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Author's Accepted Manuscript
Management of diabetic complications: AChemical constituents based approach
Randhir Singh, Navpreet Kaur, Lalit Kishore,Girish Kumar Gupta
PII: S0378-8741(13)00605-3DOI: http://dx.doi.org/10.1016/j.jep.2013.08.051Reference: JEP8308
To appear in: Journal of Ethnopharmacology
Received date: 12 March 2013Revised date: 27 August 2013Accepted date: 28 August 2013
Cite this article as: Randhir Singh, Navpreet Kaur, Lalit Kishore, Girish KumarGupta, Management of diabetic complications: A Chemical constituents basedapproach, Journal of Ethnopharmacology, http://dx.doi.org/10.1016/j.jep.2013.08.051
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Management of diabetic complications: A Chemical constituents based approach
Randhir Singh, Navpreet Kaur*, Lalit Kishore, Girish Kumar Gupta
Maharishi Markandeshwar College of Pharmacy, Maharishi Markandeshwar University,
Mullana-Ambala, Haryana 133207, India
*Corressponding Author:
Navpreet Kaur
+91-8295954281
[email protected]
ABSTRACT
Ethnopharmacological relevance: Long term hyperglycemia leads to development of
complications associated with diabetes. Diabetic complications are now a global health problem
without effective therapeutic approach. Hyperglycemia and oxidative stress are important
components for the development of diabetic complications. Over the past few decades, herbal
medicines have attracted much attention as potential therapeutic agents in the prevention and
treatment of diabetic complications due to their multiple targets and less toxic side effects.
Aim of study: To review current available knowledge of medicinal herbs for attenuation or
management of diabetic complications and their underlying mechanisms.
Material and methods: Bibliographic investigation was carried out by scrutinizing classical text
books and peer reviewed papers, consulting worldwide accepted scientific databases (SCOPUS,
PUBMED, SCIELO, NISCAIR, Google Scholar) to retrieve available published literature. The
inclusion criteria for the selection of plants based upon all medicinal herbs and their active
compounds with attributed potentials in relieving diabetic complications. Moreover, plants which
have potential effect in ameliorating oxidative stress in diabetic animals have been included.
Results: Overall, 238 articles were reviewed for plant literature and out of the reviewed
literature, 127 articles of were selected for the study. Various medicinal plants/plant extracts
containing flavonoids, alkaloids, phenolic compounds, terpenoids, saponins and phytosterol type
chemical constituents were found to be effective in the management of diabetic complications.
This effect might be attributed to amelioration of persistent hyperglycemia, oxidative stress and
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modulation of various metabolic pathways involved in the pathogenesis of diabetic
complications.
Conclusion: Screening chemical candidate from herbal medicine might be a promising approach
for new drug discovery to treat the diabetic complications. There is still a dire need to explore the
mechanism of action of various plant extracts and their toxicity profile and to determine their
role in therapy of diabetic complications. Moreover, a perfect rodent model which completely
mimics human diabetic complications should be developed.
Keywords: Diabetic complications, medicinal plants, oxidative stress.
List of Compounds studied in this article: Breviscapine, Costunolide, Eremanthin, Icariin,
Luteolin 6-C-(60 0-O-trans-caffeoylglucoside), Puerarin, Rhein.
Abbreviations
AGE Advanced glycation end products
BB rats BioBreeding rats
BB/Wor rats BioBreeding/Worcester rats
BBZDR/Wor rats BioBreeding Zucker Diabetic rats
b.d. Twice daily dose
b.w. Body weight
DAG Diacyl glycerol
DPN Diabetic peripheral neuropathy
DRG Dorsal root ganglion
FOS Fructooligosaccharides
G-6-P Glucose-6-phosphate
GK rats Goto-Kakizaki rats
GLP-1 Glucagon like peptide-1
GPx Glutathione peroxidase
GSH Glutathione
HbA1c Glycosylated haemoglobin A1c
HDL High-density lipoprotein
i.g. Intragastric route
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i.p. Intraperitoneal injection
IGF Insulin-like growth factor
IU International units
LBP-4 Lycium barbarum Polysaccharides-4
LDL Low-density lipoprotein
MAPK Mitogen activated protein kinase
MNCV Motor nerve conduction velocity
NCV Nerve conduction velocity
NF-κB Nuclear factor kappa B
NGF Nerve Growth Factor
NO Nitric oxide
NOD Non-obese diabetic mice
o.d. Once daily dose
OLETF rats Otsuka Long Evans Tokushima Fatty rats
p.o. per os (oral administration)
PKC Protein Kinase C
PPAR α Peroxisome proliferators-activated receptor α
PPAR γ Peroxisome proliferators-activated receptor γ
RNS Reactive nitrogen species
ROS Reactive oxygen species
SNCV Sensory nerve conduction velocity
STZ Streptozotocin
TBARS Thiobarbituric acid reactive substances
TGF-β Transforming growth factor-β
TNF-α Tumour necrosis factor-α
v/v Volume by volume
VEGF Vascular endothelial growth factor w/w Weight by weight WBN/Kob rats Wistar Bonn/Kobori rats ZDF rats Zucker Diabetic Fatty rats
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Contents
1. Introduction……………………………………………………………………………..5 2. Material and methods………………………………………………………………….8 3. Animal models for diabetic complications……………………………………………9 4. Results…………………………………………………………………………………..11
4.1 Mechanism of action……………………………………………………………….11 4.2 Percentage of the active constituents………………………………………………11 4.3 Flavonoids…………………………………………………………………………..11 4.4 Alkaloids…………………………………………………………………………….12 4.5 Phenolic compounds……………………………………………………………….13 4.6 Terpenoids………………………………………………………………………….14 4.7 Saponins…………………………………………………………………………….14 4.8 Polysaccharides…………………………………………………………………….15 4.9 Phytosterols…………………………………………………………………………15 4.10 Tannins…………………………………………………………………………….16 4.11 Miscellaneous……………………………………………………………………..17
5. Discussion and conclusion…………………………………………………………….18 6. Future needs in this area of research ……………………………………………........22
Acknowledgement…………………………………………………………………………….22 References………………………………………………………………………………….........22
1. Introduction:
Chronic hyperglycemia causes many of the major complications of diabetes, including
nephropathy, retinopathy, neuropathy, macro and microvascular damage (The Diabetes Control
and Complications Trial Research Group, 1993). The risk for microvascular and neuropathic
complications is related to both duration of diabetes and the severity of hyperglycemia
(Hoogwerf, 2005). In particular, diabetes increases the risk of microvessel disease (Qiu et al.,
2008; Yuan et al., 2007). As a result, serious conditions such as retinopathy, neuropathy and
nephropathy are frequently encountered among patients with diabetes. Diabetic retinopathy is
estimated to account for 5% of all cases of blindness globally (Resnikoff et al., 2004) and up to
50% of patients receiving renal replacement therapy have diabetic nephropathy (Kutner et al.,
2012). Diabetic peripheral neuropathy (DPN) is associated with considerable morbidity,
mortality and diminished quality of life and affects up to 50% of people with diabetes (Tesfaye,
2010). In absolute numbers, against the estimated global prevalence of diabetes of 472 million by
2030, DPN is likely to affect as many as 236 million people worldwide
(http://www.idf.org/diabetesatlas/).
Hyperglycemia is a pre-requisite for the development of diabetic complications and in
chronic diabetes, hyperglycemia instigates activations of hexosamine biosynthetic pathway,
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sorbitol-aldose reductase pathway (Dunlop, 2000), mitogen activated protein kinases (MAPKs)
(Koshikawa et al., 2005) and protein kinase C (Meier et al., 2007). Further, hyperglycemia
increases the expression of growth factors and cytokines such as transforming growth factor-β
(TGF-β), vascular endothelial growth factor (VEGF), platelet-derived growth factor, insulin-like
growth factor (IGF) and tumour necrosis factor-α (TNF-α). Reactive oxygen species (ROS) are
important arbitrator factors involved in all these events (Brownlee, 2001; Wolf et al., 2005) and
activate intracellular signal transduction and transcription cascades, in which MAPKs and
nuclear factor kappa B (NF-kB) play the most significant roles, (Lee et al., 2007; Valko et al.,
2007) and damages proteins, lipids, and nucleic acids by oxidation (Figure 1).
Clinical studies have demonstrated that chronic diabetic complications occur late after
disease onset, reflecting structural abnormalities in nerves, kidney, retina and blood vessels, with
the appearance strongly correlated with the duration of the diabetes and the level of glycemic
control (Resnick and Howard, 2002). Large clinical trials have demonstrated that normalization
of glycemia can greatly reduce the incidence of diabetic complications (UK Prospective Diabetes
Study Group, 1998; The Diabetes Control and Complications Trial Research Group, 2000).
However, in clinical practice, normalizing blood glucose is not a trivial task and almost 50% of
diabetic subjects fail to reach the recommended target of an HbA1c lower than 7% (Hoerger et
al., 2008). Based on present perceptive of pathophysiology of diabetes mellitus, plentiful
pharmacological and non-pharmacological interventions have been employed in the previous
fifty years in order to treat hyperglycemia and interrupt the progression of disease. However,
most of the observed initial improvements in hyperglycemia are not constant because of the
progressive nature of disease (Kahn et al., 2006; Del et al., 2007). These pharmacotherapies also
have undesired side effects, such as hypoglycemia, weight gain, gastrointestinal symptoms and
peripheral oedema, variable effects on β-cell function and decline (Black et al., 2007; Del et al.,
2007).
Antioxidant defences and cellular redox status should be considered as central player in
diabetes and its complications (West, 2000). Increased oxidative stress and depleted antioxidant
defence in diabetes and its complications are well established (Evans et al., 2002; Choi et al.,
2008). Hyperglycemia and increased production of reactive oxygen species (ROS) resulting in
increased oxidative stress with over-activation of NADPH oxidase are important components of
metabolic syndrome (Demircan et al., 2008). Moreover, insulin resistance is also positively
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associated with systemic oxidative stress. Oxidative stress leads to the development of diabetes
mellitus by activating stress-signaling pathways such as NF-κB (Davi et al., 1999). Contribution
of oxidative stress to diabetic complications may be tissue specific, mainly in microvascular
diseases which occur only in diabetic patients. Thus antioxidant treatment coupled with other
treatments for diabetic complications would most likely be effective in ameliorating these
complications (Scott and King, 2004).
Hence, there is a clear need for additional interventions to decrease the impact of high
glucose and oxidative stress among those subjects who do not manage to reach normoglycemia.
From the ancient time, plants are used as an essential component of traditional medicine systems
(Fang et al., 2005). Many of these medicinal plants and herbs had been priced for their
medicinal, flavouring and aromatic qualities for centuries. Plants are rich source of secondary
metabolites like flavonoids, alkaloids, terpenoids, tannins etc. and that have been implicated in
several therapeutic approaches. Over three-quarters of the world population relies mainly on
plants and plant extracts for health care. Herbs are mine of medicinal agents and a large number
of medicinal herbs are found to be efficacious, cheap and safe in preventing diabetes and diabetic
complications. Moreover, use of herbal medicines for the treatment of diabetic complications is
very important in developing countries where, the cost of conventional medicines is a burden to
the population. More than 30% of the entire plant species, at one time or other was used for
medicinal purposes (Farnsworth et al., 1985). The herbal products today symbolize safety in
contrast to the synthetics which are regarded as unsafe to human and environment. The blind
dependence on synthetics is over and people are returning to the naturals with hope of safety and
security. Even the allopathic system of medicine has adopted large number of plant-derived
drugs which form an important segment of the modern pharmacopoeia (Dhar et al., 2000). The
medicinal values of plants have been tested by trial and error method for a long time by
numerous workers. Even today great opportunities are still open for scientific investigations of
herbal medicines for cure of diabetes and its complications. Current knowledge and interest in
traditional medicine has led to the rapid development in the pharmacotherapy of diabetic
complications. The information collected from the current data is important in preserving
indigenous knowledge as well as in the discovery of newer compounds with significant potential
for the treatment of diabetic complications.
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This review comprises of plants and parts of plants including the active chemical
constituents, mechanism of action of active constituents responsible for attenuation of
hyperglycemia, oxidative stress and amelioration of diabetic complications.
2. Material and methods:
In this review, bibliographic investigation was carried by scrutinizing peer reviewed
articles from worldwide scientific databases available during 2000-2012. Scientific databases
including SCOPUS, PUBMED, SCIELO, NISCAIR, Google Scholar were used to retrieve
articles and only relevant studies published in English were considered. Botanical names were
verified from published literature and database (International Plant Names Index, 2012 and
www.theplantlist.org). The inclusion criteria for the selection of plants includes (i) medicinal
herbs with reported animal studies in diabetic complications, (ii) compounds isolated from plants
with attributed potentials in relieving diabetic complications, (iii) plants which have potential
effect in ameliorating oxidative stress in diabetic animals, (iv) Plants/their parts/extracts used as
antioxidants in diabetic animals, antihyperlipidemic, anticataract have been considered as useful
in delaying diabetic complications, (v) We filtered the published literature according to Gertsch
(2009) and Butterweck and Nahrstedt (2012) criteria. According to them, for in vitro testing IC50
values should be below 100 μg/ml for extracts and below 25 μM for pure compounds (Cos et al.,
2006; Butterweck and Nahrstedt, 2012). For in vivo studies, reporting activities in plant extracts
at doses >200 mg/kg are not likely to have any practical utility (Gerstch, 2009).
3. Animal models for diabetic complications.
Diabetic complications are the major reason for morbidity and mortality among diabetic
patients (Nicholson, 2006). Etiology of these complications is multifactorial with many
pathogenetic mechanisms. Identification of underlying mechanisms is of greatest importance to
better understand the failures with existing treatments and to develop new approaches for
diagnosis and therapy of complications associated with diabetes (Pop-Busui et al., 2006).
Animal models have been used in an attempt to develop innovative therapies to ameliorate
diabetic complications particularly to define the role of some molecules involved in the
pathophysiology. Diabetic animal models which are used in order to characterize these
mechanisms are often without human correlation. So, validation of these models is of particular
importance (Said, 2007). An ideal animal model showing the range of human diabetic
microvascular complications have not been developed yet for many reasons. For example type 2
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diabetes mellitus patients often develop hypertension but many animals do not develop similar
condition (Gurley, 2006; Ruster and Wolf, 2010). Diabetic complications develop in a different
manner in various diabetic rodents depending upon the type of strain, type of diabetes and the
age occurrence of diabetes. So the selection of appropriate animal model is of utmost importance
for the better understanding of diabetic complications.
In type 1 diabetes, STZ induced animal models are widely accepted to study
manifestations of diabetic nephropathy. Characteristic oxidative stress develops in STZ induced
model which is lacking in other models for diabetes (Lubec et al., 1998). High doses of STZ
results in nephropathy due to hyperglycemia induced renal cytotoxicity (Kraynak et al., 1995;
Katoh et al., 2000). In case of Non obese diabetic (NOD) mice, onset of hyperglycemia results in
complete insulin deficiency and thus absolute dependence of animals on insulin therapy. This
model is mainly used to study immune-pathogenesis of islet cell destruction than diabetic
nephropathy (Sharma and Ziyadeh, 1994). Goto-Kakizaki rats (GK rats) develop injury similar to
human diabetic nephropathy. This model develops epithelial-mesenchymal transition which is
considered a major mechanism of tubule-interstitial fibrosis and tubular atrophy in diabetic
nephropathy (Phillips et al., 1999). The increasing use of knock out and transgenic mice to test
the role of various molecule in the pathophysiology of diabetic nephropathy requires a simple
model to prevent time consuming back-crossing experiment and thus STZ based models are still
used frequently despite of various disadvantages (Ruster and Wolf, 2010). In diabetic neuropathy
models, STZ animals are highly hyperglycemic leading to several ill conditions, involving all
pathological mechanisms. STZ rodent models and BioBreeding rats (BB rats) develop nerve
conduction changes consistent with an axonal neuropathy, similar to those seen in the diabetic
patient (Green et al., 1997). In human neuropathy, these nerve conduction changes are associated
with axonal degeneration (Feldman et al., 2002). In case of type 2 diabetes, GK and Zucker
Diabetic Fatty rats (ZDF rats) suits better for the experimental studies of diabetic neuropathy.
BioBreeding/Worcester rats (BB/Wor-rats) show activation of the polyol pathway, reduced
activity of Na+/K+-ATPase in nerves and a greater decrease in Motor nerve conduction velocity
(MNCV) than Sensory nerve conduction velocity (SNCV) after 5-week duration of type 1
diabetes.
Significant fibre loss is already detectable in sural nerves of BB/Wor-rats after 4 months
of diabetes and increases after 11 months (Sima and Kamiya, 2006). In addition, the
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development of sympathetic autonomic neuropathy in BB/Wor-rats is characterized by
neuroaxonal dystrophic changes of terminal axons (Schmidt et al., 2004). The BioBreeding
Zucker Diabetic rats (BBZDR/Wor rat) is a suitable model which fully encompasses the ability
to study the complications that affect human type 2 diabetic patients (Tirabassi et al., 2004).
BB/Wor-rats and BBZDR/Wor-rats are outbreed from same BB background, provides unique
comparison models representing type 1 and 2 diabetes (Sigaudo-Roussel et al., 2007).
Pathogenesis of diabetic retinopathy has been studied using animal models. Most studies
on diabetic retinopathy till date have used type 1 diabetic animal models (Kern, 2009; Zheng and
Kern, 2010). STZ-induced model reproduces early symptoms of diabetic retinopathy, such as
loss of retinal pericytes and capillaries, thickening of the vascular basement membrane, vascular
occlusion and increased vascular permeability (Kern and Mohr, 2007). These diabetic models are
mostly used to demonstrate early changes of diabetic retinopathy. Studies of advanced
proliferative retinal changes cannot be carried out in these models because they die before
proliferated diabetic retinopathy could be detected. Proliferative changes were reported in the
pre-retinal vitreous of Wistar Bonn/Kobori rats (WBN/Kob rats), showing intra-retinal
angiopathy accompanied by newly formed vessels and significant hyalinization of intra-retinal
vessels (Tsuji et al., 2009). Hence, this might be useful as an animal model for progressive
diabetic retinopathy. Otsuka Long Evans Tokushima Fatty rats (OLETF rats) are not suitable for
studying diabetic retinopathy because the formation of acellular capillaries and pericyte ghosts
typical of human diabetic retinopathy are not accelerated in these rats (Matsuura et al., 2005).
GK rats are useful for investigating the retinal microcirculatory changes caused by type 2
diabetes over an extended period of time because of the moderate and stable diabetic state
(Miyamoto et al., 1996). Key features to consider when choosing an animal model of diabetic
retinopathy includes: the structural and biochemical features of the visual system compared with
humans; the ability to perform genetic manipulations; the availability and cost of the model;
methods available for disease characterization and validation; the time course of pathological
changes; and ethical, moral and legal issues.
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4. Results:
Overall, 238 articles were reviewed for plant literature having proved effect of plant
extracts or isolated constituents in laboratory animals against diabetic complications and referred
for citation. Out of the reviewed literature 127 articles were chosen as per Gertsch (2009) and
Butterweck and Nahrstedt (2012) criteria. All the plants are categorized according to their
creditworthy active constituents. Moreover, plants which have potential for attenuation of
diabetic complications i.e. on the basis of strong antioxidant and anti-hyperglycemic activity are
also mentioned.
4.1 Mechanism of action:
Active chemical constituents attenuate diabetes and diabetic complications through
different mechanism of action. The detailed mechanisms of various chemical constituents
playing a significant role in attenuation of diabetic complications are presented in Figure 2.
4.2 Percentage of the active constituents:
Mechanism involved in the amelioration of diabetic complications depends on the plant
constituents present in the various species. Out of the total 133 plants studied, flavonoids (30%),
terpenoids (17%) and polyphenolic compounds (6%) were found to be effective in attenuation of
diabetic complications (Figure 3).
4.3 Flavonoids
Flavonoids are reputed compounds known for their health promoting properties due to
their high antioxidant capacity. Flavonoids have been described to be excellent free radical
scavenging agents. It is this reputation of the flavonoids that have received much attention in the
mainstream of pharmaceutical research especially in the management of diabetic complications
(Yao et al., 2004). Flavonoids are the most widespread polyphenolic compounds with
hypoglycemic and antidiabetic properties and constitute the active biological principals of most
medicinal plants (Czinner et al., 2000; Carini et al., 2001; Suzgec¸ et al., 2005; Tepe et al.,
2005). Hyperglycemia provokes irreversible tissue damage by the protein oxidation reaction,
leading to the formation of advanced oxidation protein products. Flavonoids mainly act by
inhibiting free radical formation and propagation of free radical reactions through hydrogen
donation and aromatic hydroxylation (Hanasaki et al., 1994). Flavonoids reduce oxidative stress
leading to less degradation of GSH or either increases the biosynthesis of GSH. Flavonoid also
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leads to the regeneration of pancreatic β-cells, reduces necrosis and degeneration and thus, may
be effective in treating hyperglycemia thereby preventing diabetic complications (Sefi et al.,
2010). Flavonoids having phenolic groups are found to be effective antioxidants due to their
redox properties and chemical structure. These compounds function as (i) chain-breaking
electron donors by reducing ROS, (ii) as chelating metal ions which initiate the reaction, (iii) as
chain-breaking electron acceptors by oxidizing R, and (iv) as detoxificant of intermediary
oxygen reactive products of lipoperoxidation by increasing available GSH (Sefi et al., 2012).
The flavonoidal rich fractions increase insulin release in-vitro from pancreatic islets and decrease
levels of LDL, triglycerides and increases HDL level. Both these actions are found to be through
dual up-regulation of both the peroxisome proliferators-activated receptors (PPARα and PPARγ)
up to 3–4 folds. It was found that flavonoid rich fractions have both hypoglycemic and
hypolipidemic effects in the management of diabetes (Sharma et al., 2008). Intracellular
accumulation of sorbitol leads to chronic complications of diabetes such as neuropathy,
retinopathy and cataracts. Flavonoids like kaempferol and quercetin, show significant inhibitory
effects on NO production and thus exert beneficial effects on hyperglycemia of diabetic animals
(Fang et al., 2008). Both kaempferol and quercetin could inhibit the expression of iNOS,
cyclooxygenase- 2 and reactive C-protein and down-regulate the NF-κB pathway, which
contributed to the anti-inflammatory effects of these two flavonoids in Chang liver cells (Garcia-
Mediavilla et al., 2007). Now a day, increasing evidence shows that the inflammatory response is
closely involved in the pathogenesis of type 2 diabetes. Kaempferol and quercetin as multi-
targeting compounds not only activate PPARγ but also inhibit inflammatory signaling, resulting
in satisfactory amelioration of hyperglycemia and lesser adverse effects (Fang et al., 2008).
Icariin isolated from Epimedium brevicornum is useful in the management of diabetic
retinopathy by modulating both endothelial markers (RECA) and Collagen-IV (Col-IV)
expression in retinal microvessls and Thy-1 and Brn3a expression in retinal ganglion cells at a
dose of 5 mg/kg/day (p.o.) (Xin et al., 2012). Icariin can also evidently relieve renal damage in
rats with diabetic nephropathy, which might be related to modulating the expression of Col IV
and TGF-β1 protein (Qi et al., 2011). Similarly, Erigeron breviscapus (Vaniot) Hand.-Mazz. was
found to have protective effect in the pathogenesis of diabetic cardiomyopathy via the PKC/NF-
kappaB/c-fos signal transduction pathway (Wang et al., 2009) and Pueraria lobata (Willd.)
Ohwi ameliorated retinal pigment epithelial cell apoptosis partly induced by peroxynitrite for
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diabetic retinopathy (Hao et al., 2010). Plants containing flavonoids as their major active
constituent are listed in Table 1.
4.4 Alkaloids
Alkaloids produce anti-hyperglycemic action by potentiating pancreatic secretion of insulin from
β-cell of islets or by enhancing transport of blood glucose to peripheral tissue (Gulfraz et al.,
2011). Significant attenuation in diabetic complications was found with Aegle marmelos (L.)
Correa which ameliorated cardiomyopathy (Bhatti et al., 2011). Alkaloids like berberine are
able to restore the reduced glutathione (GSH) content in diabetic liver which play an important
role in prevention of diabetic complications. Berberine prevents neuronal damage due to
ischemia/oxidative stress (Asai et al., 2007) and also reduces glucose-6-phosphate (G-6-P)
enzyme activity which results in restoration of hepatic glycogen content and blood glucose,
modulates enzymes responsible for glucose metabolism, reducing oxidative stress and thus helps
in restoring antioxidant status (Singh and Kakkar, 2009). Like berberine a variety of other
alkaloids also take part in the amelioration of diabetic complications. Aqueous extract of the
leaves of Murraya koenigii (Linn.) significantly improved renal function and antioxidant status
in STZ-induced diabetic rats (Yankuzo et al., 2011). A list of plants containing alkaloids as
active constituent is mentioned in Table 1.
4.5 Phenolic compounds
The major challenge in diabetes research is to define not only the cause effect
relationship between various risk factors and complications, but also to comprehend the effects
of therapeutic agents that are beneficial in the management of diabetic complications. The
scavenging ability of the phenolics is mainly due to the presence of hydroxyl groups. Being a
potent radical scavenger it inhibits the free radical mediated formation of AGEs and thus are
beneficial for counteracting the complications associated with diabetes (Elberry et al., 2011).
Phenolic compounds were found to lower blood glucose in STZ induced diabetic rats. Moreover,
enhanced insulin secretion by regeneration of β-cells reduces oxidative stress and modulates
enzymes responsible for glucose metabolism (Gandhi et al., 2011). Phenolic compounds increase
the levels of GSH and reverses increased levels of lipid peroxidation in diabetic rats, thus
contribute in the effective management of diabetes and associated toxic manifestations
(Dewanjee et al., 2009a). Hyperglycemia generates ROS, which in turn cause lipid peroxidation
and membrane damage (Hunt et al., 1988). Plants rich in phenolic content have been reported to
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possess higher antioxidant activities than vitamins and synthetic antioxidants.The phenolic
compounds show a significant increase in antioxidant enzymes including glutathione peroxidase,
glutathione reductase and glutathione S-transferase in the diabetic and moreover, increased GSH
level and decreased malonaldehyde levels and oxidative stress indicating their ability to reduce
blood glucose concentration, and subsequent oxidation. Proto-catechuic acid, caffeic acid
isolated from Hibiscus sabdariffa L. (Lee et al., 2009) and mangiferin isolated from Mangifera
indica L. attenuated diabetic nephropathy in STZ-induced diabetes in male Sprague-Dawley
rats (Li et al., 2010). Plants containing such phenolic compounds effective in preventing diabetic
complications are listed in Table 1.
4.6 Terpenoids
Triterpenoids present in medicinal plants also stimulates release of insulin from pancreas
and ameliorates oxidative stress, thus can be effective in management of diabetes and related
complications (Afolayan and Sunmonu, 2011). Costunolide (Sesquiterpene compound)
stimulated the β-islets to secrete insulin by inhibiting the expression of nitric oxide synthase
resulting in normo-glycemic and hypolipidemic activity and hence it can be used as a drug for
treating diabetes (Eliza et al., 2009a). Eremanthin (sesquiterpene lactone) stimulates insulin
release from β-cells and increase sensitivity of insulin to uptake glucose. It also significantly
decreased glycosylated hemoglobin (HbA1c), serum total cholesterol, triglyceride, LDL-
cholesterol and at the same time markedly increased HDL-cholesterol and serum protein. Thus,
eremanthin possessed hypoglycemic and hypolipidemic activities and hence it could be used as a
drug for treating diabetes (Eliza et al, 2009b). Boswellic acid isolated from the Boswellia serrata
Triana & Planch (Rao et al., 2013) was found to be very effective at a dose of 10 mg/kg in-vivo
and 10, 50 and 100 μg/ml for in-vitro assay. It acts by inhibiting the aldose reductase and
formation of AGEs. Similarly, a number of terpenoids isolated from the medicinal plants were
also found to be effective at very small doses e.g. costunolide, erematin, loganin and corosolic
acid. A wide range of other terpenoidal moieties also take part in the attenuation of diabetic
complications and the plants containing such moieties are listed in Table 1.
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4.7 Saponins
Saponins are also important active constituents which can be used for management of
diabetic complications. Saponins isolated from medicinal plants are found to be renoprotective as
they reduce fasting blood glucose and albuminuria, reverses the glomerular hyperfilteration state
and ameliorates proliferative glomerular pathological changes during the early stages of diabetic
nephropathy in rat models (Zhang et al., 2009). Saponins produce a significant reduction in
blood glucose and lipid profile. This hypoglycemic action is due to the nature of saponins to
stimulate remnant β-cells to produce insulin (Meliani et al., 2011). Total araliosides obtained
from Aralia elata (Miq.) Seem. significantly prevented diabetes-induced cardiac dysfunction and
pathological damage through up-regulation of L-type calcium channel current in cardiac cells
and decreased connective tissue growth factor (Xi et al., 2009). Panax quinquefolius L. has
preventive effects on diabetic nephropathy and it works through a combination of mechanisms
such as anti-hyperglycemic and antioxidant activities (Sen et al., 2012). Plants containing
saponin moieties helpful in preventing various diabetic complications are listed in Table 1.
4.8 Polysaccharides
Polysaccharides increases serum insulin secretion in diabetic rats. The possible
mechanism of action of polysaccharides for their antidiabetic activity could be correlated with
promoting insulin secretion by closure of K+-ATP channels, membrane depolarization and
stimulation of Ca2+ influx, an initial key step in insulin secretion (Fenglin et al., 2009). They also
diminish serum total cholesterol and triglyceride level significantly and these effects may be due
to low activity of cholesterol enzymes or low level of lipolysis which are under the control of
insulin (Sharma et al., 2003). Among all the polysaccharides containing medicinal herbs, Lycium
barbarum L. was found to be very effective in diabetic complications. Lycium barbarum
Polysaccharides-4 (LBP-4) isolated form Lycium barbarum L. significantly prevented renal
damage in diabetic rats and also attenuated diabetic retinopathy (Zhao et al., 2009). Fructo-
oligosaccharides (FOS) increased insulin-positive pancreatic cell mass distributed in small cell
clusters within the exocrine parenchyma. FOS increase plasma levels of Glucagon like peptide-1
(GLP-1) and consequently its systemic effects i.e. release of insulin, inhibition of glucagon and
somatostatin, and maintenance of β-cell mass. In type 1 diabetic patients, endogenous GLP-1
regulates postprandial glucose excursions by modulating glucagon levels and β-cell
responsiveness to glucose (Habib et al., 2011). Diabetic-dependent alterations in urinary albumin
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excretion, creatinine clearance, kidney hypertrophy and basement membrane thickening were
attenuated by FOS present in yacon (Smallanthus sonchifolius) decoction. The expression of
molecular markers of diabetic nephropathy such as Col IV, laminin-1, fibronectin and collagen
III were also diminished in the S. sonchifolius-treated group (Honore et al., 2012). Plants
containing polysaccharide as active consitituents are listed in Table 1.
4.9 Phytosterols
Phytosterols like cardinolides play an important role in the prevention of diabetic
complications by ameliorating oxidative stress and altering antioxidant enzyme levels (Kumar
and Padhy, 2011). Persistent hyperglycemia associated with diabetes has been shown to increase
the production of free radicals through glucose auto-oxidation and protein glycation. High level
of glucose is known to induce ROS and upregulate TGF-β1 and extracellular matrix expression
in glomerular mesengial cells. Inhibition of these changes by antioxidants strengthens the role
played by ROS in mediating glucose-induced renal injury. Antihyperglycemic and antioxidant
effect of steroidal components of plants help in preventing renal complications associated with
diabetes (Kumar and Padhy, 2011). Diosgenin, a major steroidal sapogenin from Dioscorea
nipponica Makino, was found to increase Nerve Growth Factor (NGF) levels in the sciatic nerve
of diabetic rats and also increased the NCV. NGF may play a major role in the pathogenesis of
diabetic neuropathy. This spirostane-type steroid was also found to increase neurite outgrowth in
PC12 cells and diosgenin-treated diabetic mice showed reduced disarrangement of the myelin
sheath and increased area of myelinated axons measured by electron microscope studies. It
exhibited improvement in the damaged axons thereby; reversing functional and ultra-structural
changes and induces neural regeneration in a diabetic neuropathy model (Kang et al., 2011). α-
Glucosidase inhibitors block the actions of α-glucosidase enzymes in the small intestine, which
is rate-limiting in the conversion of oligosaccharides and disaccharides to monosaccharides,
necessary for gastrointestinal absorption. Postprandial glucose peaks may be attenuated by
delayed glucose absorption. Thus reduces total range of postprandial glucose levels
(Bellamkonda et al., 2010). List of plants containing phytosterols as active constituent is
provided in Table 1.
Page 17
4.10 Tannins
Tannins play an important role in preventing diabetic complications by reducing the
formation of AGEs and oxidative stress (Soman et al., 2010; Soman et al., 2013). Omara et al.,
in 2012, found that tannins present in A. Nilotica (L.) almost restored the normal
histopathological architecture of kidney of STZ-induced diabetic rats and produced significant
improvement in glomerular size and damage in diabetic nephropathy in rats. List of plants
containing tannins as active constituent is provided in Table 1.
4.11 Miscellaneous
Amino acid like S-allyl cysteine decreased plasma glucose level, TBARS, hydroperoxide
and GSSG in diabetic rats. In addition, the levels of plasma insulin, superoxide dismutase,
catalase, GPx and reduced GSH level were also increased. Amino acid reduces oxidative
damage, inhibits lipid peroxidation and enhances cellular antioxidant defence. Therefore amino
acids can be useful in management of diabetes and the related complications (Saravanana and
Ponmurugan, 2011). STZ induced diabetic nephrology and modulated the oxidative stress in
kidney whereas treatment with Diallyl disulphide and trisulphide isolated from Allium sativum
L. produced a significant decrease in TBARS generation, accompanied by a significant increase
in the GSH level (Mariee et al., 2009; Ou et al., 2010; Chang et al., 2011). Moreover, α-hydroxy
succinamic acid from Eugenia jambolana Lam. (Tanwar et al., 2010) reported to show
significant attenuation of renal dysfunction.
Curcuminoids (curcumin obtained from rhizomes Curcuma longa L.) significantly lower
plasma glucose level and attenuate oxidative stress leading to amelioration of cardiomyocyte
hypertrophy, myocardial fibrosis and left ventricular dysfunction. It acts by inhibiting PKC-α
and β2-MAPK pathway which may be useful as an adjuvant therapy for the prevention of
diabetic cardiomyopathy (Soetikno et al, 2012). Curcumin was also reported to treat diabetic
nephropathy at a dose of 150 mg/kg (p.o.) (Huang et al., 2013). Some other important plants
which can be used for the management of the treatment for neuropathy or renal dysfunctions are
Magnolia officinalis Rehder & E.H.Wilson (Eun-Jin et al., 2007), Salacia oblonga Wall.
(Huang et al., 2008), Paeonia lactiflora Pall. (Jianfang et al., 2009) andHydrangea paniculata Siebold (Zhang et al., 2012). Plants containing various potential active constituents responsible
in preventing diabetic complication are listed in Table 1.
Page 18
5. Discussion and conclusion
Prolonged exposure to high glucose concentrations (hyperglycemia) promotes the
development of microvascular complications associated with diabetes mellitus (The
Diabetes Control and Complications Trial Research Group, 1993; UKPDS, 1998; Koya et
al., 2003). Such complications affects the kidneys (nephropathy), eyes (retinopathy), heart
(cardiomyopathy), nerves (neuropathy) and blood vessels (Michael, 2001; Yazdanparast et
al., 2007). It is well accepted that, the high oxidative stress in diabetics considerably
contributes to the complication of this disease (Baynes and Thorpe, 1999) and excessive
production of free radicals is an observed phenomenon in association with diabetic
complications (Young et al., 1995). Management of diabetic complications with minimal
side effect is still a major challenge to the medical system. This lead to extensive
exploration of potent natural anti-diabetic products with fewer side effects. Current
research on natural molecules and products primarily focuses on plants since they can be
sourced more easily and be selected on the basis of their ethno-medicinal use (Verpoorte
et al., 2005). Medicinal plants serves as a rich source of novel biologically active
compounds and a very few of them have been thoroughly investigated for diabetic
complications. Among 60 families, Asteraceae constitutes 6 %; Fabaceae 6%; Apiaceae 3
%; Scrophulariaceae 4%; Caeselpiniaceae, Combretaceae, Leguminosae and Myrtaceae
each having 2% of medicinal plants respectively. Among all, Asteraceae and Fabaceae
families contain maximum number of plants with potential effects in management of
diabetic complications. Among plant parts, leaves have been maximally utilized for
management of diabetic complications. Among various parts of plants used in the study
are leaves (29%), roots (14%), whole plant (10%), fruits (9%), seeds (6%), flowers (5%),
aerial parts (2%), stem (1%), and root barks, rhizomes, latex, etc. in small proportion.
Polyphenolic compounds, flavonoids, terpenoids, saponins, polysaccharides and alkaloids
are the major chemical moieties present in the plant species in these families and these
major secondary metabolites tend to reverse/delay diabetic complications by decreasing
the persistant hyperglycemia, decreasing the formation of ROS, by increasing the
secretion of insulin from β-cells and by inhibiting the formation of AGEs.
Page 19
Flavonoids have been described as excellent free radical scavenging agents which
effectively protect against aldose reductase activity and protein damage (albumin
glycation) thereby, preventing either the enzymatic conversion of (a) glyceraldehyde to
glycerol and (b) glucose to sorbitol, thus replenishing the depletion of NADPH levels
known to envisage cytoprotective action against oxidative stress by modulating polyol
pathway (Kumarappan and Mandal, 2008). Similarly, various medicinal plants containing
alkaloids as active constituents were also found to be effective in the management of
hyperglycemia. Phenolic compounds are found in abundance in medicinal plants and
effective in attenuating oxidative stress and inhibiting the AGE formation, which are
implicated in the pathogenesis of diabetic microvascular complications. The scavenging
ability of the phenolic compounds is mainly due to the presence of hydroxyl groups
(Jagtap and Patil, 2010). Triterpenoids present in medicinal plants also stimulate release of
insulin from pancreas and ameliorates oxidative stress, thus can be effective in
management of diabetes and related complications (Afolayan and Sunmonu, 2011).
Medicinal plants, with their structurally diverse molecular constituents have been
utilized for the treatment of diabetic complications since millennia. Herbs are natural
products and their chemical composition varies depending on several factors, such as
botanical species, the anatomical part of the plant used (seed, flower, root, leaf, and so on)
and environmental conditions. This variability can result in significant differences in
pharmacological activity: involving both pharmacodynamic and pharmacokinetic issues.
But despite of growing research in this field, question still arises that how meaningful are
the data in which unrealistically high doses of extracts/pure compounds are necessary to
achieve a pharmacological effect? In the previous literature, it was found that, test
substance was administered at high doses e.g., ethanolic extract of Artemisia dracunculus
L. (Watcho et al., 2011) was administered at a dose of 500 mg/kg/ day (p.o.) to ameliorate
diabetic neuropathy; 70% aqueous ethanolic extract Brassica oleracea var capitata
(Kataya et al., 2008) was administered at a dose of 1 g/kg (p.o.) to attenuate diabetic
nephropathy; decoction of flowers of Chrysanthemum morifolium Linn. (Hu et al., 2012)
prevented diabetic retinopathy at a dose of 5 g/kg (p.o.) whereas, a dose of 1g/kg (p.o.) of
aqueous ethanolic extract (70%) of Glycyrrhiza glabra L. (Kataya et al., 2011) was used
for prevention of diabetic nephropathy. Similarly, aqueous extract of Astragalus
Page 20
membranaceus Moench (Tam et al., 2011) at a dose of 0.98g/kg (p.o.) was used to treat
diabetic foot ulcer; 13.33 g/kg (p.o.) of aqueous extract of fruits of Momordica charantia
L. (Tripathi and Chandra, 2009) was used for antiatherogenic effect and 1 g/kg/ day (p.o.)
astragalus polysaccharides of Astragalus membranaceus Moench (Chen et al., 2010)
prevented diabetic cardiomyopathy. There is a trend to attribute pharmacological effect to
almost every plant and if these claims would be true, we already would have cure for all
vulnerable diseases (Gertsch, 2009). Nevertheless the public is often misled to believe that
all natural treatments are inherently safe. The main question that has not been often
answered satisfactorily deals with the triad absorption/metabolism/efficacy of herbs and
their extracts and is actually an important unsolved problem in judging their many alleged
health effects (Firenzuoli et al., 2004). In this review, we filtered the published literature
according to Gertsch (2009) and Butterweck and Nahrstedt (2012) criteria.
In some of the publications reviewed, we found that the test substance was
administered i.p. which further not represent ethnomedical route of administration. For
example, aqueous extract of Artemisia campestris L. was administered at a dose of 200
mg/kg (i.p.) for alleviating diabetic nephropathy (Sefi et al., 2012); Zingiber officinalis
Roscoe was administered at a dose of 500 mg/kg (i.p) for management of diabetic
nephropathy (Al-Qattan et al., 2008); aqueous extract of Phellodendron amurense Rupr.
was administered at a dose of 250 mg/kg i.p. for inhibiting oxidative stress (Young-Mi et
al., 2000); aqueous extract of Berberis vulgaris L. was administered at a dose of 62.5
mg/kg i.p. (Meliani et al., 2011). Instead enteral route should be adopted to administer
drug because it allows administration of large amount of non-sterile solutions. Moreover,
absorption of the substance takes place over the whole length of gastro-intestinal tract
(Nebendahl and Hauff, 2011).
Such ethnomedical approach for diabetic complications is a practical, cost-
effective and rational treatment. Therefore, it is prudent to look for options in herbal
medicine for diabetic complications. This review emphasized on a compelling need to
investigate an immense range of plants for isolating new chemical entities which would be
potentially used in the treatment of diabetic complications. The ultimate objective in drug
discovery and development should be the production of safe and effective remedies, not
the introduction, of elegant molecular entities into medicine often without discernible
Page 21
therapeutic advantages over the traditional formulations. In addition, basic consideration
on how to perform pharmacological assays need to be taken into account such as
physicochemical properties of the testing material, choice of realistic doses, adequate test
models and appropriate route of administration. Due to the large and growing use of
natural-derived substances all over the world, herbal-derived remedies need a powerful
and deep assessment of their pharmacological qualities and safety issues in the treatment
of diabetic complications. Thus, explanatory and pragmatic clinical studies would be
useful and complementary in the acquisition of reliable pre-clinical data. Implementing
these criteria in research, would help restore credibility of pharmacological research with
natural products in the field of diabetic complications.
6. Future needs in this area of research
Majority of the plants used traditionally to cure diabetes have not been explored
experimentally for the treatment of diabetic complications. In the last few decades,
increasing attention has been paid to the development of herbal medicines as a newly
emerging treatment for diabetic complications. Although plant extracts or individual
compounds derived from plants exhibit high potential but the underlying molecular
mechanism has not been sufficiently elucidated. There is still a dire need to explore the
mechanism of action of various plant extracts and their toxicity profile to determine their
role in therapy of diabetic complications. Nevertheless, current experimental models
regarding the effect of natural plants in diabetic complications need to be improved. A
perfect rodent model which completely mimics human diabetic complications should be
developed. Standardization of a suite of models could aid in the beneficial development of
new drugs and lead to a much broader understanding of this pernicious disease. More
individual compound should be isolated from the plant extract and be tested for the
efficacy in the treatment of diabetic complications. The findings based on the preclinical
data need to be confirmed in patients by further randomised placebo-controlled clinical
trials. Such an ethnomedical approach for the treatment of diabetic complications is
practical, cost effective and logical. The goals of medicine no matter to which group it
belongs are the same, “welfare of the patient”.
Page 22
Acknowledgement: The authors highly acknowledge the financial grant provided by
Department of Science and Technology, New Delhi, Government of India for this Project (F.
NO. SB/FT/LS-359/2012).
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Table 1: Description of plants containing various active constituents and their action in diabetic complications
Plant name
Family Parts of plant used
Active constituents
Dose, route of administration
Animal model
Positive control Inference
Flavonoids
Anacardium occidentale L. (Olatunji et al., 2005)
Anacardiaceae
Stem bark
(-)-epicatechin, kaempferol, quercetin rhamnoside and β-sitosterol-3β-D-glucoside
200 mg/kg b.w. (p.o.) methanolic extract
Albino rats fed with 25% w/w fructose
---- Antihyperglycemic, antioxidant and improvement in plasma lipids
Angelica acutiloba (Siebold & Zucc.) Kitag. (Liu et al., 2011)
Apiaceae
Roots
Flavonoids 50, 100, 200 mg/kg/ day (p.o.)
STZ-induced diabetes in animal model
---- Ameliorates glycation-mediated renal damage
Cajanus cajan (L.) Millsp. (Habib et al., 2010)
Fabaceae
Leaves
Pinostrobin, quercetin, vitexin and cajanin stilbene acid
150 mg/kg (p.o.) methanolic extract
STZ-induced diabetes in Swiss albino mice
Glibenclamide (60 mg/kg, i.p.); atrovastatin (80 mg/kg, i.p.)
Hypolipidemic and hypoglycemic effects
Camellia sinensis (L.)
Theaceae
Leaves
Catechins 200 mg/kg b.w. (p.o.) aqueous
STZ-induced diabetes in male
---- Reduced hyperglycemia induced
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Kuntze (Kumar et al., 2012)
extract Wistar rats
retinal oxidative stress
Cannabis sativa L. (Comelli et al., 2009)
Cannabaceae
Flowers
Epigallocatechin-3-gallate
15 and 30 mg/kg (p.o.)
STZ-induced diabetes in male Wistar rats
---- Prevented diabetic neuropathy
Carum carvi L. (Sadiq et al., 2010)
Apiaceae
Seeds
Quercetin and carvone
30 and 60 mg/kg b.w. (p.o.) aqueous extract
STZ-induced diabetes in male Wistar rats
---- Renoprotective in diabetic rats
Cassia occidentalis L. (Verma et al., 2010)
Caesalpiniaceae
Whole plant
Flavonoids 200 mg/kg (p.o.) Pet ether, chloroform and aqueous extracts
Alloxan induced diabetes in male albino Wistar rats
Metformin (0.5g/kg, p.o.)
Antidiabetic and improved serum lipid profile
Cinnamomum tamala (Buch.‐Ham.) T.Nees & Eberm. (Kumar et al., 2012)
Lauraceae
Leaves
Flavonoids 100 and 200 mg/kg (p.o.) cinnamon oil
STZ-induced diabetes in male albino Wistar rats
Glibenclamide (0.6 mg/kg, p.o.)
Antihyperglycemic and antioxidant effects in diabetic rats
Croatian propolis
---- Whole plant
Flavonoids Water and ethanol extract 50 mg/kg
Alloxan induced diabetes in male
---- Prevented diabetic nephropathy
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(Orsolic et al., 2012)
(p.o.) and female CBA inbred mice
Epimedium brevicornum (Bao and Chen, 2011)
Berberidaceae
Leaves
Icariin
30 and 120 ml/kg/day (i.g.) icariin
STZ-induced diabetes in male Wistar rats
---- Improvement in cardiac function by alleviating oxidative stress
Epimedium brevicornum (Xin et al., 2012)
Berberidaceae
Leaves
Icariin
5 mg/kg/ day (p.o.) icariin
STZ-induced diabetes in male Sprague-Dawley rats and retinal ganglion cells
---- Ameliorated STZ-induced diabetic retinopathy
Epimedium brevicornum (Qi et al., 2011)
Berberidaceae
Leaves
Icariin
Icariin 80 mg/kg, (i.g.)
STZ-induced diabetes in male Sprague-Dawley rats
---- Relieved renal damage in diabetic nephropathy
Erigeron breviscapus (Vaniot) Hand.‐Mazz. (Wang et al.,
Asteraceae
Herb Breviscapine 10 and 25 mg/kg/ day (p.o.) breviscapine
STZ-induced diabetes in male Sprague-Dawley rats
---- Protective effect in the pathogenesis of diabetic cardiomyopathy via the PKC/NF-
Page 46
2009) kappaB/c-fos signal transduction pathway
Erigeron breviscapus (Vaniot) Hand.‐Mazz. (Wang et al., 2010)
Asteraceae
Herb Breviscapine 10 and 25 mg/kg/ day (p.o.) breviscapine
STZ-induced diabetes in male Sprague-Dawley rats
---- Amelioration in cardiac dysfunction and regulation of myocardial Ca(2+)-cycling proteins
Eugenia jambolana (Sharma et al., 2008)
Myrtaceae
Seeds
Flavonoids 50 and 100 mg/100g b.w./day (p.o.) flavonoids rich methanolic extract
STZ-induced diabetes in male albino Wistar rats
---- Hypoglycemic and hypolipidemic
Ficus exasperata Vahl (Adewole et al., 2012)
Moraceae
Leaves
Flavonoids 100 mg/kg/day (p.o.) aqueous extract
STZ-induced diabetes in male Wistar rats
---- Ameliorates STZ-induced nephrotoxicity
Ginkgo biloba L. (Welt et al., 2001)
Ginkgoaceae
Leaves
Quercetin 100 mg/kg b.w. (p.o.) ethanolic extract
STZ-induced diabetes in male Wistar rats
---- Protective against hypoxic damage on myocardial
Page 47
microvessels in diabetic rats
Ginkgo biloba L. (Perez de Silva et al., 2011)
Ginkgoaceae
Leaves
Quercetin 50 mg/kg b.w. (p.o.) ethanolic extract
STZ-induced diabetes in male Wistar rats
---- Neuroprotective
Helicteres isora L. (Kumar and Murugesan, 2008)
Sterculiaceae
Bark Flavonoids 100 mg, 200 mg/kg (p.o.) aqueous extract
STZ-induced diabetes in Wistar albino rats
Tolbutamide (250 mg/kg, p.o.)
Antidiabetic and hypolipidemic activity
Ipomoea batatas (L.) Poir. (Fenglin et al., 2009)
Convolvulaceae
Leaves
Flavonoids 50, 100, 150 mg/kg daily (p.o.)
Alloxan induced diabetes in male mice of original Kun-ming strain
Glibenclamide (0.25 mg/kg, p.o.)
Antidiabetic and antihyperlipidemic activity
Opuntia megacantha Salm‐Dyck (Bwititi et al., 2001)
Cactaceae
Leaves
Flavonoids 20 mg/100 g b.w. (p.o.) aqueous extract
STZ-induced diabetes in Sprague-Dawley rats
---- Modulation of renal water and sodium in diabetic rats
Ougeinia
Leguminosae
Bark Flavonoids 200mg/kg (p.o.)
Alloxan induced
Glibenclamide (3 mg/kg, p.o.)
Antidiabetic and
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oojeinensis (Roxb.) Hochr. (Velmurugan et al., 2011)
ethanolic extract
diabetes in Swiss albino mice and Wistar rats
hypolipidemic activity
Phaseolus vulgaris L. (Venkateswaran et al., 2002)
Fabaceae
Seeds, pods
Flavonoids 200 mg/kg b.w. (p.o.) aqueous extract
STZ-induced diabetes in male Wistar rats
Glibenclamide (0.6 mg/kg, p.o.)
Antidiabetic; antihyperlipidemic; antioxidant activity
Phaseolus vulgaris L. (Venkateswaran and Pari, 2002)
Fabaceae
Seeds, pods
Flavonoids 200 mg/kg b.w. (p.o.) aqueous extract
STZ-induced diabetes in male Wistar rats
Glibenclamide (0.6 mg/kg, p.o.)
Antioxidant effect in STZ-induced diabetic rats
Phyllostachys nigra (Lodd.) Munro (Hee Ju et al., 2010)
Poaceae Leaves
Luteolin 6-C-(60 0-O-trans-caffeoylglucoside)
1, 10, 50 μM Luteolin 6-C-(60 0-O-trans-caffeoylglucoside)
RGC-5 cells
Epigallocatechin gallate and N-Acetylcysteine
Attenuates oxidative stress in transformed retinal ganglion cells (RGC-5 cells) death
Pongamia pinnata (L.) Pierre
Fabaceae
Flowers
Flavonoids 100-500 mg/kg b.w. (p.o.) ethanolic extract
Alloxan induced diabetes in male albino
Glibenclamide (0.6 mg/kg, p.o.)
Antihyperglycemic and antilipidperoxidative
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(Punitha and Manoharan, 2006)
Wistar rats
activity
Pongamia pinnata (L.) Pierre (Badole et al., 2011)
Fabaceae
Flowers
Flavonoids, cycloart-23-ene-3 β, 25-diol (B2)
1 mg/kg (p.o.) cycloart-23-ene-3 β, 25-diol (B2)
STZ-nicotinamide induced diabetes in male Wistar rats
---- Protection of vital organs in STZ-induced diabetic rats by Cycloart-23-ene-3 β, 25-diol
Pterocarpus santalinus L.f. (Kondeti et al., 2010)
Leguminosae
Bark Isoflavones 100 and 150 mg/kg b.w. (p.o.) ethyl acetate fractions of ethanolic extract
STZ-induced diabetes in male albino Wistar rats
Glibenclamide (20 mg/kg b.w., p.o.)
Hypoglycemic and hypolipidemic activity
Pueraria lobata (Willd.) Ohwi (Sun et al., 2002)
Fabaceae
Roots
Puerarin 200 mg/kg (p.o.) puerarin
Alloxan induced diabetes in Kunming mice
---- Antihyperlipidemic activity
Pueraria lobata (Willd.) Ohwi (Li et al.,
Fabaceae
Roots
Puerarin 80 mg/kg/day (i.p.) puerarin
STZ-induced diabetes in male Sprague-Dawley rats
Insulin (2-4 IU/kg, s.c.)
Protection against diabetic nephropathy
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2009) Pueraria lobata (Willd.) Ohwi (Hao et al., 2010)
Fabaceae
Roots
Puerarin Puerarin 140mg/kg/ day
RPE cells fromC57BL/6 mice eyes and STZ-induced male Sprague-Dawley rats
---- Ameliorated retinal microvascular dysfunction
Rheum officinale Baill. (Gao et al., 2010)
Polygonaceae
Roots
Rhein 150 mg/kg/day rhein (p.o.)
Diabetic db/db mice
Simvastatin Protection against diabetic nephropathy progression
Rubia cordifolia L. (Patil et al., 2006)
Rubiaceae
Roots
Rubiadin 100, 200 mg/kg (p.o.) alcoholic extract
Alloxan induced diabetes in albino mice
---- Antihyperglycemic, antistress and nootropic effects
Silybum marianum (L.) Gaertn. (Vessal et al., 2010)
Asteraceae
Seeds
Silibinin 100 mg/kg (p.o.) silibinin
STZ-induced diabetes in male Sprague-Dawley rats
---- Prevents diabetic nephropathy
Terminalia paniculata Roth (Ramachandran et al.,
Combretaceae
Bark Flavonoids 100 and 200 mg/kg (p.o.) aqueous extract
STZ-induced diabetes in female Wistar rats
Glibenclamide (5 mg/kg, p.o.)
Hypoglycemic, hypolipidemic and antioxidant effects
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2012) Vaccinium arctostaphylos L. (Feshani et al., 2011)
Ericaceae
Fruits
Chlorogenic acid, anthocyanins, flavonols and procyanidins
200 mg/kg b.w. (p.o.) ethanol extract
Alloxan induced diabetes in male Wistar rats
Acarbose (20 mg/kg b.w., p.o.) and Metformin (100 mg/kg b.w., p.o.)
Antihyperglycemic, antioxidant and triglyceride lowering activity
Zingiber officinale Roscoe (Bhandari et al., 2005)
Zingiberaceae
Rhizomes
Flavonoids 200 mg/kg (p.o.) ethanol extract
STZ-induced diabetes in Wistar rats
Gliclazide (25 mg/kg, p.o.)
Prevents diabetic dyslipidaemia
Zingiber officinale Roscoe (Ramudu et al., 2011)
Zingiberaceae
Rhizomes
Flavonoids 200 mg/kg/ day b.w. (p.o.) ethanolic extract
STZ-induced diabetes in Wistar rats
Glibenclamide (0.6 mg/kg b.w., p.o.)
Attenuated progression of diabetic structural nephropathy
Alkaloids
Aegle marmelos (L.) Correa (Bhatti et al., 2011)
Rutaceae
Leaves Alkaloids, phenylpropanoid
200 mg/kg (p.o.) of ethanolic extract
Alloxan induced diabetes in Wistar rats
Tolbutamide (100 mg/kg, p.o.)
Ameliorated cardiomyopathy
Capparis spinosa L. (Eddouks
Capparaceae
Fruits Alkaloids and glucosonates
20 mg/kg b.w. (p.o.) aqueous extract
STZ-induced diabetes in male
Vanadate (Na+VO3
−) Hypolipidemic activity
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et al., 2005)
Wistar rats
Crinum asiaticum L. (Indradevi et al., 2012)
Amaryllidaceae
Leaves Alkaloids 200 mg/kg b.w. (p.o.) ethanolic extract
Alloxan induced diabetes in male albino Wistar rats
---- Attenuated hyperglycemia-mediated oxidative stress and antioxidant competence in hepatic tissues of diabetic rats
Gymnema montanum Hook.f. (Ramkumar et al., 2009)
Asclepiadaceae
Leaves Alkaloids 200 mg/kg b.w. daily (i.g.) ethanol extract
Alloxan induced diabetes in male albino Wistar rats
Glibenclamide 0.6 mg/kg b.w. daily (i.g.)
Prevented renal damage associated with diabetic oxidative stress
Justicia adhatoda L. (Gulfraz et al., 2011)
Acanthaceae
Roots, leaves
Vasicine and vasicinone
50 and 100 mg/kg (p.o.) ethanol extract
Alloxan induced diabetic rats
Glibenclamide (5 mg/kg, p.o.), glucose (5 mg/kg) and insulin (5 IU)
Hypoglycaemic and hypolipidemic activity
Murraya koenigii (L.) Spreng. (Yankuzo et al., 2011)
Rutaceae
Leaves Alkaloids 200 mg/kg b.w. (p.o.) aqueous extract
STZ-induced diabetes in Sprague-Dawley rats
Insulin (0.5 IU/kg/day, i.p.)
Hypoglycemic and delays diabetic nephropathy
Piper longum
Piperaceae
Fruits Piperine 200 mg/kg b.w. (p.o.), ethyl
STZ-induced
---- Anti-hyperglyc
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L. (Kumar et al., 2011)
acetate and ethanolic extract
diabetes in male albino Wistar rats
emic; attenuates oxidative stress in diabetic rats
Phenolic compounds
Biophytum sensitivum (L.) DC. (Gacche and Dhole, 2011)
Oxalidaceae
Whole plant Polyphenols
Water and ethanolic extract
In-vitro on rat lens
Quercetin was used as standard
Anti-cataract activity
Diospyros peregrina (Gaertn.) Gürke (Dewanjee et al., 2009a)
Ebenaceae
Fruits Polyphenolic compounds
50 and 100 mg/kg/day (p.o.) aqueous extract
STZ-induced diabetes in male Wistar rats
Glibenclamide (1 mg/kg/day, p.o.)
Hypoglycemic, hypolipidemic activity and augments oxidative stress in STZ-nicotinamide induced diabetic rats
Diospyros peregrina (Gaertn.) Gürke (Dewanjee et al., 2009b)
Ebenaceae
Fruits Polyphenolic compounds
150 mg/kg/day (p.o.) methanolic extract
STZ-induced diabetic rats
Glibenclamide (0.6 mg/kg, p.o.)
Antidiabetic and antioxidant activity
Hibiscus Malva Flowers Proto- 100 and 200 STZ- ---- Attenuates
Page 54
sabdariffa L. (Lee et al., 2009)
ceae catechuic acid, caffeic acid
mg/kg /daymethanolic extract
induced diabetes in male Sprague-Dawley rats
diabetic nephropathy
Hibiscus sabdariffa L. (Wang et al., 2011)
Malvaceae
Herb Polyphenols
100 mg/kg aqueous extract (p.o.)
STZ-induced diabetes in male Sprague-Dawley rats
---- Attenuates diabetic nephropathy via improving oxidative status
Mangifera indica L. (Li et al., 2010)
Anacardiaceae
Leaves Mangiferin
15 and 45 mg/kg (i.g.) magiferin
STZ-induced diabetes in male Wistar rats
---- Attenuated diabetic nephropathy
Morus rubra L. (Sharma et al., 2010)
Moraceae
Leaves Polyphenolic compounds
100, 200 mg/kg b.w. aqueous extract by orogastric cannula
STZ-induced diabetes in male albino Wistar rats
Glibenclamide 0.6 mg/kg by orogastric cannula
Hypoglycemic and antiatherosclerotic activity
Solanum torvum Swartz. (Gandhi
Solanaceae
Fruits Phenolic compounds
200 mg/kg/day (p.o.) methanol extract
STZ-induced diabet
Glibenclamide (10 mg/kg, p.o.)
Antidiabetic and antioxidant activity
Page 55
et al., 2011)
es in male albino Wistar rats
Terminalia bellerica (Gaertn.) Roxb. (Latha and Daisy, 2011)
Combretaceae
Fruits Gallic acid
5, 10 and 20 mg/kg b.w. (p.o.) gallic acid
STZ-induced diabetes in male Wistar rats
Standard synthetic gallic acid (10 and 20 mg/kg, p.o.)
Insulin-secretagogue and antihyperlipidemic effects
Terpenoids
Aster koraiensis Nakai (Eunjin et al., 2010)
Asteraceae
Aerial parts
Sesquiterpene glucosides
100 and 200 mg/kg/day (p.o.) ethanolic extract
STZ-induced diabtes in Wistar rats
---- Prevented diabetic nephropathy
Boswellia serrata Triana & Planch (Rao et al., 2013)
Burseraceae
Gum resin
Boswellic acid
10 mg/kg b.w. (p.o.) boswellic acid for in-vivo assay; 10, 50 and 100 μg/ml for in-vitro assay
in-vitro aldose reductase inhibition activity using rat lens and rat kidney homogenate; Wistar albino rats for in-vivo study
Quercetin (10 mg/kg b.w., p.o.) for in-vivo assay; 1.0, 5.0 and 10.0 μg/ml for in-vitro assay
Inhibited aldose reductase inhibitor and formation of advanced glycation end products
Page 56
Cissus sicyoides L. (Viana et al., 2004)
Vitaceae Leaves Linalool and α-tocopherol
100 and 200 mg/kg (p.o.) daily of aqueous extract
Alloxan-induced diabetes in male Wistar rats
---- Hypoglycemic and anti-lipemic activity
Cornus officinalis L. (Qi et al., 2008)
Cornaceae
Fruits
Triterpene acids
50 mg/kg (i.g.) medication with total triterpeme acids
STZ-induced diabetes in male Wistar rats
---- Alleviated diabetic cardiomyopathy
Cornus officinalis L. (Gong et al., 2012)
Cornaceae
Fruits
Terpenes 80 mg/kg (p.o.) terpenes
Alloxan inducing diabetic mice
---- Alleviated diabetic cardiomyopathy
Cornus officinalis L. (Jiang et al., 2012)
Cornaceae
Fruits
Loganin 5 and 10 mg/kg (i.g.) loganin
STZ-induced diabetes in male Sprague-Dawley rats
---- Renoprotective in diabetic nephropathy
Costus speciosus Siebold & Zucc. (Eliza et al., 2009a)
Costaceae
Roots
Costunolide 5, 10, 20 mg/kg b.w. (p.o.) costunolide
STZ-induced diabetes in male Wistar rats
Glibenclamide (0.6 mg/kg b.w., p.o.)
Antidiabetic; antilipidemic effect; reduced oxidative stress in STZ-induced diabetic rats
Costus speciosus Siebold &
Costaceae
Roots
Eremanthin 5, 10, 20 mg/kg b.w. (p.o.) eremanthin
STZ-induced diabetes
Glibenclamide (0.6 mg/kg b.w.,
Antidiabetic; antilipide
Page 57
Zucc. (Eliza et al., 2009b)
in male Wistar rats
p.o.) mic activity
Costus speciosus Siebold & Zucc. (Eliza et al., 2010)
Costaceae
Roots
Costunolide and eremanthin
Costunolide and eremanthin 20 mg/kg b.w. (p.o.)
STZ-induced diabetes in male Wistar rats
Insulin (3 IU/kg b.w.)
Reduced oxidative stress in STZ-induced diabetic rats
Cuminum cyminum L. (Dhandapani et al., 2002)
Apiaceae Seeds Cuminlaldehyde, γ-terpinene, O-cymene, β-pinene, 2-caren-10-al, trans-carveol and myrtenal
200, 400 and 600 mg/kg (p.o.) cumin powder
STZ-induced diabetes in Wistar rats
Glibenclamide (10 mg/kg, p.o.)
Reduced hyperglycemia, oxidative stress, and formation of advanced glycated end products
Kaempferia parviflora Wall. ex Baker (Malakula et al., 2011)
Zingiberaceae
Rhizomes
Terpenoids 100 mg/kg b.w. (p.o.) ethanol extract
STZ-induced diabetes in male Sprague-Dawley rats
---- Prevented vascular complications of diabetes
Lagerstroemia speciosa (L.) Pers. (Rao et al., 2013)
Lythraceae
Leaves Corosolic acid
10 mg/kg b.w. (p.o.) corosolic acid for in-vivo assay; 10, 50 and 100 μg/ml for in-vitro assay
in-vitro aldose reductase inhibition activity using rat lens and rat
Quercetin (10 mg/kg b.w., p.o.) for in-vivo assay; 1.0, 5.0 and 10.0 μg/ml for in-vitro assay
Inhibited Aldose reductase and formation of advanced glycation end products
Page 58
kidney homogenate; Wistar albino rats for in-vivo study
Ocimum gratissimum L. (Rao et al., 2013)
Lamiaceae
Leaves Ursolic acid
10 mg/kg b.w. (p.o.) ursolic acid for in-vivo assay; 10, 50 and 100 μg/ml for in-vitro assay
In-vitro aldose reductase inhibition activity using rat lens and rat kidney homogenate; Wistar albino rats for in-vivo study
Quercetin (10 mg/kg b.w., p.o.) for in-vivo assay; 1.0, 5.0 and 10.0 μg/ml for in-vitro assay
Inhibited aldose reductase and formation of advanced glycation end products
Origanum majorana L. (Gutierrez, 2012)
Lamiaceae
Aerial parts
Arbutin, carnosic acid, carnosol and ursolic acid
200 mg/kg/day (p.o.) methanol extract
STZ-induced male Wistar rats and in-vitro Glycation of proteins
Glibenclamide
Inhibited the formation of advanced glycation end products and reduced oxidative stress
Psidium guajava
Myrtaceae Leaves Total triterpenoid
60, 120 mg/kg (p.o.) total
STZ-induced
Rosiglitazone (3mg/kg,
Nephroprotective
Page 59
L. (Kuang et al., 2012)
s triterpenoids diabetes in male albino Wistar rats
p.o.) activity
Santalum album L. (Kulkarni et al., 2012)
Santalaceae
Heartwood
Santalol, santyl acetate and santalene
10 mg/kg b.w., b.d. (p.o.) pet ether fraction
STZ-induced diabetic model
Metformin (30�mg/kg b.w., p.o.)
Antihyperglycemic and antihyperlipidemic activity
Scoparia dulcis L. (Latha et al., 2004)
Scrophulariaceae
Whole plant
Scoparic acid, scopadiol, scopadulcic acid and scopadulin
200 mg/kg b.w., (p.o.) aqueous extract
STZ-induced diabetes in male Wistar rats
---- Antidiabetic and reduced oxidative stress
Scoparia dulcis L. (Pari and Latha, 2006)
Scrophulariaceae
Whole plant
Scoparic acid, scopadiol, scopadulcic acid and scopadulin
200 mg/kg b.w., (p.o.) aqueous extract
STZ-induced diabetes in male Wistar rats
Glibenclamide (0.6 mg/kg/ day b.w., p.o.)
Antihyperlipidemic and antidiabetic activity
Scoparia dulcis L. (Latha et al., 2009)
Scrophulariaceae
Whole plant
Scoparic acid D
10, 20 and 40 mg/kg (p.o.) scoparic acid D
STZ-induced diabetes in male Wistar rats
---- Antihyperglycemic activity
Scoparia dulcis L. (Pari and Latha, 2004)
Scrophulariaceae
Whole plant
Scoparic acid, scopadiol, scopadulcic acid and scopadulin
200 mg/kg b.w. (p.o.) aqueous extract
STZ-induced diabetes in male albino Wistar rats
Glibenclamide (0.6 mg/kg, p.o.)
Antidiabetic and reduced oxidative stress
Scoparia dulcis L. (Pari and Latha,
Scrophulariaceae
Whole plant
Scoparic acid, scopadiol, scopadulcic
200 mg/kg b.w. (p.o.) aqueous, ethanol and chloroform
STZ-induced diabetes in male
Glibenclamide (0.6 mg/kg, p.o.)
Reduced oxidative stress
Page 60
2005) acid and scopadulin
extract albino Wistar rats
Syzygium cordatum Hochst. ex Krauss (Mapanga et al., 2009)
Myrtaceae Leaves Oleanolic acid and methyl corosolate
60 mg/kg, (p.o.) oleonolic acid
STZ-induced diabetes in male albino Wistar rats
---- Renoprotective activity
Terminalia chebula Retz. (Senthilkumar and Subramanian, 2007)
Combretaceae
Fruits Arjungenin, arjunglucoside I, chebulosides I andII.
200 mg/kg b.w. (p.o.) ethanol extract
STZ-induced diabetes in Wistar rats
Glibenclamide (0.6 mg/kg, p.o.)
Anti-diabetic and anti-oxidant activity
Saponins
Aralia elata (Miq.) Seem. (Xi et al., 2009)
Araliaceae
Root bark Aralosides 4.9, 9.8 and 19.6 mg/kg b.w. (p.o.) araliosides
STZ-induced diabetes in male Wistar rats
---- Prevented diabetic cardiomyopathy
Artemisia afra Jacq. (Afolayan and Sunmonu, 2011)
Asteraceae
Leaves and stem
Saponins 50 and 100 mg/kg b.w. (p.o.) aqueous extract
STZ induced diabetes in Wistar albino rats
---- Hypoglycemic and reduced oxidative stress in STZ-induced diabetic rats
Asparagus racemosus Willd.
Asparagaceae
Roots Steroidal saponins, isoflavones and
100 and 250 mg/kg/ day (p.o.) ethanolic
STZ-induced diabetes in Wistar
Aminoguanidine hydrogen
Ameliorated diabetic nephrop
Page 61
(Somani et al., 2012)
polysaccharides
extract rats carbonate (1g/L, p.o.)
athy
Bacopa monnieri Linn. (Kapoor et al., 2009)
Scrophulariaceae
Whole plant Bacoside A and bacoside B
50, 125 and 250 mg/kg b.w. (p.o.) aqueous-ethanolic extract
STZ-induced diabetes in albino Wistar male rats
Glibenclamide (0.6 mg/kg b.w., p.o.)
Modulated antioxidant responses in brain and kidney of diabetic rats
Fomes fomentarius (L.) Fr. (Jeong-Sook, 2005)
Polyporaceae
Fruits Saponins, terpenes
100 mg/kg b.w. (p.o.) aqueous extract
STZ-induced diabetes in male Sprague-Dawley rats
---- Hypoglycemic, hypolipidemic and increased antioxidant enzyme level in diabetic rats
Gongronema latifolium Benth. (Ugochukwu and Cobourne, 2003)
Asclepiadaceae
Leaves
Saponins and pregnanes
100 mg/kg (p.o.) daily of aqueous and ethanol extract
STZ-induced diabetes in male Wistar rats
---- Ameliorates renal oxidative stress
Panax ginseng (Chang-Hwa et
Araliaceae
Leaves Ginsenosides 40, 200 mg/kg (p.o.) aqueous extract
STZ-induced diabetes in male
---- Reactivated antioxidant
Page 62
al., 2005) Sprague-Dawley rats
enzymes, reducing free radicals produced excessively in diabetic complications
Panax quinquefolius L. (Sen et al., 2012)
Araliaceae
Roots Ginsenosides 200 mg/kg b.w. (p.o.) alcohol extract
STZ- induced diabetes in Male C57BL/6 mice; male db/db mice
Insulin pellets releasing 0.5 IU of insulin to prevent ketonuria (1 IU/day)
Prevented diabetic nephropathy
Panax quinquefolius L. (Sen et al., 2013)
Araliaceae
Roots Ginsenosides 200 mg/kg b.w. (p.o.) alcoholic root extract
STZ-induced diabetes in C57BL/6 mice and db/db mice
---- Attenuated diabetic cardiomyopathy and diabetic retinopathy
Quillaja saponaria Molina (Fidan and Dundar, 2008)
Rosaceae Plant powder
Glucoside saponin
Standard rat feed+100ppm powder (Nutrafito)
STZ-induced diabetes in male Wistar rats
---- Hypoglycemic, hypocholesterolemic, and antioxidant activity
Page 63
Yucca schidigera Roezl ex Ortgies (Fidan et al., 2008)
Agavaceae
Plant powder
Steroidal saponin
Standard rat feed+100ppm powder (Sarsaponin 30)
STZ-induced diabetes in male Wistar rats
---- Hypoglycemic, hypocholesterolemic and antioxidant effects
Polysaccharides
Cichorium intybus L. (Pushparaj et al., 2007)
Asteraceae
Whole plant Inulin 125 mg/kg b.w. (p.o.) daily of ethanolic extract
STZ-induced diabetes in male Sprague-Dawley rats
Metformin (500 mg/kg, p.o.)
Hypoglycemic and hypolipidemic activity
Ganoderma lucidum (Meng et al., 2011)
Ganodermataceae
Fungal material Polysaccharides
50, 100 and 200 mg/kg polysaccharides (p.o.)
STZ-induced diabetic rats
---- Attenuated myocardial fibrosis of diabetes
Lycium barbarum L. (Li, 2007)
Solanaceae
Fruits Polysaccharides
50, 100 and 200 mg/kg (p.o.) polysaccharides
STZ-induced diabetes in male Wistar rats
---- Renoprotective activity in diabetic rats
Lycium barbarum L. (Zhao et al., 2009)
Solanaceae
Fruits Polysaccharides-4 (LBP-4)
10 mg/kg b.w. (p.o.) LBP-4
STZ-induced diabetes in Wistar rats
---- Renoprotective activity in diabetic rats
Portulaca oleracea L.
Portulacaceae
Whole plant Polysaccharides
200 mg/kg daily (p.o.) polysaccharid
Alloxan induced diabetes in
Glibenclamide (4 mg/kg,
Hypoglycemic; hypolipi
Page 64
(Fenglin et al., 2009)
es male mice of original Kun-ming strain
p.o.) demic activity
Smallanthus sonchifolius (Poepp.) H.Rob. (Honore et al., 2012)
Asteraceae
Leaves Fructooligosaccharides
10% leaves water decoction (70 mg dry extract/kg/ day b.w., p.o.)
STZ-induced diabetes in male Wistar rats
---- Antidiabetic, hypolipidemic activity and prevented diabetic nephropathy
Phytosterols
Calotropis procera (Aiton) Dryand. (Kumar and Padhy, 2011)
Asclepiadaceae
Latex Cardinolides, lignans and flavanol glycosides
100 mg/kg/ day (p.o.) aqueous extract
Alloxan induced diabetes in Wistar rats
Glibenclamide (10mg/kg, p.o.)
Antioxidant and antihyperglycemic activity and prevented renal complications
Commiphora mukul (Hook. ex Stocks) Engl. (Bellamkonda et al., 2010)
Burseraceae
Gum resin Guggalsterones
200 mg/kg b.w. (p.o.) daily aqueous extract
STZ-induced diabetes in Wistar albino rats
---- Antidiabetic, antioxidant and improved atherogenic profile
Dioscorea nipponica
Dioscoreaceae
Rhizomes Diosgenin 10 mg/kg (p.o.) diosgenin
Rat PC12 pheochromocytoma
Nerve growth factor
Attenuated diabetic
Page 65
Makino (Kang et al., 2011)
cells and alloxan induced male ICR mice and SD rats
(1mg/kg, s.c.)
neuropathy
Dioscorea nipponica Makino (Kim et al., 2011)
Dioscoreaceae
Rhizomes Diosgenin 100 mg/ml ethanolic extract and 10 mg/ml ethylacetate extract
PC-12 cells and DRG (Dorsal root ganglion) neurons
---- Attenuated diabetic neuropathy
Tannins
Acacia nilotica (L.) Delile (Omara et al., 2012)
Leguminosae
Pods Tannins and polyphenols
150 mg/kg b.w. (p.o.) aqueous methanolic extract
STZ-induced diabetes in male Sprague-Dawley rats
Glibenclamide (25 mg/kg, p.o.)
Prevented diabetic nephropathy
Parkinsonia aculeata L. (Leite et al., 2007)
Caesalpiniaceae
Leaves and flowers
Tannins, flavonoids and sterols
125 mg/kg (p.o.) aqueous extract
Alloxan induced diabetes in male Wistar rats
Insulin (3 IU/day, s.c.)
Antihyperglycemicand antihyperlipidemic activity
Parkinsonia aculeata L. (Leite et al., 2011)
Caesalpiniaceae
Leaves and flowers
Tannins, flavonoids and sterols
125 mg/kg (p.o.) hydroalcoholic extract (1:1)
Alloxan induced induced in male Wistar rats
Insulin (3 IU/b.d., s.c.)
Renoprotective effects in diabetic rats
Psidium guajava L. (Soman et
Myrtaceae
Leaves Tannins 25 and 50 mg/kg b.w./day (p.o.)
STZ-induced diabetes in female
---- Beneficial for preventing
Page 66
al., 2010) methanolic extract
Sprague-Dawley rats
cardiovascular complications in diabetes
Psidium guajava L. (Soman et al., 2013)
Myrtaceae
Leaves Tannins 25 and 50 mg/kg/day b.w. methanolic extract (i.g.)
STZ-induced diabetes in Female Sprague-Dawley rats
---- Prevented cardiovascular complications associated with diabetes
Miscellaneous
Allium sativum L. (Patumraj et al., 2000)
Alliaceae
Bulbs Diallyl disulfide and diallyl trisulfide;
100 mg/kg b.w. (p.o.) garlic extract
STZ- induced diabetes in albino Wistar rats
Aspirin (10 mg/kg b.w., p.o.)
Prevents diabetic cardiomyopathy
Allium sativum L. (Mariee et al., 2009)
Alliaceae
Bulbs Diallyl disulfide and diallyl trisulfide;
200 and 400 mg/ kg b.w. (p.o.) fresh garlic homogenate
STZ-induced diabetes in male Sprague-Dawley rats
---- Prevented diabetic nephropathy by reducing oxidative damage to kidney
Allium sativum L. (Ou et al., 2010)
Alliaceae
Oil Diallyl disulfide and diallyl trisulfide
10, 50, or 100 mg/kg b.w. every two days (p.o.) garlic oil
STZ- induced diabetes in albino Wistar rats
---- Prevents diabetic cardiomyopathy
Page 67
Allium sativum L. (Chang et al., 2011)
Alliaceae
Oil Diallyl disulfide and diallyl trisulfide
10, 50, or 100 mg/kg b.w. every two days (p.o.) garlic oil
STZ-induced diabetes in male Wistar rats
---- Prevents diabetic cardiomyopathy
Allium sativum L. (Saravanana and Ponmurugana, 2011)
Alliaceae
Bulbs S-allyl cysteine
150 mg/kg b.w. (p.o.) S-allyl cysteine
STZ-induced diabetes in Wistar albino rats
Glyclazide (5 mg/kg b.w., p.o.)
Ameliorated oxidative stress
Amaranthus viridis L. (Pandhare et al., 2012)
Amaranthaceae
Stem β-carotene 100, 200 mg/kg b.w. (p.o.) aqueous extract
STZ-induced diabetes in albino Wistar rats
Glibenclamide (0.5 mg/kg, p.o.)
Antidiabetic; antihyperlipidemic and antioxidant activity
Amaranthus viridis L. (Ashok Kumar et al., 2012)
Amaranthaceae
Whole plant β-carotene 200 mg/kg/day (p.o.) methanolic extract
Alloxan induced diabetes in Swiss albino wistar rats
Glibenclamide (10 mg/kg, p.o.)
Antidiabetic; antihyperlipidemic and antioxidant activity
Capparis decidua (Forssk.) Edgew. (Zia-Ul-Haq et al., 2011)
Capparaceae
Leaves, flowers and fruits
Amino acids, fatty acids, tocopherols, sterols, glucosinolate and phenolic content
100 μg/ml of methanolic extract of leaves, fruits and flowers
In-vitro assays
---- Antidiabetic; reduced oxidative stress
Cinnamomum osmophlo
Lauraceae
Leaves
Cinnamaldehyde
1, 10 and 100 μM Cinnamaldeh
Renal interstitial fibroblasts
---- Inhibited renal tubuloin
Page 68
eum Kaneh. (Chao et al., 2010)
yde (NRK-49F)
terstitial fibrosis in diabetic nephropathy
Curcuma longa L. (Huang et al., 2013)
Zingiberaceae
Rhizomes Curcumin 150 mg/kg curcumin (p.o.)
STZ-induced diabetes in Sprague-Dawley rats
---- Prevented diabetic nephropathy
Curcuma longa L. (Soetikno et al., 2012)
Zingiberaceae
Rhizomes Curcumin 100 mg/kg /day (p.o.) curcumin
STZ-induced diabetes in Sprague-Dawley rats
---- Prevented diabetic cardiomyopathy
Embelia ribes Burm.f. (Bhandari and Ansari, 2009)
Myrsinaceae
Fruits Embelin 200 mg/kg/day (p.o.) ethanol extract
STZ-induced diabetes in male Wistar rats
---- Attenuate iso-induced oxidative stress in diabetic rats
Eugenia jambolana Lam. (Tanwar et al., 2010)
Myrtaceae
Fruits α-hydroxy succinamic acid
10, 15 and 20 mg/kg b.w. (p.o.) α-hydroxy succinamic acid
STZ-induced diabetes in male albino Wistar rats
Glibenclamide (0.6 mg/kg b.w., p.o.)
Attenuate renal dysfunction
Gymnema sylvestre (Retz.) Schult. (Sugihara et al., 2000)
Asclepiadaceae
Leaves Gymnemic acid IV
3.4-13.4mg/kg (p.o.) gymnemic acid IV
STZ-induced diabetes in male Wistar rats
Glibenclamide (0.6 mg/kg, p.o.)
Antihyperglycemic, hypolipidemic and strong
Page 69
antioxidant activity in diabetic rats
Gymnema sylvestre (Retz.) Schult. (Daisy et al., 2009)
Asclepiadaceae
Leaves Dihydroxy gymnemic triacetate
5, 10,20 mg/kg b.w. (p.o.) dihydroxy gymnemic triacetate
STZ-induced diabetes in male Wistar rats
Insulin (3 IU/kg b.w.)
Hypoglycemic and hypolipidemic activity
Hericium erinaceus (Bull.) Persoon (Wang et al., 2005)
Hericiaceae
Fruit
D-threitol and arabinitol
20, 100, 200 mg/kg b.w. (p.o.) methanol extract
STZ-induced diabetes in male Wistar rats
---- Hypoglycemic and hypolipidemic activity
Hydrangea paniculata Siebold (Zhang et al., 2012)
Hydrangeaceae
Herb Skimmin 7.5, 15 and 30 mg/kg (p.o.) skimming
STZ-induced diabetes in adult Wistar rats
Losartan (10 mg/kg, p.o.)
Suppressed diabetic nephropathy
Lycium barbarum L. (Song et al., 2012)
Solanaceae
Fruits Taurine 0.001, 0.01, 0.1, 0.5, 1, 10 mg/ml methanol extract and 0.001, 0.01, 0.1, 0.5, 1, 10 mM taurine
ARPE-19retinal epithelial cell line
Rosigitazone (10mM)
Delayed progression of diabetic retinopathy
Magnolia officinalis Rehder & E.H.Wilson (Eun-Jin et al., 2007)
Magnoliaceae
Cortex Magnolol 100 mg/kg b.w. (p.o.) magnolol
Non-obese type 2 diabetic Goto-Kakizaki (GK) rats
---- Retarded diabetic nephropathy
Mirabilis Nycta Roots Astraglaosid 10 and 20 STZ- Glibencl Hypolip
Page 70
jalapa L. (Sarkar et al, 2011)
ginaceae
e II, IV, VI; flazin, gingerglycolipid A, 3,4-dihydroxy benzaldehyde, p-hydroxy benzaldehyde, β-sitosterol and daucosterol
mg/kg b.w. (p.o.) ethanol extract
induced diabetes in male albino Wistar rats
amide (1mg/kg b.w., p.o.)
idemic and hypoglycemic activity
Mucuna pruriens (L.) DC. (Murugan et al., 2009)
Leguminosae
Leaves Dietary fiber, glycosides and alkaloids
150 mg/kg (p.o.) toluene, chloroform, ethyl acetate and n-butanol fractions
Alloxan induced diabetes in Wistar albino rats
Glibenclamide (10 mg/kg b.w., p.o.)
Hypoglycemic and hypolipidemic activity
Nigella sativa L. (Sankaranarayanan and Pari, 2011)
Ranunculaceae
Seeds Thymoquinone
80 mg/kg b.w. (i.g.) thymoquinone
STZ-nicotinamide induced diabetes in male albino Wistar rats
---- Antidiabetic, antioxidative and neuroprotective activity
Paeonia lactiflora Pall. (Jianfang et al., 2009)
Paeoniaceae
Roots Paeoniflorin 5, 10 and 20 mg/kg paeoniflorin (p.o.)
STZ-inducde diabetes in female Harlan Sprague–Dawley pathogen-free rats
---- Prevented diabetic nephropathy
Peucedanum pastinacifolium
Apiaceae
Aerial parts Furanocoumarines
125 mg/kg b.w. (p.o.) hydroalcoholic (70:30)
STZ-induced male Wistar
Glibenclamide (5 mg/kg b.w.,
Hypoglycemic and hypolipi
Page 71
Boiss. & Hohen. (Movahedian et al., 2010)
extract rats p.o.) demic activity
Phyllanthus simplex Retz. (Shabeer et al., 2009)
Euphorbiaceae
Whole plant Phyllanthin and gallic acid
Petroleum ether (200 mg/kg); ethyl acetate (100 and 200 mg/kg); Methanol (125 mg/kg); aqueous fractions (150 mg/kg) (p.o.)
Alloxan induced diabetes in Charles Foster albino rats
Glibenclamide (10 mg/kg, p.o.)
Antidiabetic and normalized alterations in antioxidant enzymes and antioxidant parameters in liver and kidney of diabetic rats
Salacia oblonga Wall. (Huang et al., 2006)
Celastraceae
Roots Salicinol and kotalanol
100 mg/kg (p.o.) aqueous extract
Zucker diabetic fatty (ZDF) rats
---- Antihyperlipidemic and antiobesity activity
Salacia oblonga Wall. (Krishnakumar et al., 2000)
Celastraceae
Roots Salicinol and kotalanol
Antilipidperoxidative activity
Salacia oblonga
Celastraceae
Roots Salicinol and kotalanol
100 mg/kg (p.o.) water
Zucker diabetic
---- Inhibited
Page 72
Wall. (Huang et al., 2008)
extract fatty rats cardiac fibrosis and cardiac hypertrophy
Siraitia grosvenorii (Swingle) C.Jeffrey ex A.M.Lu & Zhi Y.Zhang (Xiang-Yang et al., 2008)
Cucurbitaceae
Fruits Mogrosides 100 mg/kg (p.o.) mogrosides
Alloxan induced diabetic mice
XiaoKeWan-pill (894 mg/kg)
Prevented oxidative stress and hyperlipidemia
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Figure 1: Possible molecular mechanism for diabetic complications. Hyperglycemia in
combination with oxidative stress triggers the detrimental pathways of polyol, PKC, AGE and
hexosamine extending to consequences like, redox imbalance, alterations in gene expression,
modified transcription factors which further enhances oxidative stress leading to various diabetic
complications. G-6-P Glucose-6-phosphate, DAG diacyl glycerol, PKC protein kinase C, ROS
reactive oxygen species, RNS reactive nitrogen species, AGE advanced glycation end products,
NCV nerve conduction velocity, NF-κB nuclear factor kappa and MAPK mitogen activated
protein kinase.
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Figure 2: Mechanism of action of various chemical constituents in diabetes and diabetic
complications
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Figure 3: Major Chemical constituents of plant species used in the management of diabetic
complications.
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Graphical Abstract
