Trends in Food Science & Technology 68 (2017) 1e13

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Review

Anthocyanins as promising molecules and dietary bioactive

components against diabetes e A review of recent advances
Vemana Gowd a, Zhenquan Jia b, Wei Chen a, *
a
Department of Food Science and Nutrition, National Engineering Laboratory of Intelligent Food Technology and Equipment, Key Laboratory for Agro-
Products Postharvest Handling of Ministry of Agriculture, Zhejiang Key Laboratory for Agro-Food Processing, Zhejiang University, Hangzhou 310058, China
b
Department of Biology, The University of North Carolina at Greensboro, Greensboro, NC 27412, USA

a r t i c l e i n f o a b s t r a c t

Article history: Background: Diabetes is a metabolic disorder characterized by presence of chronic hyperglycaemia. Thus,
Received 4 June 2017 strategies to maintain blood glucose levels are critical for the treatment of this devastating disease.
Received in revised form Anthocyanins are naturally occurring compounds widely available in berries, and increasing evidence
20 July 2017
demonstrates a positive relationship between consumption of anthocyanins rich foods and lowers dia-
Accepted 21 July 2017
Available online 25 July 2017
betes complications.
Scope and approach: This review highlights recent findings on the anti-diabetic effects of anthocyanins in
various organs and particularly emphasizes on the studies that investigated the cellular and molecular
Keywords:
Anthocyanins
mechanisms involved in the beneficial effects of this bioactive molecules.
Diabetes Key findings and conclusions: Over the past two decades, numerous studies have demonstrated that
Oxidative stress anthocyanins can exert the beneficial effects in diabetes by acting on various molecular targets and
Insulin resistance regulate different signalling pathways in multiple organs and tissues such as liver, pancreas, kidney,
AMPK adipose, skeletal muscle and brain. Anthocyanins can lower blood glucose levels by protecting b-cells,
improving insulin resistance, increasing insulin secretion, improving liver function, and inhibiting car-
bohydrate hydrolyzing enzymes. The antidiabetic properties of anthocyanins may also attribute to their
antioxidant capacity. Taken together, anthocyanins may be a novel small molecule for the prevention and
treatment of diabetes.
© 2017 Elsevier Ltd. All rights reserved.

1. Introduction cells to use insulin against glucose. However, both circumstances

Diabetes mellitus (DM) is a noncommunicable and severe
endocrine metabolic disorder which has the ability to induce
serious complications in various organs (C. Zhang et al., 2012). The
number of DM affected people are increasing day by day, and
approximately the number would reach to around 300 million by
the year 2025 (King, Aubert, & Herman, 1998). According to WHO
studies, by 2030, DM would be the 7th leading cause of death
worldwide (Mathers & Loncar, 2006). DM is characterised by an
increase in blood glucose levels (Gowd & Nandini, 2015;
Joladarashi, Salimath, & Chilkunda, 2011), which is due to either
paucity of insulin secretion by pancreatic b-cells or inefficiency of
* Corresponding author. Department of Food Science and Nutrition, Zhejiang
University, 866 Yuhangtang Road, Xihu District, Hangzhou 310058, China.
E-mail address: zjuchenwei@zju.edu.cn (W. Chen).
can affect the glucose uptake and its disposal by cells (Gowd,
Gurukar, & Chilkunda, 2016). In the absence of proper medical
care, DM can lead to severe secondary complications such as kidney
failure, liver dysfunction (Manna, Das, Ghosh, & Sil, 2010; Ritz,
2006), blindness, heart attack, stroke, and nerve damage (Kam
et al., 2016). Therefore, maintenance of normal blood glucose
levels is mandatory for adequate body function. In human body
glucose homeostasis is controlled by various organs including
pancreas, liver, brain, intestine, adipose and muscle tissue with
their sophisticated network of various hormones and neuropep-
tides. Among all organs pancreas play a critical role in glucose
homeostasis by secreting glucose lowering hormone insulin and its
opponent glucagon (Roder, Wu, Liu, & Han, 2016).
Reactive oxygen species (ROS) plays an important role in a va-
riety of processes such as cell proliferation, inflammation and
apoptosis (Covarrubias, Hernandez-Garcia, Schnabel, Salas-Vidal, &
Castro-Obregon, 2008). At small doses, ROS plays a major role in the

http://dx.doi.org/10.1016/j.tifs.2017.07.015
0924-2244/© 2017 Elsevier Ltd. All rights reserved.
2 V. Gowd et al. / Trends in Food Science & Technology 68 (2017) 1e13
immune system and helps in maintenance of redox balance.
However, over accumulation of ROS and free radicals can lead to
oxidative stress (OS) and oxidative damage (T. Bao et al., 2016;
Chen, Xu, Zhang, Li, & Zheng, 2016; Srinivasan, 2014) which
further cause a deleterious effect to the antioxidant defence system.
In the long run, OS causes mutations, and damage to various
macromolecules such as DNA, protein, lipids, membranes and or-
ganelles such as mitochondria (Wei Chen, et al., 2016; Choi, Lee,
Park, & Han, 2016; Rahman, Hosen, Islam, & Shekhar, 2012). Over
accumulation of free radicals and ROS implicate in the development
of age-related diseases and chronic disorders such as DM, cancer,
atherosclerosis, neurodegenerative disorders (Chen et al., 2010;
Chen, Su, Huang, Feng, & Nie, 2012; Chen et al., 2009; Rahman
et al., 2012).
Oxidative stress plays an influential role in the implication of
DM complications. Sustained hyperglycaemia can promote OS and
thereby decrease the antioxidant defence mechanism through the
formation of advanced glycation end products (AGEs) (Bonnefont-
Rousselot et al., 2004). OS itself can play a critical role in genesis
and progression of DM complications by causing perturbations to
antioxidant defence system (Rains & Jain, 2011). It has a detri-
mental effect on protein, nucleic acids, and lipid moieties during
DM and eventually leads to manifestation of micro and macro-
complications (Giacco & Brownlee, 2010). Various feasible path-
ways were studied in investigating the possible routes of OS during
hyperglycaemia including increase in polyol pathway flux, AGEs
formation, overproduction of superoxides by the mitochondrial
electron transport chain (METC) or activation of protein kinase-C
(Rains & Jain, 2011). Hence, OS is an unfavourable process during
DM, and DM can be managed by minimising the OS. Oxidative
stress during DM can be decreased by inhibition of carbohydrate
hydrolyzing enzymes such as a-amylase and a-glucosidase. The
enzyme a-glucosidase is found in mucosal brush border which
helps in digestion of oligosaccharides into monosaccharides
(Hadrich, Bouallagui, Junkyu, Isoda, & Sayadi, 2015), whereas a-
amylase is found mostly in saliva and helps in conversion of starch
into absorbable molecules (Kim, Rioux, & Turgeon, 2014). Several
drugs have been reported to treat DM, for example, acarbose is a
glucosidase inhibitor, which is often prescribed to DM patients.
However, the use of acarbose-like molecules often produces side
effects like diarrhoea and other intestinal disturbances. Hence their
usage is limited in DM treatment (Boue, Daigle, Chen, Cao, &
Heiman, 2016). Life style and dietary habits are critical factors
determining the onset and progression of DM. A proper diet
including increase in proportion of fruits and vegetables can delay
or prevent the manifestation of DM or improve the condition of
individuals with an established DM complications (Sancho &
Pastore, 2012). The benefits associated with a healthy diet can be
attributed to higher concentrations of antioxidants found in fruits
and vegetables such as flavonoid-polyphenolic compounds, to-
copherols, and carotenoids (Ames, Shigenaga, & Hagen, 1993;
No€thlings et al., 2008; Xu et al., 2017). Among flavonoid-
polyphenolic compounds, anthocyanins are coloured pigments
which possess potent antioxidant properties. Numerous studies
have reported the antioxidant activities of anthocyanins and their
beneficial effects on health during inflammation, cancer, obesity
and DM (Bowen-Forbes, Zhang, & Nair, 2010; Guo & Ling, 2015;
Ka€hko € nen & Heinonen, 2003).
In this review, we describe the DM and glucose homeostasis,
role of OS in DM, modulation of DM by anthocyanins and antho-
cyanin rich sources in various organs and discussion of possible
mechanisms involved. In addition, we also describe the antidiabetic
effect of anthocyanins via inhibiting carbohydrate hydrolysing
enzymes.
1.1. Anthocyanins
Anthocyanins are water-soluble polyphenolic pigments and
secondary metabolites of plant products (Bunea et al., 2013), which
are widely found in fruits and vegetables (Basu, Nguyen, Betts, &
Lyons, 2014; Chen, Su, Xu, Bao, & Zheng, 2016; T. Wu, Tang, et al.,
2013; T. Wu, Yu, et al., 2013). Anthocyanins are often referred to
as flavonoids and are responsible for red-orange to blue-violet
colours in various parts of plants especially in edible berries (Tao
Bao et al., 2016; Chen, Xu, et al., 2016c; Liobikas, Skemiene,
Trumbeckaite, & Borutaite, 2016; L. Zhang et al., 2017). To date,
approximately 700 structurally different anthocyanins have been
identified in nature, and the number is steadily increasing. An-
thocyanins are found as aglycon derivatives called as anthocyani-
dins, and there are approximately 30 identified anthocyanidins till
date. However, six of the anthocyanidins such as cyanidin, delphi-
nidin, malvidin, peonidin, pelargonidin, and petunidin are pre-
dominantly found in nature among all identified anthocyanidins
(Kamiloglu, Capanoglu, Grootaert, & Van Camp, 2015; Prior & Wu,
2006; X.; Wu et al., 2006). Among dietary consuming flavonoids,
anthocyanins are most consuming flavonoids in the form of daily
diet. Approximately 180e225 mg per day anthocyanins could be
consumed according to US dietary consumption (Kamiloglu et al.,
2015; McGhie & Walton, 2007).
2. Diabetes and regulation of glucose homeostasis
Diabetes and glucose homeostasis are related to assure normal
body function, the maintenance and control of blood glucose levels
is mandatory. The maintenance of relatively constant blood glucose
levels is controlled by various organs of the body including
pancreas, liver, brain, intestine, adipose and muscle tissue with
their sophisticated network of various hormones and neuropep-
tides. As a major exocrine and endocrine organ, pancreas plays a
key role in glucose homeostasis by secreting glucose lowering
hormone insulin and its opponent glucagon (Roder et al., 2016)
(Fig. 1). Regulation of hormone and peptide secretion by pancreas
affects glucose homeostasis which contributes in onset of DM and
its complications. Opposing and balancing action of insulin and
glucagon, two hormones secreted by pancreas, preserve and
maintain blood glucose levels within a range (4.4e6.1 mM)
(Aronoff, Berkowitz, Shreiner, & Want, 2004). Increase in exoge-
nous blood glucose levels followed by meals stimulates b-cells to
secrete insulin to counteract elevated blood glucose levels
(Komatsu, Takei, Ishii, & Sato, 2013). Insulin induces liver glyco-
genesis and inhibits gluconeogenesis, initiates the glucose uptake
from various tissues such as muscle and adipose tissue thereby
facilitating maintenance of normal blood glucose levels by
removing exogenous glucose from blood stream. However, sus-
tained elevated insulin levels may result in combined impotence of
muscle and adipose tissue to facilitate glucose uptake and of the
liver to supress glucose output which is referred to as insulin
resistance, a hall mark of type 2 diabetes (Khan & Pessin, 2002).
Whereas, glucagon secreted from a-cells plays exactly contrasting
role to insulin. During sleep or fasting time a-cells secretes
glucagon to promote hepatic glycogenolysis to maintain normal
glucose levels in which glucose can be produced from stored
glycogen in liver. In addition, glucagon also stimulates gluconeo-
genesis in liver and kidney during prolonged fasting to maintain
blood glucose levels in a range (Freychet et al., 1988). Impaired
insulin secretion by pancreatic b-cells or loss of cellular response to
insulin such as insulin resistance can increase blood glucose levels.
Sustained hyperglycaemia can lead to formation of AGEs followed
by inducing OS and causing perturbations to protein moieties
(Sancho & Pastore, 2012). Prolonged exposure to high blood glucose
 V. Gowd et al. / Trends in Food Science & Technology 68 (2017) 1e13
concentrations will result in the manifestation of various micro and
macrovascular complications. Retinopathy, nephropathy, non-
alcoholic fatty liver disease (NAFLD), cardiomyopathy, and neu-
ropathy are most severe secondary complications associated with
sustained hyperglycaemia which are known to affects eyes, kidney,
liver, heart and nerves (Gowd et al., 2016; Patel & Santani, 2009).
The review below will highlight recent findings on the anti-diabetic
effects of anthocyanins in various organs including pancreas, liver
and adipose to regulate glucose homeostasis as well as the cellular
and molecular mechanisms involved in the beneficial effects of
anthocyanins.
2.1. Pancreas dysfunction in manifestation of diabetes mellitus, and
the anti-diabetic action of anthocyanins
Diabetes mellitus is associated with impairment in pancreatic b-
cells. In general, DM is classified as type1 and type2 based on the
function of pancreatic b-cells. Type1 DM is typically referred to as
insulin dependent in which loss of insulin secretion by b-cells is due
to destruction. Type2 DM is referred to as non-insulin dependent,
in which peripheral resistance of cells to insulin and in the long run
which can lead to the destruction of b-cells in the pancreas (Gowd
et al., 2016; Zunino, 2009). Few studies depicted that anthocyanins
and anthocyanin rich foods can protect pancreatic b-cells and
stimulate insulin secretion (Table 1). Increased expression of in-
sulin transcript was observed in pancreatic cells from alloxan-
induced diabetic rats upon treatment with anthocyanin rich
extract V. arctostaphylos. The increase in insulin transcripts might
be attributed to stimulation of surviving b-cells or increased pro-
duction of insulin from remnant b-cells (Feshani, Kouhsari, &
Mohammadi, 2011). However, the exact mechanisms of
anthocyanin-stimulated insulin secretion and b-cell protection
remain largely unclear (Hong et al., 2013). Hence, more studies are
needed to elucidate the exact mechanism of anthocyanins-
mediated insulin secretion, b-cell protection and subsequent
maintenance of glucose homeostasis.
Dysfunction and inadequate compensation of pancreatic b-cells
associated with hyperglycaemia can lead to onset of OS. Antioxi-
dant enzymes such as catalase, superoxide dismutase (SOD), and
Fig. 1. Maintenance of normal blood glucose levels by pancreas. Pancreas secrete glucagon to counteract decrease in blood glucose levels. Glucagon promotes liver glygenolysis and
gluconeogenesis to increase blood glucose levels to normal. Whereas pancreas secrete insulin after meals to counteract increased blood glucose levels. Insulin promotes glucose
uptake from muscle and adipose tissue. Insulin also promotes glycogenesis and inhibit gluconeogenesis in order to maintain normal blood glucose levels.
3
glutathione peroxidase (GPx) are obligatorily required by the
pancreas to fight against ROS and free radicals. Nevertheless,
pancreatic islets are known for poor expression of aforementioned
antioxidant enzymes, hence, pancreatic b-cells are highly suscep-
tible to OS (Drews, Krippeit-Drews, & Dufer, 2010; Tiedge, Lortz,
Drinkgern, & Lenzen, 1997). Therefore, modulation of antioxidant
enzymes and their activity is one of the strategic method involved
in the protection of pancreatic b-cells, thereby management of DM.
Miscellaneous findings from in-vitro and in-vivo studies displayed
the protective role of anthocyanins against pancreatic b-cell
dysfunction via modulating the antioxidant enzymes suggesting
the possible role of anthocyanins in the management of DM and
related complications (Sancho & Pastore, 2012) (Fig. 2) (Table 1).
Anthocyanins from Cornelian Cherry (Cornus mas) tend to regulate
b-cell function thereby disclosing their antidiabetic properties.
Anthocyanins supplementation to mice (C57BL/6) fed with high-fat
diet prevented glucose intolerance and resulted in 26% decrease in
weight gain. Further, lipid accumulation and triglyceride concen-
trations were significantly minimized in the liver of mice treated
with anthocyanins. Immunostaining of mouse pancreatic sections
disclosed that anthocyanins treatment prevented b-cell dysfunc-
tion and elevated the insulin levels (Bolleddula Jayaprakasam,
Olson, Schutzki, Tai, & Nair, 2006). Cyanidin-3-glucoside (C3G)
isolated from mulberry fruits was found to be cytoprotective during
glucose-induced apoptosis in MIN6N pancreatic b-cells. Generation
of ROS, DNA fragmentation and the rate of apoptosis were effec-
tively depleted followed by C3G supplementation supporting the
hypothesis that antidiabetic effect of anthocyanins is associated
with decreasing OS and increasing antioxidant defence system (Lee,
Kim, Park, et al., 2015). Protective role and antioxidative property of
anthocyanins against DM are further supported by evidence in
which OS was induced by exploring MIN6N pancreatic b-cells to
H2O2 (Lee, Kim, Song, et al., 2015). H2O2 treatment stimulated
various pro-apoptotic processes such as generation of ROS, DNA
fragmentation, lipid peroxidation (LPO), and caspase-3-activation,
thereby increasing the rate of apoptosis. In addition, H2O2 activated
the mitogen-activated protein kinases (MAPKs), such as extracel-
lular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase
(JNK) and p38 MAPK. However, ROS production was plausibly
 4 V. Gowd et al. / Trends in Food Science & Technology 68 (2017) 1e13

prevented; ERK and p38 MAPK phosphorylation were effectively

Prevention and control and diabetes and its comorbidities (Sun

C57BL/6 mice fed with high-fat Glucose tolerance prevention, decrease in weight gain, decrease in Improved metabolic parameters which are known to involve in

Cytoprotective and phototherapeutic agent for the prevention

inhibited followed by C3G treatment. C3G treatment also regu-

Antidiabetic activity (B. Jayaprakasam, Vareed, Olson, & Nair,

Antidiabetic activity via b-cell protection thereby increase in
insulin secretion and AMPK activation in liver (Huang et al.,
lated the intrinsic apoptotic pathway associated proteins cyto-
pathogenesis of metabolic disorders such as diabetes and

chrome C, and caspase-3 which belongs to Bcl-2 family. These

results suggested that anthocyanins are potential antidiabetic

Increase in expression of IGF-II, IGFBP2, and 3, VEGF, modulation in Antidiabetic activity (Johnson & de Mejia, 2016)
agents via their potent antioxidative properties (Lee, Kim, Song,
liver, preserved the islet architecture, and improved b-cell function obesity (Bolleddula Jayaprakasam et al., 2006)

et al., 2015).
Among tested anthocyanins and polyphenols, the anthocya-
of diabetes (Lee, Kim, Park, et al., 2015)
Antidiabetic activity (Hong et al., 2013)

nins derived from purple corn had a remarkable impact on b-cell

function and insulin secretion. Purple corn anthocyanins treat-
ment protected pancreatic b-cells from high glucose-induced OS,
and improved insulin secretion capacity of b-cells, however, the
exact mechanism is not known (Hong et al., 2013). The C57BL/KsJ
db/db mice supplemented with anthocyanin-rich purple corn
extract (PCE) showed approximately 68% decline in blood glucose
levels compared to control group. In addition, PCE treatment
Significance

et al., 2012)

increased the AMP-activated protein kinase (AMPK) phosphor-

ylation and decreased the phosphoenolpyruvate carboxykinase
2015)

2005)

and glucose 6-phosphatase (G6P) genes in liver, whereas the

expression of glucose transporter 4 (GLUT4) was increased in
glycolysis and fatty acid metabolism in liver and fat tissues, increase
Decrease in fasting blood glucose levels, 2- fold increased C-peptide

ROS, increase in cell viability, increase in insulin like growth factor

prevention of b-cell damage, increase in insulin content, improved
Decrease in ROS generation, DNA fragmentation, rate of apoptosis,

b-cell protection and Increase in insulin secretion, reduced blood

and adiponectin levels, decrease in glycated haemoglobin levels,

skeletal muscle. Further morphological studies revealed that PCE

Decrease in H2O2 induced cell death, decrease in mitochondrial

and insulin protein, reduced blood glucose, and increase in oral

lipid accumulation and reduce in triglycerides concentration in

appreciably inhibited the b-cell damage and increased the insulin

in AMPK phosphorylation, increase in skeletal muscle GLUT4,
glucose levels, prevented oral glucose tolerance (OGTT), and

decrease in glucose 6-phosphatase gene expression in liver

DPP4 and its substrate GLP-1, increase in insulin secretion

secreting activity thereby increasing insulin content (Huang

et al., 2015). These findings proposed that PCE can manage con-
sequences of DM via increasing insulin secretion and activating
liver AMPK followed by pancreatic b-cell protection in C57BL/KsJ
db/db mice. Another study on antidiabetic effect of anthocyanin-
decrease in glycated haemoglobin (HbA1C)

Increase glucose induced insulin secretion

rich Chinese wild blueberry extract validated the effect of an-

thocyanins against glucolipotoxicity-induced INS832/13 b-cell
dysfunction and cell death (J. Liu et al., 2015). Noticeably, INS832/
and increase in insulin secretion

13 b-cells treated with extract showed decrease in ROS and in-

Studies associated with pancreatic b-cells to prove antidiabetic activity of anthocyanins and anthocyanin rich sources.

crease in antioxidant defence system compared to control cells.

Reduced intracellular triglyceride levels in treated cells were
accompanied by restoration of intracellular insulin content and
glucose tolerance

lowering basal insulin secretion. Further, extract treated cells

were resulted in increase in glucose-stimulated insulin secretion
thereby elevating insulin secretion index (J. Liu et al., 2015).
Outcome

2.2. Regulation of glucose metabolism in liver, and modulation by

anthocyanins during diabetes
b-cells/C57BL/KsJ db/db mice
MIN6N pancreatic b-cells

As a prime site in the body liver is involved in critical functions

Rat insulinoma cell line
C57BL/KsJ db/db mice

such as metabolism and regulation of glucose and lipids. In

INS-1/Male ICR mice
HIT-T15 pancreatic

addition, liver plays a fundamental role in glycogen storage,

INS-1832/13 cells
In vitro/in vivo

plasma protein synthesis and detoxification (T. Bao et al., 2016).

iNS-1E cells

Also this organ plays a critical role in plasma glucose buffering

either by net hepatic glucose utilization or net hepatic glucose
production based on need (Ko €nig, Bulik, & Holzhütter, 2012).
diet

During DM either lack of insulin secretion by pancreatic b-cells or

inability of other tissue cells to utilize secreted insulin against
Purified anthocyanin powder
pelargonidin 3-O-galactoside

Fermented anthocyanin rich

delphinidin 3-O-galactoside,

Cyanidin-3-glucoside (C3G)

glucose can result in regulation of hepatic glucose homeostasis

pelargonidin-3-galactoside
Cyanidin-3-glucoside rich
cyanidin 3-O-galactoside,

Anthocyanin rich extract

Delphinidin-3-glucoside
Pure Compound/extract

eventually leading to the elevated blood glucose concentrations.

Cyanidin-3-galactoside,
Purified anthocyanins

Increase in hepatic glucose production during DM can be

attributed to defect in net hepatic glycogen synthesis or
augmented gluconeogenesis and glycogenolysis. Hence, repres-
blackberry fruits beverages

sion of gluconeogenesis, glycogenolysis and hepatic glucose

extract

output by increasing hepatic glycogen synthesis is one of the

strategic targets in prevention of hyperglycaemia. AMPK is a
major contributing factor in liver which helps in maintenance
Cornelian cherries

Chinese bayberry

and control of hepatic glucose and lipid metabolism. AMPK is a

(Cornus mas)

Mulberry fruits

critical energy sensing pathway to stimulate glucose uptake

c. mas fruits
Purple corn

Purple corn

c. officinalis

Blueberry/

(Sharma et al., 2008). AMPK activation by natural products

claimed to have favourable effects in treatment of DM (Hardie,
Source
Table 1

2013). Anthocyanins and anthocyanin rich foods also help in

maintenance of hepatic glucose homeostasis via different
 V. Gowd et al. / Trends in Food Science & Technology 68 (2017) 1e13
Fig. 2. Anthocyanins and their protective role during diabetes and associated complications in various tissues such as liver, kidney, pancreas, skeletal muscle, and adipose tissue.
pathways (Table 2). Diabetic mice treated with anthocyanin rich
bilberry extract showed hepatic AMPK activation which resulted in
reduced blood glucose concentrations followed by elevated insulin
sensitivity (Fig. 2). Hepatic AMPK activation was accompanied by
repression in hepatic glucose production and lipid accumulation.
Meanwhile acetyl-CoA carboxylase was inactivated, and major
regulators of lipid metabolism such as PPARa, acyl-CoA oxidase,
and carnitine palmitoyltransferase-1A were upregulated
(Takikawa, Inoue, Horio, & Tsuda, 2010). Consistent results were
found by other researchers, where anthocyanin rich mulberry fruit
extract increased the level of AMPK phosphorylation in liver
thereby inhibiting gluconeogenesis and stimulating the glycogen
synthesis. Increase in insulin sensitivity, and reduced hepatic
glucose production followed by treatment with anthocyanin-rich
mulberry fruit extract was found to be via AMPK phosphorylation
(Choi et al., 2016). Similar findings were found in in-vitro and in-
vivo studies, after treatment with anthocyanin-rich (cyanidin-3-O-
glucoside especially) blood orange juice, and its secondary
metabolite protocatechuic acid (PCA). Besides AMPK activation,
C3G and PCA treatment also repressed AMPK downstream kinase
mTOR/S6K both in-vitro and in-vivo. In addition, GLUT1 and GLUT2
expressions were increased after C3G and PCA consumption in liver
(Talagavadi, Rapisarda, Galvano, Pelicci, & Giorgio, 2016) (Fig. 2). In
another study, anthocyanin-rich mulberry extract increased
glucose consumption followed by promoting glycogen synthesis
and reducing gluconeogenesis in HepG2 cells (Fig. 2). The mecha-
nism of mulberry anthocyanins extract-mediated glucose meta-
bolism was associated with the activation of PI3K/AKT signalling
pathway (F. Yan, Dai, & Zheng, 2016). PI3K/AKT signalling pathway
is known to be positively correlated to modulation in glycogen
synthesis via inhibition of key molecules that are necessary for
5
gluconeogenesis (Yan, Dai et al., 2016) (Fig. 2). Further findings from
same authors suggested that mulberry anthocyanin extract is po-
tential in modulation of insulin resistance and amelioration of DM
complications. HepG2 cells cultured in high glucose and palmitic
acid developed insulin resistance, while anthocyanin extract
modulated the regulated glucose metabolism thereby increasing
glucose consumption, and glycogen synthesis eventually leading to
alleviation in insulin resistance (Yan, Dai et al., 2016).
2.3. Diabetes-induced oxidative stress and de-novo lipid synthesis
in liver and protective role of anthocyanins
Diabetes is also considered as a signal for liver disorders which
starts from simple non-progressive steatosis to severe non-
alcoholic steatohepatitis which can further leads to cirrhosis and
hepatocellular carcinoma (Zhu, Jia, Wang, Zhang, & Xia, 2012). In-
crease in intracellular de-novo lipid synthesis during DM is a major
contributing factor in the manifestation of liver complications. As
we discussed above, anthocyanins and anthocyanin-rich supple-
ments can help in maintenance of glucose homeostasis. In addition,
anthocyanins can also improve liver function by inhibiting de-novo
lipid synthesis during DM thereby preventing fatty liver develop-
ment (Table 2). Conversion of glycerol-3-phosphate and acyl-CoA
into phosphatidic acid, a precursor of TAG and glycer-
ophospholipids is a rate limiting step in the glycerol 3-phosphate
pathway. Researchers found a novel mechanism in fatty liver
development during DM, which is mediated by liver GPTA1 acti-
vation followed by translocation of mtGPTA1 from endoplasmic
reticulum to the outer mitochondrial membrane. Cyanidin 3-O-b-
glucoside treatment to hepatocytes cultured in high glucose con-
ditions inactivated GPTA1 and inhibited translocation of mtGPTA1
 6
Table 2
Protective role of anthocyanins in liver against diabetes and its associated complications.

Source Pure compound/ In vitro/In vivo Outcome Significance

extract

C. mas fruits Diet containing C57BL/6mice Decrease in lipid accumulation and triglycerides concentrations in Improvement in major metabolic parameters of metabolic disorders
anthocyanins liver, elevated insulin levels, Decrease in body weight gain, such as diabetes, prevented development of fatty liver (Bolleddula
improved glucose tolerance Jayaprakasam et al., 2006)
Cyanidin-3-O- b Pure C3G HepG2 cells, Male KKAy mice Suppression of de-novo lipogenesis via reducing the GPAT1 activity Novel mechanism of liver protection from lipid accumulation during

V. Gowd et al. / Trends in Food Science & Technology 68 (2017) 1e13

-glucoside thereby preventing mtGPAT1 translocation from endoplasmic diabetes via inhibiting mtGPAT1 activity (Guo et al., 2011)
reticulum to outer mitochondrial membrane, increase in PKC
phosphorylation, amelioration of hepatic steatosis in mice
Blood orange juice C3G and its Murin hepatic cell line, C57BL/6 AMPK activation, dampening of mTOR/S6K, increase in expression Improvement in glucose homeostasis, therapeutic agent against type 2
secondary mice of liver GLUT1 and GLUT4, improved glucose tolerance, increase in diabetes (Talagavadi et al., 2016)
metabolite insulin sensitivity
Blueberries protocatechuic acid Type 2 diabetic mice Ameliorated hyperglycaemia, improved insulin sensitivity, AMPK Novel finding suggesting antidiabetic activity of anthocyanins via
Anthocyanin rich activation, suppression of intracellular glucose production, and lipid activation of AMPK, improving liver function (Takikawa et al., 2010)
extract content in liver, inactivated acetyl-CoA carboxylase, upregulated
liver PPARa, acyl-CoA oxidase, and carnitinepalmitoyltransferase-
1A
Mulberry fruits Anthocyanin HepG2 cells, db/db mice Alleviated insulin resistance in liver cells, increase in consumption Decrease in fasting blood glucose, cholesterol levels, serum insulin,
extract of glucose, glucose uptake, and glycogen content. Decrease in leptin and increase in adiponectin levels. The mitigation of insulin
enzyme activities of phosphoenolpyruvate carboxykinase (PEPCK) resistance in HepG2 cells via activation of PI3K/AKT pathway (Yan, Dai
and glucose-6-phosphatase (G6Pase) followed by inhibition of PGC- et al., 2016)
1a and FOXO1. Improved AKT phosphorylation and glycogen
synthase kinase-3b
Mulberry fruits Anthocyanin HepG2 cells Increase in glucose consumption and glycogen content, decrease in Regulation of glucose metabolism through PI3K/AKT pathway,
extract glucose production, increase in phosphorylation of AKT, and inhibition of gluconeogenesis, therapeutic target in treatment of type 2
glycogen synthase kinase-3b diabetes (F. Yan, Zhang, Zhang, & Zheng, 2016)
Cyanidin-3-O- b Standard C3G HepG2 cells, db/db mice Reduction in high glucose induced ROS followed by increase in Novel antioxidative defence mechanism via PKAeCREB, and prevention
-glucoside expression of glutamateecysteine ligase, increase in of high glucose induced oxidative stress and hepatic steatosis
phosphorylation of CREB via protein kinase A (PKA) activation, suggesting major role of anthocyanins in treatment of diabetes in liver
increase in liver GSH synthesis, amelioration in hepatic steatosis, (Zhu et al., 2012)
followed by reduction in oxidative stress
Mulberry fruits Anthocyanin HepG2 cells, Inhibited diabetes induced ROS and free radical accumulation, and Antidiabetic effect of MAE was via regulation of AMPK/ACC/mTOR
extract Db/db mice improved mitochondrial function signalling pathway (Fujie Yan & Zheng, 2017)
 V. Gowd et al. / Trends in Food Science & Technology 68 (2017) 1e13 7

thereby suppressing intracellular de-novo lipogenesis (Fig. 2).

pathway, therapeutic agent to treat kidney failure during

ligand-receptor system linked to renal VEGFR2 signaling
Inactivation of GPTA1 followed by treatment with anthocyanin

followed by amelioration of DN via phosphorylation of

Antagonized glomerular angiogenesis via Angpt-Tie-2

protective effect of anthocyanins in treatment of DN

was via phosphorylation of protein kinase C (Fig. 2) and mem-

Prevented high glucose induced mesangial fibrosis,

Therapeutic agent in prevention of diabetic kidney

improving renal function thereby ameliorating DN
Prevention of renal apoptosis and oxidative stress,
PPARa-LXRa-ABCA1-dependent cholesterol efflux,
brane translocation to phosphorylate the mtF0F1-ATPase b -sub-
unit, and to reduce its enzymatic activity (Guo, Li, Ling, Feng, &
Xia, 2011).

glomerulosclerosis (Li, Kang, et al., 2012)

Oxidative stress also has a detrimental effect on liver function
during DM, in the long run it can lead to liver dysfunction. OS
mediated reduction in antioxidant defence system is associated
with relentless and sustained chronic hyperglycaemia (Brownlee,

diabetes (Kang et al., 2013)

2001; Chen, Feng, Huang, & Su, 2012; Chen et al., 2011; Chen, Su,

AMPK (Koh et al., 2015)

Xu, & Jin, 2017; Mantena, King, Andringa, Eccleston, & Bailey,

(Li, Lim, et al., 2012)

2008). Therefore, targeting OS is a favourable strategy in preven-

(Du et al., 2015)

tion of DM-mediated liver disorders (Chandrasekaran,

Significance
Swaminathan, Chatterjee, & Dey, 2010; Rains & Jain, 2011; Zhu
et al., 2012). DM-mediated hepatic oxidative damage in db/db
mice was found to be ameliorated by cyanidin-3-O-b-glucoside
supplementation. Further, in-vitro studies where HepG2 cells

inhibition in activity of acetyl-CoA carboxylase, sterol regulatory

Increase in cholesterol efflux, ABCA1 expression, PPARa, LXRa,
decrease in proinflammatory molecules such as ICAM1, MCP1,

Attenuation in fibrosis biomarkers type IV collagen, and CTGF,

glomerular angiogenesis, diminished in angiopoietin proteins
cultured in high glucose conditions delineated the protective role

Alleviation in intra renal lipid accumulation, improvement in

attenuation in mesangial hyperplasia, protected from severe

metalloproteinase expression, decrease in tissue inhibitor of
glomerular matrix expansion and inflammation, increase in

Decrease in connective tissue growth factor (CTGF), type IV

accumulation of collagen in kidney glomeruli repression in

of anthocyanin on DM-induced hepatic oxidative damage via

collagen expression, increase in membrane type-1 matrix

matrix metalloproteinase-2 expression, dampening ECM

endothelial marker PECAM-1, integrin b3, prevention of

AMPK phosphorylation, activation of PPARa and PPARg,

activation of GSH synthesis (Zhu et al., 2012). Recent finding

degradation, decrease in inflammation, ICAM1, MCP-1,

Decrease in expression of VEGF, HIF-1a, attenuation in

albuminuria, lowered plasma glucose, ameliorated the

and dampened in induction and activation of VEGFR2
revealed that high glucose and palmitic acid-induced OS, free
radical accumulation, and mitochondrial dysfunction in HepG2

protein expressions of nephrin, and podocin

cells were partly recovered by anthocyanin-rich mulberry extract
(MAE) treatment. In addition, MAE extract supplementation
markedly mitigated pancreatic injuries in diabetic mice. MAE
protected hepatocytes against hyperglycaemia induced OS via
regulation of AMPK/ACC/mTOR pathway (Fujie Yan & Zheng,

dampened NFkB translocation

2017) (Fig. 2).

element-binding protein 1
In summary, published reports suggest that activation of AMPK
in the liver in the regulation of glucose homeostasis and lipid

TGFb1, and NFkB

synthesis is a main signalling pathway involved in anthocyanin-
mediated amelioration of DM complications in liver.
Outcome

2.4. Diabetic nephropathy and anthocyanins

Nephropathy is one of the major secondary complications of

HRMC, HUVEC, C57BLKS/J db/

DM, which leads to the end-stage kidney failure. The prevalence of

diabetic nephropathy (DN) has been constantly increased. The
HGECs, C57BLKS/J mice

HRMC, C57BLKS/J mice

exact mechanism behind DN during hyperglycaemia is not
known. However, studies on the high glucose-induced accumu-
Diabetic nephropathy and protective role by anthocyanin/anthocyanin rich sources.

In vitro/in vivo

lation of AGEs, and cytokines modulation have been postulated as

miscellaneous mechanisms in kidney (Kang, Lim, Lee, Yeo, & Kang,
HK-2 cells
db mice

2013). Hyperglycaemia promotes the lipid accumulation and

HRMC

infiltration of inflammatory cytokines in the kidney. Evidence

suggests that pathogenesis of DN is associated with lipotoxicity
and inflammation. Further, it has been proven that the proin-
flammatory cytokines such as monocyte chemoattractant protein-
Purple corn anthocyanins

Purple corn anthocyanins

Anthocyanin rich extract

Anthocyanin rich extract

1 (MCP1), transforming growth factor-b1 (TGF-b1), and intercel-

Pure compound/extract

lular adhesion molecule-1 (ICAM1) play a prominent role in the

development of DN (Du et al., 2015). During hyperglycaemia the
transcription factor such as nuclear factor-kB (NFkB) is known to
Pure C3G

translocate from the cytoplasm to the nucleus thereby triggering

the expression of proinflammatory cytokine genes that can induce
and amplify the inflammation. This process further accounts for
the glomerulosclerosis and tubulointerstitial fibrosis during sus-
tained hyperglycaemia (Du et al., 2015; Vendrame & Klimis-Zacas,
2015).
Anthocyanins and anthocyanin-rich sources have been impli-
SE; Glycine max L.

cated in the amelioration of DN complications such as glomerular

inflammation and glomerulosclerosis (Fig. 2) (Table 3). Studies on
Purple corn

Purple corn

Purple corn

purple corn anthocyanins portrayed the protective role of an-

thocyanins in diabetes associated glomerulosclerosis. Mesangial
Source
Table 3

C3G

cell proliferation and extracellular matrix accumulation are major

feasible factors in provocation of glomerulosclerosis during
8 V. Gowd et al. / Trends in Food Science & Technology 68 (2017) 1e13
diabetes. It has been reported that the mesangial cells cultured in
high glucose atmosphere resulted in substantial increase in con-
nective tissue growth factor (CTGF) and type IV collagen secretion.
However, purple corn anthocyanins supplementation ameliorated
the extracellular matrix accumulation followed by causing pertur-
bations to transforming growth factor b (TGF-b)-SMAD signalling
(Li, Lim, et al., 2012). Purple corn anthocyanins inhibited the
proinflammatory cytokines expression such as ICAM1 and MCP1,
both are responsible for CTGF expression and mesangial inflam-
mation. This study was further demonstrated the protective role of
purple corn anthocyanins against inflammation via dampening the
NF-kB translocation in high glucose-exposed cells (Li, Lim, et al.,
2012). In diabetic kidney, the infiltration and stockpiling of mac-
rophages was found to be antagonized by purple corn anthocyanins
via disturbing the mesangial IL-8-Tyk-STAT signalling pathway
(Kang et al., 2012). In-vitro and in-vivo studies on purple corn an-
thocyanins during hyperglycaemia further indicated the thera-
peutic role of anthocyanins in the treatment of diabetes
glomerulosclerosis which was accompanied by amelioration of
severe albuminuria and kidney filtration dysfunction. Anthocya-
nins evidenced in repression of protein expression such as nephrin
and podocin, which are essential proteins in the filtration barrier
function of the glomerular capillary wall (Li, Kang, et al., 2012). As
discussed earlier, still literature is scarce to illustrate the exact
mechanism involved in pathogenesis of DN. In addition to inflam-
mation and accumulation of extracellular matrix proteins, lip-
otoxicity is also one of the causative factors in the pathogenesis and
progression of nephropathy through transforming the filtration
process of glomeruli (Herman-Edelstein, Scherzer, Tobar, Levi, &
Gafter, 2014). Numerous studies have been reported that crucial
energy sensor called AMPK is abundantly expressed in normal
kidney, which plays a prominent role in the normalisation of lipid,
glucose metabolism and energy imbalances (Decleves et al., 2014;
Ruderman, Carling, Prentki, & Cacicedo, 2013). AMPK activity is
found to be reduced in diabetic kidneys (Decleves et al., 2014;
Ruderman et al., 2013). Therefore, activation of AMPK during DM
can attenuate the lipotoxicity, oxidative stress, inflammation, and
endothelial dysfunction (Srivastava et al., 2012). Anthocyanin-rich
seoritae extract supplementation activated AMPK thereby hinder-
ing the OS and lipotoxicity in diabetic mice (Koh et al., 2015).
Further, anthocyanins were also improved the glomerular matrix
expansion and ameliorated the inflammation in diabetic mice (Koh
et al., 2015). Besides, the treatment with anthocyanin inhibited the
OS and apoptosis in human glomerular endothelial cells cultured in
high glucose conditions (Koh et al., 2015). High glucose-induced
cholesterol accumulation and inflammation were profoundly
inhibited by anthocyanins via activation of LXRa pathway in HK-
2 cells. Anthocyanins enhanced the cholesterol efflux and choles-
terol efflux regulatory protein ABCA1 expression in cells subjected
to high glucose. In addition, they also found decrease in expression
of proinflammatory cytokines such as ICAM1, MCP1, TGF-b1 as well
NF-kB (Du et al., 2015).
2.5. Diabetic retinopathy and anthocyanins
Sustained hyperglycaemia can induce diabetic retinopathy (DR)
that is a serious specific neurovascular complication of both type 1
and type 2 diabetes (Solomon et al., 2017). Prolonged exposure to
high glucose concentrations can lead to diabetic macular edema,
retinal detachment, vitreous haemorrhages, and neovascular
glaucoma followed by fragile small blood vessels within the retina.
Retinopathy during diabetes could pose a permanent blindness if
left untreated (Ting, Cheung, & Wong, 2016). Although remarkable
attention has been focussed on dietary constituents to prevent
onset and progression of DM, there are only few successful dietary
intervention studies regarding prevention and progression of DR.
Morimitsu et al. examined the effect of anthocyanin monomers
isolated from grape skin extract on diabetic cataract. Five antho-
cyanin monomers of grape skin extract such as delphinidin 3-
glucoside, C3G, P3G, peonidin-3-glucoside and malvidin-3-
glucoside potentially inhibited the lens opacity suggesting that
the dietary supplementation of anthocyanins during diabetes can
protect from cataract (Morimitsu et al., 2002). In another study
researchers found that anthocyanins from blueberry can protect
retinal cells from diabetes-induced OS and inflammation (Song,
Huang, & Yu, 2016). Antioxidant capacity of retina was upregu-
lated followed by blueberry anthocyanin supplementation (Song
et al., 2016).
During recent decades, significant improvement was seen in the
treatment of DR. However, the exact mechanism by which DM is
affecting the retina and its function remains unclear. Plethora of
studies stipulated that the OS plays a significant role in pathogen-
esis of DR and DM complications could be managed by reducing OS
via decreasing the blood glucose concentrations. Therefore, OS in
retina could be considered as a therapeutic target in treatment of
DR. In addition, the molecules like anthocyanins would be of great
importance because of their potent properties as a-glucosidase and
a-amylase enzyme inhibitors and strong antioxidant in nature.
Therefore, more studies are needed in this area to find the exact
mechanism of anthocyanins against DR.
2.6. Effect of diabetes on other tissues and modulation by
anthocyanins
Apart from liver, adipose tissue is also appraised as an important
metabolic and endocrine organ and is involved in the regulation of
glucose and lipid metabolism and produces a variety of hormones
and cytokines such as adiponectin, tumour necrosis factor-alpha
(TNF-a), interleukin-6 (IL6), plasminogen activator inhibitor-1,
and leptin (Hajer, van Haeften & Visseren, 2008). Adiponectin
derived from adipose tissue has an insulin-sensitizing and anti-
atherogenic activity. Therefore, plummet in plasma adiponectin
concentrations is directly proportional to metabolic disorders such
as DM, obesity, and insulin resistance (Kadowaki et al., 2006; Ouchi,
Parker, Lugus, & Walsh, 2011; Ryan et al., 2003; Weyer et al., 2001).
Adiponectin also plays a pivotal role in the cardiovascular system
functioning through modulation of endothelial dysfunction.
Restoration of adiponectin expression during diabetes-induced
endothelial dysfunction is a strategic pathway, which would be
beneficial for the maintenance of cardiovascular function. Studies
found that C3G treatment can restore the endothelium-dependent
relaxation of the aorta in diabetic mice (Y. Liu, Li, Zhang, Sun, & Xia,
2014). Besides, C3G treatment also increased the adiponectin
expression/secretion in cultured adipocytes via transcription factor
forkhead box O1 (Foxo1). In addition, improved flow-mediated
dilation and increased serum adiponectin concentrations were
observed in pure anthocyanin treated type 2 diabetic patients
suggesting that anthocyanin treatment could prevent diabetes-
induced endothelial dysfunction through adiponectin thereby
protecting the cardiovascular system (Y. Liu et al., 2014) (Fig. 2). A
decrease in body and white adipose tissue weight was also found in
anthocyanin C3G treated diabetic mice, which was accompanied by
a decline in the size of the adipocytes in white adipose tissue (Y. Liu
et al., 2014). Anthocyanin treated 3T3-L1 preadipocytes resulted in
differentiation into smaller, insulin sensitive adipocytes thereby
promoting glucose uptake and insulin signalling (Matsukawa,
Inaguma, Han, Villareal, & Isoda, 2015). Anthocyanins are known
to ameliorate the hyperglycaemia and increase the insulin sensi-
tivity via activation of AMPK. Since AMPK plays a significant role in
the regulation of glucose and lipid metabolism, activation of AMPK
 V. Gowd et al. / Trends in Food Science & Technology 68 (2017) 1e13
is a strategic pathway in the treatment of diabetes and related
complications. Studies found that supplementation of anthocyanin-
rich blueberry extract significantly activated the AMPK in skeletal
muscle, white adipose tissue and liver of the diabetic mice. AMPK
activation was accompanied by upregulation of glucose transporter
4 in skeletal muscle and white adipose tissue followed by repres-
sion of glucose production and lipid accumulation in the liver
(Takikawa et al., 2010). These results suggest antidiabetic role of
anthocyanins in skeletal muscle and adipose tissue (Takikawa et al.,
2010) (Fig. 2). Mulberry anthocyanin extract supplementation
ameliorated the hyperglycaemia, decreased the accumulation of
triglycerides and cholesterol levels and increased the adiponectin
levels in diabetic mice (Yan, Dai, & Zheng, 2016). They found the
possible mechanism behind the antidiabetic effect of anthocyanins,
in which changes in metabolic parameters were partially associated
with AKT and downstream targets activation in skeletal muscle,
adipose tissue, and liver of the diabetic mice (Fujie Yan et al., 2016)
(Fig. 2). In a nutshell, these findings indicate the potential antidi-
abetic effect of anthocyanins and anthocyanin-rich sources in
skeletal muscle and adipose tissue.
3. Mechanism of anti-diabetic activity of anthocyanins
3.1. Mechanism of actions of anthocyanins via oxidative stress
Hyperglycaemia-induced OS is a notorious factor in the patho-
genesis and progression of DM (Baynes & Thorpe, 1999; Ceriello,
2000). DM and OS are interlinked. An imbalance in free radical
production or ROS and perturbations in antioxidant defence system
is a major causative factor in DM associated complications. There-
fore, inhibition or modulation of OS is a strategic therapeutic target
in the prevention or delay in onset of DM complications (Sancho &
Pastore, 2012). Glucolipotoxicity-induced OS is one of the primarily
observed events in DM. Pancreatic b-cells (INS832/13) treated with
anthocyanin-rich extracts of wild Chinese blueberry (Vaccinium
spp.) successfully reduced the ROS, and boosted the antioxidant
defence system thereby plummeting the hyperglycaemia promoted
glucolipotoxicity (J. Liu et al., 2015). Pancreatic b-cells are highly
susceptible to OS because of their low expression of antioxidant
enzymes such as catalase, SOD, and GPx in pancreatic islets (Evans,
Goldfine, Maddux, & Grodsky, 2003; Sancho & Pastore, 2012;
Tiedge et al., 1997). Studies on streptozotocin-induced DM model
showed that anthocyanins are protective against DM-induced OS
and hindering the insulin resistance. Anthocyanins phenomenally
suppressed the OS markers such as malondialdehyde and restored
the superoxide dismutase and catalase activity in diabetic rats
(Nizamutdinova et al., 2009). The pancreatic tissue of diabetic rats
was preserved by anthocyanins through regulation in caspase-3,
Bax, and Bcl-2 proteins. Besides, an increase in expression of
GLUT4 proteins in membrane fractions of heart and muscle tissues
was found followed by anthocyanin treatment (Nizamutdinova
et al., 2009). Oxidative stress-mediated glycated haemoglobin
during DM has been appraised as a progressive factor in the evo-
lution of pathological complications. Sustained hyperglycaemia can
instigate haemoglobin glycation and its mediated iron release (Roy,
Sen, & Chakraborti, 2008). In addition, sustained hyperglycaemia
can also induce carbonyl formation and free radical production in
haemoglobin. These factors stipulate the coalition between OS and
glycated haemoglobin in the course of DM complications. Antho-
cyanins are validated bioactive molecules and therapeutic agents in
amelioration of DM complications via modulating OS. Treatment of
anthocyanin pelargonidin was found to ameliorate DM complica-
tions in streptozotocin-induced diabetic rats via modulating OS
mediated haemoglobin glycation, thereby supporting the evidence
of an association between OS and haemoglobin glycation in DM
9
conditions (Roy et al., 2008). In another study, a diet supplemented
with 0.1% boysenberry anthocyanins resulted in minimized oxi-
dised glutathione levels in liver and decrease in thiobarbituric acid
reactive substances (TBARS) in streptozotocin-induced diabetic rats
(Sugimoto, Igarashi, Kubo, Molyneux, & Kubomura, 2003). Eleva-
tion in TBARS, oxidized glutathione, a decrease in concentrations of
SOD and catalase are indicators of lipid peroxidation and defects in
the antioxidant system in DM conditions (Roy et al., 2008; Sancho &
Pastore, 2012; Sugimoto et al., 2003). In another finding, supple-
mentation of diet with 0.5% of anthocyanin-rich black rice extract
to Sprague-Dawley rats exhibited a reduction in OS by lowering
TBARS and reduced glutathione in the blood (Guo et al., 2007).
Intraperitoneal injection of 3 mg/kg anthocyanin named pelargo-
nidin to diabetic Wistar rats restored the SOD, catalase and nor-
malised the MDA levels in serum (Roy et al., 2008). Similar findings
were found with supplementation of anthocyanins from black
soybean seed coats in streptozotocin-induced diabetic rats
(Nizamutdinova et al., 2009). Further, oral administration of an
anthocyanin-rich ethanolic extract of Vaccinium Arctostaphylos fruit
to alloxan-induced diabetic rats showed an increase in concentra-
tions of antioxidant markers such as catalase, SOD, and GPx
(Feshani et al., 2011). These findings suggest that modulation of OS
and improving antioxidant defence system during DM by antho-
cyanins could be a strategic therapeutic target in prevention and
treatment of DM complications.
3.2. Mechanism of actions of anthocyanins via inhibition of
carbohydrate metabolizing enzymes
Experimental studies demonstrated the antidiabetic effect of
anthocyanins from various sources. Various strategies have been
investigated so far to study the antidiabetic effect of anthocyanins.
Inhibition studies on carbohydrate digestive enzymes such as a-
amylase and a-glucosidase suggest that anthocyanins are potent
inhibitors of these enzymes that help in modulation of DM.
Ingested carbohydrate digestion starts with a-amylase and this
enzyme hydrolyses the starch like molecules into smaller peptides
such as amylose, and amylopectin (Englyst, Liu, & Englyst, 2007;
Sales, Souza, Simeoni, & Silveira, 2012). On the other hand, a-
glucosidase acts on sucrose and maltose like molecules, converting
them into absorbable monomers such as glucose and fructose (Van
de Laar et al., 2005; Yu, Yin, Zhao, Liu, & Chen, 2012). This leads to
the higher availability of free glucose in the gut lumen, which in-
fluences the higher uptake of glucose. Higher uptake of glucose
may contribute to infiltration of more glucose into blood stream
thereby causing hyperglycaemia. Synthetic inhibitory drugs such as
acarbose haven been employed to inhibit the carbohydrate hy-
drolyzing enzymes during DM management. Nevertheless, there is
an increase in interest in finding novel natural agents which can
successfully inhibit carbohydrate hydrolyzing enzymes due to side
effects of synthetic inhibitory agents. Inhibition of starch digestive
enzymes by dietary anthocyanins may represent a biochemical
rationale in delivering antidiabetic effects and benefits of diet rich
in anthocyanins. Anthocyanins have been found to be effective
against carbohydrate hydrolyzing enzymes in the management of
DM (Matsui et al., 2002; Matsui et al., 2001). Anthocyanins inhibit
the pancreatic a-amylase and a-glucosidase in the gut lumen; then
anthocyanins interact with intestinal sugar transporters sodium-
dependent glucose transporter 1 and glucose transporter 2 to
reduce glucose infiltration into the blood stream/circulation
thereby decreasing the postprandial hyperglycaemia (Castro-
Acosta, Lenihan-Geels, Corpe, & Hall, 2016). More often anthocya-
nins are used in extract form with the combination of other poly-
phenols. Therefore, it is difficult to tag the inhibitory activity to a
specific anthocyanins or polyphenols. Attributable specific enzyme
10 V. Gowd et al. / Trends in Food Science & Technology 68 (2017) 1e13
activity of anthocyanins could be defined by investigating indi-
vidual or combination of specific group of anthocyanins against
carbohydrate hydrolyzing enzymes. Cyanidin-3-rutinoside (C3R)
was tested for its a-glucosidase inhibitory activity. C3R, a natural
anthocyanin inhibited the a-glucosidase from baker's yeast in a
dose depend response (Adisakwattana et al., 2004). This study
suggested C3R as a new class of a-glucosidase inhibitors
(Adisakwattana et al., 2004). Researchers investigated the natural
anthocyanin cyanidin-3-galactoside against a-glucosidase as alone
and in combination with acarbose, a synthetic a-glucosidase in-
hibitor. Caynidin-3-galactoside showed inhibition of both sucrose
and maltase enzyme activity (Adisakwattana, Charoenlertkul, &
Yibchok-Anun, 2009). In 2010, in vitro studies by the same
research group investigated the structure activity relationship of
cyanidin and its glycosides against intestinal a-glucosidases and
pancreatic a-amylase (Akkarachiyasit, Charoenlertkul, Yibchok-
Anun, & Adisakwattana, 2010). They found that cyanidin and its
glycosides are potent inhibitors of intestinal sucrose than maltase.
Further chanidin-3-galactoside and C3G were found to be more
specific in inhibition of intestinal sucrose and pancreatic a-amylase.
Their specific activity was intensified when the group of anthocy-
anins such as C3G, cyanidin-3-galactoside, or cyanidin-3,5-
diglucosides were used in combination with low concentrations
of synthetic inhibitor acarbose (Akkarachiyasit et al., 2010). Same
research groups found more interesting results when they inves-
tigated the C3R against enzymes. C3R is widely found in black-
currants, and the results were comparable with previous findings
(Adisakwattana, Yibchok-Anun, Charoenlertkul, & Wongsasiripat,
2011). Sucrase but not maltase was effectively inhibited by the
cyanidin-3-rutionoside, these findings also revealed that the
enzymatic inhibitory activity of cyanidin-3-rutionoside was more
potent than cyanidin-3-galactoside, and this may be attributed to
disaccharide structure of rutinose (Adisakwattana et al., 2011).
Sugar units linked to anthocyanins play an important role in
exerting biological activity. This was supported by studies on
enzyme inhibitory activities of cyanidin-3-arabinoside, and cyani-
din-3-xyloside (Braunlich et al., 2013). Cyanidin-3-arabinoside was
found to have more potent enzyme inhibitory activity than cyani-
din-3-xyloside. In other study, anthocyanins-rich muscadin grapes
were analysed for their antidiabetic activity. cyanidin and cyanidin-
3, 5-diglucoside were tested for their inhibitory activities. cyanidin
was found to be a more potent inhibitor of a-glucosidase and a-
amylase than its glycoside form (You, Chen, Wang, Luo, & Jiang,
2011). This study also suggests that anthocyanins exert stronger
a-glucosidase activity after intestinal enzyme b-glucosidase
digestion. These results are in line with previous findings that an-
thocyanins are stronger lipase inhibitors than any other bioactive
compounds (You et al., 2011). Anthocyanins from bitter melon
(Momordica charantia Linn.) have also shown potent a-amylase and
a-glucosidase inhibitory activity, and inhibitory activities were
appreciable compared to synthetic inhibitor acarbose (Gudr, 2016).
The comparison of inhibition action of four anthocyanins such as
C3G, cyanidin-3, 5-glucoside, C3R, peonidin-3-glucoside were
evaluated through in vitro and in silico methods. They found that all
four anthocyanins completely inhibited the porcine pancreatic a-
amylase. Exclusive bonding of all four anthocyanins to an active site
of pancreatic a-amylase was verified by in silico molecular docking
studies. These studies also proved that among all anthocyanins,
cyanidin-3-glucoside was tended to have more potent a-amylase
inhibition activity (Sui, Zhang, & Zhou, 2016).
3.3. Future perspectives
While anthocyanins have been shown to increase pancreatic cell
proliferation and insulin secretion, the mechanisms remain
unclear. Thus, more studies are needed to elucidate how exactly
anthocyanins induce insulin secretion and cell proliferation.
Nutrient sensitising pathway called hexosamine biosynthetic
pathway (HBP) has been implicated in the development of micro-
vascular complications of DM (Fantus, Goldberg, Whiteside, &
Topic, 2006). Increase in HBP flux is also involved in the implica-
tion of endoplasmic reticulum stress, inflammation, lipid accumu-
lation, imbalances in glucose and fatty acids metabolism (Sage
et al., 2010). Accumulation of extracellular matrix components
and protein glycosylation are associated with increase in HBP flux.
Therefore, evaluating the antidiabetic effect of anthocyanins with
respect to HBP in various tissues could shed a light on better un-
derstanding of antidiabetic activity of anthocyanins and develop-
ment of new dietary functional foods.
There are considerable findings in deciphering the role of di-
etary anthocyanin rich supplementation in modulation of DM and
its comorbidities. However, dietary guidelines to recommend
supplements of anthocyanins are still lacking. Thus, more studies
need to be done to evaluate the appropriate dosses of anthocyanins
required for their use against DM and its associated problems
clinically.
Abbreviations
DM, Diabetes mellitus; ROS, Reactive oxygen species; OS,
Oxidative stress; ACNS, Anthocyanins; AGEs, Advanced glycation
end products; SOD, Superoxide dismutase; GPx, Glutathione
peroxidase; C3G, Cyanidin-3-glucoside; C3R, Cyanidin-3-
rutinoside; MAPKs, Mitogen-activated protein kinases; ERK,
Extracellular signal-regulated kinase; JNK, c-Jun NH2-terminal ki-
nase; AMPK, AMP-activated protein kinase; G6P, Glucose 6-
phosphatase; GLUT4, Glucose transporter type 4; CTGF, Connec-
tive tissue growth factor; TGF-b1 Transforming growth factor-b1;
MCP1, Monocyte chemoattractant protein-1; ICAM1, Intercellular
adhesion molecule-1; IL6, Interleukin-6; TNF-a, Tumour necrosis
factor-alpha.
Conflict of interest
The authors declare that they do not have any conflict of
interest.
Acknowledgements
This work was supported by Grants from National Key Tech-
nology R&D Program of China (2016YFD0401201) and the Funda-
mental Research Funds for the Central Universities
(2017QNA6006).
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