1 s2.0 S0378874115300775 Main

Journal of Ethnopharmacology 175 (2015) 567616
Contents lists available at ScienceDirect
Journal of Ethnopharmacology
journal homepage: www.elsevier.com/locate/jep
Review
Diabetes mellitus and its management with medicinal plants:

A perspective based on Iranian research
Arezou Rezaei a,b,n, Azad Farzadfard c, Atefe Amirahmadi a,b, Maasoomeh Alemi a,b,
Mitra Khademi d
a
School of Biology, Damghan University, Damghan, Iran

Institute of Biological Sciences, Damghan University, Damghan, Iran
c
School of Biology, College of Science, University of Tehran, Tehran, Iran
d
Institute for Advanced Studies in Basic Sciences, Zanjan, Iran
b
art ic l e i nf o
a b s t r a c t
Article history:
Received 2 December 2014
Received in revised form
10 August 2015
Accepted 11 August 2015
Available online 14 August 2015
Ethnopharmacological relevance: Complementary and alternative medicine has been increasingly used to
treat chronic illnesses, such as diabetes mellitus. However, various limitations in terms of their application and efcacies exist. Furthermore, there is still much to be done to discover the right herbal
medicine for diabetes.
Aim of the study: This paper aims to evaluate previous herbal studies on the management of diabetes
mellitus, to address their strengths and weaknesses and propose a general framework for future studies.
Approach and methods: Data sources such as PubMed, ScienceDirect, Scopus, SpringerLink, and Wiley
were searched, limited to Iran, using 36 search terms such as herbal, traditional, medicine, and phytopharmacy in combination with diabetes and related complications. Reviewed articles were evaluated
regarding the use of botanical nomenclature and included information on (1) identity of plants and plant
parts used, (2) the processing procedure, and (3) the extraction process. The main outcomes were extracted and then surveyed in terms of the efcacies of herbs in the management of diabetes mellitus.
Then a comparative study was performed between Iranian and non-Iranian studies with respect to herbs
best studied in Iran.
Results: Of the 82 herbs studied in Iran, only six herbs were endemic and 19 were studied in detail.
Although most of the reviewed herbs were found to decrease the level of blood glucose (BG) and/or
glycated hemoglobin (HbA1C) in both Iranian and non-Iranian studies, information on their pharmacological mechanisms is scarce. However, the level of HbA1C was measured in a limited number of
clinical trials or animal studies. Available information on both short- and long-term use of studied herbs
on diabetes related complications and functions of involved organs as well as comorbid depression and/
or simultaneous changes in lifesyle is also insufcient. Furthermore, little or no information on their
phytochemical, toxicological, and herbdrug interaction properties is available. It is worth noting that the
efcacy of the reviewed herbs has been studied scarcely in both humans and animals regarding both
Iranian and non-Iranian studies. A signicant number of reviewed articles failed to cite the scientic
name of herbs and include information on the processing procedure and the extraction process.
Conclusions: Treatment of diabetes mellitus as a multifactorial disease using herbal medicines requires a
comprehensive approach. In order to discover the right herbal medicine for the management of diabetes
many other important factors than the levels of BG, HbA1C and insulin should be considered. According
to our criteria, all the reviewed herbs suffered from inadequate investigation in human, animal and in
vitro models in this respect, whereas they are worth investigating further. However, more research on
endemic plants and the traditional history of herbal medicine is warranted. In our opinion, the pharmacological, toxicological, and phytochemical information should be obtained before clinical trials.
Furthermore, information such as botanical scientic nomenclature, side effects, and toxicity will improve the quality and validity of publications in herbal research. In particular, designing a database
Keywords:
Diabetes
Herbal medicines
Researches
Evaluation
Iran
Corresponding author at: School of Biology, Damghan University, Damghan, Iran.

E-mail address: arezaei@du.ac.ir (A. Rezaei).
http://dx.doi.org/10.1016/j.jep.2015.08.010
0378-8741/& 2015 Elsevier Ireland Ltd. All rights reserved.
568
A. Rezaei et al. / Journal of Ethnopharmacology 175 (2015) 567616
covering all valid information about herbs and/or diseases will decrease unnecessary costs and increase
the efciency of research.
& 2015 Elsevier Ireland Ltd. All rights reserved.
Contents
1.
2.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 568
Approach and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 569
2.1.
Denition of herb . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 569
2.2.
Data sources and study selections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 569
2.2.1.
Included criteria and data extraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 569
2.2.2.
Excluded criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 569
2.3.
Evaluation of reviewed articles and botanical scientic nomenclature. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 569
2.4.
Traditional applications of reviewed herbs in traditional Iranian medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 569
2.5.
Available toxicological information on reviewed herbs in Iranian studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 569
2.6.
Phytochemical analysis of reviewed herbs in Iranian studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 573
2.7.
Sorting main outcomes and selecting best-studied herbs from Iranian studies to evaluate them in non-Iranian studies . . . . . . . . . . . . 573
3. Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 573
3.1.
Evaluation of the reviewed articles. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 573
3.1.1.
Botanical scientic nomenclature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 573
3.2.
Traditional applications of reviewed herbs in Iranian medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 573
3.3.
Available toxicological information of the reviewed herbs in Iranian studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 573
3.4.
Phytochemical analysis of reviewed herbs in Iranian studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 575
3.5.
Sorting main outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 575
3.6.
Selection of the best-studied herbs for managing DM from Iranian studies and their evaluation in non-Iranian studies. . . . . . . . . . . . 582
4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 582
4.1.
The preconditions of the studies on herbal medicines for the management of DM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 582
4.1.1.
The quality and safety of herbal medicines and product standardization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 582
4.1.2.
Side effects and toxicity of the herbs and herbdrug interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 583
4.2.
Implications for research. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 584
4.2.1.
Animal models of diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 584
4.2.2.
Clinical trial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 584
4.2.3.
Pharmacological mechanisms of the herbs: drug discovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 584
4.3.
Lifestyle as an effective way to prevent and manage diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 585
4.4.
The weaknesses of the reviewed articles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 585
4.5.
The strengths of the reviewed articles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 586
4.6.
Proposing a framework for future studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 607
4.6.1.
General considerations for herbal research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 607
4.6.2.
Specic issues for studies on diabetes mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 607
4.7.
Limitation of our study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 607
5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 607
Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 608
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 608
1. Introduction
Diabetes mellitus (DM), characterized by chronic hyperglycemia, is a metabolic disorder caused by a combination of factors,
including genetics and lifestyle (Ryan, 2007; WHO, 2014a). Type
1 diabetes (T1DM; insulin-dependent, immune-mediated, or juvenile-onset diabetes) is an autoimmune disease of the pancreas
(IDF, 2013; Ryan, 2007), whereas type 2 diabetes (T2DM; non-insulin-dependent diabetes or adult-onset diabetes) is more associated with the development of insulin resistance (IDF, 2013; Ryan,
2007) or a reduction in insulin production and release (Ryan,
2007) than with antibodies.
As a multifactorial disorder, diabetes can be managed only with
comprehensive and holistic approaches. At present, T1DM cannot
be prevented (IDF, 2013), although its onset can be prevented or
delayed (IDF, 2013; WHO, 2014b). Patients who seek conventional
health care tend to use herbs and related products (Winslow and
Kroll, 1998), probably because various chemical and biochemical

hypoglycemic agents have prominent side effects (Li et al., 2004).
Although medicinal plants have been used since ancient times,
and complementary and alternative medicine (CAM) has been
increasingly used to treat chronic illnesses such as diabetes (reviewed by (DiNardo et al., 2012)), various concerns, criticisms, and
suggestions have been raised with respect to the application and
efcacy of herbs (Alissa, 2014; Chan et al., 2012; Efferth and Kaina,
2011; Geil and Shane-McWhorter, 2008; Raynor et al., 2011; Rivera
et al., 2014; Uzuner et al., 2012). Despite enormous scientic research on the efcacy of herbs for the treatment of diabetes for a
considerable period of time, certain results have not been achieved
yet.
The aim of the present study was to identify and address the
strengths and weaknesses of the extensive ongoing studies and
propose a general framework for future studies. Accordingly, we
selected the best-studied herbs from Iranian research with respect
569
Table 1
Search terms used in combination with Iran, diabetes, and related complications such as retinopathy, nephropathy, neuropathy, obesity, and metabolic disorders to nd
Iranian studies investigating herbal medicines in the management of diabetes (please see Section 2.2 for more details).
Botanical, medicine
Botany, medicinal, herb
Botany, medicinal, plants
Folk, medicine
Galenical
Herb, drug
Herbal, medicine
Herbalism
Herbology
Medical, herbalism
Medicinal, ora
Medicinal, herbage
Medicinal, herbs
Medicinal, plants
Medicinal, vegetation
Narcotic, herb
Narcotic, plant
Pharmaceutical, herb
to their efcacy in the management of DM and related complications. To elucidate further areas of research, we conducted a
comparative study between Iranian and non-Iranian studies in
terms of these selected herbs.
2. Approach and methods

2.1. Denition of herb
This review is based on the denition of herb provided by
Winslow and Kroll (1998): (1) a owering plant whose stem above
ground does not become woody and persistent, and (2) a plant
valued for its medicinal properties, avor, scent, etc. A broader
denition includes fungi, fruits, roots, and vegetables. Furthermore, enzymes, minerals, and hormones are included when referring to herbal medicine.
2.2. Data sources and study selections
Data sources such as PubMed, Scopus, ScienceDirect, Wiley, and
SpringerLink up to the end of 2012, were searched, limited to Iran,
using 36 search terms listed in Table 1. Based on the results, another search was carried out with new keywords including diabetes and related complications such as nephropathy, neuropathy, retinopathy, obesity, and metabolic disorders to nd Iranian
studies on the efcacy of herbal medicines in the prevention and
treatment of diabetes.
2.2.1. Included criteria and data extraction
All human, animal, and in vitro studies on diabetes and related
complications, including retinopathy, nephropathy, neuropathy,
cardiovascular
disease,
hypercholesterolemia/hypertriglyceridemia, metabolic syndrome, and obesity, were included. Two reviewers independently extracted data from the articles including
common and scientic names of herbs, study design, experimental
groups, dose, duration, sample size, results, and side effects.
2.2.2. Excluded criteria
Review articles, letters to the editor, unpublished data such as
thesis, and published studies from countries other than Iran were
omitted. Two reviewers independently examined the title and
abstract of each article to avoid duplications. In the case of duplicated publications, we attempted to extract all available data
and refer them to the base study.
2.3. Evaluation of reviewed articles and botanical scientic
nomenclature
Reviewed Iranian articles with full text available were evaluated by a three-score system developed by Chan et al. to assess
the following aspects of herbs or herbal materials: (i) identity of
Pharmaceutical, plant
Pharmacodynamic, herb
Pharmacodynamic, plant
Pharmacokinetic, herb
Pharmacokinetic, plant
Pharmacology, herb
Pharmacology, plants
Pharmacotherapy, herb
Pharmacotherapy, plant
Pharmacy, herb
Pharmacy, plant
Phytomedicine
Phytopharmacy
Phytotherapy
Plant, drug
Remedy, herb
Remedy, plant
Traditional, medicine
plants and plant parts used, (ii) the processing procedure, and (iii)
the extraction process. Accordingly, identity of plants and plant
parts used (maximum score10) included the location of harvesting or specication of a commercial source (score1), Latin
scientic name (score 2), herbarium voucher specimens deposited/voucher number (score 3), herbarium voucher specimen
verication by named botanist (score1), DNA bar coding
(score1), post-harvest treatment (score1), and perceived
quality and reproducibility of treatment (score 1). Processing
procedure (maximum score 5) included whether the absence of
processing has been indicated clearly (score5) or whether the
quality and reproducibility of the process have been perceived
(score15). Extraction process (maximum score 10) included
detailed extraction procedure (score 1), yield (score2), perceived quality and reproducibility of process, identication of the
extracts (score 2), chromatographic proling (score 2), targeted
determination of key constituent, or nontargeted metabolomics
(score3) (Chan et al., 2012).
It is to be noted that articles with valid commercial sources of
herbs such as Merck, Sigma, and Sigma-Aldrich were excluded
from the scoring evaluations. In order to compare the three aspects of evaluation (iiii) in the reviewed articles, the average of
the subsets of each aspect was calculated. Then the sum of these
averages for each aspect was used to compare all reviewed articles
according to (i) identity of plants and plant parts used, (ii) processing procedure, and (iii) extraction process.
The appropriate scientic name (Latin binomial) and endemicity of all herbs mentioned in the reviewed articles have been
validated taxonomically according to Ghahreman and Attar (1999)
Mozaffarian (2008), and www.theplantlist.org. Botanical scientic
nomenclatures applied in the reviewed articles were evaluated
according to Rivera et al. (2014).
2.4. Traditional applications of reviewed herbs in traditional Iranian
medicine
The abstracts and introductions of the reviewed articles were
searched for information on the various aboriginal medical uses of
the relevant herbs. Furthermore, PubMed was searched for the
scientic names of the reviewed herbs and traditional Iranian
medicine (TIM).
2.5. Available toxicological information on reviewed herbs in Iranian
studies
The full text of the reviewed Iranian articles, in particular the
material and methods section, were searched with keywords such
as toxic, liver, hepat-, kidney, and renal for toxicological
information.
Family
Local name
Scientic name (Latin binomial)
Names in articles
Study model (number of

studies)
Amaranthaceae
Baroutak
Amaranthus caudatus L.
Amaranthus caudatus L (A. caudatus)
Amaryllidaceae
Tareh farangi
Allium ampeloprasum L. (syn: A. porrum L.)
Allium porrum L.
Mousir
Allium ascalonicum L.
shallot (Allium ascalonicum)
Piaz
Allium cepa L.
Allium cepa (onion)/Allium cepa/quercetin
Piaz-e alborzi
Allium elburzense Wendelboe
Allium elburzense Wendelbo
Sir
Allium sativum L.
Human
(0)
Human
(0)
Human
(0)
Human
(0)
Human
(0)
Human
(0)
Human
(0)
Human
(0)
Human
(0)
Human
(0)
Human
(0)
Human
(0)
Human
(0)
Human
(0)
Human
(0)
Human
(0)
Human
(0)
Human
(0)
Human
(0)
Human
(0)
Human
(0)
Human
(0)
Human
(0)
Human
(0)
Human
(0)
Human
(0)
Human
(0)
garlic (Allium sativum)/garlic
Mousir
Allium stipitatum Regel (syn: A. hirtifolium Boiss.)
Anacardiaceae
Somagh
Rhus coriaria L.
Rhus coriaria L. (sumac)/Rhus coriaria
Apiaceae (Umbelliferae)
Shevid
Anethum graveolens L.
Anethum graveolens/Anethum graveolens (dill)
Zireh siah
Carum carvi L.
Arecaceae
Allium hirtifolium (Persian shallot)
Carum carvi
s
Geshniz
Coriandrum sativum L.
Havij
Daucus carota L.
Golpar
Heracleum persicum Desf. ex Fisch., C.A.Mey. &Av-Lall.
Coriander (Coriandrum sativum L.)

Carrot
Heracleum persicum
Karafs-e Bakhtiari
Kelussia odoratissima Mozaff.
Amirkabiria odoratissima (umbelliferae)
Razianeh kouhi
Peucedanum pastinacifolium Boiss. & Hohen.
peucedanum pastinacifolium
Khorma
Phoenix dactylifera L.
date fruit (Phoenix dactylifera L. Arecaceae)
Asteraceae (Compositae) Boumadaran
Achillea santolinoides subsp. wilhelmsii (K. Koch) Greuter (syn: A. wilhelmsii Achillea wilhelmsii
K. Koch)
Achillea tenuifolia Lam. (syn: A. santolina L.)
Achillea santolina L. (Compositae)
Dermaneh
Artemisia aucheri Boiss.
Artemisia aucheri
Golrang
Carthamus tinctorius L.s
Carthamus tinctorius L. (Compositae)
Kasni
Cichorium intybus L.s
Chicory, Cichorium intybus L

s
Khar maryam
Silybum marianum (L.) Gaertn.
Boraginaceae
Gol asali
Arnebia euchroma (Royle) I.M.Johnst.
Arnebia euchroma
Brassicaceae
Kala mgol
Brassica oleracea L.
Broccoli sprouts
Alaf-e-cheshmeh
Nasturtium ofcinale R. Br.
Caryophyllaceae
Choubak
Acanthophyllum squarrosum Boiss.
Acanthophyllum squarrosum
Cucurbitaceae
Hendevaneh aboujahl Citrullus colocynthis (L.) Schrad.
Silybum marrianum (silymarin)/silymarin/milk thistle
Citrullus colocynthis (Schrad)/Citrullus colocynthis
(0); animal (1); in vitro

(3); animal (0); n vitro
570
Table 2
Family, local, and scientic names and names introduced in reviewed articles of studied herbs or related compounds in Iranian studies with the number of studies in human, animal, and in vitro systems.
Cucumis sativus L.
Cucumis sativus
Equisetaceae
Dome asb
Equisetum arvense L.
Equisetum arvense L. (Equisetaceae)
Ericaceae
Siah gileh
Vaccinium arctostaphylos L.
Vaccinium arctostaphylos
Fabaceae (Leguminosae)
NOT
Cyamopsis tetragonoloba (L.) Taub.
guar gum
Soya
Glycine max (L.) Merr.
soy
Shirin bayan
Glycyrrhiza glabra L.
licorice
Younjeh
Medicago sativa L.
Alfalfa (Medicago sativa)
Younjeh-e Zard
Melilotus ofcinalis (L.) Pall.
Melilotus ofcinalis/semelil (angipars )
Mashak-e satouri
Securigera securidaca (L.) Degen and Dor.
Tamr-e hendi
Tamarindus indica L.
Securigera securidaca/Securigera securidaca (L.) (Degen and

Doerer)
Tamarindus indica
Shabdar
Trifolium pratense L.
red clover (Trifolium pratense) legume family

s
Shanbelileh
Trigonella foenum-graecum L.
Fagaceae
Balout
Quercus infectoria G. Olivier
Quercus infectoria
Hypericaceae
Goleraei
Hypericum perforatum L.
Hypericum perforatum
Iridaceae
Zaafaran
Crocus sativus L.s
Crocus sativus L. (saffron)/crocin
Juglandaceae
Gerdou
Juglans regia L.
Lamiaceae (Labiatae)
Goush barreh
Phlomis anisodonta Boiss.e.s
Golder
Rydingia persica (Burm.f.) Scheen and V.A. Albert (syn. Otostegia persica
(Burm.f.) Boiss.) e.s
Salvia ofcinalis L.
Maryam goli
Trigonella foenum-graecum (fenugreek)/fenugreek
Persian walnut (Juglans regia L.)/Walnut (Juglans regia L.)/Juglans regia L.

Phlomis anisodonta
e.s
Otostegia persica
Salvia ofcinalis L/Salvia ofcinalis (sage)
Marzeh
Satureja khuzistanica Jamzad
Maryam nokhodi
Teucrium polium L.s
Lythraceae
Anar
Punica granatum L.
Malvaceae
Chay-e maki
Hibiscus sabdariffa L.
pomegranate/pomegranate seed (Punica granatum L.)/Punica

granatum
sour tea (Hibiscus sabdariffa)
Panirak
Malva sylvestris L.
Malva sylvestris
Okaliptous
Eucalyptus globulus Labill.
Myrtaceae
Satureja Khuzestanica/Satureja khuzestanica Jamzad

Teucrium polium
Eucalyptus globulus (eucalyptus)/Eucalyptus globulus
Oleaceae
Zeitoun
Olea europaea L.
Plantaginaceae
Barhang
Plantago ovate Forssk.
Psyllium husk/Plantago ovate Forsk.
Poaceae (Gramineae)
Jo-e dosar
Avena sativa L.
Oat breads
Jo
Hordeum vulgare L.
Barley breads
Gandom
Triticum sp.
Wheat germ
Olea europaea L./Olive (Olea europaea L.)

571
Human
(0)
Human
(0)
Human
(0)
Human
(0)
Human
(0)
Human
(0)
Human
(0)
Human
(0)
Human
(0)
Human
(0)
Human
(0)
Human
(1)
Human
(1)
Human
(0)
Human
(0)
Human
(0)
Human
(0)
Human
(1)
Human
(0)
Human
(1)
Human
(3)
Human
(0)
Human
(0)
Human
(0)
Human
(0)
Human
(1)
Human
(0)
Human
(0)
Human
(0)
Human
(0)
Khiar
572
Table 2 (continued )
Polygonaceae
Fagopyrum esculentum Moench
Buckwheat
Torshak
Rumex patientia L.
Rumex patientia
Ranunculaceae
Siah daneh
Nigella sativa L.
Nigella sativa
Rosaceae
Sib
Malus domestica Borkh.
Apple cider vinegar/apple
Albalou-Gilas

Prunus cerasus L.
Apple
Sour cherry/cherry
Badam
Prunus dulcis (Mill.) D.A.Webb (syn: Amygdalus communis L.)
Almond/Amygdalus communis
Gol-e mohammadi
Rosa damascena Mill.
Rosa damascena Mill/Rosa damascena
Limou torsh
Citrus aurantiifolia (Christm.) Swingle
Lime (Citrus aurantifolia)
Sodab
Ruta graveolens L.
Ruta graveolens
Santalaceae
Darvash
Viscum album L.s
African mistletoe (Viscum album)/Viscum album
Scrophulariaceae
Gol-e meimouni
Scrophularia deserti Delile
Scrophularia deserti
Solanaceae
Gojeh farangi
Lycopersicum esculentum Mill.
tomato
Theaceae
Chay
Camellia sinensis (L.) Kuntze
Urticaceae
Gazaneh
Urtica dioica L.s
Camellia sinensis or tea/green tea/Camellia sinensis (Theaceae)/

black tea (BT)
Urtica dioica/nettle (Urtica dioica)/Urtica dioica L. (Urticaceae)
Vitaceae
Angour
Vitis vinifera L. (syn: V. sylvestris C.C.Gmel.)
Vitis sylvestris/vinegar (grape)
Vitis sp.
grape/red wine
Rutaceae
Xanthorrhoeaceae
Sabr-e zard-e tebbi
Aloe vera (L.) Burm.f.s
Aloe vera
Zingiberaceae
Khoulanjan
Alpinia ofcinarum Hance
Zard choubeh
Curcuma longa L.
turmeric
Zanjebil
Zingiber ofcinale Roscoe
ginger
Allium sativum L.
Salvia ofcinalis L.
Teucrium polium L.
Cinnamomum verum J.Presl (syn: C. zeylanicum Blume)
Punica granatum L.
Nigella sativa L.
Anethum sp.
Cichorium sp.
Fumaria sp.
Terminalia bellirica (Gaertn.) Roxb.
Terminalia chebula Retz.
Phyllanthus emblica L. (syn: Emblica ofcinalis Gaertn.)
Saccharomyces cerevisiae Meyen ex E.C. Hansen
Allium sativum
Salvia ofcinalis
Teucrium polium
Cinnamomum zeylanicum
Punica granatum
Nigella sativa
Anethum
Cichorium
Fumaria
Terminalia belerica Roxb./Itrifal Saghir (triphala)
Terminalia chebula Retz. /Itrifal Saghir (triphala)
Emblica ofcinalis L./Itrifal Saghir (triphala)
brewers yeast
Amaryllidaceae
Sir
Maryam goli
Maryam nokhodi
Lauraceae
Darchin
Lythraceae
Anar
Ranunculaceae
Siah daneh
Apiaceae (Umbelliferae) Shevid
Asteraceae (Compositae) Kasni
Papaveraceae
Shah tareh
Combretaceae
Garomzangi
Phyllanthaceae
Fugi
NOT
Mokhammer
e: endemic to Iran, s: selected herbs (please see Sections 2.7 and 3.6 for more details).
polyherbal compounds. Scientic names (Latin binomials) of the herbs are based on theplantlist.org.
Human
(0)
Human
(0)
Human
(0)
Human
(0)

Human (1); animal (1); in vitro

(0)
(0)
(0)
(0)
(0)
(0)
(0)
(0)
(1)
(1)
(0)
(0)
(0)
(0)
(0)
(0)
* Human (0); animal (1); in vitro (0)

(0)
NOT
2.6. Phytochemical analysis of reviewed herbs in Iranian studies

Relevant information was obtained from the material and
methods and result sections of the reviewed Iranian articles.
2.7. Sorting main outcomes and selecting best-studied herbs from
Iranian studies to evaluate them in non-Iranian studies
All reported results were extracted and classied into three
groups based on the following factors: (1) the effects on the anthropometric assessments, the signs of diabetes (polydipsia and
polyphagia), the levels of blood glucose (BG) and glycated hemoglobin (HbA1C), and lipid prole; (2) the pharmacological
mechanisms of the herbs; and (3) DM-related complications and
the function of the pancreas, liver, and cardiovascular and immune
systems.
In case 2, the following strategies of Western medicines and
herbs were considered: (1) to decrease carbohydrate absorption,
(2) to stimulate insulin secretion, (3) to improve insulin sensitivity,
(4) to increase peripheral glucose uptake, (5) to potentiate endogenous incretins, (6) to inhibit hormones that increase BG levels, (7) to decrease oxidative stress and increase antioxidant defense, (8) to decrease cell apoptosis, (9) to increase glycogenesis or
inhibit hepatic glycogenolysis, and (10) to improve microcirculation in the body (reviewed by (Li et al., 2004; Z. Wang et al., 2013)).
The most useful herbs were selected from Iranian studies based
on their efcacies in these mechanisms to evaluate their effectiveness in the management of DM in non-Iranian studies. Accordingly, a search limited to English-language studies was conducted with the scientic names of the selected herbs and diabetes in the data source PubMed to nd relevant non-Iranian
studies.
573
graecum, S. khuzestanica, C. sinensis (L.) Kuntze, and U. dioica, was

investigated in human, animal, and in vitro models. Only six of the
studied herbs, including Allium elburzense Wendelbo, Allium stipitatum Regel (syn: A. hirtifolium Boiss.), Kelussia odoratissima
Mozaff., R. persica (Burm.f.) Scheen and V.A. Albert (syn: Otostegia
persica (Burm.f.) Boiss.), Phlomis anisodonta Boiss., and S. khuzistanica Jamzad, were endemic to Iran (Table 2).
3.1. Evaluation of the reviewed articles
The articles with full text available were evaluated according to
a system introduced by Chan et al. ( 2012). From a total of 139
scanned articles with full text available, 16 articles were excluded
from the evaluation as they used commercial sources (Section 2.3).
The total score of the remaining 123 articles is shown in appendices AC under the score column. Accordingly, 49 cases (39.8%)
ranged from 10 to 19 points (maximum of total score25), and the
remaining (51.2%) scored 19 points, with the exception of 11
studies (8.9%), which scored zero.
The averages of the scores for the identity of plants and plant
parts used (aspect i), processing procedure (aspect ii), and extraction process (aspect iii) (Section 2.3) were 3.59 (from the total
score of 10), 1.80 (from the total score of 5), and 2.28 (from the
total score of 10), respectively.
3.1.1. Botanical scientic nomenclature
Latin scientic names were used in 103 of a total of 155 reviewed articles (66.4%). Common names apart from the Latin scientic names were used in the remaining 52 articles (33.6%). The
botanist identifying the herbs was only introduced in 21 studies
(38.2%). Voucher specimens were deposited in herbariums in only
57 studies (36.8%).
3.2. Traditional applications of reviewed herbs in Iranian medicine
3. Findings
A total of 155 Iranian studies were surveyed, with 139 in fulltext format. The data in all of the tables are drawn from the
available 139 full-text articles and 16 abstracts. Iranian studies on
the efcacy of a total of 82 herbs and herbal compounds (78 herbs
belonging to 36 families, three polyherbal compounds, and a
fungus) in the treatment and management of DM and related
complications up to the end of 2012 were reviewed. All studied
herbs or related compounds are alphabetically listed according to
their family in Table 2. The design of the study, plant parts, intervention, dose, duration, and main outcomes (related to the
treatment group) of the Iranian studies in human, animal, and in
vitro models are shown in appendices AC, respectively. Most
studies were conducted on the remedial effects of only a sole herb
or related compounds, but some studies were conducted on
multiple herbs.
From a total of 82 herbs and herbal compounds studied by Iranian researchers, 35, 63, and eight herbs were evaluated for their
efcacy in human, animal, and in vitro models, respectively. Of the
82 studied herbs, the efcacy of only 15 plants including Allium
sativum L., Rhus coriaria L., Anethum graveolens L., Citrullus colocynthis (L.) Schrad., Securigera securidaca (L.) Degen and Dor.,
Trigonella foenum-graecum L., Juglans regia L., Salvia ofcinalis L.,
Satureja khuzistanica Jamzad, Punica granatum L., Prunus cerasus L.,
Prunus dulcis (Mill.) D.A. Webb (syn: Amygdalus communis L.),
Camellia sinensis (L.) Kuntze, Urtica dioica L., and Vitis sp. was
evaluated in both human and animal studies. Four herbs including
Quercus infectoria G. Olivier, Rydingia persica (Burm.f.) Scheen and
V.A. Albert (syn: Otostegia persica (Burm.f.) Boiss.), Teucrium polium
L., and Olea europaea L. were studied in both animal and in vitro
models. Only the efcacy of four herbs, including T. foenum-
Of the 139 reviewed Iranian articles with full text, 31 (22.3%)

referred to Iranian traditional usages, nine (6.5%) to both Iranian
and non-Iranian traditional applications, and 40 (28.8%) only to
non-Iranian traditional usages of the studied herbs in the abstract
and/or introduction sections. The remaining 59 (42.4%) articles did
not refer to the aboriginal usage of the studied herbs. However,
most of the reviewed papers mentioned the benecial properties
of herbs such as their antioxidant, anticancer, anti-inammatory,
and antimicrobial activities. Only four studies from 16 articles with
abstracts mentioned the traditional usage of the studied herbs. A
summary of the traditional applications of the studied herbs is
shown in Table 3.
In addition to extracting information on their traditional use
from the reviewed articles, PubMed was searched with the scientic names of these herbs used in TIM. Accordingly, we found
that only seven of the 19 selected herbs were traditionally used as
well as 11 of the rest, but we did not nd any valid report on the
traditional use of the remaining 65 studied herbs including 12 of
the 19 selected herbs in TIM, which are also not included in
Table 3.
3.3. Available toxicological information of the reviewed herbs in Iranian studies
Of the 139 reviewed articles with full text available, only 41
(29.5%) directly studied herbs from a toxicological point of view. Of
these 41 mentioned articles, ve also investigated the nontoxicity
of the studied herbal interventions referring to other studies
(Haeri et al., 2012; Huseini et al., 2006; Kamali et al., 2012; Mansouri et al., 2012; Mousavi et al., 2010). Furthermore, the cytotoxicity, hepatotoxicity, and toxicity of the dosages used were
574
Table 3
A summary of traditional uses of studied herbs.
Latin binomial
Traditional usages
Achillea tenuifolia Lam.

Achillea santolinoides subsp. wilhelmsii (K.Koch) Greuter
Allium cepa L.
Allium elburzense Wendelboe
Hypoglycemic agent (Yazdanparast et al., 2007)

Pulmonary conditions (Asgary et al., 2000)
Diabetes (Jelodar et al., 2005)
Edible vegetable, diabetes, cardiovascular diseases, hypertension, hypercholesterolemia,
antirheumatic, aphrodisiac, anthelminthic (Zolfaghari et al., 2012)
Antiatherogenic, some gastrointestinal and infectious complaints, atherosclerosis (Movahedian et al., 2006)
Abscesses, cough, poisoning, parasites, worms, digestive and circulatory problems, snakebites, hemorrhoids, abdominal pain, loss of appetite and pneumonia (Jabbari et al.,
2005); Lowering blood pressure and improving lipid prole (Eidi et al., 2006); diabetes
(Jelodar et al., 2005)
Diabetes (Huseini et al., 2012)
Epilepsy (Abdollahi Fard and Shojaii, 2013)
Antihyperlipidemic, anti-hypercholesterolemic, carminative, antispasmodic, sedative,
diuretic, galactogogue (Hajhashemi and Abbasi, 2008; Mansouri et al., 2012; Yazdanparast
and Bahramikia, 2008), anti-inammatory, diuretic, and antispasmodic, and strengthens
the brain (Naseri et al., 2012)
Edema, burn, wound; carminative, antimicrobial, and anti-inammatory activities (Pirbalouti et al., 2012)
High blood pressure, liver diseases, fever (Mozaffari-Khosravi et al., 2009a, 2009b); mental
and physical fatigue (Jazayeri et al., 2014)
Diabetes, purgative, avoring agent (Asgary et al., 2012)
Diabetes, digestive disorders, antibacterial, antiulcerogenic, atulence, colic pain, bronchitis, cardiovascular diseases, hypertension (Haidari et al., 2011)
Hypoglycemic agent (Ghamarian et al., 2012), xerostomia (Chamani et al., 2011)
Diabetes (Huseini et al., 2009; Khoshvaghti and Hamidi, 2012; Rahbar and Nabipour, 2010;
Rahimi et al., 2012); purgative, anti-inammatory, analgesic, hair growth promoting,
abortifacient, antiepileptic (Rahimi et al., 2012)
Food additive, fevers, sore throat, coughs, common cold and indigestion (Asnaashari et al.,
2010); alertness, antiatulent, uplifting and cheering the spirit, common cold, anti-inammatory (Jazayeri et al., 2014)
Diabetes, indigestion, rheumatism, and pain in the joints (M. Eidi et al., 2009)
Sedative, tonic, stimulant of the stomach, expectorant (Mousavi et al., 2010); antidepressant, hypnotic, anti-inammatory, hepatoprotective, bronchodilatory, aphrodisiac,
inducer of labor, and emmenagogue (Hosseinzadeh and Nassiri-Asl, 2013)
Diabetes, anti-fever demulcent (Mousavi et al., 2010)
Diabetes (Soleimani et al., 2007a)
Diabetes (Bokaeian et al., 2010; Mahmoudzadeh-Sagheb et al., 2010a, 2010b; Nakhaee
et al., 2009)
Gastric ulcers, bronchitis and sore throat, infections caused by viruses (Hajiaghamohammadi et al., 2012); gastric ulcers, hepatic disorders, malaria (Esmaeili et al., 2009)
Carminative, digestive aid, antimicrobial, tonic, antiepileptic, and aphrodisiac (Panahi
et al., 2011); female contraceptive, painkiller (Hajhashemi et al., 2009; Hemati et al., 2012)
High blood pressure, liver diseases, and fever (Mozaffari-Khosravi et al., 2009a, 2009b)
Mental performance (Hasanein and Shahidi, 2011)
Diabetes, rheumatic pain, fever, skin diseases, malaria (Asgary et al., 2008a, 2008b); cough,
stomachache, cancer (Kamyab et al., 2010); skin inammations, hyperhidrosis, ulcers,
diarrheic, helminthic, septic, and astringent properties (Mohammadi et al., 2012); antimicrobial, antihelminthic, astringent, and keratolytic (Jazayeri et al., 2014)
Anti-inammatory (Asgary et al., 2004)
Edema, burn, wound, carminative, antimicrobial and anti-inammatory activities (Pirbalouti et al., 2012); diabetes, edema, burn, wound; cold, cough; carminative, antimicrobial
and anti-inammatory; astringent, hemostatic, gray hair, man sex power reconstituent
(Pirbalouti et al., 2010)
Depurative, diuretic, expectorant, hypoglycemic, odontalgic, stimulant and stomachic,
hypertension, and cardiovascular diseases (Bahramikia and Yazdanparast, 2008)
Infertility, epilepsy (Abdollahi Fard and Shojaii, 2013; Harat et al., 2008; Kolahdooz et al.,
2014)
Diabetes (A. Eidi et al., 2009); diabetes and hypertension (Kaeidi et al., 2011)
Diabetes (Ebrahimpoor et al., 2011)
Antihyperlipidemic, anti-inammatory, analgesic, diuretic, antispasmodic, antihypertension, antihyperglycemic, antitumor, antibacterial, antiplatelet aggregation activities (Movahedian et al., 2010)
Stimulants, tonic, analgesic, antidiabetic, antipyretic, antidiarrheal, antiallergy, antiulcer,
and antihemorrhoids (Sarkhail et al., 2007)
Diabetes, emollient (Ziai et al., 2005)
Edema, burn, wound, carminative, antimicrobial and anti-inammatory activities (Pirbalouti et al., 2012)
Edema, burn, wound, carminative, antimicrobial and anti-inammatory activities (Pirbalouti et al., 2012); diabetes, edema, burn, wound; cold, cough; carminative, antimicrobial,
and anti-inammatory; astringent, hemostatic, gray hair, man sex power reconstituent
(Pirbalouti et al., 2010)
Menstrual bleeding, digestive disorders, and headache(Gholamhoseinian et al., 2012)
Table spice, adjustment of blood lipids in diabetic patients (Mohammadi et al., 2010)
Menstrual bleeding, digestive disorders, and headache (Gholamhoseinian et al., 2012);
Cardiovascular stimulant, mild laxative, anti-inammatory, and cough suppressant (Jazayeri et al., 2014)
Allium ampeloprasum L.
Allium sativum L.s
Aloe vera (L.) Burm.f.s

Arnebia euchroma (Royle) I.M.Johnst.

Carthamus tinctorius L.s
Carum carvi L.
Cichorium intybus L.s
Citrullus colocynthis (L.) Schrad.s
Citrus aurantiifolia (Christm.) Swingle
Coriandrum sativum L.s

Crocus sativus L.s
Cucumis sativus L.
Eucalyptus globulus Labill.s
Heracleum persicum Desf. ex Fisch., C.A. Mey. & Av-Lall.
Juglans regia L.s
Kelussia odoratissima Mozaff.e

Malva sylvestris L.

Nigella sativa L.
Olea europaea L.s
Rydingia persica (Burm.f.) Scheen and V.A. Albert
Peucedanum pastinacifolium Boiss. and Hohen.
Phlomis anisodonta Boiss.e,s

Prunus dulcis (Mill.) D.A.Webb
Punica granatum L.s
Quercus infectoria G. Olivier

Rhus coriaria L.
e,s
575
Table 3 (continued )
Latin binomial
Traditional usages
Ruta graveolens L.
Aching pain, eye problems, rheumatism, and dermatitis (Toserkani et al., 2012); male
contraceptive (Harat et al., 2008)
Salvia ofcinalis L.
Diabetes (Kianbakht et al., 2011)
Satureja khuzistanica Jamzade,s
Analgesic and antiseptic (Abdollahi et al., 2003; Kaeidi et al., 2013; Saadat et al., 2004;
Tava et al., 2011; Vosough-Ghanbari et al., 2010); antidiabetic (Kaeidi et al., 2013)
Scrophularia deserti Delile
Edema, burn, wound, carminative, antimicrobial and anti-inammatory activities (Pirbalouti et al., 2012)
Securigera securidaca (L.) Degen & Dor.
Diabetes, hyperlipidemia (Garjani et al., 2009); antiepileptic, chronotropic, diuretic, and
hypokalemic activities (Garjani et al., 2009; Hosseinzadeh et al., 2002)
Diabetes (Mahmoudzadeh-Sagheb et al., 2010a, 2010b)
Teucrium polium L.s
Diabetes (Ardestani et al., 2008; Bahramikia and Yazdanparast, 2012; Mirghazanfari et al.,
2010; Nosrati et al., 2010; Shahraki et al., 2007); hypoglycemic (Esmaeili and Yazdanparast,
2004; Monfared and Pournourmohammadi, 2010); mental performance (Hasanein and
Shahidi, 2012); anti-inammatory, antibacterial, and antihypertensive (Rasekh et al.,
2001); analgesic and antilipidemic (Shahraki et al., 2007); antidepressant (Bahramikia and
Yazdanparast, 2012)
Trigonella foenum-graecum L.s
Diabetes (Haeri et al., 2012, 2009; Jelodar et al., 2005); hyperlipidemia (Haeri et al., 2009);
antinociceptive, gastrointestinal disorders, astringent, diarrhea, oral aphthous, and hematopoiesis (Javan et al., 1997; Jazayeri et al., 2014)
s
Urtica dioica L.
Hypoglycemic (Ahangarpour et al., 2012; Farzami et al., 2003; Fazeli et al., 2008; Golalipour and Khori, 2007); diabetes (Golalipour et al., 2010; Jahanshahi et al., 2009); rheumatic pain, cold, cough, antiasthmatic, diuretic, hemostatic, hypertensive, antidandruff
(Golalipour et al., 2007); rheumatoid arthritis, hypertension and allergic rhinitis, and
cardiovascular disease (Golalipour et al., 2010); rheumatic pain, urinary tract infections,
and bladder stone (Nassiri-Asl et al., 2009)
Vaccinium arctostaphylos L.
Diabetes (Feshani et al., 2011)
s
Viscum album L.
Diabetes, chronic cramps, stroke, stomach problems, heart palpitations, to lower blood
pressure, difculties in breathing, and hot ashes in menopause (Shahaboddin et al.,
2011); diabetes, stroke, circulatory system, and heart function (Adaramoye et al., 2012)
Vitis vinifera L.
Peptic ulcer (Farzaei et al., 2013)
Headache, cold, arthritis (Alizadeh-Navaei et al., 2008); xerostomia (Chamani et al., 2011)
Polyherbal compound (Allium sativum L.; Salvia ofcinalis L.; Teucrium polium Diabetes (Shaee-Nick et al., 2012)
L.; Cinnamomum verum J.Presl; Punica granatum L.; Nigella sativa L.)
Latin binomials (scientic names) are based on theplantlist.org.
studied in three reviewed articles (Huseini et al., 2009; Panahi

et al., 2011; Shahraki et al., 2007). Please see Appendices A, B, and
C for human, animal, and in vitro studies, respectively. In most
articles, the safety of the studied dosages was characterized by
evaluating the functional parameters of the liver and/or kidney.
The activity of paraxonase was measured in studies on S. securidaca (Garjani et al., 2009) and P. granatum (Parsaeyan et al., 2012),
with an insignicant change in activity observed in hyperchlosterolemic rats of the rst study and an increased activity in
patients with T2DM in the latter. In a study on C. colocynthis
(Khoshvaghti and Hamidi, 2012), severe and mild diarrhea were
observed in the control and C. colocynthis-treated diabetic groups,
respectively, when orally administered capsules containing C. colocynthis at a dosage of 100 mg/kg per day. Furthermore, salivation, anorexia, weight loss, and sometimes recumbency were observed in the control group during the duration of this study.
The safety of used doses of O. europaea and Crocus sativus L. has
been studied in vitro (Kaeidi et al., 2011; Mousavi et al., 2010). The
acute toxicity of the ethanol extract of S. securidaca has been reported more often than of the aqueous extract (Hosseinzadeh
et al., 2002).
Accordingly, the herbs were not toxicologically evaluated in 98
of the 139 articles with full text available (70.5%). However, nine
studies referred to other studies for information on the nontoxicity
of herbs (Baluchnejadmojarad et al., 2003; Fallahzadeh et al., 2012;
Ghamarian et al., 2012; Mirghazanfari et al., 2010; MozaffariKhosravi et al., 2009a; Sabzghabaee et al., 2011; Shahaboddin
et al., 2011; Tabassi et al., 2006; Tava et al., 2011). The toxicity of
the studied herbs was also mentioned in some of these studies
referring to other studies (Mirghazanfari et al., 2010; Shahaboddin
et al., 2011; Tabassi et al., 2006).
In the abstracts of 16 articles with no full text available, information on the history of toxicological studies was lacking. No
side effect or signicant change in the activity of liver enzymes
and serum creatinine was observed in diabetic patients treated
with S. securidaca seeds (Fallah Huseini et al., 2006). In a rat model
of nephropathy, the use of Silybum marianum (L.) Gaertn. reduced
the serum urea and urine protein levels, but the serum creatinine
level remained unchanged (Vessal et al., 2010). The activity of liver
enzymes was also reduced in diabetic rats after treatment with A.
hirtifolium (Hosseini et al., 2012).
3.4. Phytochemical analysis of reviewed herbs in Iranian studies
The phytochemical issues for 17 of 82 studied herbs (20.5%)
were only raised in a total of 22 from 139 reviewed articles (16%).
Spectrophotometry, gas chromatography/mass spectrometry,
high-performance liquid chromatography, and thin-layer chromatography were used to measure the metabolites. The types of
compositions were noted in most studies, and the amount of
compositions was exactly noted in only a few studies (Table 4).
3.5. Sorting main outcomes
Table 5 presents a comparison of the main outcomes obtained
from all studied herbs, which have been sorted as explained in
Section 2.7. Under part A (Parameters in DM), the effects of
herbal medicines on the levels of BG and HbA1C, lipid prole,
anthropometric assessments, and the signs of diabetes are shown.
As can be seen, treatment with most of the studied herbs decreased the level of BG in both humans and animals, although
conicting results were obtained, such as S. khuzestanica, which
576
Table 4
Available phytochemical analysis of reviewed herbs extracted from Iranian studies.
Method
Phytochemicals
Used part of plants
References
Allium elburzense
Wendelbo
Standard phytochemical
methods and NMR
analysis
Qualitative phytochemical screening: avonoids, steroids, phenols, glycosides, lipids, and saponins with the absence
of anthraquinones; NMR analysis: signals of glycoterpenoid nature of the mixture containing singlet methyls (0.8
1.1) and anomeric protons of glycosyl part (ca. 45), implying previously isolated saponins (16), that is, furastanols
as elburzensosides.
The only identied and quantied bioactive: a mucopolysaccharide named acemannan.
The amount of total avonoids based on hyperoside and anthocyanins in 100 g of extract is 0.379 7 0.02 g and
24.17 1.29 mg, respectively.
Five components were characterized: Alpha-pinene 1%, Alpha-phellandrene 321%, Limonene 281%, dill-ether 81%,
Carvone 28 1%
The total phenol and total avonoid contents of the AGE were 105.2 mg of gallic acid equivalents/g of the dried
extract and 58.2 mg of catechin equivalents/g of the dried extract, respectively.
Approximately 22 main compounds: Limonene (28.27%), -terpineol (19.61%), p-cymene (8.6%), and -pinene (5.7%)
Bulbs, methanol extract
Zolfaghari et al.
(2012)
Leaf Gel
Aerial parts, ethanol extract
(stems, leaves, and owers)
Aerial parts, essential oil
Huseini et al. (2012)

Kabiri et al. (2011)
Alkaloids, steroids, avonoids, tannins, and saponins; anthraquinones were absent
Seeds, Hydroalcoholic extract
Aloe vera (L.) Burm.f.

HP-TLC
Amaranthus caudatus L. Spectrophotometry
GC-FID and GC-MS
FCR and colorimetric

methods
GC-MS
Citrus aurantiifolia
(Christm.) Swingle
Cucumis sativus L.
Hypericum perforatum
L.
Standard phytochemical
methods
TLC

Olea europaea L.
HPTLC
Prunus cerasus L.
Spectrophotometry
Punica granatum L.
Chemical analysis
Saccharomyces cerevisiae Meyen ex E.C.

Hansen
Saturej khuzistanica
Jamzad
Satureja khuzistanica
Jamzad
Securigera securidaca
(L.) Degen & Dor.
Trigonella foenumgraecum L.
Urtica dioica L.
Atomic absorption
spectroscopy
Urtica dioica L.
Urtica dioica L.
Urtica dioica L.
Vitis vinifera L.
GV/MS
GV/MS
Phytochemical screening
and TLC
TLC; IR spectroscopy, NMR
and GC analysis
TLC
TLC and purity tests,
spectrophotometry
spectrophotometry
spectrophotometry
Aerial sections, crude extracts

Fruits, essential oil
Naphthodianthrones 0.10.15% (w/w) (0.3% hypericin and 0.7% pseudohypericin); hyperforin 3% (w/w); avonoids Above-ground parts (leaves,
4 20% (w/w).
owers and stem), water
extract
Vitamin C 10.7 70.06 (mg/dl); Total avonoids 1.36 7 0.03 (g/100 ml); total anthocyanin 3.05 7 0.85 (mg/100 g); The Juice
density 1.0377 0.09 (g/cm3)
Phenolic compounds: oleuropein (356 mg/g), tyrosol (3.73), hydroxytyrosol (4.89), and caffeic acid (49.41) were the Leaves, ethanolic extract
main phenolic compositions of the olive leaf extract (Esmaeili-Mahani et al., 2010)
Anthocyanin 1800 mg/100 g
Juice
Major forms of fatty acids: PA (18:3) 72.0 %; oil acid (18:2) 10.7%; linol acid (18:2) 8.4 %; palmitic acid (16:0) 4.0 %; Seed oil
stearic acid (18:0) 2.6 %; trace amounts (1%) of other fatty acids, with total amount of 7.3% of SFA, 11.7% of MUFA, and
81% of PUFA; vitamin E of 36.90 mg/100 g
Chromium
Carvacrol (78.3%), 9-octadecenoic acid (13.5%), Hexadecanoic acid (6.7%), bis(2-ethylhexyl)phthalate (1.0%), and
beta-bisabolene (0.5%)
The complete details of this GC/MS will be published in future.
Flavonoids, alkaloids, tannins, and saponins. The TLC of the extract: Triterpenoid saponins with Rf values of 0.78,
0.64, and 0.47.
Fractions containing 4-hydroxyisoleucine were determined
Leaves, ethanol extract

Aerial parts, essential oil
Seeds, hydroalcoholic extract
Seeds, ethanol extract
Hajhashemi and Abbasi (2008)

Yazdanparast and
Bahramikia (2008)
Asnaashari et al.
(2010)
Minaiyan et al.
(2011)
Hasanein and Shahidi (2011)
Esmaeil (2009)
Kaeidi et al. (2011)
Ataie-Jafari et al.
(2008)
Mirmiran et al.
(2010)
Khosravi-broujeni
et al. (2012)
Kaeidi et al.
(2013)
Gholamhoseinian
and Fallah (2009)
Garjani et al.
(2009)
Haeri et al. (2009)
Six distinct fractions: (RfF1 0.96, RfF2 0.93, RfF3 0.88, RfF4 0.70, RfF5 0.60, RfF6 0.45); the weights of
Leaves, water extract
fractions eluted from 10 g of dried leaves were as follows: F1 14.75; F2 13.61; F3 7.95; F4 7.9; and F6 8.48 mg.
A high percentage of tannins and steroids and low levels of avonoids, carotenoids, and saponins
Leaves, hydroalcoholic extract
Farzami et al.
(2003)
Fazeli et al. (2008)
Vitamin C 8.02 7 0.02 (mg/dl); acetic acid 15.81% 70.04, total anthocyanin 3.25 7 1.02 (mg/100 g); avonoids
1.0717 0.06 (g/100 ml); the density and pH were 1.042 70.002 (g/cm3) and 3.58 7 0.01 respectively.
Vinegar
Golalipour and
Khori, (2007)
Golalipour et al.
(2010)
Setorki et al.
(2010)
Latin binomials (scientic names) are based on theplantlist.org.
Latin binomial
Table 5
Comparison of various parameters important for the management of diabetes mellitus according to information extracted from reviewed articles.

577
578
579
580
581
582
did not change the level of BG in humans but decreased it in animal models. The hypoglycemic effects of T. foenum-graecum have
been shown in both humans and animals, except for a report about
its ineffectiveness on BG in an animal model. Only the effect of
Eucalyptus globulus Labill. on polydipsia and polyphagia (signs of
diabetes) has been reported in animal models (Bokaeian et al.,
2010). Furthermore, the level of HbA1C was measured in a few
human or animal studies.
The pharmacological mechanisms of the studied herbs are given under part B, (Pharmacological mechanisms) Table 5. Most
of the mechanisms (Section 2.7) have been investigated in animal
models. Endogenous incretins, hormones that increase BG levels,
glycogenesis, and microcirculation, have not been reported in Iranian studies.
Part C of Table 5 (Effects on the functions of organs) shows
the effects of studied herbs on DM-related complications and
the functions of the pancreas, liver, and cardiovascular and
immune systems. Apparently, Iranian scientists have not focused
on retinopathy. Further, neuropathy was studied only in animal
models.
3.6. Selection of the best-studied herbs for managing DM from Iranian studies and their evaluation in non-Iranian studies
The main outcomes extracted from Iranian studies (appendices
AC) were categorized as explained in Section 2.7. Then, the following 19 herbs were selected for their efcacy in managing DM
and related complications, for example, lowering BG and HbA1C
levels and oxidative stress, and restoring the lipid prole and antioxidant defense: A. sativum L., Aloe vera (L.) Burm. f., Coriandrum
sativum L., Carthamus tinctorius L., Cichorium intybus L., S. marianum (L.) Gaertn., C. colocynthis (L.) Schrad., T. foenum-graecum L.,
C. sativus L., J. regia L., R. persica (Burm.f.) Scheen & V.A. Albert
(syn: Otostegia persica (Burm.f.) Boiss.), P. anisodonta Boiss., S.
khuzistanica Jamzad, T. polium L., P. granatum L., E. globulus Labill.,
O. europaea L., U. dioica L., and Viscum album L.
Appendix D presents the effectiveness of these 19 selected
herbs in managing DM as studied by non-Iranian researchers.
We did not nd any non-Iranian reports on the efcacy of R.
persica, P. anisodonta, and S. Khuzistanica, endemics to Iran, in
managing DM. It should be noted that S. marianum, C. colocynthis,
J. regia, S. khuzistanica, A. sativum, T. foenum-graecum, P. granatum,
and U. dioica were studied in both humans and animals. A. vera
was only studied in human models, and the remaining selected
herbs were studied only in animal models.
The results of the non-Iranian studies on the efcacy of 19 beststudied herbs in managing DM and related complications are
shown in Table 5, below the Iranian counterparts. As seen in part
A, Parameters in DM, the HbA1C level, the side effects, the anthropometric assessments, and the signs of DM have scarcely been
investigated in both Iranian and non-Iranian studies. Furthermore,
several conicting reports were found on the hypoglycemic effects
of A. sativum in both humans and animals; however, when taking
other reports into account, it was found to have no effect on the BG
level in animals.
Although the mechanisms of the 19 selected herbs were studied more frequently in non-Iranian studies than in Iranian studies, endogenous incretins and microcirculation were not considered in non-Iranian studies either (Table 5, part B, Pharmacological mechanisms).
As seen in part C, Effects on the functions of organs (Table 5),
most studies were conducted in animal models. Non-Iranian studies also did not investigate the effects of the mentioned herbs on
retinopathy, nephropathy, and neuropathy in humans.
4. Discussion
A search with the term Diabetes gave 4500,000 queries in
PubMed, covering different areas of the management of DM such
as cell transplantation therapy, insulin therapy, and traditional
medicine. Various systematic reviews or meta-analysis studies on
the efcacy of herbal products in the management of DM were
found. All of these studies contain highly useful information on
herbs, their phytochemical properties, and the available pharmacomechanisms (e.g., Abdollahi et al., 2012; Eddouks et al., 2014;
Hasani-Ranjbar et al., 2009, 2008; Suksomboon et al., 2011;
P. Wang et al., 2013). However, these reviews mostly involve
clinical trials, animal models, or in vitro studies. Some articles are
focused only on the properties of a single herb (e.g., El Sedef and
Karakaya, 2009; Hamidpour et al., 2014; Jurenka, 2008; Majewski,
2014; Martnez et al., 2010; Rahimi et al., 2012; Rodriguez et al.,
2010; Street et al., 2013), a specic genus (Szewczyk and Zidorn,
2014), or species (Sarin et al., 2014). Furthermore, studies on the
DM-related complications were found (e.g., Musabayane, 2012;
Song et al., 2014; Tsourdi et al., 2013). Abolhassani et al. conducted
a thorough survey of CAM in Iran (Abolhassani et al., 2012). Some
articles focused on the medicinal herbs used in Arabian countries
(A and Kasabri, 2013), India (Grover et al., 2002; Modak et al.,
2007; Rizvi and Mishra, 2013), Mexico (Andrade-Cetto and Heinrich, 2005; Andrade-Cetto, 2009), TCM (Chen et al., 2011; Grant
et al., 2009; Xie and Du, 2011), TIM (Dabaghian et al., 2012; Hosseinzadeh and Nassiri-Asl, 2013; Shojaii et al., 2011; Zarshenas
et al., 2014), and Western countries (Cravotto et al., 2010). Altogether, this volume of essays shows the rising interest in herbal
management of DM, but the reasons why these efforts did not
yield have not been traced. In the following sections, some pertinent issues including the preconditions of the herbal studies, the
implications for research, and the weaknesses and strengths of the
reviewed studies are discussed.
4.1. The preconditions of the studies on herbal medicines for the
management of DM
4.1.1. The quality and safety of herbal medicines and product
standardization
The quality of medicines including their safety and effectiveness is important (Efferth and Kaina, 2011; Kosalec et al., 2009).
The most important step in analyzing botanical and herbal preparations is sample preparation. Studies on herbal products cannot
be considered scientically valid if the tested product has not been
authenticated and characterized to ensure its reproducibility
during manufacture. The existing technologies are inadequate for
the complete analysis of constituents. The scientic community is
faced with the major challenge of formulating a simple, affordable,
and reliable standardization method or protocol for standardizing
herbal products (EFSA Scientic Committee, 2009). The signicance of the extraction procedure in determining the composition and antioxidant properties of some traditionally used
medicinal herbs has also been studied (Komes et al., 2011). However, some studies have already described some signicant features to dene the reliable results as the basis for scientic evidence-based practice (Chan et al., 2012; Uzuner et al., 2012).
According to our ndings, the quality of the studied herbs was
not generally mentioned in the reviewed articles. However, a
variety of contaminants including chemical and biological contaminants, toxic metals and nonmetals, and radioactive contaminants may be present in herbs (Kosalec et al., 2009). It is
highly likely that some of the observed contradictory or negative
effects arise from the impurities in herbs rather than the differences in the design of experiments. For instance, several studies
showed that cadmium reduces insulin levels and exerts direct
cytotoxic effects on the pancreas, hence possibly affecting the

development of some types of diabetes (Edwards and Prozialeck,
2009). The sample preparation steps (processing, extraction, and
yield) are explained in detail only in a few reviewed articles. Almost no report was found on the quality and possible contaminations of the studied herbs. Such investigations are difcult
and costly, but they are necessary for standardizing the results. In
our opinion, whether the enumerated analyses of these plants
have been performed, it should denitely be elaborated in the
material and methods section and hinted at in the abstract.
4.1.2. Side effects and toxicity of the herbs and herbdrug
interactions
Herbal therapy, especially over a proven conventional therapy,
may be toxic and dangerous (Winslow and Kroll, 1998). Toxicity
associated with herbal therapy can be categorized into four different groups based on the following factors: (1) correctly identied medicinal plants with unknown toxicity; (2) incorrectly
identied medicinal plants with toxic activity; (3) contamination
of herbs with pesticides, heavy metals, microbes, radioactivity,
organic solvents, chemical drugs, or hormones; and (4) interaction
of medicinal plants with conventional drugs (both synergistic and
antagonistic interactions can cause toxicity) (reviewed by (Efferth
and Kaina, 2011)). The rst and second group of factors highlight
the importance of the verication of herbs by the named botanist,
including details such as their botanical origin and the corresponding scientic names as noted previously (Chan et al., 2012;
Rivera et al., 2014).
Toxicity assessment involves various in vivo and in vitro techniques. In the risk assessment process, studies need to consider
the formulation of herbal products and their bioavailability. It is
necessary to combine quality application data with chronic toxicity data. However, these data are rarely available for most herbal
products. The risk assessment procedure considers the following
steps in risk characterization: (1) hazard identication, (2) dose
response assessment, and (3) exposure assessment (EFSA Scientic
Committee, 2009).
Less than 30% of the reviewed articles directly focused on the
studied herbs from a toxicological point of view. The toxicological
history of the studied herbs was mentioned in about 10% of the
reviewed articles. Collectively, we reviewed 10, 31, and two articles
on human, animal, and in vitro models, respectively, for toxicological assessments (Appendices A, B, and C, respectively). Although the toxicity assessments are time consuming, after determining the lowering effects on the BG and HbA1c levels in
animal models, the pharmacological, toxicological, and phytochemical information should be obtained before clinical trials. In
our opinion, studies focusing on a specic herb should necessarily
refer to its toxicological history; a lack of past and present records,
however, should be hinted at for future studies.
Although medicinal herbs are widely used and considered to be
safe, many of their components are susceptible to interaction with
synthetic medicines. Furthermore, many herbal preparations also
have side effects (reviewed by (Dham et al., 2006; Kosalec et al.,
2009; Springer et al., 2013)). However, few studies referred to the
side effects of the studied herbs (Fallah Huseini et al., 2006; Huseini et al., 2009), Appendix A (Iranian studies); (Kanth et al.,
2008; Said et al., 2008); Appendix D (non-Iranian studies)). In our
opinion, studies must explicitly mention the presence or absence
of side effects from these herbs.
Medicinal herbs have also been used in combination with
medications in some studies (Appendix A (Iranian studies): C.
colocynthis (Rahbar and Nabipour, 2010); S. securidaca (Fallah
Huseini et al., 2006); Plantago ovata Forssk. (Ziai et al., 2005);
Heracleum persicum Desf. ex Fisch., C.A.Mey. & Av-Lall. (Panahi
et al., 2011); Appendix D (non-Iranian studies): A. sativum (Ashraf
583
et al., 2011; Kumar et al., 2013; Liu et al., 2005); A. vera (Hotkar
et al., 2013; Parihar et al., 2004); T. foenum-graecum (Gupta et al.,
1999; Lu et al., 2008; Preet et al., 2006, 2005a, 2005b; Siddiqui
et al., 2006; Thakran and Baquer, 2003; Yadav et al., 2004)). Undesirable side effects of drugherb interactions may be especially
severe in the elderly, vulnerable individuals, or those treated with
multiple medications for chronic diseases. The risk of drug interactions increases with the number of herbal products consumed
(reviewed by (Alissa, 2014)). Although therapy combining herbs
and medications has been argued to be more effective, herbdrug
interactions have not been considered in both reviewed Iranian
and non-Iranian studies. Furthermore, the long-term duration of
side effects should not be ignored. Therefore, research in this area
should be conducted in the long term.
Although the molecular mechanisms of herbdrug interactions
are not known in all cases, basic pathways have been proposed
(reviewed by (Efferth and Kaina, 2011; Neergheen-Bhujun, 2013)).
The probability of herbdrug interactions may be higher than
drugdrug interactions. A thorough understanding of the mechanisms of herbdrug interactions is crucial for assessing and
minimizing clinical risks (reviewed by (Alissa, 2014; NeergheenBhujun, 2013)). Furthermore, the American Herbal Product Association introduced a classication of toxicities associated with
herbal therapy and safety (reviewed by (Efferth and Kaina, 2011)),
which is worth considering.
In addition, it has been argued that herbal formulations are
more effective than single herbs in managing diabetes (Wais et al.,
2012). In the reviewed articles, three polyherbal compounds were
studied in Iran. Anethum (composed of Anethum sp., Cichorium sp.,
and Fumaria sp.), known as a hypolipidemic agent, had no signicant effect on hypertriglyceridemic patients in this regard
(Mirzazade et al., 2002). Furthermore, treatment with A. graveolens
also did not signicantly change the lipid prole in patients with
hyperlipidemia (Kojuri et al., 2007) and metabolic syndrome
(Mansouri et al., 2012). It increased the lipid levels while also
lowering the triglyceride (TG) levels in rats fed a high-cholesterol
diet (HCD) (Hajhashemi and Abbasi, 2008; Yazdanparast and
Bahramikia, 2008). C. intybus restored the TG levels in streptozotocin (STZ)-induced DM in rat (Ghamarian et al., 2012). No article
investigating the efcacy of Fumaria sp. as a single herb in Iran was
found. Anethum was not selected as a potential hypoglycemic
herbal medicine because information on its exact composition was
lacking. Furthermore, its efcacy was not evaluated in DM.
Itrifal Saghir, the next reviewed polyherbal preparation, is
composed of the three medicinal fruits Phyllanthus emblica L. (syn.
Emblica ofcinalis Gaertn.), Terminalia chebula Retz., and Terminalia
bellirica (Gaertn.) Roxb. Although it is benecial in obese subjects
without any side effects (Kamali et al., 2012), its efcacy in
managing DM remains to be evaluated.
The third polyherbal compound, containing six plants (A. sativum, Cinnamomum verum J.Presl (syn: C. zeylanicum Blume), Nigella sativa L., P. granatum, S. ofcinalis, and T. polium), exhibited
antihyperglycemic and antihypertriglyceridemic activities in addition to decreasing the water intake in rats with STZ-induced
diabetes (Shaee-Nick et al., 2012). Although this compound was
worth investigating further, it was not selected for further analysis
because no information was found on its effect on serum insulin
and oxidative stress. Further, although herbs included in this
polyherbal component individually showed benecial effects on
DM in other studies, we could not conclude whether polyherbal
preparations are a better choice for managing DM than single
herbs. More detailed and comparative studies are needed in this
eld of herbal research.
584
4.2. Implications for research

4.2.1. Animal models of diabetes
The choice of the appropriate animal model would determine
the success of each study (Robinson et al., 2012). Clearly, diabetic
animal models cannot always be categorized as T1DM or T2DM,
and many of them are used to depict and study the features
common to the types of diabetes, such as hyperglycemic effects or
diabetic complications (reviewed by (Andrade-Cetto and Heinrich,
2005; Chatzigeorgiou et al., 2009)). Diabetogenic agents such as
alloxan and STZ can induce many subtypes and features of T1DM
or T2DM (Breyer et al., 2005; Gross et al., 2004; Kim et al., 2006;
Obrosova et al., 2006; Oztrk et al., 1996; Rees and Alcolado,
2005). Besides, even if an animal model is expected to delineate
one specic type of diabetes, there is no proof of its actual
homology with the same type of diabetes in the human model
(reviewed by (Chatzigeorgiou et al., 2009)).
The experimental animals used in the reviewed articles include
chicken, dog, mice, rabbit, and rat. Experimental models other
than alloxan- and STZ-induced diabetes, which were among the
most studied models of DM and its related complications, are as
follows: fructose-induced insulin resistance and DM; genetically
inherited DM; high-fat-diet-induced DM; nonalcoholic steatohepatitis induced by an insulin-resistant, methionine/choline-decient diet; non-insulin-dependent DM; obesity; ketotifen-induced
weight gain; Zucker diabetic fatty; and STZnicotinamide-induced
DM and T2DM with nonalcoholic fatty liver disease.
As seen in Appendix B, from a total of 155 reviewed Iranian
articles, 106 articles in animal models were found to evaluate the
efcacy of 63 herbs. This indicated that, at best, each herb has
been evaluated possibly twice in animal models. Considering the
lack of adequate information on toxicological and phytochemical
properties of the studied herbs, all herbs suffered from inadequate
investigation in animal models.
Several concerns have been raised on the reliability of animal
experiments (van der Worp et al., 2010), but herbs found to be
suitable for animals need to be studied in humans. However, before commencing studies in human models, it is necessary to investigate the safety and benecial aspects of herbs in proper animal models. In this respect, only a scant number of the herbs selected in the present study can be subject to human trials, unless it
is argued that animal studies do not accurately predict their efcacy in humans (van der Worp et al., 2010) where herbs are traditionally being used. Therefore, their efcacy could be evaluated
immediately in human trials. Accordingly, it is worth investigating
the hypoglycemic effects of herbs in humans, which reduce the BG
and HbA1C levels and oxidative stress, and restore the lipid prole
without side effects in any animal models.
4.2.2. Clinical trial
The clinical trials used to elucidate the effectiveness of the
present reviewed herbs in human models include crossover shortterm; double-blind controlled; double-blind placebo-controlled;
double-blind randomized; double-blind, randomized, placebocontrolled; quasi-experimental; randomized casecontrol; randomized, placebo-controlled, crossover; randomized, double-blind
casecontrol; randomized, open-label; randomized, semi-experimental; sequential randomized controlled; and single-blind, placebo-controlled studies.
The efcacy of 37 from a total of 82 studied herbs (44.6%) was
evaluated in 43 clinical trials. With respect to Table 2, and Appendices B and D, most of the reviewed herbs, the 19 selected
herbs in particular, were only evaluated in animal models (Section
4.2.1). Human studies conducted on the selected herbs included
ve of S. marianum (Iranian studies), A. sativum, and A. vera (nonIranian studies); three of C. colocynthis (Iranian studies), O.
europaea, and T. foenum-graecum (non-Iranian studies); two of J.

regia, A. sativum, and U. dioica (Iranian studies); and one of S.
khuzestanica, A. vera, and T. foenum-graecum (Iranian studies). The
longest duration of the clinical trials in Iranian and non-Iranian
studies are 12 weeks (S. marianum (Fallahzadeh et al., 2012; Huseini et al., 2006); A. graveolens (Mansouri et al., 2012); polyherbal
compound (Mirzazade et al., 2002); polyherbal compound (Kamali
et al., 2012); Melilotus ofcinalis (L.) Pall. (Hasani-Ranjbar et al.,
2012) (Appendix A, Iranian studies)) and 24 weeks (A. sativum
(Ashraf et al., 2011)), 14 weeks (O. europaea (Wainstein et al.,
2012)), 12 weeks (A. sativum (Ashraf et al., 2005; Kumar et al.,
2013); O. europaea (de Bock et al., 2013); T. foenum-graecum (Lu
et al., 2008) (Appendix D, non-Iranian studies)), respectively.
Other trials were conducted within 4 h to 10 weeks.
Obviously, the hypoglycemic effects of the reviewed herbs have
been scarcely studied in human models. Therefore, concrete trials
investigating the advantages and disadvantages of medicinal herbs
are warranted.
Herbal medicines are inherently different from conventional
pharmacological treatments. One of the crucial questions is whether the currently used conventional clinical trial methodologies
are sufcient for assessing the efcacy of herbal medicines. In
particular, it is argued that socioeconomic, cultural, and psychological variables should be integrated with clinical and diagnostic
parameters to assess the efcacy of herbal medicine (EFSA Scientic Committee, 2009). However, no alternative is available
currently.
4.2.3. Pharmacological mechanisms of the herbs: drug discovery
Considering the pharmacological mechanism proposed for
herbs (Section 2.7) and the number of studies that have investigated the BG and HbA1C levels, lipid prole, signs of diabetes,
and DM-related complications, further studies may be required
until the herbal medicine appropriate for treating DM is discovered. Although incorporating all of these properties in medicines is idealistic, their basic aspects should be considered in both
in vivo and in vitro studies. For instance, very few Iranian and nonIranian studies investigated the effect of herbs on the level of
HbA1C or the function of pancreas, liver, and kidney, in addition to
their hypoglycemic effects. The effects of factors such as endogenous incretins and microcirculation were not investigated.
Diabetic complications, knowledge of having T2DM, and the
duration of diabetes are known risk factors for depression specic
to diabetes (Oladeji and Gureje, 2013). Comorbid depression can
result in several issues such as neglect of medication and self-care
management, poor glycemic control, and an elevated risk of
complications (Oladeji and Gureje, 2013). PubMed produced no
result when searched using the scientic names (Latin binomial)
of the selected reviewed herbs along with the keywords depression and diabetes, except in the case of A. sativum, A. vera,
and U. dioica, which have rarely been studied. Nevertheless, studies on depression in diabetes are ongoing. Although physicians
and specialists are qualied to comment on this topic, probably
some signs of DM such as polydipsia, polyphagia, body weight
loss, frequent urination, extreme weakness and tiredness (IDF,
2013), and blood pressure should be considered important factors
for managing DM and related complications (IDF, 2013; TeixeiraLemos et al., 2011; H. Wang et al., 2013). Although these simple
parameters can be easily measured and their improvement can
help to alleviate some symptoms of depression and in turn to
enhance the treatment, they were considered in only few Iranian
and non-Iranian studies reviewed here.
According to the guidelines of the American Academy of Pediatrics, the ideal method of treating diabetes is to normalize the
BG and HbA1c levels. Successful control of associated comorbidities such as hypertension and dyslipidemia is also important
(reviewed by (Reinehr, 2013)). The ultimate goal of treatment is to

reduce the risk of acute and chronic DM-related complications
(Reinehr, 2013). However, studies in drug discovery should not
only consider the effects on BG and/or insulin levels but also other
factors such as antioxidant defense and alleviation of oxidative
stress (Yang et al., 2011). Furthermore, it has been suggested that
new approaches to drug discovery must target the underlying
cellular processes of apoptosis, autophagy, and inammation in
addition to oxidative stress (Maiese et al., 2013).
In short, the BG and HbA1C levels, lipid prole, and parameters
presented in the pharmacological mechanism for herbs must be
considered seriously in short-term studies, despite being studied
in few human and animal models even for the best-studied herbs,
with the exception of the BG level. For instance, the effect of
treatment with few herbs on the HbA1C level has been evaluated
in both human and animal models. There is little or no report on
the effect of the best-studied herbs on polydipsia and polyphagia
in clinical trials (Table 5, part A). According to our results, many
aspects of the pharmacological mechanism in herbs, such as insulin secretion, oxidative stress, and antioxidant defense, have
scarcely been studied in humans (Table 5, part B). In long-term
studies, the efcacy of herbs in treating DM-related complications
and their long-term side effects are to be investigated. In addition,
little or no report was found on nephropathy and the function of
the kidney, neuropathy, and retinopathy in human studies (Table 5, part C).
4.3. Lifestyle as an effective way to prevent and manage diabetes
Because diabetes is becoming increasingly prevalent with its
added nancial and social consequences, it is necessary to further
explore its prevention and early detection (Reinehr, 2013). All of
the issues outlined in Section 4.2 in addition to the required toxicological and phytochemical studies suggest that a change in
lifestyle is easier and more practical than nding a hypoglycemic
treatment.
Every culture has its own view of health, illness, and treatment.
In Persian medicine (TIM), disease prevention is of greater importance than its cure. Accordingly, the following six factors are
essential for the maintenance of good health: (1) air, (2) food and
drink, (3) sleep and wakefulness, (4) evacuation and retention,
(5) body movement and repose, and (6) mental movement and
repose (Rezaeizadeh et al., 2009). Conversely, traditional Chinese
medicine (TCM) cures ailments based on the signs and symptoms
of a patient (reviewed by (H. Wang et al., 2013)).
An increasing number of studies concur with the Iranian approach to health and illness. Multiple risk factors have been found
to be associated with T2DM, which include obesity, diet and
physical inactivity, increasing age, insulin resistance, family history
of diabetes, and ethnicity (IDF, 2013). Several indisputable prospective studies have demonstrated that sleep disturbance is a
major risk factor for insulin resistance and incident diabetes (Reutrakul and Van Cauter, 2014). Evidently large randomized controlled trials indicated that good metabolic control in both T1DM
and T2DM can delay the onset and progression of these complications (WHO, 2014a, 2014b). There is strong evidence that prediabetes (characterized by impaired fasting glucose or impaired
glucose tolerance), metabolic syndrome, and T2DM can be both
prevented and treated by increasing habitual physical activity
(reviewed by (Burr et al., 2012)). In short, drastic lifestyle changes
are the mainstay of all treatment approaches, and they should be
encouraged particularly in individuals with or at a risk of developing diabetes (Z. Wang et al., 2013).
Documentation of herbal medicine should include the following aspects: cultivation, harvesting, and technologies involved,
including plantation development and processing methods; the
585
prior validation of products used in herbal medicine; the properties of synthetic products identical or related to the active constituent(s) of the medicine; the chemistry of herbs believed to be
responsible for the activity; the results of any clinical trials carried
out on the product and aspects of marketing and trading; and legal
issues including intellectual property rights (IPRs) (EFSA Scientic
Committee, 2009). Accordingly, effective lifestyle changes, educating the public about the importance of preventing and treating
various diseases such as diabetes, and encouraging individuals to
adopt a healthy lifestyle with proper diet and physical activity
appropriate to their age and sex are believed to be the shortest and
the most efcient method.
However, in some cases, rigorous and sustained behavioral
change does not sufce (Kahn et al., 2006). For instance, the recommended therapy of lifestyle intervention to lose weight in
T2DM is not suitable for most patients (Reinehr, 2013). Accordingly, low-hazard and low-cost alternatives to pharmaceutical interventions are clearly required where lifestyle modications have
failed to adequately improve glucose tolerance (Grant et al., 2013).
Among the Iranian and non-Iranian studies reviewed here,
little or no report was found on the efcacy of the simultaneous
use of medicinal herbs, exercise, and lifestyle intervention in
managing diabetes.
4.4. The weaknesses of the reviewed articles
Of the 82 herbs and related compounds studied in the 155
reviewed Iranian articles, only six were endemic to Iran, including
A. elburzense Wendelbo, A. stipitatum Regel (syn: A. hirtifolium
Boiss.), Kelussia odoratissima Mozaff., R. persica (Burm.f.) Scheen
and V.A. Albert (syn: Otostegia persica (Burm.f.) Boiss.), P. anisodonta Boiss., and S. khuzistanica Jamzad. It is clear that the efcacy
of the reviewed herbs was studied scarcely in both human and
animal models. Most studies were conducted in animal models,
and only four herbs including T. foenum-graecum, S. khuzistanica, C.
sinensis, and U. dioica were studied in human, animal, and in vitro
models (Section 3, Table 2). Human studies on the hypoglycemic
effects of the herbs are obviously scarce (Section 4.2.2). According
to our results, most of the reviewed studies focused on parameters
such as the BG and HbA1C levels in animal models (Table 5, part
A), and not on the comprehensive effects of the studied herbs on
DM and related complications (Table 5, part C). Although several
studies have been conducted and several herbs investigated, DMrelated complications have been studied scarcely or not at all.
However, the level of HbA1C was measured in a limited number of
clinical trials or animal studies (Table 5, part A), probably due to
the difculties in its measurement (WHO, 2011). Both Iranian and
non-Iranian researchers have not studied the pharmacological
mechanisms of herbs in detail (Table 5, part B). Information on the
toxicological and phytochemical properties of the reviewed herbs
was also scarce (Sections 3.3 and 3.4, respectively). The possible
contaminations of the studied herbs were not mentioned (Section
4.2.1). Although the effects and mechanisms of herbs must be investigated comprehensively for drug discovery, the lesser-known
aspects would be interesting to study. Considering that budget is
an important factor in designing experiments in developing
countries, nancial problems may be a cause of inadequate phytochemical and toxicological studies.
According to the scoring system for the quality of articles (Chan
et al., 2012), none of the reviewed Iranian articles scored the
maximum ( 25) as they failed to cite the scientic name of the
herb and include information on the processing procedure and
extraction processes (Sections 3.1 and 3.1.1). Whereas scientic
botanical data in a study is reliable and reproducible only when
such information is provided. Apart from existing policies such as
the "Rule of 5" for publishing in journals such as JEP, journals will
586
have to establish a new guide emphasizing these criteria, as recommended previously (Chan et al., 2012; Rivera et al., 2014), for
improving the quality and validity of the nal publications.
A greater number of Iranian articles referred to non-Iranian
traditional usages of the studied herbs than their traditional Iranian usages. No valid report was found for the traditional use of
most of the reviewed herbs in Iranian studies (Section 3.2; Table 6). Because herbal medicine has been increasingly used by
chronically ill people, who may conceal the fact from their physicians, the medical staff should be familiar with the herbs traditionally used in their area and country. Therefore, researchers
should prioritize ethnopharmacological studies of herbs traditionally used in their country.
Some types of diabetes such as gestational diabetes were
completely excluded in Iranian studies. Previously rare, type 2 juvenile diabetes has become increasingly prevalent worldwide
(Reinehr, 2013; WHO, 2014c). Forasmuch as women with gestational diabetes and their offspring have a high probability of developing T2DM (IDF, 2013), studies of the efcacy of benecial
herbs on this type of diabetes are recommended.
4.5. The strengths of the reviewed articles
Almost all the investigated herbs were found to lower the BG
level, although only few human, animal, and in vitro studies were
conducted. According to Iranian as well as non-Iranian studies
with positive results, at least 19 herbs are worth investigating
further. It is worth mentioning that three herbs including R. persica
(Burm.f.) Scheen and V.A. Albert (syn: Otostegia persica (Burm.f.)
Boiss.), P. anisodonta Boiss., and S. khuzistanica Jamzad, endemic to
Iran, showed considerable therapeutic effects in both human and
animal models, but they have only been studied in Iran (Section
3.6, Table 5). As seen in Table 5, the lack of complete and comprehensive information on all 82 reviewed herbs, the 19 selected
herbs in particular, make them attractive and valuable elds of
further research. In the following, we briey mention some therapeutic applications and phytochemical properties of the 19 selected herbs. However, appendices A, B, and C (reviewed Iranian
studies) and D (reviewed non-Iranian studies) show the effects of
these herbs in details.
A. sativum L. has numerous applications in medicine, in addition to its nutritional values. The pharmacological effects of the
herb have mostly been attributed to its hypoglycemic, hypolipidemic, anticoagulant, antihypertensive, antihepatotoxic, anticancer, immunomodulatory, and antioxidant properties (reviewed
by (Baluchnejadmojarad et al., 2003)). A. sativum has been shown
to have antibiotic, antifungal, and antihypertensive properties
(reviewed by (Hosseini et al., 2007)). These properties result from
the combined curative effect of various biologically active substances (Majewski, 2014). The herb contains a variety of organosulfur compounds, amino acids, enzymes (e.g., alliinase), vitamins,
and minerals. Some sulfur compounds such as alliin and compounds produced enzymatically from alliin (e.g., allicin), ajoene,
S-allylcysteine (SAC), diallyl disulde (DADS), S-methylcysteine
sulfoxide, and S-allylcysteine sulfoxide may be responsible for the
therapeutic properties of this herb (reviewed by (Kojuri et al.,
2007; Majewski, 2014; Quintero-Fabin et al., 2013; Srinivasan,
2014; Z. Wang et al., 2013)). The main active component, alliin (Sallyl cysteine sulfoxide), has antioxidant, cardioprotective, and
neuroprotective activities. In addition, it lowers the levels of glucose, insulin, TGs, and uric acid, as well as promoting insulin resistance and reducing the cytokine levels (Quintero-Fabin et al.,
2013). Diallyl trisulde (DAT) has been reported with dilatory effects on blood vessels and antibacterial activity, among others (Liu
et al., 2014). S-methyl-L-cysteine (SMC), naturally found in Allium
plants, was found to be effective in improving high-fructose-
induced hyperglycemia and dyslipidemia (Senthilkumar et al.,

2013).
According to our data, A. sativum showed hypoglycemic effects
in both Iranian and non-Iranian studies in human and animal
models, although rats with STZ-induced diabetes showed no
change in BG level when treated with 100 mg/kg aqueous extract
of bulbs (Baluchnejadmojarad et al., 2003). Its effects on anthropometric assessments; lipid prole; serum insulin; insulin resistance; oxidative stress; antioxidant defense; nephropathy and
function of kidney; obesity and hyperlipidemia; function of cardiovascular system, liver, and pancreas have been examined in
both Iranian and non-Iranian studies. However, the effects of A.
sativum on several factors such as the signs of DM, the HbA1C
level, carbohydrate absorption, insulin secretion, hepatic glycogenolysis, retinopathy, and neuropathy need to be studied further
in both human and animal models (Table 5). No phytochemical
information on this herb was found in the reviewed Iranian articles (Table 4).
A. vera (L.) Burm.f. is potentially valuable in the treatment of
diabetes (Bunyapraphatsara et al., 1996). Aloe species have been
used for centuries for their laxative, anti-inammatory, immunostimulant, antiseptic, wound and burn healing, antiulcer, and
antitumor activities (reviewed by (Okyar et al., 2001)). A. vera gel
exhibits hypoglycemic, wound healing, and anti-inammatory effects (reviewed by (Rajasekaran et al., 2005a, 2005b)). However,
very few studies have been conducted on the characterization of
the bioactives and mechanisms mediating the antihyperglycemic
action of the aloe gel (Huseini et al., 2012). Trace elements such as
vanadium; zinc; sodium; potassium; calcium; copper; manganese;
traces of chromium (Rajasekaran et al., 2005a, Rodriguez et al.,
2010); and phytosterols including lophenol, 24-methyl-lophenol,
24-ethyl-lophenol, cycloartanol, and 24-methylene-cycloartanol
isolated from the gel have been reported to be responsible for the
antihyperglycemic effects of the gel in the animal model of diabetes (Rodriguez et al., 2010; Tanaka et al., 2006).
A. vera was found to decrease the BG and HbA1c levels in human models in the reviewed Iranian and non-Iranian studies.
Furthermore, in the non-Iranian studies, it was found to ameliorate factors such as serum insulin level, insulin resistance, oxidative stress, and antioxidant defense. However, the signs of DM, cell
apoptosis, peripheral glucose uptake, hepatic glycogenolysis, retinopathy, and nephropathy have not been studied (Table 5). One
phytochemical report on this herb, which identied and quantied
a mucopolysaccharide called acemannan from the leaf gel, was
found in the reviewed Iranian articles (Huseini et al., 2012)
(Table 4).
C. tinctorius L. has been used in TIM for the treatment of diabetes (Asgary et al., 2012). It has been used in traditional medicine
as a purgative, analgesic, antipyretic, and an antidote to poisoning.
It is useful for treating painful menstrual disorders, postpartum
hemorrhage, and osteoporosis. C. tinctorius was recently shown to
have antioxidant, analgesic, anti-inammatory, and hypoglycemic
activities (Asgarpanah and Kazemivash, 2013). Serotonin derivatives such as N-p-coumaroyl serotonin and N-feruloyl serotonin
isolated from C. tinctorius seeds showed -glucosidase inhibitory
activity (Takahashi and Miyazawa, 2012). The main constituents
reported in this herb are carthamin, carthamidin, isocarthamidin,
hydroxysafor yellow A, safor yellow A, safamin C, and luteolin.
Caryophyllene, p-allyltoluene, 1-acetoxytetralin, and heneicosane
were identied as the major components of the essential oil of C.
tinctorius owers (Asgarpanah and Kazemivash, 2013). C. tinctorius
showed considerable hypoglycemic effects in rats with alloxaninduced diabetes (Asgary et al., 2012) (Table 5). Only its -glucosidase inhibitory activity has been studied in non-Iranian research
(Takahashi and Miyazawa, 2012) (Appendix D). However, its effects on the signs of DM, the HbA1C level, insulin secretion, insulin
resistance, peripheral glucose uptake, oxidative stress, antioxidant

defense, cell apoptosis, hepatic glycogenolysis, retinopathy, nephropathy, neuropathy, and functions of the cardiovascular and
immune systems are yet to be studied (Table 5). Apparently, Iranian studies have not included phytochemical analyses of this
herb.
C. intybus L. has been used in traditional medicine to treat a
variety of diseases including high blood sugar (Ghamarian et al.,
2012; Pushparaj et al., 2007; Street et al., 2013). Although this herb
has a rich history of use in folklore, it is little investigated in terms
of phytochemistry and pharmacology (Street et al., 2013). Chicoric
acid has been identied as the major compound in its methanolic
extracts (Ghamarian et al., 2012). It has been suggested that the
potent hypercholesterolemic and hypotriglyceridemic effects of C.
intybus L. extract could be attributed to the presence of inulin, a
polymer of fructose with -(2-1) glycosidic linkages (Pushparaj
et al., 2007).
C. intybus has only been studied in animal and in vitro systems.
Although it showed some benecial effects, factors such as the
signs of DM; the HbA1C level; insulin secretion; insulin resistance;
peripheral glucose uptake; oxidative stress; antioxidant defense;
cell apoptosis; hepatic glycogenolysis; retinopathy; nephropathy;
neuropathy; and the functions of the pancreas, liver, cardiovascular, and immune systems remain to be studied (Table 5). None of
the reviewed Iranian articles reported on the phytochemical analysis of this herb.
C. colocynthis (L.) Schrad. is famous for its global medicinal
value (reviewed by (Hussain et al., 2014; Shafaei et al., 2014; Shi
et al., 2014)). Pectin, colocynthin, colocynthein, colocynthetin, and
gum are the main phytochemical constituents found in its pulp,
while xed oil and albuminoids have been isolated from its seeds,
which make the fruit pulp and seeds an important medicinal part
of this plant (reviewed by (Shi et al., 2014)). Other constituents of
the herb include glycosides, alkaloids, avonoids, and estrols
(Class A, B, K, L, J, and E) (reviewed by (Hussain et al., 2014; Shafaei
et al., 2014)).
C. colocynthis is known for its hypoglycemic effects with side
effects in both humans and animals. However, its effects on the
level of HbA1C; insulin secretion; insulin resistance; peripheral
glucose uptake; oxidative stress; antioxidant defense; cell apoptosis; hepatic glycogenolysis; retinopathy; nephropathy; neuropathy; and the functions of the pancreas, liver, cardiovascular, and
immune systems have not been studied in depth (Table 5). No
phytochemical information on this herb was found in the reviewed Iranian articles.
C. sativum L. is grown as a spice crop worldwide. The seeds
have been used to treat indigestion, diabetes, rheumatism, and
joint pain (M. Eidi et al., 2009). The total polyphenolic content of
the seeds was found to be gallic acid and avonoid (Deepa and
Anuradha, 2011). In different cultures, all parts of this herb are
used as avoring agents and/or traditional remedies to treat various disorders. The herb is a potential source of lipids (rich in
petroselinic acid) (Sahib et al., 2013).
C. sativum has only been studied in animal models. It showed
hypoglycemic effects in both Iranian and non-Iranian studies. Although 60 g of leaf extract per kilogram had no effect on BG (Jelodar et al., 2005), 200 and 250 mg of ethanol extract of seeds per
kilogram decreased the BG level (M. Eidi et al., 2009). Furthermore, it had inconsistent effects on the level of serum insulin
(Aissaoui et al., 2011; Deepa and Anuradha, 2011). Polydipsia;
polyphagia; the HbA1C level; carbohydrate absorption; insulin
secretion; insulin resistance; peripheral glucose uptake; antioxidant defense; cell apoptosis; hepatic glycogenolysis; retinopathy; nephropathy; neuropathy; and the functions of the pancreas, liver, cardiovascular, and immune systems remain to be
studied (Table 5). No phytochemical information on this herb was
587
found in the reviewed Iranian articles.

C. sativus L. is one of the most expensive spices in the world,
apart from its traditional value as a food additive and herbal
medicine (Zibaeenezhad et al., 2003). In folk medicine, saffron, the
dried stigma of the herb, is known to be efcient in alleviating and
treating ailments. In addition to the three major constituents reported, crocin, picrocrocin, and safranal, the presence of carotenoids, carbohydrates, proteins, anthocyanins, vitamins, and
minerals provides valuable insights into the health benets and
nutritional value of saffron. Of the carotenoids present in saffron,
highly water-soluble crocin (mono and diglycosyl esters of a
polyene dicarboxylic acid, named crocetin) is responsible for the
majority of its color, and it appears to possess various healthpromoting properties, such as antioxidant, antitumor, memoryenhancing, antidepressant, anxiolytic, and aphrodisiac properties
(reviewed by (Mousavi et al., 2010)).
C. sativus has only been studied in animal and in vitro systems.
It has been found to decrease the BG and HbA1C levels, but various
other factors such as the signs of DM; insulin secretion; insulin
resistance; peripheral glucose uptake; oxidative stress; antioxidant defense; cell apoptosis; hepatic glycogenolysis; retinopathy; nephropathy; neuropathy; and the functions of the pancreas, liver, and cardiovascular and immune systems need to be
studied (Table 5). On conducting phytochemical analyses, alkaloids, steroids, avonoids, tannins, saponins, and anthraquinones
were found to be absent in the hydroalcoholic extract of seeds
(Minaiyan et al., 2011) (Table 4).
E. globulus Labill. is traditionally used to treat diabetes (reviewed by (Ahlem et al., 2009; Bokaeian et al., 2010; Mahmoudzadeh-Sagheb et al., 2010a, 2010b)). It is also medicinally used as
an antiseptic and deodorant; as treatment for hoarseness, coughs,
whooping coughs, asthma and bronchitis, coryza, dysentery, diabetes, fevers and colds, toothache, diarrhea, malaria, rhinitis, tuberculosis, and snakebites; and as agents for washing and cleaning
wounds (reviewed by (Bokaeian et al., 2010; Dey et al., 2014;
Mahmoudzadeh-Sagheb et al., 2010a, 2010b)). Leaves from E. globulus are reported to have a high content of eucalyptol (cineol)
together with rutin, terpineol, sesquiterpene, alcohols, aliphatic
aldehydes, isoamyl alcohol, ethanol, terpenes, and tannins (reviewed by (Bokaeian et al., 2010; Mahmoudzadeh-Sagheb et al.,
2010a, 2010b)).
Both Iranian and non-Iranian researchers studied E. globulus
only in animal models. It was found to lower the level of BG and
alleviate polydipsia and polyphagia (the signs of DM). However, its
effects on the level of HbA1C; insulin secretion; insulin resistance;
neuropathy; and the functions of the pancreas, liver, and cardiovascular and immune systems have not yet been studied in depth
(Table 5). Furthermore, no phytochemical analysis was conducted
in Iranian studies.
J. regia L. is one of the medicinal plants used in TIM to treat
diabetes (Asgary et al., 2008b). Due to its septic and astringent
properties, it has been used to treat skin inammations, hyperhidrosis, ulcers, diarrhea, and helminth infections (reviewed by
(Mohammadi et al., 2012)). It is rich in unsaturated fatty acids,
especially linoleic and linolenic acids (Bouabdallah et al., 2014);
reviewed by (Zibaeenezhad et al., 2003). The triacylglycerol species include trilinolein, dilinoleoyl-linoleoyl-glycerol, dilinoleoyloleoyl-glycerol, and palmitoyl-dilinoleoyl-glycerol classes (Bouabdallah et al., 2014). Phenolic acid and avonoid are the two major
groups of phenolic compounds in walnut leaves. The most important phenolic acid in a walnut leaf is caffeoylquinic acid
(chlorogenic acid), and the main avonoid is quercetin (Zhao et al.,
2014); reviewed by (Asgary et al., 2008b). Walnut leaf and ridge
extracts are known to contain high amounts of strongly
588
antioxidant components such as vitamin C, vitamin E, beta-carotene, lipoic acid, quercetin, naphthoquinones, avonoids, gallic
acid, polyphenols, linoleic and linolenic acids, tannins, and folates
(reviewed by (Kamyab et al., 2010)). In the kernel oils from six J.
regia varieties, the most abundant phytosterol was b-sitosterol and
the major triterpenic alcohol and aliphatic alcohol were cycloartenol and hexacosanol, respectively. The detected volatile compounds were pentanal, hexanal, nonanal, 2-decenal, and hexanol
(Abdallah et al., 2015; Martnez et al., 2010).
J. regia has mostly been studied by Iranian researchers in animal models. Although it showed considerable hypoglycemic effects, a single dose of the aqueous extract of its septum did not
affect the BG level (the exact dose was unknown) (Sarahroodi,
2012). The signs of DM; insulin secretion; insulin resistance; peripheral glucose uptake; oxidative stress; antioxidant defense; cell
apoptosis; hepatic glycogenolysis; retinopathy; nephropathy;
neuropathy; and the functions of the pancreas, liver, and cardiovascular and immune systems remain to be studied (Table 5). This
herb was not studied from the phytochemical perspective in the
reviewed Iranian studies.
O. europaea L. Its leaves are used as antirheumatic, anti-inammatory, antinociceptive, antipyretic, vasodilatory, hypotensive,
antidiuretic, and hypoglycemic agents in traditional medicine (El
Sedef and Karakaya, 2009; Esmaeili-Mahani et al., 2010; Kaeidi et al.,
2011). Oleuropein and its derivatives such as hydroxytyrosol and
tyrosol are the main phenolic constituents of olive leaves. Furthermore, olive leaves contain caffeic acid, p-coumaric acid, vanillic acid,
vanillin, luteolin, diosmetin, rutin, luteolin-7-glucoside, apigenin-7glucoside, diosmetin-7-glucoside, 11-demethyloleuropein, 7,11-dimethyl ester of oleoside, oleasterol, leine, ligustroside, oleuroside,
and unconjugated secoiridoid aldehydes (reviewed by (EsmaeiliMahani et al., 2010; Kaeidi et al., 2011)). Oleuropein possesses a wide
range of pharmacologic and health-promoting properties including
antiarrhythmic, spasmolytic, immunostimulant, cardioprotective,
hypotensive, and anti-inammatory properties (reviewed by (AlAzzawie and Alhamdani, 2006)). Oleuropoeside isolated from the
leaves of the herb also showed hypoglycemic effects (Dekanski et al.,
2009; Gonzalez et al., 1992).
O. europaea has been studied in both human and animal systems. Although its effects on the functions of the pancreas, liver,
and cardiovascular and immune systems as well as its hypoglycemic effects have been studied outside of Iran, the signs of DM,
the level of HbA1C, insulin secretion, insulin resistance, peripheral
glucose uptake, oxidative stress, antioxidant defense, cell apoptosis, hepatic glycogenolysis, retinopathy, nephropathy, and neuropathy need to be investigated further (Table 5). The main phenolic
components of the olive leaf extract include phenolic compounds
such as oleuropein (356 mg/g), tyrosol (3.73), hydroxytyrosol
(4.89), and caffeic acid (49.41)(Esmaeili-Mahani et al., 2010)
(Table 4).
P. anisodonta Boiss. is endemic to Iran. A few pharmacological
and biological studies have been conducted on Phlomis. Some
studies have shown various properties such as anti-inammatory,
antinociceptive, immunosuppressive, antimutagenic, free radical
scavenging, antimicrobial, and antimalarial effects (reviewed by
(Sarkhail et al., 2007)). In addition, some Phlomis species are used
in folk medicine to treat diabetes (HARPUT et al., 2006). Phlomis
species constitute a rich source of different classes of glycosides
comprising triterpenoids, diterpenoids, iridoids, avonoids, phenylpropanoids and other phenolic compounds, some of which
have antioxidant, anti-inammatory, and immunosuppressant

activities (Sarkhail et al., 2003).
P. anisodonta has only been studied by Iranian researchers in
animal models. It showed hypoglycemic effects, although its effects on the signs of DM; the level of HbA1C; insulin secretion;
insulin resistance; peripheral glucose uptake; oxidative stress;
antioxidant defense; cell apoptosis; hepatic glycogenolysis; retinopathy; nephropathy; neuropathy; and the functions of the
pancreas, liver, and cardiovascular and immune systems have not
been studied (Table 5). The reviewed Iranian articles did not
contain any phytochemical information on this herb.
P. granatum L. helps prevent or treat various disease risk factors including high blood pressure, high cholesterol, oxidative
stress, hyperglycemia, and inammatory activities, in addition to a
wide number of health disorders such as diarrhea, dysentery, and
dental plaque, and to combat intestinal infections and malarial
parasites (Ismail et al., 2012; Zarfeshany et al., 2014). P. granatum
consists of about 80% conjugated octadecatrienoic fatty acids, with
a high content of 9-cis, 11-trans, 13-cis acid or punicic acid (PA),
one of the isomers of conjugated linolenic acid (CLN). The physiological activities of the seed oil can be attributed to the 9-cis, 11trans CLA derived endogenously or to PA itself (reviewed by
(Mirmiran et al., 2010)). Its juice (PJ) contains polymolecular ellagitannin compounds, such as punicalagin, which is a potent
antioxidant (reviewed by (Parsaeyan et al., 2012)). PJ is a good
source of fructose, sucrose, and glucose. It also contains simple
organic acids such as ascorbic acid, citric acid, fumaric acid, and
malic acid. In addition, it contains small amounts of all amino
acids, specically proline, methionine, and valine. Both the juice
and peel are rich in polyphenols. The largest classes include tannins and avonoids (Mahmoudzadeh-Sagheb et al., 2010a, 2010b).
PJ contains polyphenols such as anthocyanins (such as cyanidine3-glucoside, cyanidine-3,5-diglucoside, and delphindine-3-glucoside), catechins, ellagic tannins, and gallic and ellagic acids (Esmaillzadeh et al., 2004). Phenolic compounds, including avonoids
(anthocyanins, catechins, and other complex avonoids) and hydrolyzable tannins (punicalin, pedunculagin, punicalagin, and
gallic and ellagic acid), are concentrated in the peels (reviewed by
(Ismail et al., 2012)).
P. granatum showed some inconsistent effects on the BG and
serum insulin levels in humans and animals in both Iranian and
non-Iranian studies, possibly because experiment designs differed.
However, the effect of treatment on factors such as the signs of
DM; the level of HbA1C; insulin secretion; insulin resistance;
neuropathy; and the functions of the pancreas, liver, and cardiovascular and immune systems must be investigated in depth
(Table 5). According to phytochemical analysis, seed oil consists of
major forms of fatty acids including 72.0% PA (18:3); 10.7% oil acid
(18:2); 8.4% linol acid (18:2); 4.0% palmitic acid (16:0); 2.6% stearic
acid (18:0); trace amounts (1%) of other fatty acids, with a total
amount of 7.3% of saturated fatty acids (SFAs), 11.7% of monounsaturated fatty acids (MUFAs), and 81% of polyunsaturated fatty
acids (PUFAs); and 36.90 mg/100 g of vitamin E (Mirmiran et al.,
2010) (Table 4).
R. persica (Burm.f.) Scheen and V.A. Albert is a plant endemic
to Iran, used in TIM to treat malaria and fever. It has also been used
as an analgesic in toothache (reviewed by (Ganjali et al., 2013)).
However, it has been traditionally used in some regions of Iran,
Table A1
Information on human studies extracted from Iranian research.
Treatment group
Design
Used
part of
plants
Intervention, dose
Main outcomes in treatment group
Achillea santolinoides subsp. wilhelmsii (K. Koch) Greuter
Primary hypertension moderate

hyperlipidemia
Renal transplant
recipients
Double-blind placebo-controlled
clinical trial
Aerial
parts
Lipid prole (TC, TG, LDL-C, HDL-C), cardiovascular system (SBP, DBP, Asgary et al. (2000)
BP)
5-Tr
0-Tr
Single-blind, place- Cloves

bo-controlled
study
Leaves
Randomized double-blind placebocontrolled clinical
trial
?
Anthropometric assessment (BW E ); Lipid prole (TG,TC chewing

route; LDL, HDL E both routes); oxidative stress (LPO both routes),
cardiovascular system (SBP both routes; DBP chewing route, BP),
Lipid prole (TG E; TC, LDL-C; HDL-C)
Jabbari et al. (2005)
Hyperlipidemia
1520 Drops of hydroalcoholic extract

twice/day
One clove (1 g) by
chewing or
swallowing
400 mg, 1 mg of allicin/tablet 2 times/
day
One 300-mg capsule
every 12 h
Kojuri et al. (2007)
BG, HbA1c; Lipid prole (LDL, TC; TG, HDL E)
10-Ph, Tr
Immune system (MIF expression )
Mirzaei et al. (2012)
2*
Lipid prole (TG, HDL-c E; TC, LDL-CE)
Kojuri et al. (2007)
Allium sativum L.
T2DM with hyperlipidemia (hypercholesterolemia and/or

hypertriglyceridemia)
Obesity
Hyperlipidemia
Avena sativa L.
Brassica oleracea L.
Citrullus colocynthis (L.) Schrad.
Cloves
Single-blind, placebo-controlled
study
Metabolic syndrome
Double-blind, randomized, placebocontrolled trial
T2DM given oat bread
Crossover shortterm trial
T2DM (10 g/day BSP, 5 g/ Randomized douday BSP)
ble-blind clinical
trial
T2DM
Randomized double-blind clinical
trial
T2DM (10 g/day BSP
Randomized, dou(n 23), 5 g/day BSP
ble-blind, and placebo-controlled
(n 26)
study
T2DM
Sequential randomized controlled
clinical trial
T2DM with mild
Double-blind ranhypertension
domized controlled
trial
T2DM
Randomly assigned
to either the test or
control
T2DM
Nondiabetic
hyperlipidemia
Score
(max 25)
250 g/day
Anthropometric assessments (BW, BMI E); BG E; lipid prole (TG, TC, Mansouri et al. (2012) 4.5-Tr, Tx
LDL, HDLE ); serum biochem (creatinine E), liver enzyme (AST,
ALT E); cardiovascular system (BP E)
BG, lipid prole (HDL-c)
Hajifaraji et al. (2012) 6
10 g BSP/day
BGE , Serum insulin; HOMA-IR/FIRI;
Bahadoran et al.,
(2012b)
5 and 10 g BSP/day
BGE ; lipid prole (ox-LDL, TC); oxidative stress (,TOS E); antioxidant defense(),
Bahadoran et al.
(2011)
10
6 and 10 g BSP/day
BGE ; Lipid prole (HDL-C, OX-LDL/LDL, TG, AIP, LDL-cE ),
Bahadoran et al.,
(2012a)
2 times/day black tea Lipid prole (TG, LDL, apoA-I, apo-B100, lipoprotein a E ; HDL)
Mozaffari-Khosravi
et al. (2009a)
9-Tr
2 Times/day black
tea
Anthropometric assessment (BMI, Weight E); cardiovascular system

(BP E; SBP, PP)
Mozaffari-Khosravi
et al. (2009b)
1-Tr
150 ml/day in 1st

week, 300 ml/day in
2nd week, 450 ml/
day in 3rd week, and
600 ml/day in 4th
week
100-mg capsule
3 times/day
Anthropometric assessment (BW and BMI, fat massE); BGE,

HbA1c E ; oxidative stress (LPO); antioxidant defense (GSH); immune system (CRP); brinogen E,
Tirang et al. (2010)
Leaves
and
stems
Oat
breads
?
Fruits
Seeds
Extract
300-mg powdered
seed/day standard
therapy
Anthropometric assessment (BW E ); side effects , BG, HbA1c, lipid Huseini et al. (2009)
prole (LDL, HDL, TG, TCE); serum biochem (urea, creatinine E); liver
Ez (AST, ALT, ALP E); cardiovascular system (BP E)
5-Tx
Lipid prole (TG, TC; LDL-C, HDL-C E), liver Ez (AST, ALT E)
9-Tr, Tx
Rahbar and Nabipour

(2010)
589
Randomized, double-blind, placebocontrolled clinical

trial
clinical trial
Alpinia ofcinarum
Hance extract
(AOHE)
650 mg/tablet
2 times/day
References
Latin binomial
590
Table A1 (continued )
Intervention, dose
Treatment group
Design
Used
part of
plants
Curcuma longa L.
T2DM with nephropathy
Randomized, double-blind, and placebo-controlled

study
Glycine max (L.) Merr.
Postmenopausal women with the metabolic syndrome
Crossover study
Nonalcoholic fatty liver disease (NAFLD)

Dyslipidemia
Randomized controlled clinical trial

Randomized, openlabel clinical trial
T2DM
Hordeum vulgare L.
T2DM with mild

hypertension
T2DM
Juglans regia L.
Hyperlipidemia
Sequential randomized controlled

clinical trial
Double-blind randomized controlled trial
Crossover short-term
trial
Randomized casecontrol study
Randomized, doubleblind casecontrol
Quasi-experimental
study
Randomized, doubleblind clinical trial
Randomized, placebo-controlled clinical
trial
Double-blind placebo-controlled study
Quasi-experimental
study (a pilot study)
Rhizome 3 Times (500-mg

capsule, of which
22.1 mg was the active ingredient curcumin)/day
Seeds
Red meat in the
DASH diet replaced
by soy nut and soy
protein
Roots
2 g aqueous extract/
day
?
500 mg extract/
day 10 mg/day
atorvastatin
?
2 Times/day sour tea
Heracleum persicum Desf. ex

Fisch., C.A.Mey. and Av-Lall.
Hypertriglyceridemia
Lycopersicum esculentum Mill.
T2DM
Melilotus ofcinalis (L.) Pall.
T2DM
Nigella sativa L.
Hyperlipidemia
T2DM
Prunus cerasus L.
T2DM
Prunus dulcis (Mill.) D.A.Webb
Mild hyperlipidemia
Punica granatum L.
T2DM with
hyperlipidemia
T2DM
Pediatric metabolic
syndrome 18 ml/kg
per day of natural
grape juice
Hyperlipidemia
Punica granatum L.
Dyslipidemia
?
Barley
breads
?
?
Fruits
?
Seeds
Nuts
60 g/day almond
Quasi-experimental
study
Quasi-experimental
interventional study
Randomized controlled clinical trial
Fruits
40 g/day concentrated juice

200 ml/d juice
Fruits
240 ml/kg per day

juice
Seeds
400 mg oil 2 times/

day
Seeds
400-mg seed oil

(PSO) 2 times/day
Score
(max 25)
Anthropometric assessment (BW E ); NO, immune system (CRP, IL18in nut not protein, E-selectin in nut not protein), (endothelin-1,
sVCAM-1, sICAM-1, IL-2, IL-6, Serum amyloid A)E
Azadbakht et al.
(2007)
BMIE ; liver (ALT, AST)
Hajiaghamohammadi
et al. (2012)
Panahi et al. (2011)
2-Tr, Tx
Anthropometric assessments (BW, BMI E); BG E; lipid prole (TG,

HDL-C E; LDL-C, TC); Antioxidant defense (); liver Ez (AST, ALT E);
serum biochem (creatinine E)
Lipid prole (TG, TC, LDL; HDL; apoA-I, lipoprotein a E; apo-B100) Mozaffari-Khosravi
et al. (2009a)
Anthropometric assessment (BW E ); BG, HbA1c; lipid prole (HDLC, LDL/HDL, TC, LDL, TG E),
Anthropometric assessments (BW, BMI); BGE, HbA1C; lipid prole
(TC, TG, HDL, LDL E; TC, LDL in hyperlipidemic subgroup); cardiovascular system (BP),
Lipid prole (TC, LDL-C, apo-B100, TG, HDL, LPa, apo A1 E)
1-Tr
1
2
0
**
6
Ziai et al. (2005)
13-Tr
Ataie-Jafari et al.
(2008)
4-Ph
Jalali-Khanabadi et al.
( 2010)
Anthropometric assessments E; lipid prole (TG E; TC, LDL-C, TC/
Esmaillzadeh et al.
HDL-c, LDL-c/HDL-c; HDL-C E);
(2004)
BG, lipid prole (TG E; TC, LDL-C; HDL-CE ), oxidative stress (LPO), Parsaeyan et al.
others (PON1)
(2012)
Anthropometric assessment (BMI E); cardiovascular system (enHashemi et al. (2010)
dothelial-dependent dilation index ),
Anthropometric assessment (body fat, fat mass, BMI E ); insulin, insulin/glucose E; lipid prole (TC/HDL-c, TG, TG/HDL-c; LDL-c, TC,
HDL-c, ox-LDL, LDL-c/HDL-c,); HOMA-IRE ; ,
Lipid prole (TG, HDL-C, TG/HDL-c E); Immune system (TNF- E)
4-Tr, Tx
(Mozaffari-Khosravi
1-Tr
et al. (2009b)
Hajifaraji et al. (2012) 6
Zibaeenezhad et al.
(2005)
3 g oil/day
Lipid prole (TG; HDL-C, TC, LDLE)
Zibaeenezhad et al.
(2003)
200 g/day
Anthropometric assessment (BMI E); BGE ; lipid prole (apoA-I, apo- Shidfar et al. (2011)
B100E); cardiovascular system (SBP, BP), homocysteine E
2 times 100 mg/day Biochem urine (creatinine, calcium E ); Bone markers (ALP, osteocalcin, Hasani-Ranjbar et al.
pyridinoline E); Immune system (TNF-E)
(2012)
2 g (500 mg crushed BGE , Lipid prole (TG, TC, LDL; HDL E)
Sabzghabaee et al.
seed capsule)/day
(2011)
Fruits
Fruits
References
BGE , lipid prole (TG, TC, LDL, HDL E); serum biochem (BUN, crea- Khajehdehi et al.
tinie E); urine biochem (Up); immune system (TGF-, IL-8, TNF E), (2011)
cardiovascular system (BP E)
2 Times/day sour tea Anthropometric assessment (BW, BMI E); cardiovascular system
(BP E; SBP, PP),
Barley bread diet
BG, lipid prole (HDL-c)
250 g/day
20 g walnuts/day
Lipid prole (TG;HDL-c)
5.1 g 2 times/dayantidiabetic drugs

40 g/day juice

trial.
Seeds
Main outcomes in treatment group
0
5
10-Tx
0
Mirmiran et al. (2010) 14-Ph
Asghari et al., (2012)
**
Latin binomial
Saccharomyces cerevisiae Meyen

ex E.C. Hansen
Salvia ofcinalis L.
T2DM
Hyperlipidemia
Satureja khuzistanica Jamzad
T2DM with
hyperlipidemia
Securigera securidaca (L.) Degen

and Dor.
T2DM
Silybum marianum (L.) Gaertn.
T2DM (candidate for insulin therapy )

T2DM
T2DM
Triticum sp.
Hyperlipidemia
Urtica dioica L.
T2DM
T2DM
Vitis vinifera L.
Pediatric metabolic syndrome patients drink

240 ml/kg per day of
natural grape juice
Hyperlipidemia
Polyherbal compound (Anethum Hypertriglyceridemia

sp.; Cichorium sp.; Fumaria
sp.)
Polyherbal compound (Terminalia Obesity
bellirica (Gaertn.) Roxb.; Terminalia chebula Retz.; Phyllanthus emblica L.)
Clinical trial study
?
Leaves
12 tablets of
300 mg yeast/day
500-mg extract
capsule every 8 h
BG, Lipid prole (TC E ; TG, LDL-C; HDL-C)
Lipid prole (TG, TC, LDL, vLDL; HDL), liver Ez (AST, ALT E), serum
biochem (creatinine E)
Khosravi-broujeni
et al. (2012)
Kianbakht et al.
(2011)
13-Tr, Tx
Leaves
250 mg/tablet
BGE , Lipid prole (TG E ; TC, LDL-C; HDL-C), oxidative stress

(LPO E), antioxidant defense (), serum biochem (creatinine E )
Vosough-Ghanbari
et al. (2010)
14-Tr
Seeds
500-mg seed capsule 3 times/daystandard

therapy
200-mg silymarin
tablet 3 times/day
200-mg silymarin
tablet 3 times/
day standard
therapy
Three 140-mg silymarin tablet/day
Side effects-, BG E, HbA1c E , Lipid prole (LDL, HDL, TC, TGE), liver
Ez ( E ), Serum biochem (creatinine E )
Fallah Huseini et al.,

(2006)
2*-Tx
BG (BS2hpp), HbA1c, Lipid prole (LDL-C, TC)
Ramezani et al.
(2008)
2*
Seeds
Seeds
Seeds
Wheat
germ
?
Randomized double-blind control

trial
Randomized, dou- ?
ble-blind, and placebo-controlled
study
Randomized conFruits
trolled clinical trial
Double-blind con- Rhizome

trolled clinical trial
Randomized, dou- ?
ble-blind, placebocontrolled trial
Double-blind, ran- ?
domized, placebocontrolled trial
10 g/day mixed
with yoghurt or
soaked in hot
water
30 g/day
100 mg hydroalcoholic extract/
kg
100 mg hydroalcoholic extract/
kg
18 ml/kg per day
juice
Anthropometric assessments (BW E); BG, HbA1c, serum insulinE;

lipid prole (LDL, TC, TG, HDL); liver Ez (AST, ALT), cardiovascular
system (BP E);
FBG, HbA1c E; lipid prole (TG, TC, LDL, HDL-c E); oxidative stress
(LPO); serum biochem (serum creatinine E ); urine biochem (UAE);
cardiovascular sys (SBPs, DBPE); immune system (TNF-); others
(eGFR E)
BG, anthropometric assessments E, lipid prole (vLDL, TG)
Fallahzadeh et al.
(2012)
**
Bahadoran et al.
(2012b)
0*
Lipid prole (TG, TC, vLDL; LDL-C, HDL-C E)
Zakeri et al. (2009)
Immune system (TNF- E; CRP,IL-6)
Namazi et al. (2011)
2*
Oxidative stress (LPO E), antioxidant defense (), antioxidative EZ (,

GPxE)
Namazi et al. (2012)
2*
Cardiovascular system (endothelial-dependent dilation index )
Hashemi et al. (2010)
3-g capsules/day
Lipid prole (HDL; TC, TG; LDL, VLDL, lipo a E), homocysteine E)
in 3 divided doses
Lipid prole (TG, TC, HDL-C E)
2 times 5 grams/
day
**-Tx
Alizadeh-Navaei et al. 3
(2008)
Mirzazade et al.
0
(2002)
Anthropometric assessments (BW, BMI); BG, Fasting serum insulin; Kamali et al. (2012)
GTT E; lipid prole (LDL, TG, TCE); serum biochem (creatinine E);
liver enz (ALT, AST E)
T2DM with nephropathy
Semi-experimental
study
trial
Double-blind randomized controlled
trial.
Randomized, double-blind, placebocontrolled, clinical
trial
Randomized clinical trial study
Randomized, double-blind, placebocontrolled, clinical
trial
Randomized, Double-Blind, PlaceboControlled Trial
Increased, decreased, improved, E unchanged. Ph, Tr, and Tx in the column score indicate that phytochemical, traditional, and toxicological information is available in the reviewed articles, respectively. Please see appendix EAbbreviation for other abbreviations.*Articles with only available abstracts. ** Materials were purchased from a valid commercial source (Please see Sections 2.3, 3, and 3.1 for details). Latin binomials (scientic names) are based on
theplantlist.org
591
592
Table B1
Information on animal studies extracted from Iranian researches.
Latin binomial
Study
model
Design, disease
Positive control
Negative control
Used part of
plant
Intervention, dose
Main outcomes
References
Score
Acanthophyllum squarrosum Boiss.

Achillea tenuifolia Lam.
Rat
Normal??
Roots
Total saponins
BG
Tabassi et al. (2006)
12
Rat
STZ-induced DM
Nondiabetic; diabetic
Aerial parts
0.1 g extract/kg per day
Allium ascalonicum L.
Rat
Rat
Normal, insulin resistance control

Normal, Normal herb,
diabetic,
Bulbs
Allium cepa L.
Fructose-induced Insulin Resistance

STZ-induced DM
500 mg aqueous extract/kg per day

15 mg quercetin/kg per
day
Yazdanparast et al.
Anthropometric assessments (weight loss ); BG; (2007)
antioxidant defense (pancreatic GSH); antioxidative
Ez (SOD, CAT); oxidative
stress (PCO, LPO, NO,
AOPP);
BG (IPGTT), FIRI
Jalal et al. (2007)
Rat
Alloxan-induced DM
12.5% BW-supplemented diet
Rat
STZ-induced DM
Diabetic group (control

positive) and a Normal
health (control negative)
diabetic
15 mg Quercetin (QR)/
kg per day
Allium elburzense
Wendelbo
Rat
STZ-induced DM
Glibenclamide
Normal, diabetic
Bulbs
Allium elburzense
Wendelbo
Rat
STZ-induced DM
Glibenclamide
Normal, diabetic
Bulbs
Allium stipitatum Regel
Rat
STZ-induced DM
Allium ampeloprasum L.
Rabbit
HCD-induced
hypercholesterolemia
Normal,
hypercholesterolemic
Bulbs
Allium sativum L.
Rat
STZ-induced DM

diabetic
Bulbs
Hydroalcoholic (HdAE)
and butanolic extracts
(BuE) Subacute
treatment
Hydroalcoholic (HdAE)
and butanolic extracts
(BuE) acute
administration
100 and 300 mg hydroalcoholic extract/kg
250, 500, or 1000 mg
hydroalcoholic extract/
kg
Rat
STZ-induced DM

diabetic
Bulbs
0.1, 0.25, and 0.5 g extract/kg
Rat
HCD-induced
hyperlipidemia

lipogenic diet
Bulbs
Standard diet supplemented with 4% garlic
Glibenclamide
3.5
Bakhshaeshi et al.
(2012)
**-Tx
Jelodar et al. (2005)
3-Tr
Khaki et al. (2010a,

**
Anthropometric assessments (BW); BGE, serum 2010b)
insulin; lipid prole (oxLDL E); oxidative stress
(LPO); testis parameters
(serum testosterone, testes
W; degeneration, inammation ; sperm
number, sperm viability,
motility)
BG E (BuE)
Zolfaghari et al. (2012) 13Ph, Tr
BG (HdAE)
Zolfaghari et al. (2012) 13Ph,Tr
Liver Ez (AST, ALT, ALP,

LDH)
Lipid prole (atherogenic
index, LDL-C, TC),
Hosseini et al. (2012)
Anthropometric assessments (BW E); BG E; cardiovascular system (vascular function),

Anthropometric assessments; BG, serum insulin; Lipid prole (TG,
TC); liver Ez (AST, ALT);
Serum biochem (urea, uric
acid, creatinine, );
Lipid prole (atherogenic
index, TG, TC, LDL-C, VLDLC); antioxidant defense
Baluchnejadmojarad
et al. (2003)
Eidi et al. (2006)
9-Tr,
Tx
Heidarian et al. (2011)
Movahedian et al.
(2006)
2-*,
Tx
11-Tr
Apoptosis (liver tissue,

kidney cells); oxidative
stress (LPO); antioxidant
defense (TAC)
BG E, Pancreatic
parameters E
11-Tr
Rat
STZ-induced DM
Rat
Fructose-Induced Insulin Resistance

Alloxan-induced DM
Control, vehicle-treated
control, Normal herb,
vehicle-treated diabetic
Normal, insulin resistance control
Normal diet (75 days);
Normal herb; high-cholesterol diet (45 days);
high-cholesterol diet (75
days);\
Bulbs
Aqueous extract
Bulbs

Rat
Amaranthuscaudatus L.
Rabbit
HCD-induced hypercholesterolemia/atherosclerotic lesions
Rat
HCD-induced
Rat
HCD-induced
hyperlipidemia
Leaves
Rat
HCD-induced
hyperlipidemia
HCD-induced
Seeds
Rat
Arnebia euchroma (Royle)

I.M. Johnst.
Artemisia aucheri Boiss
Camellia sinensis (L.)

Kuntze
Aerial parts
45, 90, and 180 mg

powder and essential
oil/kg
Water extract of leaves
before and after the extraction of the furocoumarin content of
the leaves
Essential oil at two different doses
Single daily dose of
1-ml extract, equivalent
to 500 mg of the plant
powder
3.5
BG, Pancreatic
parameters E
3-Tr
Kabiri et al. (2011)

Lipid prole (TC, LDL-C;
HDL-C, apoA-I; TG, apoB-I,
AI, OX-LDL E); oxidative
stress (LPO); cardiovascular sys (aortic of atherosclerotic lesions E); immune system (CRP);
Lipid prole (TG, LDL-C,
Hajhashemi and AbTC; HDL)
basi (2008)
13Ph, Tr
Lipid prole (TG; TCE)
Yazdanparast and Alavi (2000)
2*
Lipid prole (TG; TCE)
Yazdanparast and Alavi (2000)

Yazdanparast and
Bahramikia, (2008)
2*
Anthropometric assessments (BW, liver W E);

BG E; lipid prole (TC, TG,
LDL, LDL/HDL, HDL);
HMG-CoA/mevalonate,
Burn wounds
Stems
Ethanol extracts
Diet supplemented with Lipid prole (TG, LDL-C;

100 mg/kg per day
HDL-C), Cardiovascular
system (atherosclerotic
thickness)
20 and 40 mg epigallo- Anthropometric assessments (BW); BG; Oxidacatechin-3-gallate
tive stress (LPO); CNS
(EGCG)/kg per day
(learning, memory, RAM
task)
200 mg alcohol extract/ Anthropometric assesskg
ments (BW); BG; Lipid
prole (TC; TG, LDL-C,
HDL-C E);
25 mg epigallocatechin- Anthropometric assess3-gallate (EGCG)/kg per ments (BW); BG; Oxidative stress (LPO), Antiday
oxidative Ez(); Cardiovascular system (vascular
function),
450 mg aqueous exBG
tract/kg
200 mg hydroalcoholic BG, serum insulin, Panextract/kg
creatic parameters , Lipid
prole (TG, TC, LDL-C,
VLDL-C), Liver Ez (AST,
ALT, ALP E)
Rat
STZ-induced DM

diabetic
Rat
STZ-induced DM, a dose

response study
Normal, diabetic
Leaves
Rat
STZ-induced DM

diabetic
Diabetic,
Green leaves
?
12-Ph
19Ph, Tr,
Tx
Pirbalouti et al. (2012) 8-Tr

(Dinani et al., 2010)
2*
(Baluchnejadmojarad
and Roghani, 2011)
**
(Haidari et al., 2012)
(Roghani and Baluchnejadmojarad,

2009)
**
(Shokrzadeh et al.,
2006)
(Asgary et al., 2012)
2
7*-Tr,
Tx
593
Normal, diabetic,
HCD
Alloxan-induced DM
Jalal et al. (2007)
Aerial parts
Rabbit
Glibenclamide
BG (IPGTT E), FIRIE
Normal, high-fat diet
Alloxan-induced DM
Rat
Silver Sulfadiazine

high-cholesterol diet,
150 mg hydroalcoholic
extracts/kg per day
Rat
Rat
Carthamus tinctorius L.
Clobrate
Aerial parts
Allium sativum L.
(); oxidative stress (LOP);

liver TC;
BG E; kidney (ACE)
Hosseini et al. (2007)
594
Table B1 (continued )
Study
model
Design, disease
Carum carvi L.
Rat
Cichorium intybus L.
Citrullus colocynthis (L.)

Schrad.
Citrus aurantiifolia
(Christm.) Swingle
Negative control
Used part of
plant
Intervention, dose
Main outcomes
References
Score
STZ-induced DM
Normal, diabetic
Seeds
1 g/kg per day
(Haidari et al., 2011)
5-Tr
Rat
Late-stage (STZ induced), early-stage

(NIA/STZ) induced
T2DM
Seeds
Normal; late diabetic
(STZ); early diabetic (NIA/
STZ)
125 mg/kg per day
(Ghamarian et al.,
2012)
8-Tr
Dog
Alloxan-induced DM
Normal, diabetic
Seeds
Mice
Normal, DMSO (normal),

ketotifen
Normal
Fruits
Rat
Ketotifen-induced
weight gain, obesity
STZ-induced DM
100 mg capsule/kg per

day
Essential oil
Anthropometric assessments E; BG; Lipid prole

(TG, HDL, TG/HDL-C E ; TC,
LDL-C);
Anthropometric assessments (BW); BG(IPGTT), HbA1c, serum insulin; Lipid prole (TC,
TG); Liver Ez (ALT);
Side effects (diarrhea); BG,
Seeds
2-Tr,
Tx
10Ph, Tr
11-Tr
Rat
Alloxan-induced DM
Normal, diabetic
Leaves
200 and 250 mg ethanol extract/kg

60 g/kg per day
Khoshvaghti and Hamidi (2012)

Asnaashari et al.
(2010)
M. Eidi et al. (2009)
Crocus sativus L.
Rat
STZ-induced DM
Normal, normal corcin,

diabetic
Stigma
50 or 100 mg/kg
Cucumis sativus L.
Rat
STZ-induced DM
Normal Glibenclamide,
diabetic Glibenclamide
Normal vehicle, diabetic vehicle,

Normal herb
Seeds
Cyamopsis tetragonoloba
(L.) Taub.
Rat
STZ-induced DM
Glibenclamide.
Normal, diabetic
Daucus carota L.
Rat
STZ-induced DM
Rat
STZ-induced DM
Rat
STZ-induced DM
hydroalcoholic (0.2, 0.4,

0.8 g/kg) and butanolic
extract (0.2, 0.4, 0.8 g/
kg)
Diet containing 0%, 5%,
10%, and 20% (w/w)
guar gum
2 Times/day, 100,
150 mg ethanolic extract/kg
50, 100, 250, and
500 mg methanol,
n-hexan, and dichloromethane extracts/kg per day
50 and 250 mg hydroalcoholic extract/kg per
day
Added to the diet (62.5
g/kg) and Drinking water (2.5 g/L)
Eucalyptus globulus Labill. Rat
Candidiasis in STZ-induced DM and Normal
Rat
STZ-induced DM
Rat
STZ-induced DM
Positive control
NPH and regular crystalline insulin
Glibenclamide
Seeds
Glibenclamide
Normal, diabetic
Normal, diabetic, Normal

C. albicans, diabetic
C.albicans, Normal C.
albicans herb
diabetic
Nondiabetic (Normal),
Diabetic,
Leaves
Leaves
Leaves
Anthropometric assessments (food intake)

BG, insulin release; pancreatic parameters
BG E, pancreatic
parameters E
Shirali et al. (2013)
Anthropometric assessments (BW E); BG,
HbA1c; lipid prole (TG, TC,
LDL; HDL); pancerase
function (HOMA-IR/FIRI);
oxidative stress(); urine
biochem (UAE)
Anthropometric assessMinaiyan et al. (2011)
ments (BW ); BG;
3
4-Tx
10Ph, Tr
Samarghandian et al.
(2012)
Khaki et al. (2010a,

2010b)
0*
Anthropometric assessments in methanolic extract; BG;
Soleimani et al.
(2007b)
7-Tr
BG, pancreaticparameters
Soleimani et al.,
(2007a)
2*
Anthropometric assessments ; BG; lipid prole

(TG, TC, LDL-C, AIP)
BG
(Bokaeian et al., 2010)

Anthropometric assessments (BW loss); BG;
Signs of DM (polydipsia,
polyphagia)
(H Mahmoudzadeh20 and 62.5 g/kg of eu- Anthropometric assessments (BW, Food intake, Sagheb et al., 2010)
calyptus in their diet,
and 2.5 g/L aqueous ex- Fluid intake); BG; Pancreatic parameters,
tract of eucalyptus in
their drinking water
(Nakhaee et al., 2009)
In diet (20 g/Kg) and
Anthropometric assessDrinking water (2.5 g/L) ments (BW, Food intake,
Fluid intake); BG,
HbA1C; Oxidative stress
3-Tr
8-Tr
6-Tr
Latin binomial

diabetic
Aerial parts
Normal, diabetic
Leaves
Nondiabetic (control negative), diabetic (control

positive)
diabetic
Leaves
Rat
STZ-induced DM
Juglans regia L.
Rat
Alloxan-induced DM
rats
Rat
Alloxan-induced DM
Mice
STZ-induced DM
Rat
STZ-induced DM
Metformin

diabetic
Leaves
Rat
STZ-induced DM
Insulin
Normal, diabetic
Septum
Kelussia odoratissima
Mozaff.
Rabbit
HCD-induced
Normal, normal herb,

high-chol diet,
Trimmed
branch tips
Rabbit
HCD-induced
Normal, chol diet
Fruits
Rat
STZ-induced DM
Malva sylvestris L.
Rat
Rat
Medicago sativa L.
Rabbit
Alloxan-induced DM
Alloxan-induced DM
rats.
HCD-induced
Glibenclamide
Leaves and
ridge
Fruits
Silver Sulfadiazine
Nitrofurazone
Normal, diabetic,
Normal, diabetic
Flowers
Flowers
Normal, high-fat diet,

Nnormal herb
Aerial parts
Nasturtium ofcinale R. Br. Rat
HCD-induced
Normal, high-fat diet
Leaves
Olea europaea L.
Rat
STZ-induced DM
Normal, diabetic,
Normal herb
Leaves
Rat
STZ-induced DM
Normal, diabetic,
diabetic vehicle
Leaves
Insulin
(Hasanein and Shahidi, 2011)
11Ph,Tr
(Sedigheh Asgary
et al., 2008)
11-Tr
(Jelodar et al., 2008)
400 mg/kg
(Kamyab et al., 2010)
2-Tr
(Mohammadi et al.,
2012)
11-Tr
(Sarahroodi, 2012)
12
Asgary et al. (2004)
7-Tr
Eidi et al. (2006)
7-Ph,
Tx
Shishehbor et al.
(2008)
0*
A single dose of aqueous extract

4 Kinds of supplemented diets
BG, insulin secretion,

glycogenolysis (GP), gluconeogenesis (PEPCK)
Anthropometric assessment (BW); BG, HbA1c,
serum insulin; Lipid prole (TC, TG, LDL, VLDL,
HDL);
BG E

Asgary et al. (2008a, )
Bahramikia and Yazdanparast (2008)
15-Tr,
Tx
A. Eidi et al. (2009)
11-Tr,
Tx
7-Ph,
Tr
595
BG E; lipid prole (LDL,

TC; HDL, TG E); oxidative
stress (LPO E), immune
system (CRP), A-OX %E
Diet supplemented with Lipid prole ((LDL-C
10 ml of apple juice
(10 ml); (HDL-C (10 ml);
TG, TC)); serum biochem
(nitrite,nitrate); immune
system (CRP); cardiovascular system (atherosclerotic thickness, brinogen, factorVII)
BG E,HbA1c, lipid prole
Standard animal food
(TG; HDL-C)
containing apple cider
vinegar (6% w/w)
Ethanol extracts
Burn wounds E
199 mg diethyl ether
CNS (wound healing)
extract/kg per day
Dietary alfalfa
BG E; Lipid prole (TG,
LDL, TCE; HDL; fatty
streak formation),
500 mg hydroalcoholic Anthropometric assessextract/kg per day
ment (body weight); lipid
prole (TC, TG, LDL-C;
HDL, LDL/HDL); liver Ez
(AST, ALT)
0.1, 0.25, and 0.5 g alBG, serum insulin; Lipid
cohol extract/kg
prole (TG, TC); liver Ez
(AST, ALT); Serum biochem (urea, uric acid,
creatinine);
300 and 500 mg exAnthropometric assesstract/kg per day
ments (BW); BG; apoptosis (activated caspase 3,
Bax/Bcl2) in spinal cord;
(PCO, LPO); Antioxidant

defense (FRAP);
12 and 25 mg extract/kg Anthropometric assessments (BW E); BG E; CNS
(learning, memory; PAL,
memory)
200 mg ethanolic exBG; HbA1c; lipid prole
tract/kg
(LDL-C, VLDL-C, cholesterol,
TG; HDL-C), Pancreatic
parameters (Size of islets of
Langerhans); serum
insulin
60 g/kg per day
BG; Pancreatic
parameters
596
Latin binomial
Study
model
Design, disease
Positive control
Negative control
Used part of
plant
Intervention, dose
Diabetic
Aerial parts
200, 350, and 500 mg/

kg per day
300 mg methanol extract/kg
STZ-induced DM
Peucedanum pastinacifolium Boiss. and Hohen.
Rat
STZ-induced DM
Glibenclamide

diabetic
Aerial parts
Phlomis anisodonta Boiss.
Rat
STZ-induced DM
Glibenclamide
Normal, diabetic,
Aerial parts
Phoenix dactylifera L.
Rat
STZ-induced DM,
neuropathy
Nondiabetic; diabetic animals; diabetic vehicle
Fruits
Aqueous extract
Prunus cerasus L.
Rat
Alloxan-induced DM
Insulin
Normal, diabetic
Fruits
Prunus dulcis (Mill.) D.A.

Webb
Punica granatum L.
Rat
Alloxan-induced DM
Silver sulfadiazine
Normal, diabetic,
Leaves
200 mg ethanolic extract/kg per day

Ethanol extracts
Rat
Rat
Alloxan-induced DM
Alloxan-induced DM
Silver sulfadiazine
Flowers
Seeds
61 g/kg per day
Rat
Normal, diabetic,
Nondiabetic (control negative), diabetic (control
positive)
Normal, diabetic
Atrovastadin, orlistat
Normal, hyperlipidemic
Galls
200 mg diethyl ether

extract/kg per day
Methanol extracts
STZ-induced DM
Aerial parts
(shoot)
Quercus infectoria G.
Olivier
Rabbit
Alloxan-induced DM
rats
HCD
Rhus coriaria L.
Rat
DM
Diabetic acarbose or
metformin
Normal vehicle alone;

diabetic vehicle alone;
Fruits
Ethanolic extract
Rat
HCD-induced
Atorvastatin
Normal control, HCD

control
Fruits
Aqueous methanol
extract
Rat
DM
Normal, acarbose
Flowers
1001000 mg methanol
extract/kg
Rabbit
HCD
Normal, hyperlipidemic,
Flowers
Methanol extracts
Atrovastadin, orlistat
Flowers
125, 250, or 500 mg

hydroalcoholic extract/
kg
100, 200, and 400 mg
methanolic extract/kg
tail-ick latency
BG
BG; (serum insulin,insulin
release), Oxidative stress
(LPO), Antioxidant defense
(liver GSH)
Lipid prole (TC, LDL-C,
TG, HDL-C, atherogenic
index),
Anthropometric assessments (BW); BG, serum
insulin; antioxidative Ez
(SOD, CAT, GPx); antioxidant defense (FRAP);
oxidative stress (LPO);
Anthropometric assessments (weight gain ());
BG E; CNS (MNCV, nerve
diameter reduction)
BG, urine biochem (creatinine, UAE)
Burn wounds
References
Score
Ebrahimpoor et al.
9-Tr
(2011)
Manzari-Tavakoli et al. 2*
(2013)
Movahedian et al.
(2010)
12-Tr
Sarkhail et al., (2007)
8-Tr
Zangiabadi et al.
(2011)
Lachin and Reza

2
(2012)
Burn wounds
BG E, pancreatic
parameters E

3
CNS (wound healing)
Pirbalouti et al. (2010)
12-Tr
Anthropometric assessments E; Lipid prole (TG,

TC, LDL; HDL E); cardiovascular system (plaque
formation)
BG; lipid prole (LDL;
HDL); antioxidative Ez
(SOD, CAT; GPxE); others
(GLUT-4, INS gene expression E); strong inhibitory effects for both intestinal sucrase and maltase activities
Lipid prole (TG, TC); liver
Ez (AST, ALT, LDH); cardiovascular sys (cardiac muscle hypertrophy, lipid droplets );
BG, intestinal carbohydrate absorption; others
(-glucosidase)
Anthropometric assessments E, lipid prole (TG,
TC, LDL; HDL E), cardiovascular system (plaque
Gholamhoseinian
et al. (2012)
10.5Tr
Mohammadi et al.
(2010)
0-Tr
Shaei et al. (2011)
11-Tx
Gholamhoseinian and
Fallah (2009)
Gholamhoseinian
et al. (2012)
10.5
Rydingia persica (Burm.f.) Rat

Scheen and V.A. Albert.
Rat
Main outcomes
formation E)
Sedaghat et al. (2011)
Anthropometric assessments E (BW E); BG; lipid prole (TG, TCE; LDLC; HDL-C); oxidative
stress (LPO), antioxidant
enz (SOD)
Toserkani et al. (2012)
BG E, lipid prole (LDL-C,
TC;HDL-C, VLDL-C, TG E),
hematological results E
(RBC, HGB, HCT, MCV, MCH,
MCHC, PLT, WBC)
BG, insulin release E
Eidi et al. (2005)
STZ-induced DM
Glibenclamide

diabetic
Seeds
Seed powder
Ruta graveolens L.
Rat
STZ-induced DM
Glibenclamide
Normal, diabetic
Aerial parts
10, 20, and 30 mg extract/kg
Salvia ofcinalis L.
Rat
STZ-induced DM
Diabetic, normal
Leaves
Methanolic extract
(100, 250, 400, and
500 mg/kg) , essential
oil (0.042, 0.125, 0.2,
and 0.4 ml/kg)
Jamzad
Rat
STZ-induced DM, HCDinduced hyperlipidemia
Pregnant control
Aerial parts
Rat
STZ-induced DM,
neuropathy
Diabetic control, normal
Leaves
Rat
Normal
Control
Aerial parts
Rat
DM
Rat
Alloxan-induced diabetic nephropathy
Scrophularia deserti Delile Rat

Securigera securidaca (L.) Rat
Degen and Dor.
Alloxan-induced DM
HCD-induced
Alloxan-induced DM,
glucose-fed
hyperglycemia
STZ-induced diabetic
neuropathy
Anthropometric assessments (food intake and

water consumptionE );
teratogenicity-, BG; lipid
prole (TG, TCE); Oxidative stress(); antioxidant
defense(),
50 and 200 mg/kg per
Anthropometric assessday
ment (weight loss); BG,
serum insulin E; CNS (hyperalgesia, motor decit,
apoptosis: activated caspase 3, Bax/Bcl2),
Essential oil, 1000 ppm BG E, liver Ez (GP,
PEPKC)
50 and 100 mg essential BG, liver Ez (GP, PEPKC),
oil (SKEO)/kg per day
others (GP expression,
PEPCK expression)
250 or 500 ppm essen- Oxidative stress (LPO);
tial oil (SKEO)
Serum biochem (urea,
creatinine,); kidney (glomerulosclerosis, glomerular
number loss, glomerular
hypertrophy)
Ethanol extracts
Burn wounds
Hydroalcoholic extract
Lipid prole (TG, LDL);
antioxidative enz (LPO);
cardiovascular system (vascular function
BG
Aqueous infusion and
an ethanol maceration
extract
100 mg/kg per day
Antioxidative Ez (); oxidative stress (LPO); kidney
(MNCV ); CNS
(hyperalgesia)
50 mg/kg
Anthropometric assessments (BW); BGE, hepatic glycogen; antioxidant
defense (TTM; CYP 3A2);
antioxidative Ez (GPX);
Mice
Silybum marianum (L.)

Gaertn.
Rat
Rat
STZ-induced DM
Normal, diabetic,
Leaves
Silver sulfadiazine
Lovastatin
Normal, diabetic,
Normal, high fat
Roots
Seeds
Glibenclamide.
Normal, diabetic
Seeds

diabetic
Control; non-treated
diabetic
8-Tr
13
Abdollahi et al. (2003) 12-Tr,

Tx
10Ph, Tr
Saadat et al. (2004)
12-Tr
Shahsavari et al.
(2009)
2*
Tava et al. (2011)
16Ph, Tr

Garjani et al. (2009)
12Ph,
TR, Tx
Hosseinzadeh et al.
(2002)
9-Tr,
Tx
Baluchnejadmojarad
et al. (2010)
**
Malekinejad et al.
(2012)
**-Tx
597
Rat
Rumex patientia L.
598
Latin binomial
Teucrium polium L.
Design, disease
Positive control
Negative control
Used part of
plant
Intervention, dose
20, 40, and 80 mg silymarin/kg
nephropathy
1.2 g extract/kg per day
Rat
nephropathy
100 mg/kg per day
Rat
STZ-induced DM

diabetic
Seeds
Rat
High-fructose-induced
metabolic syndrome
and hyperinsulinemia
Normal, Fructose-fed,
Seeds
50, 100, and 200 mg

aqueous extract /kg per
day
20 mg/0.5 ml distilled
water/100 g BWper day
Rat
STZ-induced DM
Normal, diabetic
Aerial parts
Rat
STZ-induced DM
Rat
STZ-induced DM
Control, teucriumpolium- Leaves

treated control, sodium
salicylate -treated control, vehicle-treated diabetic, sodium salicylatetreated diabetic,
Normal, diabetic control
Aerial parts
Rat
STZ-induced DM
Rat
MCD-diet-induced nonalcoholic Steatohepatitis
Rat
Rat
Mice
STZ-induced T1DM
Rat
Diabetic; sham non

diabetic

diabetic
Normal diet, MCD diet
Aerial parts
Hyperlipidemia
Diabetic
Aerial parts
STZ-induced DM
Diabetic control
Aerial parts
Aerial parts
0.5 g of plant powder/

kg
100 and 200 mg/kg per

day
0.5 g plant powder/kg
Main outcomes
liver NO, liver enz (ALP,

ALT),
Fed-BG; oxidative stress
(myeloperoxidase activity,
LPO, carbonyl and thiol
content of pancreatic tissue); antioxidant defense (
FRAP); Immune system
(TNF-, IL-1);
BG E, oxidative stress
(LPO), antioxidative EZ(),
Serum biochem (urea,
creatinine E ), urine biochem (Up), kidney (glomerular ltration rateE)
BG E, oxidative stress
(LPO), antioxidative Ez(),
serum biochem (urea,
creatinine E ),Urine biochem(Up), kidney (glomerular ltration rateE)
Pancreatic parameters
BG E, serum insulin, fasting insulin/fasting glucose

; Lipid prole (TC, TG,
vLDL, LDL; HDL); liver
enz (AST, ALT E); others
(DHEAS),
Anthropometric assessments (BW); BG; NO;
oxidative stress (PCO,
LPO); antioxidant defense
(pancreatic GSH); antioxidative Ez ();
Anthropometric assessment (BW); BG; CNS
(hyperalgesia )
BG, serum insulin, insulin

release
200 and 400 mg/kg, p.o. BG, BW loss, CNS (PAL
aqueous extract
and memory)
1 g crude and the ethyl BG, serum insulin; lipid
acetate/kg per day
prole; oxidative stress
(LPO); antioxidative Ez ();
liver Ez (AST, ALT, ALP);
liver steatosis (crude extract , acetate fraction E)
50150 mg aqueous ex- Lipid prole (TC, TG)
tract /kg
50 mg aqueous extract/ BG, lipid prole (TG, TC,
References
Score
Malihi et al. (2009)
**
Vessal et al. (2010)
0*-Tx
Vessal et al. (2010)
0*-Tx
Mahmoudzadeh-Sagheb et al. (2010a,

2010b)
Shahraki et al. (2011)
2-Tr
5-Tx
Ardestani et al. (2008) 16-Tr
Baluchnejadmojarad
et al. (2005)
15
Esmaeili and Yazdanparast (2004)

Hasanein and Shahidi
(2012)
Nosrati et al. (2010)
9-Tr
11-Tr
7-Tr,
Tx
Rasekh et al. (2001)
8-Tr
Shahraki et al. (2007)
4-Tr,
Study
model
kg
Trifolium pratense L.
Rabbit
HCD-induced
Normal, high-cholesterol
diet
Trimmed tips
Normal diet supplemented with red clover
Rat
Fructose-induced insulin resistance and

STZ-induced DM type 2

fructose-fed, diabetic
50 mg/kg per day
Rat
STZ-induced type I DM
Normal, diabetic
Seeds
50-mg unusual amino

acid (2S, 3R, 4S) 4-hydroxyisoleucine (4HOIle)/kg per day
Rat
Alloxan-induced DM
Rat
Fructose-induced insulin resistance

Normal, fructose-fed,
Leaves
Rat
STZ-induced DM
Normal, diabetic
Leaves
Rat
STZ-induced DM
Normal, diabetic
Leaves
Rat
STZ-induced DM
Normal, diabetic
Leaves
Rat
STZ-induced DM
Normal, diabetic
Leaves
Rat
STZ-induced DM
Normal, diabetic
Leaves
BG, serum insulin,

HOMA-IR/FIRI; Lipid prole (TG, vLDL, HDL; LDL,
LDL/HDL); liver Ez (AST,
ALP E ); Others (leptin)
active ingredient named BG, insulin release
F(1)
BG (preventive group is
extract/kg per day
more effective than treatment group); CNS (densities of the granule cells,
brain/BW),
BG; testis parameters
extract/kg per day
(STD,S EH E),
Anthropometric assessextract/kg
ment (BW E, kidney W E );
kidney (renal
morphometry E),
100 mg hydroalcholic
BG, pancreatic parameter
extract/kg per day
Rat
STZ-induced DM
Normal, diabetic
Leaves
extract/kg
Rat
STZ-induced DM
Normal, diabetic
Leaves
Rat
HCD-induced
Lovastatin
diet
Leaves
extract/kg per day
100 or 300 mg extract/
kg
Rat
Alloxan-induced DM
Acarbose or Metformin
Normal, Diabetic
Fruits
Urtica dioica L.
Urtica dioica L.
Vaccinium arctostaphylos
L.
50, 100, or 200 mg hydroalcholic extract/kg

per day
A single dose of ethanolic extract
Asgary et al. (2007)
Haeri et al. (2009)
14Ph, Tr,
Tx
Haeri et al. (2012)
14-Tr,
Tx
3-Tr
Ahangarpour et al.
(2012)
9-Tr,
Tx
Farzami et al. (2003)
10Ph, Tr
13Ph, Tr
Fazeli et al. (2008)
Ghafari et al. (2011)
10
Golalipour et al.
(2007)
13-Tr,
Tx
Golalipour and Khori

(2007)
13Ph, Tr,
Tx
Golalipour et al. (2010) 13Ph, Tr,
Tx
Jahanshahi et al.
(2009)
Nassiri-Asl et al.
(2009)
7-Tr
Feshani et al. (2011)
13-Tr
10-Tr,
Tx
599
BG; liver (surface area of

hepatocytes in the periportal zone, perivenouszone E, nuclear area of hepatocytes ),
BG; density of astrocytes
in the dentate gyrus (),
Anthropometric assessments; lipid prole(TG,
HDL-C E, LDL-C,TC); liver
enzyme (AST, ALT), histopathologic
BG (PBG), oral glucose
Tolerance ; lipid prole
(TG, TC, VLDL, LDL, HDL
E ); antioxidative Ez (SOD,
GPX, CAT); others (GLUT4, INS gene expression);
Tx
LDL, HDL E), liver Ez (AST,

ALT, ALP E)
FBS E ; lipid prole (TG, TC,
LDL-C; HDL-C; fatty
streak formation); immune system (CRP),
BG, lipid prole (HDL-C),
liver Ez (ASTin insulin resistance, AST E in diabetic
rats, ALTin insulin resistance and fructose-fed
rats, ALT E in diabetic rats)
Anthropometric assessments (food intake, Fluid
intake); BG, serum insulin E; lipid prole (TG, TC,
LDL; HDL); serum biochem (uric acid)
BG E, Pancreatic
parameters E
600
Latin binomial
Viscum album L.
Study
model
Design, disease
STZ-induced DM
Rat
Alloxan-induced DM
hyperglycemia
STZ-induced DM
Glibenclamide
Negative control
Used part of
plant
Negative control (vehicle, ?

STZ),
Diabetic
Leaves

diabetic
Vitis sp.
Rat
Vitis sylvestris C.C.Gmel.
Rabbit
HCD-hypercholesterolemic atherosclerosis
diet
Vitis vinifera L.
Rat
STZ-induced DM,
nephropathy
Normal, diabetic
Seeds
Poly herbal compound

(Allium sativum L.; Salvia ofcinalis L.; Teucrium polium L.; Cinnamomum verum J.Presl;
Punica granatum L.; Nigella sativa L.)
Rat
STZ-induced DM
Flavonoid of Fagopyrum
esculentum Moench;
Malus sp.
Rat
Glibenclamide (just in GTT diabetic

test)
lovostatin,
lovostatin herb
diet
A. sativum
(cloves), C. zeylanicum (bark),
N. sativa
(seeds), P.
granatum
(fruits), S. ofcinalis (areal
parts), and T.
polium (areal
parts)
?
Intervention, dose
Main outcomes
strong inhibitory activity

for both sucrase and
maltase
50 mg methanolic exAnthropometric assesstract/kg and 100 mg/kg ments (BW; liver, kidney,
and heart weight E); BG,
HbA1c; Lipid prole (TG,
LDL-C, HDL-C); liver Ez
(LDH); serum biochem
(urea); others (amylase),
500 and 1000 mg water BG, serum insulin; Antiextract/kg per day
oxidant defense();
10 mg/kg per day
BG; lipid prole (HDL-c,
LDL-c, TC,TGE); oxidative
stress (LPO), antioxidativeEz(), cardiovascular system (vascular
function),
5, and 10 ml
BG; lipid prole (LDL-C,
ox-LDL, apo-B100 in
10 ml; TG, HDL-C, apoAI E); oxidative stress (LPO
in 10 ml), liver Ez (AST,
ALTE ); serum biochem
(nitrite, nitrate E); immune system (CRP E ); cardiovascular system
(brinogen)
500 mg proanthocyani- Anthropometric assessdin extract/kg GSPE
ments E (BW E, kidneyW), oxidative stress
(LPO), Antioxidative Ez (),
Urine biochem (UAE)
Polyherbal compound
Anthropometric assessments (BW E, water intake); BG, GTT E; lipid
prole (TG, TC, HDL E);
liver Ez (AST),
10 or 100 mg Rutin /kg
Anthropometric assessments (liver W); lipid

prole (TC, LDL-C, TG,
HDL-c E); liver Ez (),
References
Score
Adaramoye et al.
(2012)
11-Tr,
Tx
Shahaboddin et al.
(2011)
Roghani and Baluchnejadmojarad
(2010)
8-Tr
Setorki et al. (2010)
8-Ph,
Tx
Mansouri et al. (2011)
4-Tx
Shaee-Nick et al.,
(2012)
5-Tr,
Tx
Ziaee et al. (2009)
**-Tx
**
Increased, decreased, improved, E unchanged. Ph, Tr, and Tx in the column score indicate that phytochemical, traditional, and toxicological information is available in the reviewed articles, respectively. Please see Appendix E
abbreviation for other abbreviations.*Articles with only available abstracts. **Materials were purchased from a valid commercial source (please see Sections 2.3, 3, and 3.1 for details). Latin binomials (scientic names) are based
on theplantlist.org.
Rat
Positive control
Table C1
Information on in vitro studies extracted from Iranian research.
Design
Controls
Used part
of plant
Camellia sinensis (L.)

Kuntze
Crocus sativus L.
Biochemical test
Acrobase ( control)
Leaves
PC12 cells
Normal, high glc culture
Stigmas
High-glucose-induced cell (PC12)

damage
C187 pancreatic cells
Leaves
Olea europaea L.
Rydingia persica (Burm.

f.) Scheen and V.A.
Albert
Jamzad
Teucrium polium L.
Urtica dioica L.
Intervention, dose
Saffron extract (5 and 25 mg/ml), crocin (10

and 50muM) and GSH (10 M)
200, 400, and 600 g/ml
Aerial parts
(shoot)
PC12 cells
Control cells were grown in normal

DMEM, and the other cells (high
glucose treated) were grown in
DMEM with 100 mM glucose
Isolated rat pancreas ?
Rat pancreatic islets
Isolated pancreatic
rat islets
Biochemical test
Biochemical test
Acrobase ( control)
Acrobase ( control)
Leaves
200 and 250 g/ml
Aerial parts Aqueous extract and methanolic extract

Aerial parts TP-Teucriumpolium L. (0.01 and 0.1 mg/mL)
alone and in combination with SOV-sodium
orthovanadate (1 mM) or SM-sodium molybdate (1 mM)
Leaves
0.5 g powder/ml
Seed and
leaves
Leaves
Main outcomes
References
Score
Others (-amylase)
Nickavar and Yousean (2011)
Glc cytotoxicity, oxidative

stress()
Apoptosis (activated caspase
3, Bax/Bcl2)
Mousavi et al. (2010)
6-Tr, Tx
7-Ph, Tr,
Tx
Insulin release
Mansouri et al. (2011)
4*
Apoptosis (activated caspase

3 and Bax/Bcl-2 ratio, DNA
fragmentation)
10-Ph,
Tr
Insulin release (aqueous extractE methanolic extract)

Insulin release
Mirghazanfari et al. (2010)
13-Tr
Monfared and Pournourmohammadi (2010)
6-Tr
9-Tr
Others (-amylase)
Esmaeili and Yazdanparast

(2004)
Others (-amylase)
Insulin release
Latin binomial
Increased, decreased, improved, E unchanged. Ph, Tr, and Tx in the column score indicate that phytochemical, traditional, and toxicological information is available in the reviewed articles, respectively. Please see Appendix E
abbreviation for other abbreviations.*Articles with only available abstracts. **Materials were purchased from a valid commercial source (please see Sections 2.3, 3, and 3.1 for details). Latin binomials (scientic names) are based
on theplantlist.org.
601
602
Table D1
Information extracted from non-Iranian research on the efcacy of the best-studied herbs selected from Iranian research.
Latin binomial
Study model
Main outcomes
References
Allium sativum L.
Human
Lipid prole (TG E, TC, LDL-C, HDL-C)

FBG, lipid prole (Tc, TG, LDL-C; HDL-C)
BG, HbA1c, serum adenosine deaminase levels and C-reactive protein, lipid prole (TC,
TG, LDL-C; HDL-C) cholesterol
Systolic blood pressures on the lower side
FBG, lipid prole (TG), serum fructosamine
(wound closure, re-epithelialization, dermal matrix regeneration), angiogenesis
Loss in body weight, BG, TBARS, serum nitrite and GSH, CNS(hyperalgesia)
Water intake, BG, TG
BG, nociceptive response
(Lipid peroxides, activities of antioxidant enzymes) in liver
MRSA viability in the kidney, plasma (bronectin, CRP, brinogen, IL-6, TNF-alpha), PAI1 activityE, AT-III and protein C activities, MDA in kidney and spleen
BG, lipid prole (TG,TC)
Oxidative stress (LPO) in plasma, erythrocyte lysate, and liver tissue homogenate, lipid
peroxidation of liver cellular membranes
Immune system (numbers of monocytes and granulocytes; lymphocyte proliferation;
TNF-, IL-4, IL-8)
BG, plasma (total thiol, ceruloplasmin activities, albumin), Oxidative stress (LPO), lipid
prole (total lipid, TC, TG), uric acid,erythrocyte lysate (total thiol, GST; LPO), in liver
homogenates (LPO, GST, and SOD activities)
(glucose intolerance, weight loss, depletion of liver glycogen)
BG, blood LPO, activity of red blood cell (RBC) antioxidant enzymes, (GSH and copper,
zinc, iron, magnesium, and selenium) restored in plasma
Cardiovascular system (cardiac contractile function, cardiac pathologic hypertrophy responses, MAPK pathways, IL-6/MEK5/ERK5 signaling pathway)
(BG, blood (urea, creatinine, bilirubin), (Alt, AST, LDH, ALP, AcP in plasma, liver, and testes)
restored to normal levels
BG, lipid prole (TC,TG), lipid peroxidation in liver and pancreas, (superoxide dismutase, catalase, glutathione peroxidase) in blood, in liver and pancreas
(fractional shortening percentage, nitrotyrosine, number of TUNEL-positive cells, caspase
3 expression, PI3K-Akt signaling pathway activities) restored in heart
(FBS,insulin,insulin resistance,TNF-, total antioxidant status, whole blood GSH, erythrocyte antioxidant enzyme activities)
Basal insulin concentration, insulin resistance index , oral glucose tolerance
BGE , garlicoi (oral glucose tolerance,proteinuria )
Hyperglycemia, insulin, dyslipidemia , oxidative stress(LPO), antioxidant defense
system,
Angiotensin II AT1 receptors in adrenal and renal tissues
BG, insulin, Lipid prole (TG, TC), Urine (Ccr; albumin, NAG),(TBARSs, GSH) in
kidney homogenates
BG, lipid prole (TC, TG, LDL-C, vLDL-C; HDL-C), liver function(ALP,ALT,AST)
Leukocyte counts , Platelet counts, platelet reactivity, plasma (factors V, VII, VIII: C, IX,
and X)
Red cell phosphatase,serum (acid, ALT, AST, ALP, amylase)
BG, HbA1C, glucose tolerance test, Insulin, TG, Blood (uric acid, NO, H2S),(TBARS,
GSH) in liver
Atherosclerosis at the coronary arteriolar, thickening of coronary capillary basement
membrane ,
BG, (oxidative stress (MDA, protein carbonyls; glycation products) and antioxidant defense (GSH, GPx, CAT)) normalized
(BG,TBARS, enzymatic antioxidants) reverted to near-control levels
BG, insulin in tissues, (iron, ferritin, transferrin, bilirubin) in serum, in tissues
Ashraf et al. (2005)

Ashraf et al. (2011)
Kumar et al. (2013)
Chicken
Mice
Rabbit
Rat
Allium sativum L.
Allium sativum L.
Rat
In vitro
In vitro
BG, HbA1C, insulin, TBARS, (total protein, albumin, thyroid hormone (T3, T4), TSH,
circulatory antioxidant levels (SOD, CAT, GSH, and GPx))
(BG, glycoprotein components (hexose, hexosamine, fucose, sialic acid) in plasma, liver,
and kidneys) normalized
(albumin, urea nitrogen, and creatinine) ,((vascular endothelial growth factor (VEGF)
and extracellular signal-regulated kinase-1 (ERK-1) expression) in kidney
(BG, HbA1C, serum insulin, Lipid prole) , mRNA and protein expression of both peroxisome proliferator-activated receptor and
Maximal intracavernous pressure (ICP)/mean arterial blood pressure (MAP), (ROS,
NADPH oxidase subunits, nitric oxide (NO)/cyclic guanosine monophosphate (cGMP)
signalling pathway, and apoptosis) normalized in cavernous tissues
Advanced glycation
All compounds (catalase and glutathione peroxidase activity, alpha-tocopherol retention
in LDL and plasma) DAS and DADS greater oxidative-delaying effects, other cysteinecontaining agents were greater in delaying glycative deterioration
GLUT4 translocation to the plasma membrane
Protective against oxidation and glycation of LDL, DAS, and DADS (greater antioxidant
activities)
Cardiac contractile dysfunction
Qidwai et al. (2000)

Sobenin et al. (2008)
Ejaz et al. (2009)
Bhanot and Shri (2010)
Hattori et al., (2005)
Kumar and Reddy (1999)
Lee et al. (2009)
Tsao et al (2007)
Shiju et al. (2013)
Abdultawab and Ayuob (2013)
Abel-Salam (2012)
Anwar and Meki (2003)
Augusti and Sheela (1996)

Chandra et al. (2008)
Chang et al. (2011)
El-Demerdash et al. (2005)
Hfaiedh et al. (2011)
Huang et al. (2013)
Sivaraman et al. (2013)
Liu et al. (2005)
Liu et al., (2006)
Madkor et al. (2011)
Mansour et al. (2013)
Mariee et al. (2009)
Nasim et al. (2011)
Ohaeri and Adoga (2006)
Ohaeri (2001)
Padiya et al. (2011)
Patumraj et al. (2000)
Kanth et al. (2008)
Saravanan et al. (2013)
Saravanan and Ponmurugan
(2012)
Saravanan et al. (2010)
Sebbagh et al. (2009)
Shiju et al. (2013)
Takemura et al. (2013)
Yang et al. (2013)
Ahmad et al. (2007)

Huang et al. (2004)
Kadan et al. (2013)

Ou et al. (2003)
Ou et al. (2010)
603
Table D1 (continued )
Latin binomial
Study model
Main outcomes
References
Human
Fasting and postprandial blood sugar, lipid prole (TC,TG), frequency of anginal attacks
FBG, cholesterol E
Body weight, BFM, FBG, fasting serum insulin, HOMA-IR
UP780 (FBG, LDL-C, fructosamine); UP780 (FBG, HbA1c, insulin, fructosamine, HOMA)
BG, Lipid prole (TG, TC E)
Wound healing , a dose-response anti-inammatory activity
Immunomodulatory activity
(BG, plasma insulin), Lipid prole (TG) in liver and plasma
BG, (LPO, PC;) in cortex and hippocampus regions
BW, BG, HOMA-IR
BG, HbA1C
FBG, TG, plasma insulin
Wound healing, Immune system (expression of TGF-1 and VEGF), (inammatory cell
inltration, angiogenesis, extracellular matrix deposition, and epithelialization )
Serum (urea, creatinine), (LPO, histological and biochemical parameters ) in kidney
Liver function (ALP, ALT) antioxidant defense (LPO, NEG; GSH) in liver tissue
Wound healing
Wound healing and closure
Wound healing
(TBARS, SOD, catalase, GSH 4 times) in heart
Random and fasting glucose , visceral fat weights , serum and hepatic lipid prole (TC,
TG, nonesteried FA), Serum (MCP1, adiponectin), expression of (SREBP-1,gluconeogenic and lipogenic enzymes; glycolysis enzyme, hepatic -oxidation enzymes, PPAR)
in liver
FBG, Lipid prole (TC, LDL-C), antioxidant activity
Hypoglycemic activity on IDDM and NIDDM, hyperglycemic activity on NIDDM
BG, HbA1C, Hb, Antioxidant defense (GSH, SOD, catalase, GPx, GST) in the liver and
kidney
FBG, plasma insulin, Liver (ALT, AST), Lipid prole (T, TG, FFA, phospholipids in
plasma, liver, kidney; LDL, vLDL)
(membrane-bound phosphatases, lysosomal hydrolases) restored in the liver and kidney
GJIC,FGF-2 stimulatory effects on GJIC of diabetic and nondiabetic broblasts, Aloe vera
extract (Proliferation of diabetic broblasts , Proliferation of nondiabetic broblasts E)
Alpha-glucosidase activities
-glucosidase inhibitor
CNS (AChE activity)
BG, serum insulinE, Lipid prole (TG, TC),G6Pase activity
Glucose uptake, adipogenesis
BG, BW, lipid prole, serum biochem (creatinine, urea, protein, bilirubin total, conjugated bilirubin, SGOT, SGPT, ALP)
ALP, GGT E; AST, LDH; BUN E
BG, insulin resistance, pancreatic beta-cell mass
A single dose (BG, insulin, Lipid proleE; IR), daily dosing (BW E, BG, insulin,
HOMA-IR, Lipid prole (TG, TC, LDL-C, HDL-C), (urea, creatinineE ), atherosclerotic
and cardioprotective indices
BG, Insulin, (oxidative stress, antioxidant enzymes, and antioxidant levels ) in kidney
Lipid prole (TC, TG, LDL, VLDL, HDL)
BG
BG, lipid prole (TG, TC, LDL-C, HDL-C), LPO, antioxidant enzymes (CAT, SOD, GPx) in
the liver,
Glc uptake, phosphorylation of AMPK/ACC and MAPKs, phosphorylation of PI 3-kinase/
AktE
weight loss , BG,
BW loss, BG, insulin, CNS (hyperphagia, polydipsia)
BG, liver glycogenE, Oxidative stress (LPO), Antioxidative Ez (catalase, SOD, GPX)
Insulin secretion
Antiglycation, antioxidation potential
71.7% of CAM users were satised with the perceived effects
Insulin sensitivity, lipidproleE, cardiovascular system (24-h ambulatory BP, carotid
intima-media thicknessE ), immune system (IL-6, IGFBP-1, IGFBP-2; IL-8, TNF-, CRP E)
HbA1c, fasting plasma insulin, postprandial plasma insulin
BW loss,BG,(insulin expression, release) , pancreatic parameters , (NO synthase expression, NO production (in peripheral tissues, in local environment of the endocrine
pancreas)), immune system (T lymphocyte proliferation, IFN, IL-17, TNF-)
BG, MDA, enzymatic and nonenzymatic antioxidants
Agarwal (1985)
Mice
Rat
Rat
In vitro
Carthamus tinctorius L.
Cichorium intybus L.
Citrullus colocynthis (L.)

Schrad.
In vitro
Rat
In vitro
Rat
Rat
Rat
Crocus sativus L.
In vitro
Eucalyptus globulus
Labill.
Mice
Juglans regia L.
Olea europaea L.
Rat
In vitro
In vitro
Human
Mice
Rabbit
Rat
Punica granatum L.
Mice
Rat
Bunyapraphatsara et al. (1996)

Choi et al. (2013)
Devaraj et al. (2013)
Yongchaiyudha et al. (1996)
Davis and Maro (1989)
Im et al. (2010)
Kim et al. (2009)
Parihar et al. (2004)
Prez et al. (2007)
Tanaka et al. (2006)
Yimam et al. (2013)
Atiba et al. (2011)
Bolkent et al. (2004)
Can et al. (2004)
Chithra et al. (1998)
Hotkar et al. (2013)
Inpanya et al. (2012)
Jain et al. (2010)
(Misawa et al., 2012)
(Moniruzzaman et al., 2012)

(Okyar et al., 2001)
(Subbiah Rajasekaran et al.,
2005)
(Rajasekaran et al., 2006)
(Rajasekaran et al., 2007)
(Abdullah et al., 2003)
(Jong-Anurakkun et al., 2008)
(Takahashi and Miyazawa, 2012)
(Ahmed and Tarannum, 2009)
(Pushparaj et al., 2007)
(Muthusamy et al., 2008)
(Agarwal et al., 2012)
(Al-Ghaithi et al., 2004)
(Sharma et al., 1990)
(Aissaoui et al., 2011)
(Deepa and Anuradha, 2011)

(Dhanapakiam et al., 2007)
(Alison M Gray and Flatt, 1999)
Sreelatha and Inbavalli (2012)
Kang et al. (2012)
Gray and Flatt (1998)
Swanston-Flatt et al. (1990)
Ahlem et al. (2009)
Gray and Flatt (1998)
Ahmad et al. (2012)
Ali-Shtayeh et al. (2012)
de Bock et al. (2013)
Wainstein et al. (2012)
Cvjetianin et al. (2010)
Al-Azzawie and Alhamdani

(2006)
El-Amin et al. (2013)
Poudyal et al. (2010)
Wainstein et al. (2012)
Parmar and Kar (2007)
BW E, BG, lipid prole (TG, TC), serum creatinineE

Cardiovascular, hepatic, metabolic signs
Starch digestion and absorption
Water consumption, BG, serum insulin, oxidative stress (, LPO), others (alphaamylase)
FBG, lipid proles (TC, TG, LDL-C, HDL-C), oxidative stress (LPO), nonenzymatic and Bagri et al. (2009)
enzymatic antioxidants (GSH, SOD, CAT)
(LPO, GSH, GFAP) in hippocampal tissue, CNS (learning and memory performances ) Shiju et al. (2013)
Collagen deposit in the heart, mRNA expression of cardiac bronectin and collagen I and Huang et al. (2005b)
604
Latin binomial
Punica granatum L.
Silybum marianum (L.)

Gaertn.
Teucrium polium L.
Study model
Rat
In vitro
Rat/mice/in
vitro
Human
Rat
Rabbit
Rat
In vitro
Rat
Rat
In vitro
In vitro
Human
Mice
Rabbit
Rat
Rat
In vitro
Urtica dioica L.
Human
Mice
Rat
In vitro
Main outcomes
III, ET-1, ETA, inhibitor-kappaBbeta and c-jun,
BG, cardiac PPAR-gamma mRNA expression, GLUT-4
BG
Oxidative stress (TBARS) in kidney and pancreas, (SOD, CAT, GR), cardiovascular system
(mean arterial BP, vascular reactivity changes), tubular degenerative changes
BG, Insulin, oxidative stress (LPO)
(broblast inltration, collagen regeneration, vascularization, epithelialization), (hydroxyproline, production of NO, NOS activity, expressions of TGF-1, VEGF, EGF)
BG, pancreatic parameters
(Aldose reductase, -amylase, and PTP1B inhibition)
BG in rat, BG in mice (after sucrose loading, after glucose loading E), In vitro (glucosidase)
hIAPPbrillization
BG, plasma insulinE
No signicant effects
Acute antihyperglycemic activities in starch-treated rats
-amylase and -amyloglucosidaseE
BG (i.g. better than ip) lipid proleE
BG(i.g. E ip), Lipid proleE
Iron-induced lipid peroxidation
BGE , 2h BGE,insulinresistance,lipid (TG,HDL-C)
TCM symptoms, BMI E, FBG, 2-h PBG, HbA1c, CSQS, hepatic and renal functions E
BG, glucose tolerance test, 24-h urinary glucose excretion, lipid prole (TG, TC, LDL-C,
vLDL-C,HDL-C E)
BW E, food intake E, BG, insulin and insulin resistance, lipid prole (TG, TC, HDL-c)
BG, insulin, Lipid prole(TC, TG, LDL-C, HDL-C)
Adipose tissues (adipocyte size, inammation, expression of inammatory genes)
2.0F group (Hepatic and plasma TG, expression of lipogenic genes)
Sub-diabetic(BG,glucose tolerance ), moderately diabetic (BG, glucose tolerance ,
HbA1C, insulin), lipid prole (TC, HDLC, TAG, PLs, FFAs)
Liver and muscle glycogen, lipid prole (TC, TG, LDL-C, VLDL-C, HDL-C), liver and heart
total lipids, (HK, GK, PK, ME, G6PD;G6Pase, SDH, AR), (SOD, GPx)
FBG, HbA1C, serum insulin
LPO (TBAR), GSH
(FBG, HbA1C, (lipid prole (TG, TC, lipoproteins ), liver (hexokinase, G-6-PD, glucose-6phosphatase) composite better than individual extract
Activities of creatine kinasein heart, skeletal muscle and liver
(activities of G6Pase and FBP) in liver and kidney
Glucose tolerance,BG; Serum insulin,insulin secretionE , liver glycogen, total antioxidant ,Glucose transport in 3T3-L1 adipocytes and insulin action
BG, (pyruvate kinase, LDH, antioxidant enzymes, protein kinase C)
BG, membrane-linked enzymes (Na K ATPase, Ca2 ATPase), antioxidant enzymes
(SOD, GST), Ca2 , oxidative stress (LPO))
BG, (MAO, membrane uidity, neurolipofuscin content, GLUT4 in brain)
(glucose-metabolizing enzymes (hexokinase, AR, SDH, G6PD); antioxidant enzymes (GPx,
GR) related metabolites (sorbitol, fructose, glucose, TBARS, GSH)) in the lenses
BG,polyol pathway enzymes and sugar accumulations in sciatic nerve
BG, HbA1C, (HKAR, SDH, G6PD, GPx, GR) in lenses
BG, (glycolytic enzymes, gluconeogenicenzymes, lipogenic enzymes) in both the liver
and kidney
FBS,LPO, antioxidant activities
References
Huang et al. (2005a)

Jafri et al. (2000)
Mohan et al. (2010)
Parmar and Kar (2008)
Yan et al. (2012)
Jain et al. (2012)
Li et al. (2005)
Cheng et al. (2012)
Maghrani et al. (2004)
A et al. (2005)
Kasabri et al. (2011)
Stefkov et al. (2011)
Ljubuncic et al. (2005)

Gupta et al. (2001)
Lu et al. (2008)
Sher et al. (2011)
Hamza et al. (2012)
Singh et al. (2010)
Uemura et al. (2010)
Uemura et al. (2011)
Moorthy et al. (2010)
Puri et al. (2011)
Puri et al. (2012)
Annida and Prince (2005)
Bera et al. (2013)
Genet et al. (1999)
Gupta et al. (1999)
Hannan et al. (2007)
Kumar et al. (2012b)
Preet et al. (2005a)
Kumar et al. (2012a)
Preet et al. (2005b)
Preet et al. (2005a)
Preet et al. (2006)
Raju et al. (2001)
Saravanan and Ponmurugan

(2010)
(Na/K ATPase activity,membraneLPO,membrane uidity) in liver, kidney and heart, Siddiqui et al. (2006)
expression of GLUT4 in heart
(rate-limiting enzymes of TCA, hydrogen shuttle system, ketone body metabolism, amino Thakran and Baquer (2003)
acid metabolism and urea cycle)) in liver, kidney and brain
(glutamate dehydrogenase, D-beta-hydroxybutyrate dehydrogenase) in liver and kidThakran et al. (2004)
ney; degenerative and early nephropathic changes
(FBG, LPO, Antioxidant activities ) in heart, kidney, and liver tissues
Tripathi and Chandra (2010)
BW , BG, cataract development
Vats et al. (2004)
BW, kidney/BW ratio, BG, HbA1c, lipid prole (TC, TG, HDL-C), hemorheological
Xue et al. (2007)
properties
((G6PD,ME,ICDH); lipogenic enzymes (ATP-CL, FAS)) in liver and kidney
Yadav et al. (2004)
(intestinal sodium-dependent glucose uptake) All fractions except A; HGPa activity in rat Al-Habori et al., (2001)
hepatocyte suspensions E; (glucagon-antagonist effect) fractions C and E
Kadan et al. (2013)
Side effect-, BG, glucose tolerance test , HbA1C (in six patients )
Said et al. (2008)
BW, BG, insulin, CNS (polydypsia, cognition, insensate neuropathy )
Patel and Udayabanu (2013)
BG, oral glucose tolerance tests (i.p. administration of WE)
Bnouham et al. (2010)
Not mentioned in abs
Ozkol et al. (2013)
Toxic effects in cultured human broblasts-, BG, glucose tolerance test
Sankar et al. (2012)
Kadan et al. (2013)
Peroxisome proliferator-activated receptors (PPARs) signaling activation
Rau et al. (2006)
605
Latin binomial
Study model
Main outcomes
References
Viscum album L.
Rat
BG, FBS, HbA1C, Lipid prole(TG, LDL-c, HDL-c), Serum biochem (urea, LDH, amylase)
BGE , insulin concentrationsE , CNS (hyperphagia, polydipsia)
Insulin secretion
Adaramoye et al. (2012)
In vitro
Swanston-Flatt et al. (1989)

Gray and Flatt (1999a, 1999b)
Increased, decreased, improved, E unchanged. Ph, Tr, and Tx in the column score indicate that phytochemical, traditional, and toxicological information is available in
the reviewed articles, respectively. Please see Appendix E abbreviation for other abbreviations. We did not nd any report on the efcacy of Rydingia persica (Burm.f.)
Scheen and V.A. Albert, Phlomis anisodonta Boiss. and Satureja khuzistanica Jamzad on the management of diabetes in non-Iranian studies (please see Sections 2.7 and 3.6 for
more information on the selection of the best-studied herbs). Latin binomials (scientic names) are based on theplantlist.org.
Table E1
Abbreviations.
(T3, T4), thyroid hormone
GP, glycogen phosphorylase
PGF, Punica granatum ower
4HO-Ile, 4-hydroxyisoleucine
ACC, acetyl-CoA carboxylase
ACE, angiotensin converting enzyme
AChE, acetylcholinesterase
AIP, atherogenic index of plasma (log TG/HDL)
GPx, glutathione peroxidase

GR, glutathione reductase
GSH, reduced glutathione
GSTs, glutathione S-transferases
GTT, glucose tolerance test
ALP, alkaline phosphatase
GV/MS, Gas chromatography/mass spectrometry
AMPK, AMP-activated protein kinase

AOPP, advanced oxidation protein products
AR, aldose reductase
ATP-CL, ATP-citrate lyase
CAT, catalase
Ccr, creatinine clearance
CME, Cichorium intybus methanolic extract
HFD, high-fat diet

hIAPP, human islet amyloid polypeptide
HK, hexokinase
HOMA-IR/FIRI, homeostasis model assessment of insulin resistance
index /last fasting insulin resistance index
HPLC, high-performance liquid chromatography
hs-CRP, high sensitive C-reactive protein
i.g., Intragastric
ICP/MAP, maximal intracavernous pressure/mean arterial blood
pressure
IFN, interferon gamma
IL-6&8&18, interleukins 6&8&18
INS, insulin gene
PI 3-kinase, phosphatidylinositol 3-kinase

PK, pyruvate kinase
PON1, Paraoxonase-1
PP, pulse pressure
PPAR, peroxisome proliferator-activated receptor and
PPARs, peroxisome proliferator-activated
receptors
SBP, systolic blood pressure
SDH, sorbitol dehydrogenase
SEh, seminiferous Epithelial Height
SGOT, glutamate oxaloacetate transaminase
CRP, C-reactive protein

CSQS, clinical symptomatic quantitative scores
Cy, cycloartanol
CYP 3A2, cytochrome P450 3A2
DBP, diastolic BP
DHEAS, Dehydroepiandrosterone
ERK-1, extracellular signal-regulated kinase-1
Ez, enzyme
FA, fatty acid
FAS, fatty acid synthase
FBG, fasting blood glucose
FBP, fructose-1,6-bisphosphatase
FBS, fast blood serum
FCR, FolinCiocalteu's reagent
FIRI, fasting insulin resistance index
FRAP, ferric reducing antioxidant power
G6Pase, glucose 6 phosphatase
G6PD, glucose-6-phosphate dehydrogenase
GFAP, glial-brilar acidic protein
GJIC, gap junctional intercellular communication
GK, glucokinase
GLUT-4, glucose transporter type-4 gene
IP, intraperitoneal
IPGTT, intraperitoneal glucose tolerance test
LDH, lactate dehydrogenase
Lo, lophenol
LPO, lipid peroxidation
MAO, monoamine oxidase
MAPKs, mitogen-activated protein kinases
MCP-1, monocyte chemotactic protein-1
MDA, malondialdehyde
ME, malic enzyme
MIF, macrophage migration inhibitory
MNCV, motor nerve conduction velocity
NAG, N-acetyl-beta-D-glucosaminidase
NO, nitric oxide
NPH, protamine Hagedorn
OGTT, oral glucose tolerance test
OSI, oxidative stress index
PAL, passive avoidance learning
PAP, phosphatidate phosphohydrolase
PBG, postprandial blood glucose
PCO, protein carbonyl content
PEPCK, phosphoenolpyruvate carboxykinase
BMI, body mass index

BP, blood pressure
BUN, Blood urea nitrogen
BW, body weight
especially in Sistaan and Baluchestan and Kerman, as it is strongly

believed to have hypoglycemic effects (Ebrahimpoor et al., 2011).
Geraniol, eugenol, cetyl alcohol, hentriacontane, caffeic acid,
p-hydroxybenzoic acid, -sitosterol, -sitosteryl acetate, -amyrin,
campesterol, and stigmasterol have been isolated from the herb
(Ayatollahi et al., 2007). Its ethanolic extract has been reported to
have anti-glycation property, which belongs to the known compound 3,7-dihydroxy-4,6,8-trimethoxy-avone (Ayatollahi et al.,
2010). Morin and quercetin are two other compounds with antioxidant activities (reviewed by (Bezenjani et al., 2012)). Four
SGPT, serum glutamat pyruvic transaminase

SOD, superoxide-dismutase
SOV, sodium orthovanadate
STD, seminiferous tubular diameter
SU, sulfonyl ureas
TAP, total antioxidant power
TBARSs, thiobarbituric acid-reacting
substances
TC, total cholesterol
TCA, tricarboxylic acid cycle
TCM, traditional Chinese medicine
TFGs, total saponins
TG, triglyceride
TGF-, transforming growth factor-
TLC, thin-layer chromatography
TNF-, tumor necrosis factor-
TOS, total oxidant status
TSP, Trigonella foenum-graecum seed powder
TTM, total thiol molecules
UAE, albumin excretion
VEGF, vascular endothelial growth factor
WC, waist circumference
ZDF, Zucker diabetic fatty
BSP, broccoli sprouts powder
known diterpenoids of to the clerodane and tetracyclic diterpene

types were also isolated from the herb (Ayatollahi et al., 2009).
R. persica has benecial effects on the levels of BG and insulin,
oxidative stress, and antioxidative defenses in animals. It has only
been studied in Iran. However, it may be worth evaluating its efcacy on other parameters such as the signs of DM; the level of
HbA1C; insulin secretion; insulin resistance; peripheral glucose
uptake; oxidative stress; antioxidant defense; cell apoptosis;
606
hepatic glycogenolysis; retinopathy; nephropathy; neuropathy;

and the functions of the pancreas, liver, and cardiovascular and
immune systems (Table 5). None of the reviewed Iranian articles
contained a phytochemical analysis of this herb.
S. Jamzad is an endemic plant to Iran and it is used as an analgesic, hypoglycemic, and antiseptic agent in folk medicine. Because it has antioxidant properties, it appears to be useful for
treating diseases related to oxidative stress such as diabetes and
hyperlipidemia (reviewed by (Kaeidi et al., 2013)). Recently, its
antiviral, antibacterial, antifungal, and antiprotozoal effects were
investigated from various species of Satureja (reviewed by (Zibaei
et al., 2012)). Carvacrol was the major constituent in the essential
oil of S. khuzistanica. The other important constituents are myrcene, para-cymene, -terpinene, linalool, 4-terpineol, eugenol, and
caryophyllene oxide (Abdollahi et al., 2003; Tava et al., 2011).
Studied only in Iran in both human and animal models, S.
khuzistanica was found to have some therapeutic effects. It showed
hypoglycemic effects, although hyperlipidemic patients with
T2DM and normal rats did not show any change in BG level when
treated with 250 mg of leaves (Vosough-Ghanbari et al., 2010) and
1000 ppm of essential oil (Saadat et al., 2004), respectively.
However, at a dosage of 50 and 200 mg/kg per day, the leaves
decreased the level of BG in STZ-induced DM and neuropathy in
rat (Kaeidi et al., 2013). It is worth investigating the effects on the
signs of DM; the level of HbA1C; insulin secretion; insulin resistance; peripheral glucose uptake; oxidative stress; antioxidant
defense; cell apoptosis; hepatic glycogenolysis; retinopathy; nephropathy; neuropathy; and the functions of the pancreas, liver,
and cardiovascular and immune systems, which have not been
studied earlier (Table 5). Phytochemical analysis of the ethanol
extract of its leaves showed the presence of carvacrol (78.3%),
9-octadecenoic acid (13.5%), hexadecanoic acid (6.7%), bis(2ethylhexyl)phthalate (1.0%), and beta-bisabolene (0.5%) (Kaeidi
et al., 2013) (Table 4).
S. marianum (L.) Gaertn. Silymarin (SMN), a avonoid complex
and the main active constituent in the seeds of S. marianumis, is a
lipophilic extract comprising three isomeric avonolignans (silybin, silydianin, and silychristin). Of these, silybin has the highest
level of activity, constituting up to 5060% of the SMN extract. This
herbal drug is currently produced by several pharmaceutical
companies and is available in most countries around the world.
SMN exerts potent antioxidant, anticancer, anti-inammatory, and
antibrotic effects (reviewed by (Fallahzadeh et al., 2012; Javed
et al., 2011; Malekinejad et al., 2012)). Traditionally, SMN has been
used as a natural remedy for digestive problems and in particular
for diseases of the liver and the biliary tract, and for menstrual
disorders and varicose veins (reviewed by (Malekinejad et al.,
2012)). SMN reduces the urinary excretion of albumin, tumor necrosis factor , and malondialdehyde in patients with diabetic
nephropathy, and it may be considered as a novel addition to the
antidiabetic nephropathy armamentarium (Fallahzadeh et al.,
2012).
S. marianum and its constituent SMN have been studied in both
human and animal models. Although its hypoglycemic effects have
been reported in some studies (Huseini et al., 2006; Maghrani
et al., 2004; Malihi et al., 2009; Ramezani et al., 2008), no change
was observed in the level of BG in other studies (Fallahzadeh et al.,
2012; Vessal et al., 2010), which may be related to differing experiment designs. Besides, the signs of DM; the level of HbA1C;
insulin secretion; insulin resistance; peripheral glucose uptake;
oxidative stress; antioxidant defense; cell apoptosis; hepatic glycogenolysis; retinopathy; nephropathy; neuropathy; and the
functions of the pancreas, liver, and cardiovascular and immune
systems need further study (Table 5). None of the Iranian articles
contained a phytochemical analysis on this herb.
T. polium L. is one of the most popular herbal medicines in the
world, and it has been used for 42000 years in traditional medicine due to its exceptional pharmacological properties. T. polium is
mainly used in folk medicine to improve mental performance
(reviewed by (Hasanein and Shahidi, 2012)). It is a medicinal herb
with antinociceptive, antioxidant, hypolipidemic, anti-inammatory, antirheumatoid, antipyretic, anti-gastric ulcer, hypolipidemic, hepatoprotective, and hypoglycemic properties (reviewed by (Baluchnejadmojarad et al., 2005; Mirghazanfari et al.,
2010)). It has been used in Iranian folk medicine to treat DM for
several centuries (Mirghazanfari et al., 2010). Phenolic compounds
such as caffeic acid, ferulic acid, and quercetin have been isolated
from the herb, an aromatic plant (Proestos et al., 2006). Phytochemical analysis of the extract of the aerial parts showed the
presence of some avonoids and avons such as 4,5-dihydroxy6,7-dimethoxyavone (cirsimaritin), 3,5-dihydroxy-4,6,7-trimethoxyavone (eupatorin), 5-hydroxy-4,7-dimethoxyavone
(apigenin-4,7-dimethylether),
and
4,5,3-trihydroxy-6,7-dimethoxyavone (cirsiliol) (reviewed by (Mirghazanfari et al.,
2010)). Bahramikia and Yazdanparast reviewed the phytochemical
and medicinal properties of T. polium (Bahramikia and Yazdanparast, 2012). Although the aqueous extract of the herb shows
strong hypoglycemic effects in experimental animals (Esmaeili and
Yazdanparast, 2004; Shahraki et al., 2007), it is not suitable for use
in humans as it is hepatotoxic (Shahraki et al., 2007); in addition,
its toxic effects on renal tubular cells need to be reevaluated (Raeian-Kopaei and Nasri, 2013).
T. polium showed benecial effects such as lowering the BG
level in both animal and in vitro systems. However, the signs of
DM; the level of HbA1C; insulin secretion; insulin resistance;
neuropathy; and the functions of the pancreas, liver, and cardiovascular and immune systems need to be investigated in depth
(Table 5). No phytochemical information on this herb was found in
any of the reviewed Iranian articles.
T. foenum-graecum L. The seed of this herb is widely used as a
herbal medicine for its hypoglycemic effects (reviewed by (Feyzi
et al., 2014; Srinivasan, 2014)). Analysis of the active and soluble
components of the seed revealed an unusual amino acid, 4-hydroxyisoleucine (4HO-Ile), which had hypoglycemic potential because it could stimulate insulin secretion from rat pancreatic islet
cells. 4HO-Ile comprises 80% of the free amino acid content, and
0.6% (w/w) of defatted seeds. To date, 4HO-Ile has only been reported in fenugreek seed (reviewed by (Feyzi et al., 2014; Haeri
et al., 2012)). In clinical studies, the hypoglycemic action of the
herb has been attributed to its content of galactomannan (reviewed by (Robert et al., 2014)). In addition, the seeds are a great
source of plant proteins, of which the main protein fractions include albumins, globulins, glutelins, and prolamines, respectively
(reviewed by (Feyzi et al., 2014)).
T. foenum-graecum is a herb noted for its hypoglycemic effects,
studied from several aspects, especially outside of Iran. Although it
did not change the BG or insulin levels in some studies (Hannan
et al., 2007; Jelodar et al., 2005) (Table 5), it is a promising herbal
remedy for the management of DM. Phytochemical analysis of the
hydroalcoholic extract of the seeds revealed the presence of alkaloids, steroids, avonoids, tannins, and saponins, and the absence of anthraquinones. However, avonoids, saponins, and
steroids were found, but alkaloids, anthraquinones, and tannins
were absent in the butanolic extract (Haeri et al., 2009). (Table 4).
U. dioica L. is the only species of Urtica to be cultivated commercially for pharmaceutical purposes (reviewed by (Farag et al.,
2013)), with benecial effects in the treatment of diabetes, prostatic hyperplasia, inammation, rheumatoid arthritis, hypertension, allergic rhinitis, kidney stones, burns, anemia, rashes, and
internal bleeding (reviewed by (Dar et al., 2013; Farag et al., 2013;
Farzami et al., 2003)). The bioactive compounds isolated from the

leaves include hydroxycinnamic acid derivatives, avonoids, fatty
acid esters, and terpenes (Dar et al., 2013). Phenylpropanoids;
caffeic acid analogs; pentacyclic triterpenoids and oxygenated
fatty acids; and lignans such as neoolivil, secoisolariciresinol, isolariciresinol, and pinoresinol are also isolated from this herb (reviewed by (Farag et al., 2013)).
U. dioica L. has been studied in both human and animal systems, it has been shown to have hypoglycemic effects. However,
the same herb decreased the serum insulin level in fructose-induced insulin resistance in rat (Ahangarpour et al., 2012) while
also increasing the parameter in rat (Farzami et al., 2003) and mice
(Patel and Udayabanu, 2013), possibly due to differing experiment
designs. The signs of DM; the level of HbA1C; insulin secretion;
antioxidant defense; cell apoptosis; hepatic glycogenolysis; retinopathy; nephropathy; neuropathy; and the functions of the
pancreas, liver, and cardiovascular and immune systems have not
yet been studied in depth (Table 5). Six distinct fractions
(RfF1 0.96, RfF2 0.93, RfF3 0.88, RfF4 0.70, RfF5 0.60, and
RfF6 0.45) were identied from the aqueous extract of the leaves.
The weights of the fractions eluted from 10 g of dried leaves were
as follows: F1 14.75, F2 13.61, F3 7.95, F4 7.9, and
F6 8.48 mg (Farzami et al., 2003). A high percentage of tannins
and steroids and low levels of avonoids, carotenoids, and saponins was reported for the hydroalcoholic extract of the leaves
(Fazeli et al., 2008; Golalipour and Khori, 2007; Golalipour et al.,
2010) (Table 4).
V. album L. has been reported to have several therapeutic applications in folk medicine, for instance, in curing or managing a
wide range of diseases such as diabetes, chronic cramps, stroke,
stomach problems, heart palpitations, high blood pressure, difculties in breathing, and hot ashes during menopause. Various
glycosides, alkaloids, viscotoxins, phenylpropanoids, tannins, lignins, and sugars have been isolated from the plant. The leaves of
the herb have been reported to contain -amyrin, tyramin, quercetin, syringin, and avoyedorinin A and B (reviewed by (Shahaboddin et al., 2011)). Further biologically active substances include
mistletoe lectins, amino acids, avonoids, triterpenes, phytosterol,
polyalcohols, and polysaccharides. Mistletoe lectins (ML I, II, and
III) have been investigated most thoroughly (reviewed by (Kienle
et al., 2009; Melzer et al., 2009)).
V. album lowers the levels of BG and HbA1C in animals, although it has been reported to make no change in the BG level
(Swanston-Flatt et al., 1989). However, its effects on parameters
such as the signs of DM; the level of HbA1C; insulin secretion;
antioxidant defense; cell apoptosis; hepatic glycogenolysis; retinopathy; nephropathy; neuropathy; and the functions of pancreas, liver, cardiovascular and immune systems need to be evaluated (Table 5). None of the Iranian articles contained a phytochemical analysis of this herb.
4.6. Proposing a framework for future studies
4.6.1. General considerations for herbal research
Regardless of the eld, the following aspects should be considered in studies on herbal medicines: (1) quality and safety of
herbal medicines and product standardization; (2) side effects,
toxicity, and herbdrug interactions; (3) design of clinical trials
and animal studies; and (4) the pharmacological mechanisms of
the herbs.
Before these can be considered, to avoid ambiguities and errors,
botanical scientic nomenclature must be precisely and appropriately used in ethnopharmacological and other studies on plants
(Rivera et al., 2014). Because these considerations are important,
607
we suggest that journals establish a new guide that includes these

criteria in their instructions for authors.
4.6.2. Specic issues for studies on diabetes mellitus
According to the guidelines of the American Academy of Pediatrics, the BG, HbA1C, and insulin levels are a priority, specically in the case of diabetes. Next, mandatory factors to be measured in both short- and long-term studies include associated
comorbidities such as hypertension and dyslipidemia, oxidative
stress and antioxidant defense, and the signs of DM. The ultimate
goal of treatment should be to decrease the risk of acute and
chronic DM-related complications (Reinehr, 2013). However, a
program of patient-specic education, prevention, and care should
be designed (Z. Wang et al., 2013). Furthermore, rational and scientic cultural and traditional teachings should be considered
more often. It is imperative that the term antidiabetic be avoided, as drugs used to treat diabetes fall under the category of
hypoglycemic agents (WHOCC, 2015).
4.7. Limitation of our study
We did not have access to the full text of 16 reviewed Iranian
articles; thus, some data were extracted in detail from abstracts
(see Section 3). We considered data obtained from all articles
equivalently, including those scoring low, because of the following
reasons: (i) some studies are likely to contain useful information
and (ii) only very few high-quality papers have been published on
many herbs (Chan et al., 2012). We also considered the outcomes
of the reviewed clinical trials without evaluating their quality and
standards (Grant et al., 2009; Iyalomhe and Imomoh, 2006;
Z. Wang et al., 2013). The study results outside of Iran were also
not evaluated according to the scoring system (Chan et al., 2012).
The team for the current review did not have a physician or an
expert on diabetes. However, a physician was consulted, where
necessary. Furthermore, the results of the present review include
herbal-related studies up to the end of 2012. Nevertheless, we
believe that the overall results did not change, because we wanted
to gauge the strengths and weaknesses of the herbal studies performed on the management of diabetes mellitus.
5. Conclusions
Medicinal herbs are extensively used to treat diseases in every
culture and civilization (EFSA Scientic Committee, 2009). However, the medicinal use of herbs has its pros and cons. Treatment of
diabetes as a multifactorial disease using herbal medicines requires a comprehensive approach. Despite the lack of an acceptable consistency among the results of the existing data regarding
the use of herbal medicines in the management of DM and the
shortcomings of the reviewed studies in the present article, considering the prevalence of DM and difculty in accessing the
treatment and medication, herbs with hypoglycemic activities are
a valuable eld of research. Although making some simple lifestyle
changes can be daunting, physical activity and diet, especially
fruits and vegetables, must be reconsidered. Of the 82 herbs studied in Iran up to 2012 in the context of DM, only 19 herbs were
best studied and six herbs were endemic. Most medicinal herbs
reviewed in this study especially the selected herbs, for example,
A. sativum L., C. sativum L., C. sativus L., J. regia L., O. europaea L., P.
granatum L., T. foenum-graecum L., and U. dioica L. are consumed
in different cultures as fruits, vegetables, and spices. Although all
of the reviewed herbs can be studied further, more research on
endemic plants and the traditional history of herbal medicine is
warranted. Researchers should prioritize ethnopharmacological
studies of herbs traditionally used in their area and country,
608
because the medical staff should be familiar with such endemic,

traditional herbs. From six of endemic herbs, only three were well
studied, including R. persica (Burm.f.) Scheen and V.A. Albert (syn:
Otostegia persica (Burm.f.) Boiss.), P. anisodonta Boiss., and S. khuzistanica Jamzad, which also showed benecial therapeutic effects.
Furthermore, due to the widespread achievements made in scientic journals and websites, apart from existing policies, journals
will have to establish a new guide including criteria such as botanical scientic nomenclature, the quality and safety of herbs,
side effects, toxicity, and pharmacological mechanism to improve
the quality and validity of the nal publications. As discussed in
this paper, reducing the blood glucose or HbA1C levels is not enough for concluding that DM is controlled. It seems essential that
researchers who are interested in the eld of medical utility of
herbs consider the various aspects of a disease before designing
and implementation of a study. Based on the reviewed Iranian and
non-Iranian studies on the use of herbal medicine, in order to
determine the hypoglycemic activity of the studied herbs and
discover the right herbal medicine for the management of DM,
many other important factors than the levels of BG, HbA1C and
insulin remained to be evaluated. Furthermore, there is a paucity
of such studies on herbal medicine in humans and animal models.
Moreover, designing a specialized database that covers all valid
accessible information such as toxicological and phytochemical
data of herbs and related components or diseases is necessary,
decreasing unwanted and unnecessary costs and increasing research efciency in any area of herbal studies. Such a database
could be linked to a virtual herbarium with comprehensive taxonomic information on the medicinal taxa. The authors are currently dening the database schema, which will be printed in the
near future.
Acknowledgment
I express my gratitude to everyone who supported me
throughout the course of this project. I am grateful to Dr. Mahdi
Khorshidi and Dr. Reza Naderi for their professional assistance. I
am thankful to Reza Farhang and Maryam Khatami for their
friendly advices at certain stages of the project work. I am sincerely grateful to A.R. Eshlaghe for his truthful and illuminating
views on a number of issues related to the project. I am also very
thankful to Professor Michael Heinrich and the great reviewers as
well as the English editor for their invaluable role in the improvement of this work.
See Appendix tables Table A1 Table B1 Table C1 Table D1
Table E1.
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Journal of Ethnopharmacology 175 (2015) 567616

Contents lists available at ScienceDirect

Diabetes mellitus and its management with medicinal plants:

School of Biology, Damghan University, Damghan, Iran

Corresponding author at: School of Biology, Damghan University, Damghan, Iran.

A. Rezaei et al. / Journal of Ethnopharmacology 175 (2015) 567616

Kroll, 1998), probably because various chemical and biochemical

A. Rezaei et al. / Journal of Ethnopharmacology 175 (2015) 567616

2. Approach and methods

Scientic name (Latin binomial)

Study model (number of

Amaranthus caudatus L (A. caudatus)

Allium ampeloprasum L. (syn: A. porrum L.)

shallot (Allium ascalonicum)

Allium cepa (onion)/Allium cepa/quercetin

Allium elburzense Wendelboe

Allium elburzense Wendelbo

garlic (Allium sativum)/garlic

Allium stipitatum Regel (syn: A. hirtifolium Boiss.)

Rhus coriaria L. (sumac)/Rhus coriaria

Anethum graveolens/Anethum graveolens (dill)

Allium hirtifolium (Persian shallot)

Heracleum persicum Desf. ex Fisch., C.A.Mey. &Av-Lall.

Coriander (Coriandrum sativum L.)

Kelussia odoratissima Mozaff.

Amirkabiria odoratissima (umbelliferae)

Peucedanum pastinacifolium Boiss. & Hohen.

date fruit (Phoenix dactylifera L. Arecaceae)

Asteraceae (Compositae) Boumadaran

Artemisia aucheri Boiss.

Carthamus tinctorius L.s

Carthamus tinctorius L. (Compositae)

Cichorium intybus L.s

Chicory, Cichorium intybus L

Silybum marianum (L.) Gaertn.

Arnebia euchroma (Royle) I.M.Johnst.

Nasturtium ofcinale R. Br.

Nasturtium ofcinale R. Br.

Acanthophyllum squarrosum Boiss.

Hendevaneh aboujahl Citrullus colocynthis (L.) Schrad.

Silybum marrianum (silymarin)/silymarin/milk thistle

Citrullus colocynthis (Schrad)/Citrullus colocynthis

(0); animal (1); in vitro

A. Rezaei et al. / Journal of Ethnopharmacology 175 (2015) 567616

Equisetum arvense L. (Equisetaceae)

Cyamopsis tetragonoloba (L.) Taub.

Glycine max (L.) Merr.

Alfalfa (Medicago sativa)

Melilotus ofcinalis (L.) Pall.

Melilotus ofcinalis/semelil (angipars )

Securigera securidaca (L.) Degen and Dor.

Securigera securidaca/Securigera securidaca (L.) (Degen and

red clover (Trifolium pratense) legume family

Quercus infectoria G. Olivier

Crocus sativus L.s

Crocus sativus L. (saffron)/crocin

Phlomis anisodonta Boiss.e.s

Trigonella foenum-graecum (fenugreek)/fenugreek

Persian walnut (Juglans regia L.)/Walnut (Juglans regia L.)/Juglans regia L.

Satureja khuzistanica Jamzad

Teucrium polium L.s

pomegranate/pomegranate seed (Punica granatum L.)/Punica