glucose in th e orienta - Panaxans A-E, glycans of ginseng (Panax ginseng CA.
tion of its hydro xyl groups. It blocks the hyperglycemic re- Meyer, Ara liaceae), show different mechan isms of action
sponse to oral doses of sucrose through inhibition of disac- despite their similar struc tur es. Panax ans A and B stimulate
charase, but does not reduce glucose-induced hyperglyce- hepatic glucose utilization by increasing the activity of glu-
mia (Rhinehart et a!. 198 7). Moranoline (38), isolated from cose-e-phosphate dehydrogenase, phosphorylase-a, and
150 R.]. Maries and N. R. Farnsworth

larizing the ~-cells by inhibiting the ATP-sensitive K+ chan-


nel, which has been suggested to be the ~-cell receptor for
sulfonylureas. The alkaloid quinine (41 in Fig. 11) is also a
potent blocker of this channel, although, unlike the sulfon-
ylureas, it also blocks Ca2+-activated K+ channels (Cook
and Ikeuchi 1989).
Intracellular cAMP also acts as a second-messenger in the
~-cells. Increasing the intracellular cAMP concentration

40 potentiates cholecystokinin- and glucose-stimulated insulin


release. The mechanism involves synergistic action with the
Fig. 10. Sapogenin of ginsenosides and panaxosides: protopana- influx of Ca2+ that occurs as a consequence of the glucose
xadiol R3 = H, protopanaxatriol R3 = OH; sugars in glycosides are metabolite-induced increase in intracellular K+ (Hill et al.
attached to oxygens at R1-R3 1987). The physiological actions of glucagon result from
stimulation of cAMP synthesis, which in pancreatic ~-cells
phosphofructokinase. Panaxan A decreases the activity of forms part of the pancreatic hormone regulatory mecha-
glucose-6-phosphatase but does not affect hepatic glyco- nism (Lamer 1980). The role of second-messengers in insu-
gen content. Panaxan B has no effect on glucose-e-phos- lin action has been reviewed by Saltiel (1990).
phatase but decreases glycogen synthetase activity and he- The most famous plant product for the stimulation of
patic glycogen content. Panaxan A does not affect plasma intracellular cAMP is forskolin (42), a diterpene from Cole-
insulin levels and insulin sensitivity, but panaxan B elevates us forskohlii (Poir.) Briquet (Lamiaceae). It is an adenylate
the plasma insulin level by potentiating insulin secretion cyclase activator which increases intracellular cAMP by
from pancreatic islets and enhances insulin sensitivity by stimulating its biosynthesis. Theophylline (43) and other
increasing insulin binding to receptors (Suzuki et al. methylxanthenes from Camellia sinensis (L.) Kuntze (Thea-
1989a,b). ceae) and !lex guayusa Loesner (Aquifoliaceae), and papav-
Ginseng contains a number of other hypoglycemic con- erine (44) from Papaver somniferum L. (Papaveraceae), are
stituents, with different mechanisms of action. Adenosine phosphodiesterase inhibitors which increase intracellular
was isolated from a water extract of the rhizomes by bioas- cAMP by preventing its breakdown (Gearien and Mede
say-guided fractionation, and was shown to enhance lipo- 1981, Hill et al. 1987, Zawalich et al. 1988). Theophylline
genesis and cyclic adenosine monophosphate (cAMP) accu- is orally hypoglycemic when administered chronically to
mulation in adipocytes, which possess specific adenosine normal rats, but this in vivo effect was not attributed to its
receptors. Some of the sterol glycosides known as ginseno- phosphodiesterase inhibition, but rather due to its induc-
sides (40 in Fig. 10) inhibited adrenocorticotropin-induced tion of intracellular Ca 2+ efflux. Increased extracellular
lipolysis and at the same doses suppressed insulin-stimulat- Cal. might enhance calcium-stimulated ATPases, which
ed lipogenesis, while others stimulated the release of insulin would result in decreased cellular ATP levels, enhanced li-
from cultured islets (Waki et al. 1982, Ng and Yeung polysis, and reduced glycogenolysis. This effect is also seen
1985). with administration of caffeine (45) (Tobin et al. 1976).
Sodium salicylate (salt of 14) inhibits cyclooxygenase,
thus preventing the metabolic cascade from arachidonic ac-
Plant Constituents that Modulate Intracellular Second-
id to the prostaglandins. Inhibition of ~-cell PGE2 synthesis
Messengers
increases glucose-induced insulin secretion because this
Pancreatic ~-cell membranes possess adenosine triphos- prostaglandin binds to specific ~-cell receptors that are cou-
phate (ATP)-sensitive K+ channels which, in the absence of pled to regulatory components that inhibit adenylate cy-
glucose, allow an efflux of K+ to contribute a hyperpolariz- clase. Inhibition of this enzyme would lead to a decrease in
ing membrane current that maintains the hyperpolarized intracellular cAMP (Robertson 1988). Additionally, arach-
resting membrane potential of the cell. Metabolites of glu- idonic acid (46) itself is an insulin secretagogue, acting to
cose and amino acids inhibit this channel, causing a reduc- mobilize Ca2+, increasing its free cytosolic concentration,
tion in the hyperpolarizing current, which leads to ~-cell and to activate protein kinase C (Metz 1988).
depolarization and voltage-dependent Ca 2+ uptake. Bind- Carbohydrate components of the diet stimulate the re-
ing of Ca 2+ to calmodulin results in microfilament contrac- lease of the hormone "gastric inhibitory polypeptide,"
tion, resulting in exocytosis of insulin from storage gran- which is thought to influence insulin secretion by elevating
ules. Intracellular ATP is believed to have a second-messen- islet ~-cell cAMP levels. The activity of cAMP is also syner-
ger role in inhibiting the K+ channel by almost 99 %, thus gized by phosphoinositide-derived second-messenger mole-
making the ~-cell very sensitive to changes in channel activ- cules generated during the phospholipase C-mediated
ity (Cook et al. 1988, Misler et al. 1989). Tolbutamide (2) cleavage of membrane phospholipids in the ~-cell. This hy-
specifically mimics the effects of glucose stimulation, depo- drolysis is thought to be activated by the interaction of ex-
Antidiabetic plants and their active constituents 151

~
HO" ""' =
" : 0
OH
" OCOCH3
" H OH

41 42 43

44 45 46

HOYjoi :"1 .& HO


~ 'OH
& H OH

OH
OH

HO
OH

OH

OH OH 0 OH 0
47 48 49

50

Fig. 11. Modulators of intracellular second-messenger systems.

tracellular hormones and agonists with a specific mem- When insulin binds to the extracellular a-subunit of its
brane receptor (Zawalich 1988) . heterodimeric cell surface receptor, the insulin-receptor
The flavonoid , (-)-epicatechin (47), isolated as the active complexes aggregate along the plasma membrane and are
principle of the traditional antidiabetic plant Pterocarpus then internalized rapidl y. Activation of a Mn 2+-dependent
marsupium Roxb. (Fabaceae), has been shown to cause an protein tyrosine kinase in the transmembrane ~-subunit en-
ATP-dependent enhancement of glucose-stimulated insulin sues, resulting in phosphorylation of the receptor and other
secretion from isolated islets, and to cause a rise in islet in- proteins with phosphate groups from ATP (Reddy and
sulin content in vivo in rats. Inhibition of cAMP phospho- Kahn 1988). Activation of a phosphatidylinositol-specific
diesterase and stimulation of insulin biosynthesis were sug- phospholipase C leads to hydrolysis of a membrane glycan
gested to be the mechanisms for the observed effects (Hii phosphoinositide. This produces a cyclic inositol phos-
and Howell 1984) . The flavonoids quercetin (48) and my- phate-glucosamine second-messenger that activates phos-
ricetin (49) have also been reported to be hypogl ycemic phodiesterase, decreasing intracellular cAMP, and also pro-
(Rahman and Zaman 1989 ), but they are known to be po- duces diacylglycerol, which activates protein kinase C (Sal-
tent inhibitors of protein tyrosine kinase (Geahlen et al. tiel et al. 1986). Protein kinase C regulates a number of en-
1989), the activity of which is essential in the post-receptor- zymes and the insulin receptor through phosphorylation
binding activity of insulin. (van de Werve 1985a).
152 R.]. Maries and N. R. Farnsworth

Some tumor-promoting phorbol esters, such as 12-0-tet- induced hepatic glycogenolysis and hyperglycemia, but not
radecanoylphorbol-13-acetate (TPA, 50), share structural glycogenolysis in skeletal muscle. These effects are not cor-
similarities with diacylglycerol, and are potent activators of related with their well-known smooth muscle effects, and
protein kinase C (van de Werve et al. 1985). Phorbol esters may not be due to a specific a-receptor effect (Weiner
are diterpenes isolated from species of Euphorbia and a few 1980). Dihydroergotamine (51 in Fig. 12) and yohimbine
other genera of the Euphorbiaceae (Kinghorn 1983), 30 (52), another a-adrenergic blocking alkaloid from Pausi-
species of which have been associated with the treatment of nystalia yohimbe (K. Schumann) Pierre (Rubiaceae), pre-
diabetes. Phorbol esters have been reported to have a num- vented epinephrine-induced inhibition of insulin release,
ber of insulinomimetic effects, including stimulation of glu- but not diazoxide-induced inhibition (Henquin et al. 1982).
cose transport, lipogenesis, and amino acid uptake. How- However, yohimbine is also a monoamine oxidase inhibitor
ever, they may reduce insulin receptor affinity for insulin, and is contraindicated for patients with diabetes (Tyler et
insulin stimulation of glucose transport and lipogenesis, al. 1993).
and basal glycogen synthesis (Sowell et al. 1988). It has Beta-adrenergic blocking agents reduce the hyperglyce-
been suggested that phorbol ester-stimulated serine phos- mic response to epinephrine by blocking its stimulation of
phorylation of insulin receptors may be associated with a cAMP production. Epinephrine-induced glycogenolysis in
decrease in the affinity of the receptor for insulin and de- heart and skeletal muscle and lipolysis in isolated rat adi-
creased receptor tyrosine kinase activity, although conflict- pocytes is inhibited. Bythese mechanisms, the non-selective
ing results have been reported (van de Werve et al. 1985a, ~-adrenergic blocking agent, propranolol, slows the post-
Obermaier et al. 1987, Sowell et al. 1988). Ishizuka et al. insulin recovery of glucose concentration and prevents the
(1991) found that phorbol esters, glucose, and insulin usual rebound of plasma glycerol, while not affecting plas-
translocatively activate protein kinase C, resulting in a sub- ma glucose or insulin concentrations in normal individuals,
sequent down-regulation of protein kinase C and insulin- or the rate or magnitude of the fall of plasma glucose after
stimulated glucose uptake in adipocytes. This contributes insulin (Weiner 1980). Beta-adrenergic blocking agents can
to impaired responsiveness of the glucose transport system also reduce insulin resistance caused by ~-adrenergic stimu-
after prolonged insulin and/or glucose exposure. Phorbol lation (Attvall et al. 1987). Kimura et al. (1988) suggested
esters can inhibit aI-adrenergic stimulation of glucose pro- a possible ~-adrenergic blockade mechanism for the hypo-
duction by inhibiting phosphorylase activity, also through glycemic activity of an orally-administered aqueous extract
their effect on protein kinase C (van de Werve et al. 1985b). of Ganoderma lucidum (Leyss. ex Fr.) P. Karst (Ganoder-
They can also inhibit glucagon-stimulated adenylate cy- mataceae).
clase, but the metabolic significance of this is much less Reserpine (53), from Rauvolfia serpentina (L.) Benth. ex
than that of their inhibition of aradrenergic effects (- Kurz (Apocynaceae), is an adrenergic blocking agent that
Garcia- Sainz et al. 1985). Tumor promotion may also be causes intracellular depletion of catecholamines and serot-
explained by phorbol ester activation of protein kinase C onin. Uptake of catecholamines is also antagonized by inhi-
(van de Werve et al. 1985a). bition of the ATP-Mg2+-dependent uptake mechanism of
the chromaffin granule membrane. A transient sympa-
thomimetic effect is seen only after parenteral administra-
Plant Hypoglycemics Acting by Adrenergic Effects
tion of relatively large doses; pharmacological effects of the
In addition to the aI-adrenergic inhibition described released catecholamines are minimal unless monoamine
above for tumor-promoting phorbol esters, a number alka- oxidase has been inhibited (Weiner 1980). Reserpine en-
loids are known to affect blood glucose levels by a similar hanced the hypoglycemic effect of insulin and the hypergly-
mechanism. In normal patients, there is no effect of n-, ~-, cemic effect of epinephrine in normal subjects. In glucose
or a+~-blockade on the slope of glucose-potentiated insulin tolerance tests it inhibited the hyperglycemic response, even
secretion. In patients with NIDDM, only selective a-adre- in diabetic patients (Ricci and Ricordati 1955). However,
nergic blockade increases glucose-potentiated insulin secre- hypoglycemia is not reported as a significant side-effect of
tion, through both a decrease in an endogenous overactive reserpine, nor are interactions with other hypoglycemic
a-adrenergic stimulation and an increase in synaptic cleft drugs listed (American Pharmaceutical Association 1976).
norepinephrine levels, which results in an increase in islet ~
adrenergic stimulation. Thus, a chronic decrease in islet a-
Photosensitizers and IDDM
adrenergic stimulation may be a useful adjunct to NIDDM
management (Broadstone et al. 1987). Insulin-dependent diabetes may arise through T-lympho-
Ergot alkaloids, occurring in fungi such as Claviceps pur- cyte mediated ~-cell destruction. One possible novel ap-
purea (Fries) Tulasne (Hypocreaceae) and at least one proach to interrupting this pathogenic process is photo-
group of higher plants, Rivea corymbosa (L.) Hallier f. and pheresis, whereby lymphocytes would be treated with a
closely related Ipomoea and Argyreia species (Convolvula- photosensitizer such as 8-methoxypsoralen (54 in Fig. 13)
ceae), are a-adrenergic blockers which inhibit epinephrine- and UVA radiation to cause a change in the antigenicity of
Antidia betic plants an d their active constituen ts 153

~
'oY oA o
OCH
3

54 55

OH Fig. 13. Plant-derived phot osensitizers.

51 52
In Vivo Techniques
Techniques for the study of hypoglycemic activity in vivo
employ animals with norm oglycemia or induced hypergly-
cemia, as well as diabetic hum ans. Meth ods used to experi-
mentally induce hyperglycemia include load ing with glu-
cose or cholesterol, treatment wit h drugs such as alloxan,
streptozotocin, 2,4- dinitrophenol, and diazoxide, hor-
mon es such as epinephr ine, glucagon, corticotro pin, soma-
totropin, and anterior pituit ary extrac t, and surgical proce-
53 dur es such as part ial or full pancreatectomy. Genetically
obese and hyperglycemic animals such as Zucker fa/fa rats
Fig. 12 . Adrenergic-blocking hypoglycemic alkaloids.
(e.g. Rosen et al. 1986, Young et al. 1991 ), yellow KK mice
(e.g. Kanamaru et al. 1985), spo nta neously diabetic mice of
the treated lymph ocytes. Th is is postulated to cause a vac- strain C57BUKsj -db/db (Suzuki and Hik ino 1989), and
cination-like effect in the patient when they are retrans- sand rats (Psammomys obesusi (e.g, Aharonson et al.
fused at repeated intervals into the patient. This ha s proved 196 9) have also been used.
effective in other aut oimmune diseases and is now in clini- The most popular in vivo model s for diabetes are rodents
cal trials for IDDM (Ludvigsson 1993 ). Phot osensitizers treated with alloxan (56 in Fig. 14 ) or stre ptozotocin (57) .
have been isolated from more than 30 flowering plant fam- Th e history and mechan ism of alloxa n, a pyrimidine deriv-
ilies (both mono cots and dicots) and represent a wide range ative, has been reviewed by Lenzen and Panten (1988), who
of chemical classes includin g: po lyacetylenes, th ioph enes, point out that, while it is a very selective to xin of pancreat-
lignans, porphyrins, quin ones, chrome nes, benzofurans, fu- ic ~-cell s through its inhib ition of glucokinase, thu s making
rofla vonoids, furocoum arins (e.g. 54 ), furochrom ones, fu- it a good model for diabetes mellitus, there are a numb er of
roqu inoline alkaloids, and ~-carbol ine alkaloids (Downum pro blems with its use. Alloxa n's chemical instability, rapid
19 86, Hudson 1990 ). A thiophene such as n-terthienyl (55) metabolism, thiol reactivity, and effects of facto rs such as
may have an advantage over 8-methoxypsoralen in these diet, age, and species, have made it almost impos sible to es-
appl ications because of its lack of genotoxicity (Mac Rae et tabli sh a clear relati on ship between the dose of alloxan and
al. 1980 , Tuveson et al. 1986). Structure-activity relation- its effective concentra tion in the pancreas. Thu s it is diffi-
ship studies of thiophenes have shown the possibility of cult to be certa in of the extent of ~-cell inhibition and ne-
achieving some cell or organism specificity despite the gen- crosis from a particular dose of alloxa n.
eral mechanism of actio n involving singlet oxygen genera - Streptozo tocin, also know n as streptozocin, is a natural
tion (Ma ries et al. 1992). nit rosou rea glycoside isolated from Strepto myces achromo-
genes, which also causes degenerat ion of pancreat ic p-cells.
A single dose in the neon atal rat can produ ce an experi men-
Plant Hypoglycemic Drug Screening tal model of NIDDM, characterized by deficient insulin
Methodology biosynth esis and release in response to glucose and dimin-
ished pancreatic insulin content. There is a selective lack of
Scientific investigation of traditional medicines, as in the sensitivity of the ~-cells to glucose and glyceraldehyde, but
examples provided above, has resulted in the discovery of a continued response to other secretagog ues. Th e insensitiv-
numb er of promi sing leads for new antidiabetic agents. ity of the islets to glucose is associated with deficient islet
Modern drug discovery require s a systematic approach to glucose metab olism, pro bably due to a streptozo tocin-in-
optimize time and resour ce use for testing the maximum duced alteration in islet mitochondri al function (Portha et
num ber of samples in bioassa ys which hopefully are predic- al. 1988) . Look ing at ad ipocyte insulin binding and glucose
tive for therapeutic efficacy. These ap proa ches to bioassay - tr ansport, however, Fant us et al. (1987) concluded that the
guided antidiabetic drug discovery can be divided into two neonat al streptozotoc in-injected rat model did not provide
main classes: in vivo and in vitro techniques. a complete representati on of hum an NIDDM.
154 R. J. Maries and N. R. Farnsworth

~2~H
H~H NHCON(NO)CH
3

56 57

Fig. 14. Commonly used drugs for creating models of diabetes 58 59


mellitus.
Fig. 15. Hypoglycemic alkaloids from Tecoma.

For a model of IDDM where there is a total absence of~ There is extensive evidence for involvement of both cellu-
cell function, pancreatectomy is sometimes used. However, lar and humoral immune phenomena in the destruction of
at least in rabbits, due to the extended distribution of the pancreatic ~-cells characteristic of IDDM (Spencer and
pancreas and its close association with the duodenum, a to- Cudworth 1983, Bottazzo 1986, Montana et al. 1989). Im-
tal pancreatectomy may not be feasible or totally successful munosuppressive drug therapy has been recommended in
if attempted. An in vivo bioassay employing surgical re- some cases of IDDM (e.g. Vardi et al. 1986). An enzyme-
moval of the pancreas and a complementary injection of al- linked immunosorbent assay (ELISA) has been developed
loxan was shown to give blood glucose values significantly as a means of quantifying humoral immune responses in
different from those of animals with only surgical interven- rats exposed to immunomodulating chemicals (Koller et al.
tion (Ibanez-Camacho et al. 1983). 1983). This assay could be used for screening plant extracts
A further complication of in vivo hypoglycemic screening and isolates for immunomodulating activity.
was described during an investigation of aqueous extracts Unquestionably, in vivo bioassays are essential to prove
of Tecoma stans Juss. (Bignoniaceae). Although initial in vi- the value of new hypoglycemic agents. However, whole an-
vo hypoglycemic screening of the extract gave inconclusive imal tests reveal relatively little about the mechanism of ac-
results, chemical investigations resulted in the isolation of tion of the compound, and it can be seen from the previous
two monoterpene alkaloids, tecomanine (58 in Fig. 15) and section that there are a great many mechanisms by which
tecostanine (59), which were shown to be hypoglycemic blood glucose levels may be reduced. Some of these mecha-
when administered i.v. or p.o. in rabbits (Hammouda et al. nisms, such as those involving hepatotoxicity, are obvious-
1964, Hammouda and Amer 1966). The crude aqueous ex- ly not useful in diabetes therapy. The lack of perfect models
tract of the plant, when administered i.v. to fasted dogs or for NIDDM and IDDM, coupled with financial restrictions
i.p. to glucose-loaded rats, produces a sharp but transient on obtaining and maintaining animals, and social restric-
(10 min) fall of arterial blood pressure and a transient tions on extensive use of animals in experimentation, indi-
(180 min) but significant hyperglycemia due to induction of cate that a more practical approach would involve a series
hepatic glycogenolysis and subsequent elicitation of insulin of in vitro prescreens before testing a potential new hypo-
release. This was followed by a slight hypoglycemia with a glycemic agent in animals. This is in agreement with the po-
maximum decrease of the blood glucose level occurring sition statement of the American Diabetes Association
from five to six hours after injection (Lozoya-Meckes and (1990) that antidiabetic research should use alternative
Mellado-Campos 1985, Meckes-Lozoya and Ibanez-Cama- methods to live animals when appropriate.
cho 1985). Further investigations determined that the in-
itial hypotension and hyperglycemia could be abolished by
In Vitro Techniques
administration of antihistamines or by filtration of the ex-
tract with a 0.5 urn pore-size membrane capable of retain- Many in vitro techniques have been developed to eluci-
ing high molecular weight compounds such as proteins and date the varied mechanisms of action of hypoglycemic
kinins, which might cause the release of histamine. The late agents discovered by in vivo bioassays. For the purpose of
hypoglycemic effect remained, and thus is not secondary to screening large numbers of plant extracts and chromato-
the initial hyperglycemia (Meckes-Lozoya and Lozoya graphic fractions in order to isolate novel hypoglycemic
1989). agents, some of these in vitro bioassays should be employed
A number of other plants, including Allium cepa, A. sati- as the first steps rather than the last steps of drug discovery.
va, Brassica oleracea, Hordeum vulgare, Oplopanax hor- Three aspects of the hypoglycemic response are common-
ridum, Phaseolus vulgaris, Saccharomyces cerevisiae, Urti- ly studied in vitro: insulin release from the pancreatic islets,
ca dioica, and Vaccinium myrtillus have been reported to peripheral insulin binding and glucose utilization, and ef-
contain hyperglycemic as well as hypoglycemic constituents fects on hepatic enzymes.
(Oliver-Bever and Zahnd 1979). Caution should therefore For studying the effect of potential hypoglycemic agents
be employed in interpreting the results of in vivo adminis- on the release of insulin, perfused pancreas, intact isolated
tration of crude extracts. islets, and dispersed islet cell techniques have been devel-
Antidia betic plants and th eir active constituents 155

oped. Cha racteristics of insulin and glucagon release from 1988) may soon rep lace radioimmunoassay as th e meth od
th ese prepar ations have been studied comparatively by of choice .
Weir et al. (19 86). Most of the origina l work was done with
tissues fro m rats, for which the exp erimental techn iques of
isolati on and culture are well establ ished (Lamer and Pohl Toxicity of Hypoglycemic Plants
1984a,b, 1985, Pipeleers 1986, 198 7, Pipeleers et al. 1991).
More appro priate to large scale screening proc edure s are If most hypog lycemic plant cons tituents have arisen
the techn iques of Ricord i et al. (1986, 1988) for the mass th rough coevolut ion as chemical defense compo unds, then
isolat ion of porcine and human pancreat ic islets. M uch of it shou ld be recognized th at for th e source plant's surviva l,
the recent work on the mechanism of sulfonylureas at the th e best strategy is a non-selective toxin which will deter
cellular and subcellular level ha s been don e with cultured ~ herbi vor y regardle ss of th e species of herbivore attacking it.
cells (e.g., Boyd 1988, Go rus et al. 1988, Ga rvey 1992 , Often th e developm ent of new drugs fro m plants does not
Lienh ard et al. 1992 ). involve increas ing the potency of the lead natu ral product
N on-in sulin-depend ent diabetes mellitus is not due just becau se th is has been optimized by millions of years of co-
to a defect in the ~-cell s, but rather to a collusion betw een evolution. Rather, th e task is to achieve optimum selectivity
~-cells , the liver, and peripheral tissues (DeFronzo 1988, and minimize gener al toxicity. Quantitative structure-activ-
1992 , Mu eckler 1990, Gra nner and O' Brien 1992 ). Hepat- ity relat ionship an alysis is an essent ial tool for achieving
ic involvement in diabetes and its therap y has been studied th is goal.
in pr imar y cultures of rat hepatocytes (e.g., Salhanick et al. Wh ile a long histor y of tradition al medicinal use ma y
1983, Rinninger et al. 1984, Mc Cormick et al. 1986 ) using suggest that a plant is relat ively non- toxic, thi s sho uld be
techniques developed by Fry et al. (1976 ) and Bellemann et confirmed by in-depth literature review and properly-con-
al. (1977). M ore recentl y, a hum an hepat oma cell line has trolled experimenta l bioassays. Some of the reports of tox-
been used to study insulin receptors (McClain and Olefsky icity for antidia betic plants ar e derived fro m case studies or
1988). Hikino 's gro up ha s don e mechan istic studies on Poison Co ntrol Center reports of hum an poisoning or inju-
plant hypoglycemic agents with a var iety of hepatic enzyme ry. Species known to contain to xic constituents, such as
preparat ions (Hikino et al. 1989a,b, Suzuki and Hikino pyr rolizidine alkaloid s, were record ed in the database for
198 9). this review as toxic, even though the actual con centrati on
For stu dying in vitro insulin resistanc e, insulin internal- in the plant may not be known.
ization, and glucose tra nspo rt in periph eral tissues, th e Infor mati on was also included from acute toxicity stud-
most commo n techniques involve cultures of skeleta l mu s- ies. Usua lly perf ormed by i.p. injection of extracts int o ro -
cle strips or cells (Beck-Ni elsen et al. 1992 ) or adipocytes dent s, they do no t necessarily relat e closely to hum an oral
derived fro m rat epididyma l pad s (Jochen and Berha nu toxicity (Irwin 1962 ). Also, the techn ique is not employed
1987) or from hum ans by surgical excisio n (Kashiwagi et with as much sta ndardiza tio n as it should be, e.g., extrac ts
al. 1983) or less invasive needle biopsy (Yki-j arv inen et al. ar e prepared differentl y, and mortality ma y be record ed af-
198 6 ). The effect of natural products on glucos e uptake ter 24 hours (der M ard erosian et al. 1976) or 7 to 14 days
and metabolism in periph eral tissu es has also been studied (Klaasen 1980). For thi s study a plant was considered tox-
by use of fragments or a homogenat e of the rat's sma ll in- ic if the median lethal dose (LD so) by i.p. administra tion in
testine (Hi kino et al. 1989a,b ). T hese meth od s could also mam mals was 500 mg/kg or less.
be ada pted to use lar ger animal tissues ava ilable fro m Approximately one -third (377 species) of the plants asso-
slaughterho uses. ciated with the tr eatm ent of diabetes are to be considered
Screen ing techn iques have been develop ed to detect in vi- toxic by the ab ove criteria, while for another third their
tro nat ural products that show immu noreactivity with safety is uncert ain. In some cases, such as the ingestio n of
guinea pig insulin (de Pablo et al. 1986), inhibitio n of long unripe akee fru it (Blighia sapida Koenig, Sapindaceae), tox-
cha in fatty acid oxid ation (Kana ma ru et al. 1985), eleva- icity is expressed in part as a pr ofound hypo glycemia
tion of intracellular cAMP concentrat ion (Swanson et al. cau sed by the constituents, hypoglycin A and B (27 and 28
198 8), and inhib ition of protein-t yrosine kinase activity in Fig. 6). There are many othe r tox icological effects of
(Geahlen et al. 19 89). pla nts which may result in hypoglycemia, such as hepato -
Finally, th e measurement of insulin levels is a critical step toxicity or ~-ad renergic blockade. Ma ny plants used to
in several of th e bioassays. Th e or iginal immunoassay tech- tr eat diab etes or show n experimenta lly to be hypoglycemic
niqu e (Wright et al. 196 8, 1971 , Ma kulu et al. 196 9) was have toxic effects unrelated to their desired effect.
replaced by a radi oimmunoassay techniqu e that ea rned a Toxicity is influ enced by the plant part, meth od of prep-
Nob el prize for its developer (Yalow 1978), and is still the aration, route of administratio n, and test organism. For ex-
most wid ely used technique. However, an enzyme-link ed am ple, th e leaves of Abrus precatorius L. (Fabaceae) are
immunosorbent assay (ELISA) wit h increased sensitivity, used in traditional medicine to tr eat diabetes, and both the
high accur acy, and grea ter practicab ility (Kekow et al. leaves and roots have been used to sweeten food s. While
156 R. J. Maries and N. R. Farnsworth

the leaves and roots are relativel y non-toxic and non-muta- Prospects for Future Antidiabetic
genic (Choi et al. 1989), the seeds contain the glycoprotein, Plant Research
abrin, one of the most potent of all known botanical toxins,
with a minimum lethal dose of 0.7 ug/kg when adminis- For both the discovery of locally available alternative
tered i.v. to mice. Sublethal doses of abrin i.v. are hypogly- medicines to treat diabetics in developing countries, and for
cemic (Fodstad et al. 1979 ), but since a single well-chewed the commercial development of new botanical hypoglyce-
seed can be fatal to a human (Lampe and McCann 1985), mic agents and adjuncts to antidiabetic therapy, the best
the seed or isolated abrin are not suitable alternative hypo- strategy will involve the study of traditional antidiabetic
glycemic agents. plants.
When calculated on the basis of dose per body weight, There will be a number of obstacles to overcome, not the
humans are generally vulnerable to a drug at a dose one- least of which is financial. To bring a new drug to market,
tenth that shown to have the same effect in experimental it will likely cost more than $300 million and 10 years to
animals; when calculated per unit of body surface area, perform the pharmacological and toxicological testing re-
toxic effects in man are usually within the same dosage quired by current strict regulations such as those of the U.S.
range as animals (Klaassen 1980). With i.p. administration, Food and Drug Administration (Soejarto and Farnsworth
the peritoneal cavity offers a large absorbing surface from 1989). Only pharmaceutical companies can afford this type
which drugs enter the circulation rapidly. The dose-re- of investment, and they will only undertake such projects if
sponse relationship might be quite different from oral ad- they can be assured of recovering their costs and making a
ministration, where absorption from the gastrointestinal profit, through patent protection. While it is possible to
tract is governed by a wide variety of factors, including pro- patent a natural product, particular applications, and de-
portion of the drug in non-ionized form, presence of food, rivatives made from it, it is difficult to obtain the degree of
gastric emptying time, decomposition of the drug by gastric patent coverage for a plant isolate that would be desired by
acids and enzymes, diffusion rate across the gastrointestinal most companies (Tyler 19 79).
epithelium, and the "first-pass effect" of gastrointestinal The cost of bringing a new plant-derived drug to market
epithelial and hepatic drug-metabolizing enzymes (M ayer could be reduced substantially by changes in government
et al. 1980). regulations regarding the methods for proving efficacy and
Since a very small dose of some toxic drugs provides im- safety of traditionally used drugs from natural sources. The
portant therapeutic effects, while a large dose of other current regulations of West Germany and those under de-
drugs with low toxicity is required to achieve the desired ef- velopment in Canada could serve as models (Morrison
fect, more useful information would be provided by the 1984, Tyler 1987, Blackburn et al. 1986, 1993, Liston
Therapeutic Index, which is generally expressed as a ratio 1986, 1987, 1990, Canada Department of National Health
of the median lethal dose to the median effective dose and Welfare 1992).
(LDsoiEDso), or the Certain Safety Factor (LD/ED 99 ) . Despite the difficulties, the financial rewards of success in
However, such information is rarely available for plants marketing plant-derived drugs are great. In the United
other than those already well known to modern pharma- States, 25 % of all prescriptions dispensed from community
cology. pharmacies in 1980 contained active principles prepared
Allergenicity and photosensitization are other aspects of from higher plants. Consumers paid more than $8 billion
toxicity that would not be revealed by regular acute toxic- for these prescription natural products, which include such
ity tests, yet are significant risks in the therapeutic use of essential medicines as vincristine, digitoxin, quinidine, and
plants, especially when employing members of the Anacar- L-dopa (Farnsworth et al. 1985).
diaceae (urushiol), Asteraceae (thiophenes, sesquiterpene The supply of medicinal plants and their active constitu-
lactones), Hypericaceae (hypericin), and Apiaceae (furano- ents can also be a problem. Of the 121 natural products
coumarins). Lewis and Elvin-Lewis (1977) and Lampe and currently in pharmaceutical usc, only 12 % are produced
McCann (1985) have tabulated many of the plants believed commercially by synthesis (Farnsworth et al. 1985). While
to cause these problems. The mutagenicity of any com- it may be technically possible to synthesize most of these
pound with potential for therapeutic use should also be ex- compounds, their chemical complexity often makes it more
amined (Ames et al. 1975, Skopek et al. 1978a,b).In gener- economical to obtain them by isolation. Collection from
al, little is known about the chronic toxicity of plants. Since the wild, cultivation, or tissue culture of medicinal plants,
diabetes mellitus is a chronic condition with no known are techniques that involve many more problems.
cure, antidiabetic drugs must be taken for the lifetime of the More than one -third of all plant-derived drugs come
patient. It is therefore important that chronic toxicity stud- from tropical rainforest species, and that proportion could
ies be performed before recommending a plant-derived be expected to rise substantially if we could learn as much
drug for antidiabetic therapy. about the phytochemistry and pharmacology of tropical
plants as we now know of temperate and subtropical
plants. Even with their greater accessibility and longer his-
Antidiabetic plants and their active constituents 157

tory of study, most temperate plants have not been exhaus- pancreatic islet culture for stimulation of insulin release
tively studied for therapeutic usefulness (Soejarto and and an adipocyte culture for insulin binding and peripheral
Farnsworth 1989). Thus, the destruction of tropical rainfo- glucose transport and metabolism. Active isolates could
rests is resulting in the loss of a tremendous natural re- then be subjected to in vitro screens for general toxicity,
source for potential new drugs, in terms of supply of the such as the brine shrimp bioassay (Meyer et al. 1982, Alko-
plants themselves, their germ plasm which would be neces- fahi et al. 1989), mutagenicity, and hepatic enzyme effects.
sary for genetic improvement of cultivated varieties and tis- Active isolates with no mutagenicity and low potential tox-
sue cultures, and their constituents which could serve as icity, could then be subjected to in vivo bioassays for hypo-
new drugs or prototypes for synthetic drug research. Hope- glycemic activity and toxicity. This method should allow
fully, the economic potential of novel drugs derived from the discovery of more natural hypoglycemic compounds
primary rainforest species could serve as an incentive for with therapeutic potential, with less use of expensive and
preservation of the rainforest and its management as a re- highly regulated live animal research.
newable resource rather than just a source of land for min- The final steps in the process of drug development for
eral and agricultural exploitation. antidiabetic agents from plants will be the pharmaceutical
The rapidity with which the rainforest is being destroyed, preparation and distribution of the proven product. Farns-
and the urgent need for alternative medicines for diabetes worth et al. (1985) and the World Health Organization
throughout the world, underscore the need for immediate (1991) have outlined the steps necessary to identify, evalu-
expansion of the current level of research on antidiabetic ate the safety and efficacy, and prepare plant-derived drugs
medicines from plants. This is probably the motivation be- for therapeutic use. In many cases the use of a standardized
hind the numerous reviews on antidiabetic plants published galenical preparation of a drug is equally efficacious and
in the last few years. much less expensive than using a purified active principle
The first step needed to accelerate antidiabetic plant re- prepared as a tablet or injection, and so would better suit
search is to compile a more comprehensive review of anti- the needs of primary health care in developing nations. De-
diabetic plants than has previously been published, which is tails of plant identification, part to be used, preparation,
being accomplished in the present work. Next, high prior- chemical and biological standardization of the extract,
ity plants need to be selected from the general list. The cri- stability of the extract, dosage regimens, therapeutic and
teria for high priority may vary from one researcher to an- side effects, drug and food interactions, and contraindica-
other, based on their particular interests, national and insti- tions, could be incorporated into the national pharmaco-
tutional health goals, and geographic location. However, poeia or a supplementary herbal formulary. A good exam-
the following general criteria may be useful: ple of this type of drug development is provided by Hans-
1. Traditional use in one or more countries. son et al. (1986), who described the steps taken to bring a
2. Experimentally determined hypoglycemic activity. proven anthelmintic preparation of Ficus glabrata (Mora-
3. Lack of detailed information on hypoglycemic constitu- ceae) latex from the folklore stage to routine professional
ents. use in local government health clinics in the Amazonian
4. Experimental evidence for low toxicity. lowlands of Peru.
5. Botanical abundance. Since most traditional uses of plants involve consumption
Thus, plants which show great promise but are already of an aqueous extract, it may be practical in many cases to
under extensive investigation would be excluded from this prepare and distribute lyophilized extracts of standardized
list, although they may be of great interest to clinical re- composition, packaged in plasticized aluminum foil enve-
searchers. Hypoglycemic plants which are uncommon or lopes. This method of preparation is relatively inexpensive,
not abundant are excluded because of potential supply within the technological means of most countries, resistant
problems, although they might be readily available to re- to decomposition by heat and humidity, easily transport-
searchers in certain locations or might be amenable to cul- able, and can provide a fixed dose, needing only to be re-
tivation. Past experience with relatively common, large constituted with boiled water. It has also been found to be
plants like the western yew (Taxus brevifolia Nutt., Taxa- acceptable to rural people accustomed to taking traditional
ceae) as a source of the anticancer drug taxol (Wall and Wa- herbal decoctions as medicines (X. Lozoya, personal com-
ni 1994) suggests that in most cases sustainable harvest of munication). Distribution can involve both modern clinics
medicinal plants from the wild is not feasible for commer- in rural areas and the organizations of traditional healers
cial drug production, so the environmental impact of har- which many countries are now encouraging to become in-
vest and agronomics (including farm and tissue culture pro- volved in cooperative efforts to improve primary health
duction) of plants being considered for development must care (Bannermann 1983).
be studied. It will be essential to involve traditional healers, educated
The best strategy for screening the high priority plant ex- local people, and medical professionals, working together
tracts and chromatographic fractions for antidiabetic activ- to derive the greatest benefit from new drugs developed
ity would be to select one or two in vitro bioassays, e.g., a from traditional remedies. Since the major diseases in devel-
158 R.]. Marles and N. R. Farnsworth

oping countries are largely brought about by a synergism Acknowledgements


between malnutrition (protein and energy) and infectious The authors wish to thank Ms. Mar y Lou Quinn and the staff of
and/or parasitic diseases, the control of diabetes will have a the NAPRALERTproject, Program for Collaborative Research in
low national priority, so any control program proposed the Pharmaceutical Sciences (PCRPS), College of Pharmacy, Uni-
must be simple and inexpensive. Some practical suggestions versity of Illinois at Chicago, for their assistance in obtaining much
for antidiabetic health care programs in developing coun- of the information on antidiabetic plants reported herein, and Dr.
A. Bingel of PCRPS for helpful suggestions and advice.
tries are provided by Bollag (1983). Finally, this must not be
an isolated effort, but rather part of a comprehensive public
health program for the development of clean water and References
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Tobin, R.B., Friend, B., Berdanier, c.n., Mehlman, M.A., De Vore, lifornia Norte. Med. Anthro. 11: 255-268,1989.
V.: Metabolic responses of rats to chronic theophylline inges- World Health Organization: Diabetes Mellitus: Report of a WHO
tion. J. Toxico!. Envir. Health 2: 361- 369, 1976. Study Group. WHO Technical Report Series 727, WHO, Gene-
Tomoda, M., Shimizu, N., Gonda, R., Kanari, M., Yamada, H., va, 1985.
Hikino, H.: Anti-complementary and hypoglycemic activities of World Health Organization: Guidelines for the Assessment of Her-
the glycans from the seeds of Malva verticil/ata. Planta Med. 56: bal Medicines. Programme on Traditional Medicines. WHO/
168-170, 1990. TRMJ91.4, \X1HO Geneva, 1991.
Tomoda, M., Shimizu, N., Oshima, Y., Takahashi, M., Murakami, Wright, P.H., Makulu, D.R., Malaisse, W.J., Roberts, N.M., Yu,
M., Hikino, H.: Hypoglycemic activity of twenty plant mucilag- P.-L.: A method for the immunoassay of insulin. Diabetes 17:
es and three modified products. Planta Med. 53: 8-12, 1987. 537-546, 1968.
Tuveson, R.W., Berenbaum, M.R., Heininger, E.: Inactivation and Wright, P.H., Makulu, D.R., Vichick, D., Sussman, K.E.: Insulin
mutagenesis by phototoxins using E. coli strains differing in sen- immunoassay by back-titration. Some characterisitics of the
sitivity to near and far UV light.]. Cbem. Eco!. 12: 933-947, technic and the insulin precipitant action of alcohol. Diabetes
1986. 20:33-45,1971.
Tyler, V.E.: Plight of plant-drug research in the United States today. Yalow, R.S.: Radioimmunoassay: a probe for the fine structure of
Econ Bot. 33: 377-383, 1979. biologic systems. Science 200: 1236-1245, 1978.
Tyler, V.E.: Herbal medicine in America. Planta Med. 53: 1-4, Yki-jarvinen, H., Nikkila, E.A., Kubo, K., Foley, ].E.: Assay of
1987. glucose transport in human fat cells obtained by needle biopsy.
Tyler, V.E., Brady, L.R., Robbers, J.E.: Pharmacognosy, 8th ed. Lea Diabetologia 29: 287-290, 1986.
and Febiger, Philadelphia, 1981. Yoshikuni, Y.: Inhibition of intestinal a-glucosidase activity and
Unger, R.H., Foster, D.W.: Diabetes Mellitus. In: Williams Text- postprandial hypoglycemia by moranoline and its N-alkyl deriv-
book of Endocrinology, 7th ed. (J.D. Wilson, D.W. Foster, eds.), atives. Agric. Bioi. Chem. 52: 121-128, 1988.
pp. 1018-1080. W.B. Saunders, Philadelphia, 1985. Young, P., Kirkham, D.M., Murphy, G.]., Cawthorne, M.A.: Eval-
van de Werve, G., Proietto, j., ]eanrenaud, B.: Tumor-promoting uation of inhibitory guanine nucleotide regulatory protein G
phorbol esters increase basal and inhibit insulin-stimulated lipo- function in hepatocyte and liver membranes from obese Zucker
genesis in rat adipocytes without decreasing insulin binding. Bi- (falfa) rats and their lean (Fa!?) littermates. Diabetologia 34:
ochem.]. 225: 523-527, 1985. 565- 569, 1991.
van de Werve, G., Proietto J., Jeanrenaud B.: Control of glycogen Zawalich, W.S.: Modulation of insulin secretion from ~-cells by
phosphorylase interconversion by phorbol esters, diacylglyce- phosphoinositide-derived second-messenger molecules. Dia-
rols, Ca 2+ and hormones in isolated rat hepatocytes. Biochem.]. betes 37: 137-141, 1988.
231:511-516,1985.
Antidiabetic plants and their active constituents 165

Zawalich, W.S., Diaz, V.A., Zawalich, K.C.: Influence of cAMP Appendix: Antidiabetic Plants
and calcium on [3H] inositol efflux, inositol phosphate accumu-
lation and insulin release from isolated rat islets. Diabetes 37: This appendix comprises an extensive list of algae, fungi,
1478-1483,1988.
and plants used ethnomedically to treat diabetes mellitus or
in some way tested for therapeutic activity against diabetes
mellitus. Since research into antidiabetic plants is ongoing
Address
in many institutions no list can claim to be comprehensive,
but this is the most complete listing published to date. The
R.]. Maries, Department of Botany, Brandon University,
information is drawn mostly from the computer database
Brandon, MB R7A 6A9, Canada.
NAPRALERT, created and maintained by the Program for
Collaborative Research in the Pharmaceutical Sciences,
College of Pharmacy, University of Illinois at Chicago. This
database is accessible through the commercial database ser-
vice STN, operated by the American Chemical Society. To
save space references have been omitted from this appendix
but are available through NAPRALERT. Given the abbre-
viated nature of the information presented, this appendix is
intended to provide only a starting point for a rational anti-
diabetic drug discovery project, and readers are encouraged
to obtain the original references for proper evaluation of
the results abstracted here.
The following paragraphs explain the type of informati-
on and abbreviations used in the appendix table:
SCIENTIFIC NAME: Latin binomials are given as they
appear in the references, with only simple typographic er-
rors corrected. Since botanical authorities were sometimes
given and sometimes omitted in the original references,
they have been omitted here for consistency and saving of
space.
ETH: Ethnopharmacological use. The number refers to
the number of countries in which the plant is used tradi-
tionally to treat diabetes.
ACTIVITY: Antidiabetic activity. +: active; =: equivocal;
-: inactive; ?: conflicting reports. Pretreatment or precondi-
tion of experimental animals: A: alloxan; B: 2,4-dinitro-
phenol; C: cholesterol; D: spontaneous diabetes; E: epi-
nephrine; G: glucose; K: corticotropin; L: glucagon; N: nor-
mal; 0: ethanol; P: pancreatectomy; S: streptozotocin; T:
somatotropin; U: unspecified; X: anterior pituitary extract;
Z: diazoxide.
PART TESTED: Abbreviations: ap: aerial parts; bl: bulb;
br: bran; cm: corm; fl: flower; fr: fruit; gl: gall; gm: gum; is:
isolate; If: leaf; mu: mucilage; rb: root bark; rn: resin; rt:
root; rz: rhizome; sb: stem bark; sd: seed; sh: shoot; sp: sap;
st: stem; sy: styles; tb: tuber; wd: wood; wp: whole plant.
ROUTE ADMIN.: im: intramuscular; in: inhaled; ip: int-
raperitoneal; iv: intravenous; po: per os; pn: per nares; sc:
subcutaneous; vt: in vitro.
ACTIVE CONSTITUENT: Constituents present which
have been reported to have blood glucose lowering activity.
TOXICITY: toxic/nontoxic: some parts toxic, other parts
nontoxic; ?: questionable toxicity.
166 R. J. MarIes and N. R. Farnsworth

FAMILY SCIENTIFIC NAME ETH ACTIVITY PART ROtITE ACTIVE TOXICITY


TESTED ADMIN. CONSTITUENT

PROTISTA Corallina rubens +N wp IV polypeptide of


Rhodophyta: Asp, Glu, Gly,
Corallinaceae Ser, and Thr
Gelidiaceae Pterocladia capillacea +A,N wp IV polypeptide
Phyllophoraceae Phyflophora nervosa -N wp IV
Phaeophyta:
Laminariaceae Laminaria ochroleuca -N wp po
Laminariaceae Saccorhiza polyschides -N wp po
Cystoseiraceae Cystoseira barbata +N wp IV polypeptide of nontoxic
Thr, Ser, Glu,
Pro, His, Val,
Met, ammonia
Fucaceae Fucus vesiculosus 1 -N wp po toxic?
Himanthaliaceae Himanthalia elongata +A,N wp IV po lysaccha ride,
protein
(unidentified)
Sargassaceae Sargassum vulgare +N wp IV polypeptide
Chlorophyta:
Codiaceae Codium tomentosum -N wp IV

FUNGI
Basidiomycotina:
Agaricaceae Agaricusbisporus +S,-N po nontoxic
Amanitaceae Amanita phafloides +N wp po phalloidin, toxic
pha llacin,
pha llacidin -
indolic
sulfur-cent.
cyclopeptides
Coprinaceae Coprinus comatus +N fr po
Exobasidiaceae Laurobasidium lauri -N fr ip
Polyporaceae Fomes[aponica +N fr
Polyporaceae Ganodermaapplanatum -S fr po
Polyporaceae Ganoderma lucidum 2 +A,E,G,N wp po glycans nontoxic
ganoderan
A andB
Polyporaceae Pachymahoelen 1 ?Y fr po
Polyporaceae Polyporus umbeflatus 1 ?A fr po
Polyporaceae Poria cocos 2 ?S,G fr po
Deutero mycotin a:
Moniliaceae Beauveria bassiana 1 ?A wp po
Ascomyco tina :
Clavicipitaceae Clauiceps purpurea +N sc po ergot alkaloids toxic
Clavicipitaceae Cordyceps cicadae +N wp ip
Saccharomycetaceae Saccharomyces cerevisiae 2 +N wp po vitamin B nontoxic
complex, Cr,
aspartate-
adenosine mix
Trichocomaceae Aspergillus niger +A,N wp po,ip
Trichocomaceae Emericefla quadrilineata +D,S,N fr po emericedin &
ernenarrune
(B-aminobetain)
PLANTAE
Lycopodiophyta:
Lycopodiaceae Lycopodium annotinum +N IV annotinine (H, iv) nontoxic?
Lycopodiaceae Lycopodium clavatum +N IV Iycopodine (H, iv) nontoxic
Selaginellaceae Selaginefla denticulata 1 toxic?
Polypodiophyta :
Actiniopteridaceae Actiniopterisaustralis -N wp po nontoxic
Angiopteridaceae Angiopteris erecta -N ap po nontoxic
Cyath eaceae Cyathea gigan tea -N ap po nontoxic
Cyatheaceae Cyathea nilgirensis -N ap po toxic
Antidiabetic plants and their active constituents 167

FAMILY SCIENTIFIC NAME ETH ACTIVITY PART ROUTE ACTIVE TOXICITY


TESTED ADMIN. CONSTITUENT

Dicksoniaceae Cibotium barometz -S rz po


Osmundaceae Osmunda regalis -N ap po toxic
Polypodiaceae Acrostichum aureum -N wp po nontoxic
Polypodiaceae Adiantum capillus-veneris 1 +N wp po toxic
Polypodiaceae Adiantum caudatum 2 ?N wp po toxic
Polypodiaceae Athyrium dialatatum -N wp po toxic
Polypodiaceae Athyrium [imbriatum -N wp po nontoxic
Potypodiaceae Blechnum occidentale -N wp po nontoxic
Polypodiaceae Cheilanthes pruinata nontoxic?
Polypodiaceae Cyclophorus parasiticus -N ap po nontoxic
Polypodiaceae Lindsaeatrapeziformia 1 toxic
Polypodiaceae Notholaena aurea 2
Polypodiaceae Polystichum setiferum -N ap po nontoxic
Polypodiaceae Pteris mertensioides -N ap po non toxic
Polypodiaceae Tectaria cicutaria -N ap po toxic
Polypodiaceae Thelypteris mettilineata -N ap po nontoxic
Polypodiaceae Woodwardia radicans -N ap po nontoxic
Equisetophyta:
Equisetaceae Equisetum arvense 1 -N wp po toxic
Equisetaceae Equisetum bogotense 1 toxic
Equisetaceae Equisetum debile -N wp po nontoxic
Equisetaceae Equisetum giganteum toxic
Gnetophyta:
Ephedraceae Ephedra distachya +A,N ,-S wp ip,po ephedrans a-e toxic?
(A, H, ip) glycans
Pinophyta
Cupressaceae Cal/itris robusta -N ap po nontoxic
Cupressaceae Cupressus funebris -N ap po nontoxic
Cupressaceae Juniperus communis 1 +S fr po
Cupressaceae Juniperus phoenicea 1 toxic?
Cupressaceae Thujopsis dolabrata 1
Pinaceae Abies pindrow 2 +N toxic
Pinaceae Pinus longifolia 1 +N If,rt,sb po nontoxic
Pinaceae Pinus roxburghii 1 +N sb,rt po
Pinaceae Pinusstrobus 1 nontoxic?
Taxaceae Taxus chinensis 1 toxic
Taxaceae Taxus cuspidata 1 +N ?
M agnolio phyta:
Liliopsida:
Alismataceae Alisma orientale 3 +A,Y,N,-S,G rz po,sc nontoxic
Alismataceae Alisma plantago-aquatica 1 -S rz po nontoxic
Amaryllidaceae Crinum defixum -N wp po toxic
Amaryllidaceae Lycoris squamigera +N bl po Iycoris-S-gluco- toxic
mannan
Arnaryllidaceae Narcissus tazetta +N bl po narcissus-t-gluco toxic!
mannan nontoxic
Araceae Acorus calamus -N rz po ?
Araceae Alocasiaindica -N rz po toxic
Araceae Amorphophalus konjac +G po konjak mannan nontoxic
(glucomannan)
(A, po)
Araceae Pinellia ternata 1 ?Y tb po
Araceae Pistia stratiotes 3 toxic
Araceae Rhaphidopbora glauca -N ap po nontoxic
Araceae Rhaphidophora lancifolia -N ap po nontoxic
Araceae Scindapsus officinalis +N fr po nontoxic
Araceae Typhonium giganteum
Arecaceae Acrocomia mexicana +A fr,rt po
Arecaceae Areca catechu -S fr po
Arecaceae Borassus (label/ifer 2 -N sp po toxic
Arecaceae Calamus thwaitesii -N ap po toxic
168 R. J. Maries and N. R. Farnsworth

FAMILY SCIENTIFIC NAME ETH ACTIVITY PART ROUTE ACTIVE TOXICITY


TESTED ADMIN. CONSTITUENT
Arecaceae Cocos nucifera 1 ?N fr,lf po nontoxic
Arecaceae Lodoicea sechellarum 1 -N fr po
Arecaceae Phoenix dactylifera 1 nontoxic
Arecaceae Serenoa serrulata 1 toxic?
Bromeliaceae Ananas comosus 1 nontoxic
Bromeliaceae Bromelia karatas 2
Bromeliaceae Tillandsia usneoides 1 +N wp po
Cannaceae Cannaagria 1 toxic?
Cannaceae Canna orientalis -N ap po toxic
Commelinaceae Forrestia mollissima -N wp po nontoxic
Commelinaceae Tradescantia multiflora 1 nontoxic?
Commelinaceae Zebrina pendula 1 nontoxic
Cyperaceae Cyperus iria 1 -N wp po toxic
Cyperaceae Cyperustegetum 1 ?
Cyperaceae Kyllinga monocephala 4
Cyperaceae Kyllinga triceps 1 -N rt po
Cyperaceae Scleria levis -N wp po toxic
Dioscoreaceae Dioscorea alata 1 ?A rz po
Dioscoreaceae Dioscorea asclepiadea +N bl
Dioscoreaceae Dioscorea batatas 3 +A,N,?G,S,Y rz ip,po dioscorans a-f nontoxic
(A, H, ip) glycans
Dioscoreaceae Dioscorea bulbifera ?N ap po nontoxic
Dioscoreaceae Dioscorea dumetorum 1 +A,N tb ip dioscoretine nontoxic?
Dioscoreaceae Dioscorea gracillima +N bl
Dioscoreaceae Dioscorea bispida 1
Dioscoreaceae Dioscorea [aponica 1 +A,N rz ip dioscorans a-f
(A, H, ip) glycans
Dioscoreaceae Dioscorea oppositifolia -N ap po nontoxic
Haemodoraceae Aletris farinosa 1 toxic
H ydrocharitaceae Ottelia alismoides -N wp po toxic
Hypoxidaceae Curculigo orchioides +A,N wp po nontoxic
Iridaceae Iris kumaonensis -N wp po toxic
Iridaceae Iris versicolor 1 toxic
Lemnaceae Lemna polyrrhiza -S wp po
Liliaceae Allium ascalonicum -N bl po nontoxic
Liliaceae Allium cepa 4 +A,E,D,G, ap,bl po,sc,ip,iv allyl-propyl nontoxic
P,?N disulfide, allicin
(diallyl disulfide
oxide) (A, H, po),
diphenylamine
Liliaceae Allium sativum 5 +A,E,G,?N, bl po allyl-propyl nontoxic
-S,C,D disulfide, allicin
(diallyl disulfide
oxide) (A, H, po)
Liliaceae Allium tuberosum -A If ip
Liliaceae Aloe africana +N If ip nontoxic
Liliaceae Aloe arborescens +A,N If po,ip arborans A and B toxic
Liliaceae Aloe barbadensis 1 +A sp po ?
Liliaceae Aloe ferox +N If ip ?
Liliaceae Aloe vera 5 +N,S,D,?A If po,iv,ip lupeol (A, po) ?
Liliaceae Anemarrhenaasphodeloides 3 +A,N,Y,?G,-S rz po,ip anemarans a-d nontoxic
(A, H, ip) (glycans)
Liliaceae Aphanamixis polystachya -N st ?
Liliaceae Asparagus cochinchinensis 1 -S rt po ?
Liliaceae Asparagus gonoclados 1
Liliaceae Chamaelirium luteum 1
Liliaceae Clintonia borealis 1
Liliaceae Colchicum luteum -N cm po toxic
Liliaceae Convallaria majalis 1 ?N,-S If po toxic
Liliaceae Gloriosa superba -N wp po toxic
Liliaceae Heterosmilax japonica 1
Antidiabetic plants and their active constituents 169

FAMILY SCIENTIFIC NAME ETH ACTIVITY PART ROUTE ACTIVE TOXICITY


TESTED ADMIN. CONSTITUENT

Liliaceae Lilium auratum +N bl po lilium-Avgluco- toxic


mannan
Liliaceae Lilium speciosum +N bl po Iilium-Svgluco- nontoxic
mannan
Liliaceae Liriope graminifolia 1 +N po nontoxic?
Liliaceae Ophiopogon [aponicus 1 +S,?A tb po
Liliaceae Polygonatum humile 1 +N convallamarin toxic
Liliaceae Polygonatum inflatum 1 +N nontoxic?
Liliaceae Polygonatum macropodum +N nontoxic?
Liliaceae Polygonatum multiflorum 1 +G rt po nontoxic
Liliaceae Polygonatum odoratum 1 +G,N rt po nontoxic?
Liliaceae Polygonatum officinale -N,S rz po nontoxic?
Liliaceae Scilla sibirica +N toxic
Liliaceae Smilax canariensis 1 nontoxic?
Liliaceae Trillium pendulum 1
Liliaceae Urginea indica +N bl po toxic?
Liliaceae Veratrum album +N alkaloids toxic
Liliaceae Veratrum californicum +E,N toxic
Liliaceae Veratrum viride +E,N alkaloids toxic
Musaceae Ensete superbum 1 +N sd nontoxic
Musaceae Musa paradisiaca 1 +C fr po nontoxic
Musaceae Musa sapientum 1 +N fl po nontoxic
Orchidaceae Cypripediumacaule 1
Orchidaceae Cypripedium calceolus 1 nontoxic
Orchidaceae Orchis latifolia 1 -N rt po
Orchidaceae Orchis mascula 1
Orchidaceae Vanda testacea -N wp po nontoxic
Pandanaceae Pandanus amaryllifolius +G rt po
Pandanaceae Pandanus furcatus -N ap,fr po toxic!
nontoxic
Pandanaceae Pandanus odoratissimus 1 +A rt po toxic
Pandanaceae Pandanus odorus -N 1 po
Poaceae Arundo donax 1 -N ap po toxic
Poaceae Avena [atua -N wp po nontoxic
Poaceae Avena sativa -D,+N,G sd po nontoxic
Poaceae Bambusa arundinacea +A,N wp po nontoxic?
Poaceae Bambusa dendrocalamus 1 +A,N If pO,lp nontoxic?
Poaceae Bambusa nutans +N ap po nontoxic
Poaceae Bamhusa vulgaris +N If po
Poaceae Bothriochloa pertusa -N wp po nontoxic
Poaceae Chrysopogon aciculatus -N wp po nontoxic
Poaceae Cinna arundinacea 1
Poaceae Coix lacbryma-iobi +A,?N ap,sd po,ip coixans a, b, nontoxic
c: (H); a (A) (ip)
Poaceae Cymbopogon citratus 1 -N rt po nontoxic
Poaceae Cymbopogon flexuosus -N wp po nontoxic
Poaceae Cymbopogon martini -N wp po toxic
Poaceae Cynodon dactylon 1 ?
Poaceae Dermostachys bipinnata 1
Poaceae Eragrostis bipinnata 1 +U,N wp nontoxic?
Poaceae Eragrostis pilosa 1 nontoxic?
Poaceae Hordeum vulgare +N nontoxic
Poaceae lmperata cylindrica -S rz po
Poaceae Oryza sativa 1 +A,N,?Y,-S;-G br,sd,rt pO,lp peptidoglycans nontoxic
oryzarans a, b, c, d;
oryzabrans a, b, c, d
Poaceae Panicummiliaceum +N wp po toxic
Poaceae Pennisetum purpureum -N ap po nontoxic
Poaceae Phragmites communis +A rz ip
Poaceae Phragmites maxima -N ap po toxic
170 R.]. Marles and N. R. Farnsworth

FAMILY SCIENTIFIC NAME ETH ACTMTY PART ROUTE ACTIVE TOXICITY


TESTED ADMIN. CONSTITUENT
Poaceae Phyllostachys bambusoides 1 +N po lupeol (A, po), toxic?
5-hydroxytrypt-
amine (H, ip)
Poaceae Poa pratensis +N wp sc nontoxic
Poaceae Saccharum officinarum +A,N st ip saccharans a, b, c, nontoxic
d, e, f: (H); c (A) (ip)
Poaceae Setaria italica -S sd po
Poaceae Sporobolus indicus -N wp po toxic
Poaceae Tripsacum laxum -N ap po toxic
Poaceae Triticum aestivum 1 +N,-G,S If,sd po,sc nontoxic
Poaceae Triticum spelta 1
Poaceae Zea mays 3 +U,?N sy po coumarin nontoxic
(A, H, po)
Pontederiaceae Monocharia hastata -N wp po nontoxic
Potamogetonaceae Potamogeton crispus +N wp
Typhaceae Typha latifolia -S pi po
Zingiberaceae Alpinia galanga 2 -N rz po
Zingiberaceae Alpinia khulanjan 1
Zingiberaceae Amomum aromaticum +N rz po toxic
Zingiberaceae Amomum subulatum +N rz po nontoxic
Zingiberaceae Costus schlechteri 1 +D wp po toxic?
Zingiberaceae Curcumalonga 2 -N rz po nontoxic
Zingiberaceae Hedychium spicatum +N rz po nontoxic
Zingiberaceae Zingiber capitatum -N wp po toxic
Zingiberaceae Zingiber officinale 1 +D,N,?Y ap,rz po nontoxic
Zingiberaceae Zingiber zerumbet 2 nontoxic
Magnoliopsida:
Acanthaceae Adhatoda vasica 1 +N If,rt po
Acanthaceae Andrographispaniculata 2 -A,N If,st po nontoxic
Acanthaceae Asteracantha longifolia 1 +N wp po lupeol nontoxic
Acanthaceae Barleria cristata +N wp po nontoxic
Acanthaceae Barleria noctiflora -N wp po nontoxic
Acanthaceae Barleria prionotis +N wp nontoxic
Acanthaceae Carvia callosa -N ap po toxic
Acanthaceae Dicliptera roxburghiana -N wp po nontoxic
Acanthaceae Dipteracanthus prostratus +N
Acanthaceae Hygrophilaauriculata +G wp po
Acanthaceae jacobinia suberecta +F IS po moranoline
Acanthaceae Nilgirianthus barbatus -N ap po nontoxic
Acanthaceae Ruellia tuberosa 1
Acanthaceae Strobilanthes boerhaavioides -N ap po nontoxic
Acanthaceae Strobilanthes crispus ?N If po nontoxic?
Acanthaceae Thunbergiamysorensis -N ap po nontoxic
Aceraceae Acer glabrum 1 toxic
Aizoaceae Glinus lotoides -N wp po toxic
Alangiaceae Alangium salviifolium +N If po nontoxic
Amaranthaceae Achyranthes aspera +A,N,-S wp po nontoxic
Amaranthaceae Aerva lanata 1 ?
Amaranthaceae Aerva sanguinolenta -N wp toxic
Amaranthaceae Cyathula capitata +U po cyasterone (A, po) nontoxic?
Amaranthaceae Gomphrena celosioides -N wp po toxic
Amaranthaceae Gomphrena globosa 1 toxic?
Amaranthaceae Pfaffia paniculata 1
Anacardiaceae Anacardium humile 1
Anacardiaceae Anacardium occidentale 9 +A,?N,-S If,sb,sd po, IV (-)epicatechin toxic
(A,ip)
Anacardiaceae Holigarna grahamii -N ap po toxic
Anacardiaceae Holigarna nigra -N ap po toxic
Anacardiaceae Mangifera indica 2 -N If po toxic
Anacardiaceae Pistacia lentiscus 1 nontoxic
Anacardiaceae Poupartia birrea 1 +A,G,-D,N If po nontoxic
Antidiabetic plants and their active constituents 171

FAMILY SCIENTIFIC NAME ETH ACTIVITY PART ROUTE ACTIVE TOXICITY


TESTED ADMIN. CONSTITUENT
Anacardiaceae Rhus aromatica 2 toxic?
Anacardiaceae Rhus chinensis 1 +N toxic?
Anacardiaceae Rhus coriaria +N po toxic?
Anacardiaceae Rhus glabra 1 toxic?
Anacardiaceae Rhus toxicodendron +N toxic
Anacardiaceae Rhus typhina 2 +P,N po,ip toxic?
Anacardiaceae Rhus wallichii -N ap po toxic
Anacardiaceae Semecarpus anacardium +N fr po ?
Anacardiaceae Spondias dulcis 1 +N fr po nontoxic?
Annonaceae Annona squamosa 1 +N If nontoxic
Annonaceae Guatteria caribea 1
Annonaceae Uvaria narum -N ap po nontoxic
Annonaceae Uvariopsis guineensis +N rt po nontoxic
Apiaceae Ammi visnaga 1 +C po dihydrosamidin toxic
(A, po)
Apiaceae Anethum graveolens +N fr po nontoxic
Apiaceae Angelicagigas -N rt po
Apiaceae Angelicashikokiana 1 nontoxic
Apiaceae Angelica sinensis 1 -S rt po
Apiaceae Apium graveolens -A,=E,+N If sc diphenylamine? nontoxic
Apiaceae Arracacia brandegei 1
Apiaceae Bupleurum [alcatum 1 +N,Y rt po toxic
Apiaceae Centella asiatica 2 -N wp po toxic
Apiaceae Cbangium smyrnioides 1 ?A rt po
Apiaceae Coriandrum sativum 3 -A,+U,S,?N sd po diphenylamine nontoxic
Apiaceae Cuminum nigrum 1 +A,N sd po nontoxic?
Apiaceae Daucus carota 4 -D,A,S,?N rt,wp po,sc toxic!
nontoxic
Apiaceae Eryngium creticum 1 nontoxic?
Apiaceae Eryngium foetidum 1 nontoxic
Apiaceae Ferula assafoetida 1 -S,N gm po ?
Apiaceae Hydrocotyle podantha -N wp po nontoxic
Apiaceae Myrrhis odorata 1 +S,N gm po
Apiaceae Petroselinum crispum +N ap po nontoxic
Apiaceae Peucedanum dana -N ap po toxic
Apiaceae Sanicula marilandica 1
Apocynaceae Allamanda cathartica -N ap po toxic
Apocynaceae Alstonia macrophylla +N wp nontoxic
Apocynaceae Alstonia scholaris +N wp nontoxic
Apocynaceae Alstonia spatulata +N sb po lupeol, lupeol nontoxic
acetate, ursolic acid
(A,po)
Apocynaceae Apocynum androsaemifolium 1 toxic
Apocynaceae Catharanthus pusillus 1 toxic?
Apocynaceae Catharanthus roseus 10 +U,?N,S,A If po catharanthine toxic
(HCI),lochnerine,
tetrahydroalstonine,
leurosine sulfate,
vindoline(HCI,
vindolinine(2HCI
(H,po)
Apocynaceae H olarrhena antidysenterica +N fr po toxic
Apocynaceae Hunteria umbellata 1
Apocynaceae Plumeria rubra +N st po nontoxic
Apocynaceae Rauvolfia serpentina 1 +D,E,N rt po reserpine (A, H) toxic
Apocynaceae Rhazya stricta 1 -A If po toxic
Apocynaceae Vinca erecta +E,N wp sc alkaloids toxic
vinsumine, vinervine
Apocynaceae Vinca major 1 -N wp po ?
172 R. J. Maries and N. R. Farnsworth

FAMILY SCIENTIFIC NAME ETH ACTIVITY PART ROtITE ACTIVE TOXICITY


TESTED ADMIN. CONSTTI1JENT
Apocynaceae Vinca minor 1 +A,E akuammidine, nontoxic
isoreserpiline,
reserpiline,
vincoamine,
vicanidine,
vinervine,
vinsumine
Apocynaceae Wrightia coccinea N fr po toxic
Aquifoliaceae Ilex guayusa 2 +S,N po guanidine nontoxic
Araliaceae Acanthopanax sessilif/orus +N nontoxic
Araliaceae Aralia chinensis -N sb IV nontoxic
Araliaceae Araliaelata 2 +A,E,G sb nontoxic
Araliaceae Araliamandshurica +G,?N If,wp sc,po nontoxic
Araliaceae Aralia nudicaulis 1 nontoxic
Araliaceae Eleutherococcus cbiisanensis +A,E po chiisanoside
(A, po) nontoxic?
Ara liaceae Eleutherococcus senticosus +A,B,E,N rt po,ip eleutherans a-g
(A,H,ip) nontoxic
Araliaceae Oplopanax horridum 1 +D,G,?N rb po nontoxic
Araliaceae Panaxginseng 2 +A,B,D,V,? rt, If po,ip ginsenoside RB-2, nontoxic
S,N,Y,O panaxans a-h, q-u
(A, H, ip) daucosterol,
nicotinic acid (A, H po),
adenosine, pyro -
glutamic acid
Ara liaceae Panax pseudoginseng var. +U,?N rt po nontoxic
notoginseng
Ara liaceae Panax quinquefolius +A,?N rt ip quinquefolans A, nontoxic
B, and C
Ara liaceae Panax repens +U rt po nontoxic
Araliaceae Scheff/era capitata -N ap po toxic
Ara liaceae Tetrapanax papyriferus +$ po nontoxic
Aristolochiaceae Aristolochiabrevipes ?
Aristolochiaceae Aristolochia fangchi +S rt po
Aristo lochiaceae Aristolochiaindica -N wp po toxic
Aristolochiaceae Aristolochiamanshuriensis 1 +N sb nont oxic
Aristo lochiaceae Aristolochia odoratissima 1 ?
Aristo lochiaceae Aristolochiastaheli 1 ?
Aristo lochia ceae Aristolochia trilobata 1 ?
Asclepiadaceae Calotropis gigantea N rt po toxic
Asclepiadaceae Caralluma edulis A,N rt po
AscJepiadaceae Cryptolepiselegans N ap po toxic
Asclepiadaceae Cryptostegia grandif/ora 1 -A,+N ap po toxic
Asclepiadaceae Decalepis hamiltonii 1
Asclepiadaceae Gymnema sylvestre 1 +A,D,X,N, If po toxic
S,E,G
Asclepiadaceae Holostemma annularis 1
Asclepiadaceae Periploca laevigata 1
Asteraceae Achilleafragrantissima 1 toxic
Asteraceae Achillea micrantha 1 ?
Asteraceae Achilleamillefolium 1 nontoxic
Asteraceae Achilleasantolina 1 -N fl IV ?
Asteraceae Achyrocline alata 1
Asteraceae Achyroclinesatureioides 1
Asteraceae Adenostemma lauenia -N wp po nontoxic
Asteraceae Ageratum conyzoides 1 ?
Asteraceae Ainsliaea latifolia -N wp
Asteraceae Ambrosia maritima 1 +D wp po nont oxic
Asteraceae Anthemis deserti +N wp iv
Asteraceae Arctium lappa 4 +A,D,?N,-S rt sc nontoxic
Asteraceae Arnica montana 1 +N wp po to xic
Antidiabetic plants and their active constituents 173

FAMILY SCIENTIFIC NAME ETH ACTIVITY PART ROUTE ACTIVE TOXICITY


TESTED ADMIN. CONSTITUENT

Asteraceae Artemisia absinthium 1 toxic


Asteraceae Artemisia abyssinica 1 +A,N wp po nontoxic
Asteraceae Artemisia afra 2 nontoxic
Asteraceae Artemisia capillaris -S ap po
Asteraceae Artemisia dracunculus 1 -S ap po
Asteraceae Artemisia berba-alba 2 +A,D,N ap po nontoxic
Asteraceae Artemisia vulgaris ?N wp po toxic
Asteraceae Atractylis gummifera +N IV carboxyatract- toxic
yloside, atractyloside
(H , iv)
Asteraceae Atractylis ovata +N po toxic?
Asteraceae Atractylodes [aponica +A,S,N rz ip,po atractans a-c ?
(A, H, ip (glycans)
Asteraceae Atractylodes lancea +A rz po
Asteraceae Atractylodes macrocephala +N,-S rz po nontoxic?
Asteraceae Bidens leucantha 2 +A wp po,ip ?
Asteraceae Bidens pilosa 2 +A wp po,ip nontoxic
Asteraceae Brachylaena elliptica 1 +N
Asteraceae Cacalia decomposita 2 +A st,rt po,ip
Asteraceae Calea zacatbecbichi 1 toxic
Asteraceae Carthamus tinctorius -N sd po nontoxic
Asteraceae Centaureaaspera 1 +N f1,lf po lupeol, nontoxic
daucosterol (A, po)
Asteraceae Centaurea calatrapa 1 +N n po,iv cnicin (H , iv) nontoxic
Asteraceae Centaurea corcubionensis +G,N,-A fl,1f po nontoxic?
Asteraceae Centaurea melitensis 3 +N fl po nontoxic
Asteraceae Centaurea pallescens 1 nontoxic?
Asteraceae Centaurea salmantica +N fl,wp IV nontoxic?
Asteraceae Centaurea seridis +G fl,wp po daucosterol, nontoxic?
ursolic acid (A, po) ,
~-sitosterol -3-~-D
-glucoside
Asteraceae Centaurea solstitialis 1 +N fl po nontoxic?
Asteraceae Centipeda minima -N wp po ?
Asteraceae Cheirolophus arbutifoiius 1
Asteraceae Cheirolophus canariensis 1
Asteraceae Chrysanthemum indicum -N fl po nontoxic
Asteraceae Chrysanthemum leucanthemum 1
Asteraceae Cichorium endivia 1 +N If nontoxic
Asteraceae Cichorium intybus 2 -A,+U,?N If,rt,wp po.sc coumarin, nontoxic
scopoletin (A, H, po)
Asteraceae Cirsium depsacolips +N rt ?
Asteraceae Cirsium ocbrocentrum ?
Asteraceae Cnicus benedictus +N cnicin nontoxic?
Asteraceae Coleosanthus squarrosus 1
Asteraceae Conyza canadensis 1 toxic?
Asteraceae Conyza incana +N ap ip
Asteraceae Cynara scolymus 1 +E,?N n po,ip oxidase nontoxic
(A, H, po, ip )
Asteraceae Dahlia pinnata +N ap po nontoxic
Asteraceae Elytropappus rhinocerotis 1
Asteraceae Erigeronannuus +N If,st
Asteraceae Erigeron canadensis 1 ?N wp po toxic
Asteraceae Erigeron pusillus 1 ?
Asteraceae Eupatorium odoratum 1
Asteraceae Eupatorium purpureum 1 +N
Asteraceae Eupatorium urticaefolium +U,-N ap po toxic
Asteraceae Eupatorium villosum 1 ?
Asteraceae Gnaphalium semiamplexicaule +N fl IV
Asteraceae Helianthus annuus +N nontoxic
Asteraceae Helianthus tuberosus -D tb po nontoxic?
174 R. J. MarIes and N. R. Farnsworth

FAMILY SCIENTIFIC NAME ETH ACTIVITY PART ROUTE ACTIVE TOXICITY


TESTED ADMIN. CONSTITUENT
Asteraceae Inula helenium +U,N po alan to lactone toxic/
(A, H,po ) nontoxic
Asteraceae Inula racemosa +G,N,D,E rt po ?
Asteraceae Inula viscosa 1
Asteraceae Ixeris dentata +A wp ip
Asteraceae Lactuca sativa 1 -A,E,?N If sc nontoxic
Asteraceae Lactucaserriola +N sd po nontoxic?
Asteraceae Lapsanacommunis 1
Asteraceae Launea nudicaulis 1 +A,N IS nontoxic
Asteraceae Leuzea carthamoides +B po
Asteraceae Matricaria aurea 1 nontoxic?
Asteraceae Mikania micrantha 1 +N ab po coumarin, nontoxic?
scopoletin, lupeol
acetate (A, H po)
Asteraceae Mulgedium alpinum +N wp po
Asteraceae Neurolaena lobata 3 +A,N If po toxic
Asteraceae Parthenium hysterophorus 2 toxic
Asteraceae Pulicaria foliolosa +N wp ?
Asteraceae Saussurea heteromalla -N wp po nontoxic
Asteraceae Schkuhria pinnata
Asteraceae Senecio nemoralis
Asteraceae Senecio tenuifolius -N wp po nontoxic
Asteraceae Siegesbeckia orientalis +N wp po nontoxic
Asteraceae Silybum marianum +N po silymarin
Asteraceae Sonchus brachyotus -N wp po nontoxic
Asteraceae Sphaeranthus indicus +N wp po toxic
Asteraceae Stevia aristata 1
Asteraceae Stevia rebaudiana 1 +A,G,?N If po stevioside (A iv),
lupeol (A, po) nontoxic
Asteraceae Taraxacum officinale 4 ?N,-S,A wp po nontoxic
Asteraceae Taraxacum palustre 1 nontoxic?
Asteraceae Terminalia arjuna +D,-N sb,ap po toxic
Asteraceae Trixis radialis 1
Asteraceae Verbesina crocata 1 +A fl,lf po, ip daucosterol, toxic?
galegine, lupeol,
lupeol acetate
(A, po,ip)
Asteraceae Verbesina encelioides +N fl po
Asteraceae Verbesina persicifolia 1 +A fl,lf po,ip toxic?
Asteraceae Vernonia malabarica -N ap po nontoxic
Asteraceae Vernonia volkameriaefolia -N ap po nontoxic
Asteraceae Vicoa indica -N wp po nontoxic
Asteraceae Vittadinia australis +N wp po nontoxic
Asteraceae Xanthium strumarium 1 +G,N rt,wp,sd po,iv,ip carboxyatract- toxic
yIoside
Balsaminaceae Impatiens balsamina 1
Basellaceae Boussingaultia baselloides 1 +S,A ap po,ip nor-rriterpenoid
saponins
Berberidaceae Berberis aristata +N rt po toxic
Berberidaceae Berberis vulgaris -N sb po,iv toxic
Berberidaceae Epimedium sagittatum +N ap po
Berberidaceae Hydrastis canadensis +N,-S rz po berberine toxic
Betulaceae Alnus nepalensis +N sb po toxic
Bignoniaceae Campsis grandiflora 1
Bignoniaceae Crescentia cujete 1 toxic
Bignoniaceae Heterophragma quadriloculare +N ap nontoxic?
Bignoniaceae Parmentiera edulis 1 -A fr,rt po,ip nontoxic
Bignoniaceae Spatbodea campanulata 1 +S sb ip
Bignoniaceae Stereospermum suaveolens +N rt po nontoxic
Bignoniaceae Tecoma mollis 1 +D If po.sc nontoxic
Antidiabetic plants and their active constituents 175

FAMILY SCIENTIFI C N AME ETH ACTIVITY PART RO UTE ACTIVE TOXICITY


TESTED ADMIN. CONSTITUENT
Bignoniaceae Tecoma stans 5 +D,N,?A If,st,wp po,ip ,iv,sc tecomanine and
tecostanine
(A, H , po, iv)
Bixaceae Bixa orellana 3 ?N ap,sd po toxic/
nontoxic
Bombacaceae Bernoullia flammea
Bombacaceae Bombax malabaricum +N fl,sb po toxi c
Bombacaceae Ceiba pentandra 1 -N rt,sb po
Bombacaceae Pachira aquatica 2
Bombacaceae Salmalia malabarica +N sb
Boraginaceae Cordia dichotoma -N ap po toxic
Boraginaceae Heliotropium subulatum +N wp po toxic
Boraginaceae Lithospermum erythrorbizon +A,N rt ip lithospermans a-c toxic
(A, H, ip glycans)
Boraginaceae Lithospermum officinale ?N ,-S If,rt po, iv nontoxic
Boraginaceae Onosma echinoides 1
Boraginaceae Symphytum officinale 1 +N po toxic
Boraginaceae Tournefortia hirsutissima 1
Boraginaceae Trichodesma zeylanicum -N wp po nontoxic
Brassicaceae Armoracia lapathifolia 1 nontoxic
Brassicaceae Brassica napiformis 1 glucokinin nontoxic
Brassicaceae Brassica oleracea 2 -E,+P,G,?N If po,sc nontoxic
Brassicaceae Brassica rapa +N rt po nontoxic
Brassicaceae Descurainia sophia +N wp po tox ic?
Brassicaceae Lepidium ruderale +A,E po lepidine (A, po ) nontoxic
Brassicaceae Lepidium virginicum nontoxic?
Brassicaceae Megacarpaea polyandra +N wp po nontoxic
Brassicaceae Nasturtium officinale 3 nontoxic
Brassicaceae Raphanus sativus 1 -N wp po nontoxic
Brassicaceae Sisymbrium columnae -N wp po nontoxic?
Buddlejaceae Buddleja officinalis 1 nontoxic?
Burseraceae Boswelliaserrata 1 +N,-S fr,st,gm po ?
Burseraceae Bursera delpecbiana -N st po nontoxic
Burseraceae Commiphora myrrha +S,N gm po nontoxic
Cactaceae Lopbophora williamsii +N toxic
Cactaceae Opuntia decumana -N ap po toxic
Cactaceae Opuntia dellenii -N fr po nontoxic
Cactaceae Opuntia ficus-indica 3 +N,?D wp po pectin (A, po) ?
Cactaceae Opuntia inermis 1 ?D,-G If po
Cactaceae Opuntia streptacantha 1 +D,?G,-P,A,N st po
Cactaceae Opuntia vulgaris 1 +U,N wp po
Cactaceae Peniocereus greggii 1
Campanulaceae Codonopsis pilosula 1 -S rt po nontoxic
Campanulaceae Codonopsis tangshen 1 nontoxic?
Campanulaceae Platycodon grandiflorum +A rt po
Cannabaceae Cannabis sativa 2 +U,?N fl,lf,rn po ,in,sc toxic
Capparidaceae Capparis spinosa 1 nontoxic
Capparidaceae Cleome droserifolia 1 ?
Caprifoliaceae Lonicera [aponica 1 +N ap po dauco stero l, nontoxic
scopoletin, ursolic
acid (A, po )
Caprifoliaceae Sambucus mexicana -N fl IV
Caprifoliaceae Sambucus nigra -N,S po nontoxic
Caprifoliaceae Viburnum acuminatum -N ap po nontoxic
Caprifoliaceae Viburnum foetens -N ap po nontoxic
Caricaceae Carica papaya 1 ?N fr,ap po nontoxic
Car yophyllaceae Paronychia argentea 1
Casuari naceae Casuarina equisetifolia 1 +N ap po nontoxic
Celastraceae Catha edulis -N If,st po toxic
Celastraceae Euonymus echinatus -N ap po toxic
Celastraceae Euonymus glaber -N ap po ?
176 R.]. Maries and N. R. Farnsworth

FAMILY SCIENTIFIC NAME ETH ACTIVITY PART ROuTE ACTIVE TOXICITY


TESTED ADM IN. CONSTITUENT
Celastraceae Euonymus indicus -N ap po
Celastraceae Hippocratia macrantha -N ap po nontoxic
Chenopodiaceae Atriplex halimus 1 +D,A,N If po Cr, Mn (A, po )
Chenopodiaceae Beta vulgaris +N ap, rt po.sc non toxic
Chenopodiaceae Hammada salicornica 1 +A,-N ap,wp po.iv N -methyltrypt- toxic
amine, scopoletin
(A,H,po)
Chenopodiaceae Spinacia oleracea +N ap po nontoxic
Clusiaceae Garcinia cola +A sd ip
Clusiaceae Garcinia indica -N ap po
Clusiaceae Garcinia mannii +U po manniflavanone
(A,po)
Clusiaceae Garcinia pedunculata -N ap po
Cneoraceae Neochamaelea pulverulenta 1
Combretaceae Anogeissus pendula -N ap po nontoxic
Combretaceae Conocarpus erectus 1
Combretaceae Terminalia bellerica 1 nontoxic
Combretaceae Terminalia catappa 1 ?
Combretaceae Terminalia chebula 2 +N fr,sb po
Connaraceae Rourea santaloides 1 toxic
Convolvulaceae Argyreia cuneata 1 ?A,D,-N If po,sc ?
Convolvulaceae Argyreia involucrata -N ap po nontoxic
Convol vulaceae Argyreia neruosa 1 -N If po
Convolvulaceae Calystegia japonica 1 toxic
Convolv ulaceae Convolvulus micropbyllus 1 toxic?
Convolvulaceae Ipomoea aquatica 1 ?
Convolvulaceae Ipomoea batatas 1 +N
Convolvulaceae Ipomoea nil +N toxic
Convolvulaceae Ipomoea purpurea -N wp po nontoxic
Convolvulaceae Merremia mammosa
Convolvulaceae Porana paniculata -N ap po toxic
Convolvulaceae Quamoclit coccinea +N ap po nontoxic
Convolvulaceae Rivea ornata 1 -N sp po
Cornaceae Cornus mas 1
Cornaceae Cornus officinalis 3 ?S,Y,G,N fr po ursolic acid nontoxic
(A, po), oleanolic
acid
Crassulaceae Bryophyllum pinnatum toxic?
Crassulaceae Rhodiola rosea +U sc nontoxic
Crassulaceae Sedum [ormosanum 1 toxic?
Cucurbitaceae Benincasa hispida 1 -N,S,G wp po toxic
Cucurbitaceae Bryonia alba +A rt im trihydroxyoctadec toxic
adienoic acid
Cucurbitaceae Bryonia cretica -N toxic
Cucurbitaceae Bryonia dioica -A,N rt po toxic
Cucurbitaceae Bryonia epigaea 1 toxic?
Cucurbitaceae Citrullus colocynthis 3 +N wp po toxid
nontoxic
Cucurbitaceae Citrullus lanatus 1 toxic?
Cucu rbitaceae Coccinia cordifolia 1 -N rt, fr po nontoxic?
Cucurbitaceae Coccinia grandis 1 nontoxic?
Cucurbitaceae Coccinia indica 3 +D,S,G,K,T, fr,lf,st,rt po qua ternary nontoxic
?A,N,-X alkaloid (? (H, po)
Cucurbitaceae Cucumis melo -N ,G,S wp po
Cucurbitaceae Cucumis sativus -N,G,S wp po
Cucurbitaceae Cucurbitamaxima 1 toxic
Cucurbitaceae Cucurbitamoschata 1 -S sd po toxic?
Cucurbitaceae Cucurbitapepo 1 toxic?
Cucurbitaceae Lagenaria siceraria 2 +D ?
Cucurbitaceae Lagenaria vulgaris 1 -N fr po
Antidiabetic plants and their active constituents 177

FAMILY SCIENTIFIC NAME ETH ACTIVITY PART ROUTE ACTIVE TOXICITY


TESTED ADMIN. CONSTITUENT
Cucurbitaceae Luffa acutangula +N ap po toxic!
nontoxic
Cucurbitaceae Luffa echinata +N ap po toxic
Cucurbitaceae Melothria heterophylla 1 toxic
Cucurbitaceae Momordica balsamina 1 nontoxic?
Cucurbitaceae Momordica charantia 12 ?A,S,D, fr,sd po,sc,iv polypeptide p toxic!
G,N,=X (A, sc), charantin: nontoxic
daucosterol + 5,25-
stigmastadien-3~-
ol-glucoside
(A,H,po)
Cucurbitaceae Momordica cochinchinensis +S tb ip
Cucurbitaceae Momordica foetida 1 +A ip foetidin = toxic?
charantin (A, ip)
Cucurbitaceae Trichosanthes anguina -N,G,S wp po
Cucurbitaceae Trichosanthes bracteata +N wp nontoxic?
Cucurbitaceae Trichosanthes cucumeroides 1 nontoxic?
Cucurbitaceae Trichosanthes dioica +G,N,-S ap,rt,sd po nontoxic
Cucurbitaceae Trichosanthes kirilowii 2 +A,N fr,rt,tb po nontoxic?
Cucurbitaceae Trichosanthes multiloba 1 nontoxic?
Cuscutaceae Cuscuta sp. -S sd po
Datiscaceae Datiscacannabina +N wp po
Dipsacaceae Dipsacus asperoides 1 -S rt po
Dipterocarpaceae Dipterocarpus indicus -N ap po nontoxic
Dipterocarpaceae Vateria indica -N ap po toxic
Dipterocarpaceae Vatica chinensis -N ap po nontoxic
Ebenaceae Diospyros insignis -N ap po nontoxic
Ebenaceae Diospyros peregrina -N ap po toxic
Elaeagnaceae Elaeagnus conferta -N ap po nontoxic
Elaeocarpaceae Elaeocarpus ganitrus +N sb po toxic
Elaeocarpaceae Elaeocarpus serratus -N ap po toxic
Ericaceae Agapetessikkimensis +N ap po nontoxic
Ericaceae Arbutus menziesii 1 toxic
Ericaceae Arctostaphylos uua-ursi 2 -S If po nontoxic
Ericaceae Rhododendron campanulatum -N ap po toxic
Ericaceae Vaccinium corymbosum +D,-N If po nontoxic
Ericaceae Vaccinium leschenaultii +N ap po nontoxic
Ericaceae Vaccinium myrtillus 2 +D,A,G,P,N ap,lf po,sc,iv neomyrtillin nontoxic
(A, H, po),
(-)epicatechin
(A,ip)
Ericaceae Vaccinium oxycoccus 1 +N nontoxic?
Ericaceae Vaccinium pennsyluanicum +D,P,G If po,iv
Ericaceae Vaccinium uitis-idaea +N If nontoxic?
Eucommiaceae Eucommia ulmoides 1 ?A,S st.lf po
Euphorbiaceae Acalypha wilkesiana -N ap po toxic
Euphorbiaceae Aporosa lindleyana +N wp po toxic
Euphorbiaceae Blachia umbellata -N ap po toxic
Euphorbiaceae Bridelia ferruginea 2 +D,G,-A If po rutin (quercetin-S- ?
neohesperidoside),
daucosterol (A, po)
Euphorbiaceae Cluytia richardiana 1 +A,N ip saudin (A, ip)
(diterpene) nontoxic?
Euphorbiaceae Croton caudatus -N fr po toxic
Euphorbiaceae Croton niveus -N toxic
Euphorbiaceae Drypetes venusta -N ap po nontoxic
Euphorbiaceae Euphorbia helioscopia -U ap po toxic
Euphorbiaceae Euphorbia hirta +U wp po toxic?
Euphorbiaceae Euphorbia pilulifera 1 +U toxic?
Euphorbiaceae Euphorbia prostrata 1 -A,+N ap po daucosterol, toxic?
lupeol, ursolic acid
(A,po)
178 R. J. Maries and N. R. Farnsworth

FAMILY SCIENTIFIC NAME ETH ACTIVITY PART ROUTE ACTIVE TOXICITY


TESTED ADMIN. CONSTITUENT
Euphorbiaceae Glochidion heyneanum -N ap po toxic
Euphorbiaceae Glochidion hohenackeri +N ap po toxic
Euphorbiaceae Glochidion sphaerogynum -N ap po nontoxic
Euphorbiaceae Jatropha curcas -N ap po toxic
Euphorbiaceae Jatrophagossypiifolia 1 toxic
Euphorbiaceae Mallotus philippinensis +N fr po nontoxic
Euphorbiaceae Phyllanthus amarus 2 toxic
Euphorbiaceae Phyllanthus emblica 4 -N sd po toxic
Euphorbiaceae Phyllanthus epiphyllanthus 1 toxic
Euphorbiaceae Phyllanthus lawii -N ap po toxic
Euphorbiaceae Phyllanthus niruri 4 +A,?N If po lupeol, lupeol toxic
acetate (A, po)
Euphorbiaceae Phyllanthus sellowianus 1 +N sb IV toxic
Euphorbiaceae Putranjiva roxburghii 1 toxic
Euphorbiaceae Ricinus communis 1 +N rt,wp po toxic
Euphorbiaceae Sapium sebiferum -N ap po toxic
Euphorbiaceae Securinega leucopyrus -N ap po nontoxic
Euphorbiaceae Securinega virosa +N sd po thioglycosides toxic
Euphorbiaceae Tragia involucrata -N ap po toxic
Fabaceae Abrus precatorius ?N ap po,sc precatorine (H, sc) nontoxic
Fabaceae Acaciaarabica 1 -N sb po
Fabaceae Acaciabenthami 1 -A,?N sb,sd po toxic
Fabaceae Acaciacatechu 1 -A,?N sd,gm po toxid
nontoxic
Fabaceae Acaciaconfusa +N N-methyltrypt- toxic
amine (H, po)
Fabaceae Acacia ferruginea -N sb toxic
Fabaceae Acaciamelanoxylon 1 +A,N sd po nontoxic
Fabaceae Acaciamodesta 1 -A,+N sd po nontoxic
Fabaceae Acacianilotica 3 -A,+N sd,gm po nontoxic
Fabaceae Acaciasenegal -N sb po nontoxic
Fabaceae Acaciasuma -A,+N sd po nontoxic
Fabaceae Adenantherapauonina -N ap po nontoxic
Fabaceae Aeschynomene indica -N wp po toxic
Fabaceae Albizia julibrissin -N ap po nontoxic
Fabaceae Albizia lathamii -N ap po toxic
Fabaceae Albizia lebbek ?N fr,rt,sb po toxic
Fabaceae Albizia moluccana 1 -A,+N sd po toxic
Fabaceae Albizia odoratissima -A,?N sd,sb po toxic
Fabaceae Albizia procera -N ap po toxic
Fabaceae Albizia stipulata 1 -A,+N sd toxic
Fabaceae Alhagia maurorum -N wp nontoxic
Fabaceae Arachis hypogaea +N sd nontoxic
Fabaceae Astragalus candolleanus -N wp po nontoxic?
Fabaceae Astragalus membranaceus +A,?N,-S rt po nontoxic?
Fabaceae Atylosia lineata -N wp po nontoxic
Fabaceae Atylosia platycarpa -N wp po toxic
Fabaceae Atylosia volubilis -N ap po nontoxic
Fabaceae Bauhinia aculeata 1 ?
Fabaceae Bauhinia candicans 1 +A,?N If po ?
Fabaceae Bauhiniaemarginata 1 ?
Fabaceae Bauhinia forficata 1 +A,P,D,N wp po daucosterol, ?
lupeol, pectin
(A, po)
Fabaceae Bauhinia manca 1
Fabaceae Bauhiniapurpurea +G If po
Fabaceae Bauhinia retusa 1 +A,N sd nontoxic
Fabaceae Bauhinia variegata +N fl quercetin nontoxic
Fabaceae Bowdichia virgilioides 1 toxic
Fabaceae Butea monosperma 2 -N If po nontoxic
Fabaceae Caesalpinia bonducella 2 ?
Antidiabetic plants and their active constituents 179

FAMILY SCIENTIFIC NAME ETH ACTIVITY PART ROUTE ACTIVE TOXICITY


TESTED ADMIN. CONSTITUENT

Fabaceae Caesalpinia coriaria -N ap po toxic


Fabaceae Caesalpinia digyna 1 -N rt po toxic
Fabaceae Cajanus cajan +N sd po nontoxic
Fabaceae Canaualia ensiformis +N sd IV canatoxin (pro tein ) toxic
Fabaceae Caragana breuispina +N ap po nontoxic
Fabaceae Cassia alata 1 +S,?N ap,1f po ?
Fabaceae Cassia auriculata 2 ?A,N fl,lf,sd
Fabaceae Cassia fistula 2 -A,?N fr,sd,sb po toxic
Fabaceae Cassia [ruticosa 1 toxic
Fabaceae Cassia [auanica -N ap po ?
Fabaceae Cassia occidentalis 1 +N, -5 If po toxic
Fabaceae Cassia sophera 2 -N sd,sb po ?
Fabaceae Cassia surattensis -N ap po toxic
Fabaceae Cassia tamala +D
Fabaceae Cassia tora -5 sd po
Fabaceae Castanospermum australe +F IS po castanospermine
Fabaceae Ceratonia siliqua 2 +D sd po nontoxic
Fabaceae Cicer arietinum +N,G fr po nontoxic
Fabaceae Crotalaria medicaginea -N wp po toxic
Fabaceae Crotalaria retusa -N ap po toxic
Fabaceae Crotalaria verrucosa -N wp po toxic
Fabaceae Cyamopsis tetragonolobus +A,D,G ,N fr,gm,sd po guar gum (H , po) nontoxic
Fabaceae Dalbergia spinosa -N ap po ?
Fabaceae Dalbergia sympathetica -N ap po toxic
Fabaceae Derris scandens -N ap po ?
Fabaceae Dolichos biflorus 1 +N sd po toxic
Fabaceae Dolichos lablab 2 +A,D,E,G,N fr,sd po toxic
Fabaceae Entada scandens -N ap po toxic
Fabaceae Erythrina indica toxic
Fabaceae Erythrina sigmoidea +N po sigmoidin b,c
(flavanones)
Fabaceae Erythrinasuberosa +N sb po toxic
Fabaceae Eysenhardtia polystachya 1 +A wp po,ip
Fabaceae Galega officinalis 2 +D,A,G,N If po,ip galegine toxic
(isoamylenegua ni
dine) (A, po , ip)
Fabaceae Gliricidia septum -N ap po toxic
Fabaceae Glycine max +N ap nontoxic
Fabaceae Glycyrrhiza glabra 2 ?N, 5,Y rt Ip,PO ~-glycyrrhetinic nontoxic
acid
Fabaceae Humboldtia brunonis -N ap po nontoxic
Fabaceae Indigofera arrecta 1 +D ?
Fabaceae Indigofera glandulosa -N wp po nontoxic
Fabaceae lndigofera mysorensis -N ap po toxic
Fabaceae Indigofera spinosa 1
Fabaceae Indigofera tinctoria +N ap nontoxic
Fabaceae Lathyrus japonicus +A sd lathyrine,
L-glutamyl- toxic?
L-Iathyrine
Fabaceae Lathyrus palustris 1 +N If po toxic?
Fabaceae Lathyrus satiuus +D,N sd po,ip toxic
Fabaceae Leucaena glauca +A,E,P,N sd po toxic
Fabaceae Leucaena leucocephala +N sd
Fabaceae Lupinus albus 5 +G,Z,N,-A,S sd,wp po lupanine, sparteine toxic
(A, po)
Fabaceae Lupinus termis 3 +A,G,=E,?S,N sd po.sc lupanine, toxic
coumarin, sparteine
(A, po)
Fabaceae Medicago sativa +5,?N If po Mn ions (H, po ),
vitamin K non toxic
Fabaceae Mezoneuron cucullatum -N ap po toxic
180 R. J. Marles and N. R. Farnsworth

FAMILY SCIENTIFIC NAME ETH ACTMTY PART ROUTE ACTIVE TOXICITY


TESTED ADMIN. CONSTITUENT
Fabaceae Milletia cinerra -U,N ap
Fabaceae Milletia kitjana 1
Fabaceae Mimosa pudica +A wp po
Fabaceae Moghania paniculata -N ap po toxic
Fabaceae Mucuna imbricata -N ap po nontoxic
Fabaceae Mucuna pruriens 1 ?N,-A fr,rt,sd po toxic!
nontoxic
Fabaceae Ononis pubescens +N ap ip
Fabaceae Parkia speciosa 1 toxic?
Fabaceae Parkinsonia aculeata -N ap po nontoxic
Fabaceae Phaseolus aureus +G sd po
Fabaceae Phaseolus coccineus 1 glucokinin nontoxic?
Fabaceae Phaseolus vulgaris 2 +N,G,?D,-S sd po nontoxic
Fabaceae Pisum sativum 2 +N
Fabaceae Pithecellobium bigeminum 1 -N ap,sd po toxic
Fabaceae Pithecellobium lobatum 1 -N sd po toxic?
Fabaceae Pongamia pinnata 1 ?N fl po ?
Fabaceae Prosopis farcata 1 nontoxic?
Fabaceae Prosopis juliflora -N ap po nontoxic
Fabaceae Psoralea pubescens 1
Fabaceae Pterocarpus marsupium 2 +A,D,X,G,N st,sb po (-)epicatechin nontoxic
(A, ip); kino gum
(H, po); ptero-
stilbene (H, po)
Fabaceae Pterocarpus santalinus 1 +S,N st,sd po nontoxic?
Fabaceae Pueraria hirsuta +N rt po nontoxic?
Fabaceae Pueraria lobata +0 fl po
Fabaceae Pueraria tuberosa 1 +N tb po nontoxic
Fabaceae Robinia pseudacacia -N ap po toxic
Fabaceae Samanea saman -N ap po toxic
Fabaceae Saraca indica 1 -N ap,fl po nontoxic
Fabaceae Securigera securidaca 1 ?N sd
Fabaceae Smitbia conferta -N wp po nontoxic
Fabaceae Sophoraangustifolia +S rt po
Fabaceae Spartium junceum 1 toxic
Fabaceae Sweetia panamensis 2 toxic
Fabaceae Tamarindus indica 1 nontoxic
Fabaceae Tephrosia purpurea 1 +A,N sd po lupeol (A, po) toxic
Fabaceae Tepbrosia villosa 1 -N If po toxic?
Fabaceae Teramnus labialis +N wp po nontoxic
Fabaceae Tetrapleura tetraptera 1 toxic
Fabaceae Trifolium alexandrinum 1 +A,D,N sd po nontoxic
Fabaceae Trifolium pratense -N wp po nontoxic
Fabaceae Trigonella foenum-graecum 4 +A,D,G,N,?S sd,wp po trigonelline, nontoxic
coumarin, nicotinic
acid (A, H, po),
nicotinamide (H, po),
fenugreekine (H, iv)
Fabaceae Uraria picta -N wp po nontoxic
Fabaceae Vicia [aba 3 nontoxic
Fabaceae Vignamungo +A sd po
Fagaceae Castanea dentata -S sd po
Fagaceae Fagus sylvatica 1 nontoxic
Fagaceae Quercus boissieri 1 ?
Fagaceae Quercus ilicifolia 1
Fagaceae Quercus infectoria 1 +N gl po nontoxic
Fagaceae Quercus lamellosa +N sb po toxic
Fagaceae Quercus lanceaefolia 1 +N sb po toxic
Fagaceae Quercus lineata +N sb po toxic
Fagaceae Quercus spicata +N sb po toxic
Flacourtiaceae Aphloia theiformis 1
Antidiabetic p la n ts and their active constituents 181

FAMILY SCIENTIFIC NAME ETH ACTIVITY PART ROUTE ACTIVE TOXICITY


TESTED ADMIN. CONSTITUENT

Flacourtiaceae Casearia esculenta 1 ?N,-D rt,sb po nontoxic?


Flacourtiaceae Casearia glauca 1 -N sb po
Flacourtiaceae Flacourtia montana -N ap po nontoxic
Flacourtiaceae Hydnocarpus alpina -N ap po nontoxic
Fumariaceae Corydalis govaniana -N wp po toxic
Fumariaceae Fumaria paruiflora 3 -A,+N ap po ?
Gentianaceae Canscora decussata 1
Gentianaceae Centaurium erythraea 2 toxic?
Gentianaceae Centaurium spicatum 1 nontoxic?
Gentianaceae Enicostemahyssopifolium 1 ?X,-N po
Gentianaceae Enicostema littorale 1 +D,X wp nontoxic
Gentianaceae Exacum bicolor -N ap po nontoxic
Gent ianaceae Gentianalutea 2 nontoxic
Gentianaceae Nymphoides oristatum -N wp po nontoxic
Gentianaceae Swertia chirayita +N,G wp po 1,8-dihydroxy- nont oxic
3, 5-dimethoxy-
xanthone
Geraniaceae Geranium maculatum +N
Geraniaceae Geranium nepalense -N wp po
Geraniaceae Geranium sp, 1
Globulariaceae Globularia alypum 1
Goodeniaceae Scaevola taccada 1 nontoxic
Hippocrareaceae Salacia chinensis 2 toxic?
Hippocrateaceae Salacia fruticosa +N
Hippocrateaceae Salacia macrosperma 1 +N If,rt toxic
H ippocrateaceae Salacia prinoides 1 +G,N rb po toxic
Hippocrateaceae Salacia reticulata 2 +N,S,G rb po lupeol (A, po) toxic?
Hydrophyllaceae Hydrolea zeylanica +N wp po toxic
Hypericaceae Hypericum uliginosum 1
Ixonanthaceae Irvingia gabonensis +D sd po
]uglandaceae [uglans regia 3 +A If sc non toxic
Krameriaceae Krameria triandra -N rt po
Lamiaceae Ajuga bracteosa -N nontoxic
Lamiaceae Ajuga iva 3 nontoxic
Lamiaceae Calamintha macrostema 1 +A st.rt po,ip ursolic acid (A, po) toxic?
Lamiaceae Calamintha umbrosa +N wp po ursolic acid (A, po) toxic
Lamiaceae Cedronella canariensis 1
Lamiaceae Coleus forskohlii +G rt iv forskolin (A, H, iv)
(diterpene)
Lamiaceae Dysopbylla rugosa -N wp po nontoxic
Lamiaceae Gomphostemma parvif/orum -N wp po toxic
Lamiaceae Hyptis suaueolens +N ap po toxic
Lam iaceae Lavandula dentata +G,-A wp po
Lam iaceae Lavandula latifolia -G,A wp po
Lamiaceae Lavandula multifida -N fl po
Lamiaceae Lavandulastoechas +G,N,-A fl po
Lamiaceae Leonotis leonurus 1 toxic
Lamiaceae Lycopus virginicus 1 +N
Lamiaceae Marrubium deserti 1
Lamiaceae Marrubium vulgare 1 nontoxic
Lamiaceae Mesona procumbens 1 +U ursolic acid (A, po)
Lamiaceae Ocimum canum +D sd, wp po
Lamiaceae Ocimum gratissimum -N wp po nontoxic
Lamiaceae Ocimum micranthum 1 nontoxic?
Lamiaceae Ocimum sanctum 1 +N If po nontoxic
Lamiaceae Origanum syriacum 1 nontoxic?
Lamiaceae Orthosiphon grandif/orus 3 +D If po ursolic acid (A, po)
Lamiaceae Orthosiphon spiralis 1 +D If
Lamiaceae Perilla [rutescens -N wp po
Lamiaceae Prunella vulgaris 2 -S ap po
Lamiaceae Salvia canariensis 1
182 R. J. Maries and N. R. Farnsworth

FAMILY SCIENTIFIC NAME ETH ACI'MTY PART ROUTE ACTIVE TOXICITY


TESTED ADMIN. CONSTITUENT
Lamiaceae Salvia fruticosa 1 -A If po
Lamiaceae Salvia lavandulaefolia 1 +A,G,N fl po nontoxic
Lamiaceae Salvia officinalis 2 -N,S If po nontoxic
Lamiaceae Salvia plebeia -N wp po toxic
Lamiaceae Salvia sclarea 1 nontoxic
Lamiaceae Scutellaria baicalensis 1 ?Y,-S rt po
Lamiaceae Sideritis pusilla 1
Lamiaceae Teucrium oliverianum 1 +A ap po nontoxic
Lamiaceae Teucrium polium 2 +U,S,N ap,wp po toxic
Lamiaceae Teucrium royleanum +N wp po toxic
Lamiaceae Thymus serpyllum 1 nontoxic
Lardizabalaceae Akebia quinata 1 toxic
Lauraceae Actinodaphnehookeri 1 -N If po ?
Lauraceae Actinodaphnemadraspatana -N If po
Lauraceae Cinnamomum campbora -N ap po nont oxic
Lauraceae Cinnamomum cassia 1 +N,?Y sb po cinnamaldehyde nonto xic
Lauraceae Cinnamomum sulphuratum -N If,sb po nontoxic
Lauraceae Cinnamomum tamala +D,-S sb,rt po toxic
Lauraceae Laurus nobilis +N If
Lauraceae Persea americana 3 nontoxic
Lauraceae Persea gratissima 1 nontoxic?
Lauraceae Sassafras albidum 1
Lecythidaceae Barringtonia acutangula +N rt po toxic
Leeaceae Leea crispa +N ap ?
Leeaceae Leeaindica +N If po toxic
Linaceae Hugonia mystax -N ap po toxic
Loganiaceae Anthocleistadjalonensis 2
Loganiaceae Anthocleistakerstingii 2
Loganiaceae Anthocleistanobilis +N sb nontoxic
Loganiaceae Anthocleistarbizophoroides +N sb nontoxic
Loganiaceae Anthocleistavogelii 2 +A,N rt po
Loganiaceae Gelsemium sempervirens +N toxic
Loganiaceae Strychnos nux-vomica 2 -N fr toxic
Loganiaceae Strychnospotatorum 1 -N If,sb,sd po,iv toxic/
nontoxic
Loranthaceae Loranthus curviflorus 1 ?A fl po ?
Loranthaceae Loranthus parasiticus -S wp po
Lorant haceae Psittacanthus calyculatus 1 +A ap po,ip toxic
Loranthaceae Viscum album +N,-S ap po toxic
Lythraceae Lagerstroemia parviflora +N ap po toxic
Lythraceae Lagerstroemia speciosa 2 +A,-U,?N If,sd po,iv nontoxic
Lythraceae Lythrum salicaria 1 +G,S,E,A,?N fl,rt,st po,iv
Lythraceae Sonneratia apetala -N ap po toxic
Magnoliaceae Michelia champaca +N sb po toxic
Magnoliaceae Talauma ovata 1 -N ,G,A toxic
Malvaceae Abelmoschus edulis +N fr,rt po okra-mucilages F,R nontoxic
Malvaceae Abelmoschus glutinotextilis +N rt po abelmoschus- nontoxic
mucilage G
Malvaceae Abelmoschusmanihot +N rt po abelmoschus-
mucilage M nontoxic
Ma lvaceae Abutilon trisulcatum 1 nontoxic
Malvaceae Althaeaofficinalis 1 +N If,rt po althaea - . nontoxic
mucilage 0, althaea-
mucilage OL
Malvaceae Decaschistia crotonifolia -N wp po toxic
Malvaceae Gossypium herbaceum 1 +A,N If po toxic
Malvaceae Hibiscus hirtus -N wp po nontoxic
Malvaceae Hibiscus syriacus +N If po hibiscus - nontoxic
mucilage SL
Malvaceae Hibiscus tiliaceus 1 +N ap nontoxic?
Malvaceae Malachra alceifolia 1
Antidiabetic plants and their active constituents 183

FAMILY SCIENTIFIC NAME ETH ACTIVITY PART ROUTE ACTIVE TOXICITY


TESTED ADMIN. CONSTITUENT

Malvaceae Malva uerticillata +N sd ip polysaccharide, pectin


Malvaceae Sida spinosa +N wp po toxic
Melastornataceae Memecylon umbellatum +N If po nontoxic
Melastornataceae Osbeckia octandra +G,-N ap po nontoxic
Meliaceae Amoora u/allicbi -N st toxic
Meliaceae Azadirachta indica 4 +A,E,X,S,?N If,sd po,iv nirnbidin, nontoxic
daucosterol
(A, H, po), other
active flavonol
glycosides
Meliaceae Carapa granatum -N ap po nontoxic
Meliaceae Cedrela toona +N If po toxic
Meliaceae Dysoxylum binectariferum -N fr po toxic
Menisperrnaceae Anamirta cocculus -N ap po toxic
Menisperrnaceae Cissampelos pareira 1 ?
Menisperrnaceae Cocculus cordifoiius 1 -N wp po
Menisperrnaceae Cocculus hirsutus -N ap po nontoxic
Menisperrnaceae Pibraurea chloroleuca 1 toxic
Menisperrnaceae Sciadotenia amazonica 1
Menispermaceae Sciadotenia toxifera 1 toxic
Menisperrnaceae Stephaniaglabra +N rt po toxic
Menispermaceae Tinospora cordifolia 2 +N st po ?
Menisperrnaceae Tinospora crispa 1 +A,G,-N st po,iv
Menisperrnaceae Tinospora tuberculata 1 toxic?
Moraceae Artocarpusaltilis 2 toxic?
Moraceae Artocarpusintegrifolia +D,N If po
Moraceae Cecropia mexicana 1
Moraceae Cecropia obtusifolia 1 +A,P If,st po,ip,iv toxic
Moraceae Cecropia peltata 2 -N If ?
Moraceae Cecropia surinamensis 1 ?
Moraceae Ficus asperrima -N ap po toxic
Moraceae Ficus bengbalensis +D,N,G,?A,P sb,sp po bengalenoside nontoxic?
(flavonoid-glycosi
de ), daucosterol,
lupeol, scopoletin
(A,H,po)
Moraceae Ficus benjamina -N ap po nontoxic?
Moraceae Ficus callosa -N ap po toxic
Moraceae Ficus carica 2 toxic?
Moraceae Ficus glomerata 1 +N sb po
Moraceae Ficus bispida -N ap po nontoxic?
Moraceae Ficus racemosa 2 ?A,N,-S sb,wp,fr po daucosterol, toxic
lupeol, lupeol
acetate (A, po)
Moraceae Ficus religiosa 3 +A,X,?N rb,rt po daucosterol (A, po) nontoxic?
Moraceae Ficus talbotii -N ap po nontoxic?
Moraceae Humulus lupu/us +D,?S,-N If po humulone, nontoxic
lupulone (+5, po )
Moraceae Morus alba 4 +D,S,E,F, If,rb po,sc,ip phytosterol nontoxic
G,N,?A glycosides,
scopoletin
(A, H, po); moran a
(A,H,ip)
glycoprotein,
moranoline
Moraceae Morus australis 1 nontoxic
Moraceae MoTUs bombycis +N po nontoxic?
Moraceae Morus nigra 2 +D,N If po phytosterol
glycosides,
scopoletin
(A,H,po) nontoxic
184 R.]. Maries and N. R. Farnsworth

FAMILY SCIENTIFIC NAME ETH ACTIVITY PART ROUTE ACTIVE TOXICITY


TESTED ADMIN. CONSTITUENT
Moraceae Myrianthus arboreus 1 +D sb po
Moraceae Plecospermum spinosum -N ap po nontoxic
Moringaceae Moringa pterygosperma 1 +A,-N fr,lf,st po nontoxic
Myrsinaceae Aegiceras corniculatum -N ap po toxic
Myrsinaceae Ardisianeriifolia -N ap po toxic
Myrsinaceae Embeliaviridiflora -N ap po toxic
Myrsinaceae Myrsine africana -N wp po toxic
Myrtaceae Aulomyrciahostmanniana 1
Myrtaceae Eucalyptus alba -N ap po toxic
Myrtaceae Eucalyptus citriodora 2 +A,N If po myrtillin nontoxic
Myrtaceae Eucalyptus cloeziana -N ap po nontoxic
Myrtaceae Eucalyptus globulus 5 -D,N,+A,S If po,ip calyptoside nontoxic
(A,H,po)
Myrtaceae Eucalyptus robusta 1 nontoxic
Myrtaceae Eugenia jambolana 1 +S,-G sd po
Myrtaceae Eugenia uniflora -N If po
Myrtaceae ]ambosa laeta -N ap po nontoxic
Myrtaceae Myrtus communis 1 +S If,st po nontoxic
Myrtaceae Pimenta officinalis 1 +N nontoxic
Myrtaceae Psidiumguajava 3 +A,D,?N ap,fr,lf po,ip brahmic acid nontoxic
Myrtaceae Syzygium alternifolium 1 nontoxic?
Myrtaceae Syzygium aromaticum +S,-N sh,ap po nontoxic
Myrtaceae Syzygium cerasoides +N ap ?
Myrtaceae Syzygium cumini 6 +A,D,?N,S ap,sd po antimellin nontoxic
(glycoside)
Myrtaceae Syzygium hemisphericum -N ap po toxic
Myrtaceae Syzygium jambos 2 toxic
Myrtaceae Syzygium montanum -N ap po nontoxic
Nyctaginaceae Bougainvillea spectabilis +A,G,N If po pinitol (+A,N, po) nontoxic
Nyctaginaceae Salpianthus arenarius 1 +A fl po,ip
Nyctaginaceae Salpianthus macrodontus 1
Nymphaeaceae Nelumbo nucifera 1 +G,Ej-N,S fl.rz.sd po nontoxic
Nymphaeaceae Nymphaea lotus 1 +N rt po toxic?
Nymphaeaceae Nymphaea nouchali ?N wp,rt po toxic
Oleaceae Forsythia suspensa +S fr po
Oleaceae ]asminum rigidum -N ap po nontoxic
Oleaceae ]asminum rottlerianum -N ap po nontoxic
Oleaceae Olea europaea 4 +U,N If po scopoletin nontoxic
(A, H, po)
Oleaceae Olea polygama -N ap po toxic
Onagraceae Epilobium birsutum 1 toxic?
Onagraceae Epilobium royleanum +N wp po toxic
Onagraceae Fuchsia magellanica -N ap po
Orobanchaceae Aeginetiaindica 1
Orobanchaceae Cistanche tubulosa +N wp toxic
Oxalidaceae Averrhoabilimbi +N If toxic?
Oxalidaceae Averrhoacarambola -N ap po ?
Oxalidaceae Biopbytum sensitivum 2
Oxalidaceae Oxalis corniculata +N If,st po toxic
Oxalidaceae Xanthoxalis corniculata +G,N wp po
Paeoniaceae Paeonia albiflora 1 +S,?Y rt po
Paeoniaceae Paeonia emodi -N wp po
Paeoniaceae Paeonia moutan 1 +G,L,N,?Y,-S rb po,iv
Paeoniaceae Paeonia obovata 1 +N rt po
Papaveraceae Argemone mexicana -N fl IV nontoxic
Papaveraceae Chelidonium majus 1 +Nj-S,N rt;lf iv.po toxic
Papaveraceae Glaucium flavum 1 +G,N,-A po
Papaveraceae Papaver somniferum +N alkaloids toxic
Passifloraceae Passiflora quadrangularis 1 toxic
Pedaliaceae Sesamum indicum +N
Piperaceae Heckeria subpeltata -N ap po nontoxic
Antidiabetic plants and their active constituents 185

FAMILY SCIENTIFIC NAME ETH ACTIVITY PART ROUTE ACTIVE TOXICITY


TESTED ADMIN. CONSTITUENT
Piperaceae Pipercubeba 1 nontoxic
Piperaceae Piperguineense 1 ?
Piperaceae Piperlongum +N wp po nontoxic
Piperaceae Pipernigrum 1 nontoxic
Pittosporaceae Pittosporum floribundum -N ap po toxic
Plantaginaceae Plantago asiatica +N,-S sd po plantago- nontoxic
mucilage A
Plantaginaceae Plantago himalaica +N wp nontoxic?
Plantaginaceae Plantago lanceolata -N wp po nontoxic
Plantaginaceae Plantago major 1 nontoxic
Plantaginaceae Plantago ouata +D sd po
Polemoniaceae Loeselia mexicana 1 +A wp po,ip
Polygonaceae Calligonum comosum +A,N ap po
Polygonaceae Fagopyrum cymosum -N wp po nontoxic
Polygonaceae Fagopyrum esculentum ?N sd po nontoxic
Polygonaceae Polygonum aviculare 3 +N,-A rt nontoxic
Polygonaceae Polygonum bistorta 1 nontoxic?
Polygonaceae Polygonum cuspidatum +N wp po nontoxic?
Polygonaceae Polygonum multiflorum 1 ?A rt po
Polygonaceae Polygonum reynoutria +N If,st po
Polygonaceae Rheum officinaIe 1 ?Y rz po
Polygonaceae Rumex acetosa +N If,st po nontoxic
Polygonaceae Rumex [aponicus +N If po nontoxic?
Polygonaceae Rumex nepalensis -N wp po nontoxic
Polygonaceae Rumex nervosus 1 nontoxic?
Polygonaceae Rumex patientia 1 nontoxic
Polygonaceae Rumex vesicarius +N sd po
Portulacaceae Portulaca oleracea 1 +N,?A sd,wp po nontoxic
Portulacaceae Talinum portulacifolium 1
Proteaceae Grevillea robusta -N ap po nontoxic
Punicaceae Punica granatum 1 ?N ap,fl po toxic!
nontoxic
Pyrolaceae Chimapbila umbellata 1 ?N If po nontoxic
Rafflesiaceae Cytinus hypocistis 1
Ranunculaceae Aconitum carmichaelii 1 +A,Y,N,-S rt ip aconitans a-d toxic
(A, H, ip)
Ranunculaceae Aconitum moschatum 1 toxic
Ranunculaceae Aconitum violaceum 1 toxic
Ranunculaceae Caltha palustris -N wp po toxic
Ranunculaceae Cimicifuga racemosa +N toxic
Ranunculaceae Clematis armandii 1 toxic
Ranunculaceae Clematis barbellata -N ap po toxic
Ranunculaceae Clematis montana -N ap po ?
Ranunculaceae Coptis chinensis 1 +A,D,N rz po berberine toxic
(A, H, po)
Ranunculaceae Coptis teeta 2 +N rz po
Ranunculaceae Naravelia zeylanica -N ap po toxic
Ranunculaceae Nigella sativa 1 +A,-S,N sd po nontoxic
Rhamnaceae Ceanothus americanus 1
Rhamnaceae Colubrina glomerata 1
Rhamnaceae Ziziphus jujuba 1 +N,-A If po alkaloids
Rhamnaceae Ziziphus rugosa +N sb flavonoid toxic
glycosides:
quercetin-3-0-
rhamnoside,
myricetin-3-0-
rhamnoside
Rhamnaceae Ziziphus vulgaris 1 +N,?Y,-A If,fr po nontoxic
Rhizophoraceae Bruguiera conjugata -N ap po toxic
Rhizophoraceae Ceriops roxburghiana -N ap po nontoxic
Rhizophoraceae Ceriops tagal 1 +N sb po toxic
186 R. J. MarIes and N. R. Farnsworth

FAMILY SCIENTIFIC NAME ETH ACTMTY PART ROUTE ACTIVE TOXICITY


TESTED ADMIN. CONSTITUENT

Rhizophoraceae Kandelia candel 1 -N sb po


Rhizophoraceae Kandelia rheedii 1 toxic?
Rhizophoraceae Rhizophora mangle 1
Rhizophoraceae Rhizopbora mucronata 1 +N,-N ap,sb po
Rosaceae Agrimoniaeupatoria 2 +S,-N If po
Rosaceae Alchemilla vulgaris 1 -S,N If po
Rosaceae Crataegus azarolus 1 nontoxic?
Rosaceae Crataegus pubescens 1 nontoxic?
Rosaceae Cydonia oblonga 1 nontoxic
Rosaceae Eriobotrya japonica ?A,N ap po,ip toxic
Rosaceae Filipendula ulmaria 1 -S wp po
Rosaceae Fragaria vesca 1 +A If sc nontoxic
Rosaceae Poterium ancistroides 4 -S,+G,N ap po tormentic acid (H,
po) inactive A, po
Rosaceae Prunusamygdalus 1 +N If toxic
Rosaceae Prunusdavidiana +A,S st ip
Rosaceae Prunuspersica 2 -N ap po toxic
Rosaceae Pyrus communis 1 nontoxic
Rosaceae Pyrusmalus 1 +D,-N fr nontoxic
Rosaceae Rosa canina 1 +N nontoxic
Rosaceae Rosa multiflora +S fr po
Rosaceae Rosa rugosa +N,-S rt ip
Rosaceae Rosa sericea -N ap po toxic
Rosaceae Rubus coreanus 1 nontoxic
Rosaceae Rubus fruticosus 2 +A,G,-S,N If po toxic
Rosaceae Rubus idaeus -A,=E,+N If sc nontoxic
Rosaceae Rubus micropetalus -N ap po nontoxic
Rosaceae Rubus nutantiflorus -N wp po nontoxic
Rosaceae Rubus paniculatus -N ap po nontoxic
Rosaceae Rubus ulmifolius 1 nontoxic?
Rosaceae Sarcopoterium spinosum 1 +A,D,N wp,rb po
Rubiaceae Anthocephalusindicus +N sb po toxic
Rubiaceae Borreria verticillata 1 toxic
Rubiaceae Canthium sp. 1 +D sb po toxic?
Rubiaceae Cephalanthus glabrata 1
Rubiaceae Cinchona officinalis 1 +N sb po quinine
Rubiaceae Coffea arabica +N sd po nontoxic
Rubiaceae Coutarea hexandra 1
Rubiaceae Coutarea latiflora 1 +A,-D,N wp po coutareoside
(hydroxycoum-arin
glucoside) (A, po)
Rubiaceae Gardenia jasminoides +G geniposide
Rubiaceae Gardenia taitensis 1 nontoxic?
Rubiaceae Hamiltonia suaveolens 1 +A,E,N rt po nontoxic
Rubiaceae Hedyotis biflora +A ap po nontoxic?
Rubiaceae Ixora arborea -N ap po nontoxic
Rubiaceae Ixora coccinea -N ap po nontoxic
Rubiaceae Morinda citrifolia 1 -N ap po nontoxic
Rubiaceae Mussaenda glabra -N ap,fr po ?
Rubiaceae Oldenlandia biflora 1 +A wp po
Rubiaceae Psychotria dalzellii -N ap po toxic
Rubiaceae Psychotria monticola -N wp po toxic
Rubiaceae Randia dumetorum +N fr,sb po nontoxic
Rubiaceae Rubia cordifolia +N ap po nontoxic
Rubiaceae Wendlandia wallichii -N ap po toxic
Rutaceae Aegle marmelos 2 +G,-A,S,?N fr,lf,rt po daucosterol,
lupeol, scopoletin
(A, H, po)
Rutaceae Boenninghausenia albiflora +N wp po nontoxic
Rutaceae Casimiroa edulis 1
Rutaceae Citrusaurantiifolia 1 -N ap po diphenylamine? toxic/
nontoxic
Antidiabetic plants and their active constituents 187

FAMILY SCIENTIFIC NAME ETH ACTIVITY PART ROUTE ACTIVE TOXICITY


TESTED ADMIN. CONSTITUENT

Rutaceae Citrus aurantium 2 ?Y fr po diphenylamine? nontoxic


Rutaceae Citrus bergamia 1 diphenylamine? nontoxic?
Rutaceae Citrus limon 1 diphenylamine? nontoxic
Rutaceae Clausena pentapbylla -N ap po nontoxic
Rutaceae Feronia limonia 1 +N fr po nontoxic
Rutaceae Monieratrifolia 1
Ruraceae Murraya koenigii 1 +A,N If po nontoxic
Rutaceae Phellodendron amurense 1 +N, ?S,G rt,sb po ?
Rutaceae Toddalia asiatica -N ap po toxic
Rutaceae Zanthoxylum alatum +N st po toxic
Rutaceae Zanthoxylum ovalifolium -N ap po nontoxic
Sabiaceae Sabia lanceolata -N ap po toxic
Sabiaceae Sabia limoniacea -N ap po nontoxic
Salicaceae Populus tremuloides 1 nontoxic?
Salicaceae Salix nigra +N f1,sb ?
Salicaceae Salix tetrasperma -N ap po salicylic acid
(A, H, po)
Salvadoraceae Salvadora persica +G rt po nontoxic
Santalaceae Santalum album +N wd po nontoxic
Sapindaceae Blighia sapida +E,P,N fr po hypoglycins a
and b (H, po ) toxic
Sapindaceae Dodonaea viscosa +N wp
Sapindaceae Sapindus laurifolius -N ap po toxic
Sapotaceae Bumelia sartorum 1 +A,N ,-E rb po toxic
Sapotaceae Lucuma lucentifolia 1
Sapotaceae Madhuca longifolia 1 -N sb po
Sapotaceae Mimusops elengi 1
Sapotaceae Pouteria tomentosa +N wp po nontoxic
Saururaceae Anemopsis californica 1
Saururaceae Houttuynia cordata +A wp ip
Saxifragaceae Bergenia stracheyi +N rt po nontoxic
Saxifragaceae Chrysosplenium tricbospermum -N wp po nontoxic
Saxifragaceae Heuchera americana 1
Saxifragaceae Hydrangea altissima -N ap po toxic
Saxifragaceae Hydrangea arborescens 1 toxic
Saxifragaceae Hydrangea paniculata +N mu,sb po panic ulatan toxic!
mucilage nont oxic
Schisandraceae Schisandra chinensis +U,?A,-S fr po nontoxic
Scroph ulariaceae Angeloniagrandiflora -N wp po nontoxic
Scrophulariaceae Angelonia salicariaefolia -N ap po nontoxic
Scrophulariaceae Anticharisarabica 1
Scrophulariaceae Antirrhinum glaucum 1 nontoxic
Scrophulariaceae Capraria biflora 3 +A If po,ip toxic
Scrophulariaceae Cymbalaria muralis 1 -N wp po
Scrophulariaceae Hemiphragma heterophyllum -N wp po nontoxic
Scrophulariaceae lsoplexis canariensis 1
Scrophulariaceae lsoplexis isabelliana 1
Scrophulariaceae Kickxia ramosissima 1 -N wp po nontoxic
Scrophulariaceae Leucophyllum texanum 1
Scroph ulariaceae Mazus surculosus +N wp
Scrophulariaceae Pedicularis rhinanthoides +N wp nontoxic?
Scrophulariaceae Rehmannia glutinosa 3 +D,N,?Y, rt po iridoid glycoside nontoxic
A,G,S rehmannioside D
Scrophulariaceae Rehmannia lutea 1 +N rt po rehmanin nontoxic?
Scrophulariaceae Scoparia dulcis 3 +A,?D,N wp po ?
Scrophulariaceae Scrophularia aquatica 2
Scrophulariaceae Scrophularia buergeriana 1 toxic
Scrophulariaceae Scrophularia glabrata 1 toxic?
Scrophu lariaceae Scrophularia ningpoensis 1 ?A rt po
Scrophulariaceae Scrophularia nodosa 2
Scrophulariaceae Striga gesneroides 1 -N wp po
188 R. j. MarIes and N. R. Farnsworth

FAMILY SCIENTIFIC NAME ETH ACTIVITY PART ROlITE ACTIVE TOXICITY


TESTED ADMIN. CONSTITUENT
Scrophulariaceae Torenia asiatica
Simaroubaceae Ailanthus altissima -N ap po toxic
Simaroubaceae Ailanthus excelsa -N sb po toxic
Simaroubaceae Brucea mollis -N ap po toxic
Simaroubaceae Quassia amara 1 toxic
Solanaceae Atropa belladonna +N If po toxic
Solanaceae Capsicum annuum +N fr po,ip capsaicin nontoxic
Solanaceae Capsicum frutescens 1 ?N ap,sd po toxid
nontoxic
Solanaceae Cestrum nocturnum -N ap po toxic
Solanaceae Datura querdfolia +N wp po toxic
Solanaceae Hyoscyamus niger 1 toxic
Solanaceae Lycium barbatum +N,-S fr po guanidine ?
derivatives and
flavonoids
Solanaceae Lycium chinense 1 +N,?A,-S fr, rb po lupeol, scopo letin nontoxic
(A,po)
Solanaceae Lycopersicum esculentum +N toxid
nontoxic
Solanaceae Nicotiana tabacum +N toxi c
Solanaceae Physalis angulata 1 toxic?
Solanaceae Physalis ixocarpa 1 ?
Solanaceae Physalis peruuiana -N wp po toxic
Solanaceae Solanum argillicolum 1 toxic?
Solanaceae Solanum indicum +N fr po
Solanaceae Solanum nigrum 1 lupeol (A, po) toxic
Solanaceae Solanum sanitwongsei 1 +N fr po lupeol (A, po) nontoxic
Solanaceae Solanum torvum 2 -N fr po lupeol (A, po) toxic?
Solanaceae Solanum trilobatum 1 +N fr po lupeol (A, po) toxic?
Solanaceae Solanum tuberosum +N tb po lupeol (A, po), nontoxic
dietary effect
Solanaceae Withania coagulens +D po
Solanaceae Withania somnifera +D,-N wp po toxic
Stachyuraceae Stachyurusbimalaicus +N
Sterculiaceae Abroma augusta 1 -N wp po nontoxic
Sterculiaceae Eriolaena quinquelocularis -N ap po toxic
Sterculiaceae Helicteres isora 1 -N sd,sb po nontoxic
Sterculiacea e Heritiera minor +N ap
Stercu liaceae Pterospermum acerifolium -N If po non toxic
Styraceae Styrax benzoin +N IS ip sumaresinoleic toxic
acid
Symplocaceae Symplocos gardneriana -N ap po nontoxic
Symplocaceae Symplocos racemosa -N ap po nontoxic
Symplocaceae Symplocos theaefolia +N If po nontoxic
Tamaricaceae Tamarix canariensis 1
Theaceae Camellia sinensis 1 +S,A,N If po theophylline, nontoxic
diphenylamine,
epicatechin,
epigallocatechin,
gallocatechine,
caffeine
Theaceae Gordonia obtusa -N ap po toxic
Tiliaceae Corchorusolitorius +N If po nontoxic
Tiliaceae Grewiaasiatica +A,P If,sb po
Tiliaceae Grewia hirsuta -N ap po
Tiliaceae Grewia serrulata -N ap po toxic
Tiliaceae Grewia tiliaefolia -N ap,sb po toxic
Turneraceae Turneradiffusa 1 +A wp po,ip toxic
Ulmaceae Trema guineensis -N If po
Ulmaceae Trema orientalis -N ap po nontoxic
Urticaceae Urtica dioica 5 +E,G,-N,S wp po nontoxic
Antidiabetic plants and their active constituents 189

FAMILY SCIENTIFIC NAME ETH ACTIVITY PART ROUTE ACTIVE TOXICITY


TESTED ADMIN. CONSTITUENT

Urticaceae Urtica urens +N nontoxic?


Valerianaceae Nardostachys jatamansi 1 nontoxic
Valerianaceae Valeriana edulis 1 +A rt po,ip ?
Valerianaceae Valeriana mexicana 1 ?
Valerianaceae Valeriana officinalis 2 +A rt po,ip nontoxic
Valerianaceae Valeriana procera 1 ?
Valerianaceae Valeriana sorbifolia 1 +A rt po,ip
Verbenaceae Citharexylum subserratum -N ap po nontoxic
Verbenaceae Clerodendrum infortunatum +N wp po nontoxic
Verbenaceae Clerodendrum phlomoides 1 +A,D,E,N wp po ?
Verbenaceae Clerodendrum serratum -N wp po ?
Verbenaceae Gmelinaarborea +N st po nontoxic
Verbenaceae Holmskioldia sanguinea -N ap po toxic
Verbenaceae Lippiagraveolens 1 nontoxic
Verbenaceae Premna integrifolia 1 +N rt,sb po toxic!
nontoxic
Verbenaceae Premna latifolia +N sb po nontoxic
Verbenaceae Premna obtusifolia +N st,rt
Verbenaceae Tectona grandis 1 ?N If po,iv nontoxic
Verbenaceae Verbena bonariensis +N wp po nontoxic
Verbenaceae Verbena officinalis 1 -N wp po ?
Verbenaceae Vitex trifolia -N ap po nontoxic
Violaceae Viola canescens -N wp po nontoxic?
Vitaceae Cissus repens -N wp po nontoxic
Vitaceae Vitis bracteolata -N ap po toxic
Zygophyllaceae Balanites aegyptiaca +S fr po
Zygophyllaceae Guaiacumofficinale 1 toxic
Zygophyllaceae Larrea tridentata 1
Zygophyllaceae Peganum harmala 1 +A,S,-G sci po toxic
Zygophyllaceae Zygophyllum coccineum 1 nontoxic
Zygophyllaceae Zygophyllum cornutum 1 -A,+G,?N If po nontoxic?