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Department of Clinical Analysis, Center of Health Sciences, Federal University of Santa Catarina,
Campus Universitario, Trindade, 88040-970, Florianopolis, SC, Brazil
b Department of Pharmacology, Center of Biological Sciences, Federal University of Santa Catarina,
Campus Universitario, Trindade, 88049-900, Florianopolis, SC, Brazil
Received 1 March 2007; received in revised form 26 October 2007; accepted 26 October 2007
Available online 4 November 2007
Abstract
Although medicinal plants have been historically used for diabetes treatment throughout the world, few of them have been validated by scientific
criteria. Recently, a large diversity of animal models has been developed to better understand the pathogenesis of diabetes mellitus and new drugs
have been introduced in the market to treat this disease. The aim of this work was to review the available animal models of diabetes and some in
vitro models which have been used as tools to investigate the mechanism of action of drugs with potential antidiabetic properties. In addition, a
MEDLINE/PUBMED search for articles on natural products, pancreatectomy and diabetes mellitus treatment published between 1996 and 2006
was done. In the majority of the studies, natural products mainly derived from plants have been tested in diabetes models induced by chemical
agents. This review contributes to the researcher in the ethnopharmacology field to designs new strategies for the development of novel drugs to
treat this serious condition that constitutes a global public health.
2007 Elsevier Ireland Ltd. All rights reserved.
Keywords: Diabetes mellitus; Animal models; Genetic studies; Natural products
Contents
1.
2.
3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
In vivo animal models of diabetes mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1. Pharmacological induction of diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2. Surgical models of diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3. Genetic models of diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3.1. Animal strains that spontaneously develop diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3.2. Genetically engineered diabetic mice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.4. Other models of type 2 diabetes to evaluate the reduction of pancreatic -cell mass . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
In vitro studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1. In vitro studies on insulin secretion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.1. Studies using isolated pancreatic islet cell lines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.2. Studies using insulin-secreting cell lines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2. In vitro studies on glucose uptake . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Abbreviations: ADP, adenosine diphosphate; AE, aqueous extract; AT, acute treatment; ATP, adenosine triphosphate; BB rat, Bio Breeding Laboratories rat;
BuOH, n-butanol fraction; Ca2+ , calcium; CH2 Cl2 , methylene chloride extract; CH3 Cl, chloroform extract; db/db mouse, monogenic model of obesity (leptin
resistant); DNA, deoxyribonucleic acid; DPP-4, dipeptidyl peptidase-4; EtOAc, ethyl acetate fraction; EtOH, ethanolic extract; GK rat, Goto-Kazikasi rat; GLUT,
glucose transporter; Hex, hexane fraction; i.p., intraperitoneal route; i.v., intravenous route; IGFs, insulin-like growth factors; MeOH, methanolic extract; NOD
mouse, non-obese diabetic mouse; Ob/Ob mouse, monogenic model of obesity mouse (leptin deficient); OLETL rat, Otsuka Long-Evans Tokushima Fatty rat; p.o.,
oral route; STZ, streptozotocin; ZK rat, Zucker rat.
Corresponding author. Tel.: +55 48 99614846; fax: +55 48 32440936.
E-mail addresses: saleh@ccs.ufsc.br, taniafrode@zipmail.com.br (T.S. Frode).
0378-8741/$ see front matter 2007 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.jep.2007.10.038
174
4.
5.
6.
1. Introduction
The increasing worldwide incidence of diabetes mellitus in
adults constitutes a global public health burden. It is predicted
that by 2030, India, China and the United States will have the
largest number of people with diabetes (Wild et al., 2004). By
definition, diabetes mellitus is categorized as a metabolic disease
characterized by hyperglycemia resulting from defects in insulin
secretion, insulin action, or both. The vast majority of cases of
diabetes fall into two broad etiopathogenetic categories. In one
category, type 1 diabetes, the cause is an absolute deficiency
of insulin secretion. In the other, much more prevalent category, type 2 diabetes, the cause is a combination of resistance to
insulin action and an inadequate compensatory insulin-secretory
response (American Diabetes Association, 2005).
Despite the great interest in the development of new drugs to
prevent the burden of complications associated with this disease
and the raised interest in the scientific community to evaluate
either raw or isolated natural products in experimental studies
(Fig. 1), few of them were tested in humans (Liu et al., 2004;
Vuksan and Sievenpiper, 2005; Johnson et al., 2006; Jung et al.,
2006; Matsui et al., 2006). Nevertheless, natural supplements
are widely used around the world to treat diabetes, but medical
research does not support their effectiveness. In these studies the
low methodological quality, small sample size of tested patients,
and limited number of trials deserve caution in the interpretation of the positive data and require further examination in
high-quality trials (Liu et al., 2004). Nowadays, clinical treatment of diabetes targets both insulin deficiency and resistance
and more recently the prevention of pancreatic -cell function
decline (Hansotia and Drucker, 2005) (Table 1).
The aim of this work was to review the available animal models of diabetes in order to provide adequate tools to investigate
the mechanism of action of drugs with potential antidiabetic
properties. Considering that there is a marked overlap between
type 1 and 2 diabetes mellitus either in human beings or in ani-
179
180
180
180
mal models, some classical models for each type of this disease
cannot also be sustained (Chaparro et al., 2006; Donath and
Ehses, 2006). However, it is cited, when appropriated along
the text, which category (type) the described model fits better.
The information in this review was obtained by searching
MEDLINE/PUBMED for literature published in English from
1996 to 2006, using terms natural products, pancreatectomy and
diabetes mellitus treatment. The decision of which model of diabetes to use for any particular protocol is mainly influenced by
local resources. Ideally, preclinical experiments should be initially carried out in vivo, and be complemented, when possible,
with in vitro studies to explore and advance in the mechanism
of action of a natural product.
2. In vivo animal models of diabetes mellitus
Diabetes can be induced by pharmacologic, surgical or
genetic manipulations in several animal species. Most experiments in diabetes are carried out on rodents, although some
studies are still performed in larger animals. The classical model
employed by Banting and Best was pancreatectomy in dogs
(Bliss, 2000). It is also described prone strains to diabetes mellitus that have been employed in several researches (Chen and
Wang, 2005; Rees and Alcolado, 2005; Masiello, 2006). Currently, the murine model is one of the most used due to the
availability of over 200 well-characterized inbred strains and the
ability to delete or over-express specific genes through knockout and transgenic technologies (Rees and Alcolado, 2005;
Masiello, 2006).
2.1. Pharmacological induction of diabetes
The majority of studies published in the field of ethnopharmacology between 1996 and 2006 employed these models.
Streptozotocin (STZ, 69%) and alloxan (31%) are by far the
most frequently used drugs and this model has been useful for the
study of multiple aspects of the disease. Both drugs exert their
diabetogenic action when they are administered parenterally:
intravenously, intraperitoneally or subcutaneously. The dose of
these agents required for inducing diabetes depends on the
animal species, route of administration and nutritional status.
According to the administered dose of these agents, syndromes
similar to either type 1, type 2 diabetes mellitus or glucose intolerance can be induced (Lenzen et al., 1996; Mythili et al., 2004).
Protocols are available any where, being critical the pH and type
of buffer employed as well as the preparation of the solution of
either alloxan or streptozotocin in the day of the experiments
(Yu et al., 2000; Gupta et al., 2005a,b; Lei et al., 2005; Babu et
al., 2006; Miranda et al., 2006).
175
Table 1
Drugs available to treat diabetes mellitus
Insulin deficiency
Insulin and its analogs
Sulphonylureas, glinides
Insulin resistance
Metformin
Glitazones
Alpha-glucosidase inhibitors
The cytotoxic action of these diabetogenic agents is mediated by reactive oxygen species, but both drugs differ in their
mechanism of action (Federiuk et al., 2004; Lei et al., 2005).
Alloxan and the product of its reduction, dialuric acid, establish a redox cycle with the formation of superoxide radicals.
These radicals undergo dismutation to hydrogen peroxide with
a simultaneous massive increase in cytosolic calcium concentration, which causes rapid destruction of pancreatic -cells
(Szudelski, 2001). The range of the diabetogenic dose of alloxan
is quite narrow and even light overdosing may be generally toxic
and may cause the loss of many animals. This loss is likely
to stem from kidney tubular cell necrotic toxicity, in particular when too high doses of alloxan are administered (Lenzen
et al., 1996). The most frequently used intravenous dose of
alloxan in rats is 65 mg/kg, but when it is administered intraperitoneally (i.p.) or subcutaneously its effective dose must be higher
(Federiuk et al., 2004). For instance, an intraperitoneal dose
below 150 mg/kg may be insufficient for inducing diabetes in
this animal species (Katsumata et al., 1992). In mice, doses vary
among 100200 mg/kg by intravenous route (i.v.) (Machado et
al., 2001; Miranda et al., 2006).
Streptozotocin enters the pancreatic -cell via a glucose
transporter-GLUT2 and causes alkylation of deoxyribonucleic
acid (DNA). Furthermore, STZ induces activation of poly adenosine diphosphate ribosylation and nitric oxide release. As a
result of STZ action, pancreatic -cells are destroyed by necrosis
(Mythili et al., 2004). In adult rats, 60 mg/kg is the most common dose of STZ to induce insulin dependent diabetes (Patel et
al., 2006), but higher doses are also used. STZ is also efficacious
after intraperitoneal administration of a similar or higher dose,
but single doses below 40 mg/kg may be ineffective (Katsumata
et al., 1992). In general, rats are considered diabetic if tail
blood glucose concentrations in fed animals are greater than
200300 mg/dl, 2 days after STZ injection. A model of type 2
diabetes can be induced in rats by either i.v. (tail vein) or i.p.
treatment with STZ in the first days of life. At 810 weeks of age
and thereafter, rats neonatally treated with STZ manifest mild
basal hyperglycemia, an impaired response to the glucose tolerance test, and a loss of pancreatic -cell sensitivity to glucose
(Pascoe and Storlien, 1990). It has been observed that STZ at
first abolished the pancreatic -cell response to glucose, but a
temporary return of responsiveness then appears which is followed by its permanent loss (Mythili et al., 2004). In adult mice,
STZ given in multiple low doses (40 mg/kg, i.v. for 5 days) (Rees
and Alcolado, 2005) induces an insulin dependent diabetes that
is quite similar to the autoimmune forms (islet inflammation and
-cell death) of type 1 diabetes. On the other hand, a single dose
between 60 and 100 mg/kg of STZ (Lei et al., 2005; Sharma
et al., 2006), administered systemically can also cause insulin
176
Table 2
List of studied natural products with putative antidiabetic effects tested in either in vivo or in vitro models in the period of 20052006 (source: PUBMED, English
language)
Plant (family)
Material
Treatment
Drug-induced
diabetes
Results
References
EtOH/leaves
i.p., 14 d
STZ-rat
Narendhirakannan et al.
(2006)
AE/seeds
AE/fruits
p.o., 14 d
p.o., 30 d
STZ-rat
STZ-rat
Glucose, glycosylated
hemoglobin, C-peptide,
glucose
tolerance,glycogen, insulin
Glucose
Glucose, insulin
EtOH, isolated
compounds/leaves
EtOH/leaves
p.o., 28 d
db/db mice
p.o., 21 d
STZ-rat
Glycosylated hemoglobin
A1c
Glucose, lipids
p.o., 21 d
STZ-rat
Gluose; insulin
p.o., 1030 d
STZ-rat
p.o., 10 d
p.o., 15 d
Glycosylated hemoglobin,
glucose tolerance
Glucose, lipids
Amaranthus esculantus
(Amaranthaceae)
Annona squamosa
(Annonaceae)
Hintonia standleyan
(Rubiaceae)
Hypoxis hemerocallidea
(Hypoxidaceae)
Leonotis leonurus
(Lamiaceae)
Lepidium sativum
(Brassicaceae)
Lycium barbarum
(Solanaceae)
Malmea depressa
(Annonaceae)
Mangifera indica
(Anacardiaceae)
Momordica charantia
(Cucurbitaceae)
p.o., 14 d
Alloxan-rabbit
STZ-rat,
alloxan-rabbit
STZ-rat
p.o., 7 d
STZ-mice
Glucose
p.o./i.p., AT
STZ-rat
Glucose
Ojewole (2005a)
p.o.,14 d
STZ-rat
Glucose
p.o., 15 d
STZ-rat
Glucose
AAE/stem barks
p.o., 12 d
STZ-rat
AAE, isolated
compounds/stem
barks
AE, EtOH, isolated
compounds/fruitpulp/seeds
EtOH/bulbs
p.o., 10 d
STZ-rat
Glucose, glycosylated
hemoglobin, glycogen,
lipids, oxidative stress
Glucose, lipid
peroxidation, insulin
p.o., AT
STZ-rabbit
p.o., 14 d
STZ-rat
p.o., 21112 d
STZ-rat
alloxan
Glucose tolerance,
glucose, oxidative stress
MeOH, isolated
compounds/stem
barks
AE/fruits
p.o., AT
STZ-rat
Glucose
p.o., AT
STZ-mice, rat
Glucose
Guerrero-Analco et al.
(2005); Navarrete and Mata
(2005)
Ojewole (2006)
AE/leaves
p.o., AT
STZ-mice, rat
Glucose
Ojewole (2005b)
AE/leaves
STZ-rat
Glucose
Isolated
compound/fruits
AE, EtOH,
BuOH/roots
AE/stem barks
p.o., 2126 d
STZ-rat
p.o., AT
STZ-rat
i.p., AT
SZT-rat
Glucose
Ojewole (2005c)
MeOH, isolated
compounds/gourd
AE/leaves
p.o., AT
SZT-mice
SZT-rat
STZ-rat,
alloxan-rat
Glucose
Fruit-pulp
Averrhoa bilimbi
(Oxalidaceae)
Baccharis trimera
(Myrtaceae)
Bryophyllum pinnatum
(Crassulaceae)
Canarium schweinfurthi
(Burseraceae)
Chamaemelum nobile
(Asteraceae)
Coscinium fenestratum
(Menispermaceae)
p.o., 2730 d
Glucose, glycosylated
hemoglobin, oxidative
stress, glycogen
177
Table 2 (Continued )
Plant (family)
Material
Treatment
Drug-induced
diabetes
Results
References
AE/seeds
p.o., 30 d
STZ-rat
Sathishsekar and
Subramanian (2005)
Fruits
p.o.,21 d
Alloxan-rat
Glucose, glycosylated
hemoglobin, oxidative
stress, lipid peroxidation
Glucose, lipids
AE, EtOH/leaves
p.o., 30 d
STZ-rat
Glucose, glycosylated
hemoglobin
p.o., AT
Psidium guajava Linn.
(Myrtaceae)
Raphanus sativus
(Brassicaceae)
Retama raetam (Fabaceae)
Salvia ofcinalis (Lamiaceae)
Scoparia dulcis
(Scrophulariacae)
AE/leaves
p.o., AT
STZ-rat
Glucose
Ojewole (2005d)
AE/whole plant
p.o., 21 d
STZ-rat
AE/whole plant
AE/leaves
AE/whole plant
i.v., AT
p.o., 14 d
p.o., 2142 d
STZ-rat
STZ-rat, mice
STZ-rat-in
vitro/in vivo
Strobilanthes crispus
(Acanthaceae)
Syzygium cordatum
(Myrtaceae)
Syzygium cumini (synonym
Tamarindus indica
(Caesalpiniaceae)
Taxus yunnanensis
(Taxaceae)
Terminalia chebula
(Combretaceae)
Terminalia superba
(Combretaceae)
Trema orientalis (Ulmaceae)
Tremella mesenterica
(Combretaceae)
Triticum repens P. Beauv.
(Gramineae)
Viscum album L.
(Loranthaceae)
Zizyphus spina-christi
(Rhamnaceae)
AE/leaves
p.o., 21 d
STZ-rat
Glucose
Glucose gluconeogenesis
Glucose, lipids,
3-hydroxy-3-methylglutaryl
(HMG)-CoA reductase
activity, oxidative stress,
insulin
Glucose
AE/leaves
p.o., 28 d
STZ-rat
p.o., 714 d
STZ-mice, rat
Glucose
i.p., AT
STZ-rat
Glucose
p.o., AT
STZ-rat
Glucose
p.o., 14 d
STZ-rat
Glucose
p.o., AT
p.o., 14 d
STZ-rat
STZ-rat
Glucose
Glucose
p.o., AT
STZ-rat
Glucose
AE, EtOH/whole
plant
BuOH, isolated
compounds/leaves
p.o., 7 d
STZ-rat
p.o., AT
STZ-rat
Glucose, lipidic
peroxidation
Glucose, insulin
AAE: Alcoholic extract, AE: aqueous extract, AT: acute treatment, BuOH: n-butanol fraction, CH2 Cl2 : methylene chloride extract, CH3 Cl: chloroform extract,
EtOAc: ethyl acetate fraction, EtOH: ethanolic extract, GLUT-4: glucose transporter, Hex: hexane fraction, i.p.: intraperitoneal route, MeOH: methanolic extract,
p.o.: oral route, and STZ: streptozotocin.
the plant and highlight the need to further advance in their characterization. In line with this hypothesis, Tanaka et al. (2006) had
isolated several compounds with antihyperglycemic properties
from Aloe vera leaves (Tanaka et al., 2006). The identification of
these products explains, in part, why these compounds present
antioxidant, antihyperglycemic, antilypemic properties and even
enhance the process of wound healing in diabetic and nondiabetic animals (Okyar et al., 2001; Sharma et al., 2003, 2006;
Pepato et al., 2005; Rajasekaran et al., 2005; Tanaka et al., 2006).
Due to the nonspecific action of compounds isolated from
extracts of natural products, some studies have aggregated additional in vitro protocols to the in vivo studies such as liver
perfusion to evaluate glucose influx inhibition (Chung et al.,
2006), gastrointestinal absorption methodologies and antiox-
178
Fig. 2. Number of papers that tested natural products in prone strains to diabetes
published in the period of 19962006 (source: PUBMED, English language,
accessed in 06-11-2007).
179
180
Babu, P.V., Sabitha, K.E., Shyamaladevi, C.S., 2006. Green tea impedes dyslipidemia, lipid peroxidation, protein glycation and ameliorates Ca2+ -ATPase
and Na+ /K+ -ATPase activity in the heart of streptozotocin-diabetic rats.
Chemico-Biological Interactions 162, 157164.
Banskota, N.T., Nguyen, Y., Tezuka, T., Nobukawa, S., Kadota, S., 2006.
Hypoglycemic effects of the wood of Taxus yunnanensis on streptozotocininduced diabetic rats and its active components. Phytomedicine 13, 109
114.
Bliss, M., 2000. The Discovery of Insulin. University of Chicago Press, Chicago,
USA, pp. 3211418.
Boloker, J., Gertz, S.J., Simmons, R.A., 2002. Gestational diabetes leads to the
development of diabetes in adulthood in the rat. Diabetes 51, 14991506.
Breyer, M.D., Bottinger, E., Brosius, F.C., Coffman, T.M., Fogo, A., Harris,
R.C., Heilig, C.W., Sharma, K., 2005. Diabetic nephropathy: of mice and
men. Advances in Chronic Kidney Disease 12, 128145.
Chaparro, R.J., Konigshofer, Y., Beilhack, G.F., Shizuru, J.A., McDevitt, H.O.,
Chien, Y.H., 2006. Nonobese diabetic mice express aspects of both type 1
and type 2 diabetes. Proceedings of the National Academy of Sciences of
the United States of America 103, 1247512480.
Chen, D., Wang, M.W., 2005. Development and application of rodent models
for type 2 diabetes. Diabetes, Obesity and Metabolism 7, 307317.
Choi, S.B., Park, C.H., Choi, M.K., Jun, D.W., Park, S., 2004. Improvement
of insulin resistance and insulin secretion by water extracts of Cordyceps
militaris, Phellinus linteus, and Paecilomyces tenuipes in 90% pancreatectomized rats. Bioscience, Biotechnology, and Biochemistry 68, 2257
2264.
Chung, M.Y., Rho, M.C., Le, S.W., Park, H.R., Lee, I.A., Kim, D.H., Jeune, K.H.,
Lee, H.S., Kim, Y.K., 2006. Inhibition of diacylglycerol acyltransferase by
betulinic acid from Alnus hirsute. Planta Medica 72, 267269.
Clark, S.A., Borland, K.M., Sherman, S.D., Rusack, T.C., Chick, W.L., 1994.
Staining and in vitro toxicity of dithizone with canine, porcine, and bovine
islets. Cell Transplant 3, 299306.
Clee, S.M., Attie, A.D., 2006. The genetic landscape of type-2 diabetes in mice.
Endocrinology Reviews 28, 4883.
Dimo, T., Ngueguim, F.T., Kamtchouing, P., Dongo, E., Tan, P.V., 2006. Glucose lowering efficacy of the aqueous stem bark extract of Trema orientalis
(Linn) Blume in normal and streptozotocin diabetic rats. Die Pharmazie 61,
233236.
Donath, M.Y., Ehses, J.A., 2006. Type 1, type 1.5, and type 2 diabetes: NOD
the diabetes we thought it was. Proceedings of the National Academy of
Sciences of the United States of America 103, 1221712218.
Eddouks, M., Lemhadri, A., Zeggwagh, N.A., Michel, J.B., 2005a. Potent hypoglycaemic activity of the aqueous extract of Chamaemelum nobile in normal
and streptozotocin-induced diabetic rats. Diabetes Research and Clinical
Practices 67, 189195.
Eddouks, M., Maghrani, M., Michel, J.B., 2005b. Hypoglycaemic effect of
Triticum repens P. Beauv in normal and diabetic rats. Journal of Ethnopharmacology 102, 228232.
Eddouks, M., Maghrani, M., Zeggwagh, N.A., Michel, J.B., 2005c. Study of the
hypoglycaemic activity of Lepidium sativum L. aqueous extract in normal
and diabetic rats. Journal of Ethnopharmacology 97, 391395.
Eidi, A., Eidi, M., Esmaeili, E., 2006. Antidiabetic effect of garlic (Allium
sativum L.) in normal and streptozotocin-induced diabetic rats. Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
13, 624629.
El-Demerdash, F.M., Yousef, M.I., El-Naga, N.I., 2005. Biochemical study on
the hypoglycemic effects of onion and garlic in alloxan-induced diabetic
rats. Food and Chemical Toxicology 43, 5763.
Esmaeili, M.A., Yazdanparast, R., 2004. Hypoglycaemic effect of Teucrium
polium: studies with rat pancreatic islets. Journal of Ethnopharmacology 95,
2730.
Fadzelly, A.B., Asmah, R., Fauziah, O., 2006. Effects of Strobilanthes crispus tea
aqueous extracts on glucose and lipid profile in normal and streptozotocininduced hyperglycemic rats. Plant Foods for Human Nutrition 61, 712.
Federiuk, I.F., Casey, H.M., Quinn, M.J., Wood, M.D., Ward, W.K., 2004. Induction of type-1 diabetes mellitus in laboratory rats by use of alloxan: route
of administration, pitfalls, and insulin treatment. Comparative Medicine 54,
252257.
181
Latha, M., Pari, L., 2005. Effect of an aqueous extract of Scoparia dulcis on
plasma and tissue glycoproteins in streptozotocin induced diabetic rats. Die
Pharmazie 60, 151154.
Lei, Y.C., Hwang, J.S., Chan, C.C., Lee, C.T., Cheng, T.J., 2005. Enhanced
oxidative stress and endothelial dysfunction in streptozotocin-diabetic rats
exposed to fine particles. Environmental Research 99, 335343.
Lenzen, S., Tiedge, M., Jorns, A., Munday, R., 1996. Alloxan derivatives as
a tool for the elucidation of the mechanism of the diabetogenic action of
alloxan. In: Shafrir, E. (Ed.), Lessons from Animal Diabetes. Birkhauser,
Boston, pp. 113122.
Lelliott, C., Vidal-Puig, A.J., 2004. Lipotoxicity, an imbalance between lipogenesis de novo and fatty acid oxidation. International Journal of Obesity and
related Metabolic Disorders 28, 2228.
Lima, C.F., Azevedo, M.F., Araujo, R., Fernandes-Ferreira, M., Pereira-Wilson,
C., 2006. Metformin-like effect of Salvia ofcinalis (common sage): is
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