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International Journal of Food Properties


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Anti-Diabetic Potential of Phenolic


Compounds: A Review
a
Md. Ali Asgar
a
Department of Crop Science and Technology, University of
Rajshahi, Rajshahi, Bangladesh
Accepted author version posted online: 13 Aug 2012.Version of
record first published: 02 Nov 2012.

To cite this article: Md. Ali Asgar (2013): Anti-Diabetic Potential of Phenolic Compounds: A Review,
International Journal of Food Properties, 16:1, 91-103

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International Journal of Food Properties, 16:91103, 2013
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ISSN: 1094-2912 print / 1532-2386 online
DOI: 10.1080/10942912.2011.595864

ANTI-DIABETIC POTENTIAL OF PHENOLIC COMPOUNDS:


A REVIEW

Md. Ali Asgar


Department of Crop Science and Technology, University of Rajshahi, Rajshahi,
Bangladesh
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Starch is the main carbohydrate in human nutrition. Starch digestibility can vary from a
rapid digestion to indigestibility. Therefore, postprandial glycaemic control in type 2 dia-
betics is of great interest in the context of worldwide health concerns. Although powerful
synthetic inhibitors of starch digestive enzymes, such as acarbose, are available to con-
trol postprandial hyperglycemia, plant-based enzyme inhibitors are potentially safer. Natural
enzyme inhibitors, such as wheat albumin, the Phaseolus vulgaris -amylase inhibitor, and
several phenolic compounds, have the potential to serve as a remedy against hyperglycemia-
induced chronic diseases. The inhibition of -amylase and -glucosidase is mediated by
different phenolics found in varieties of raspberry. Maltase inhibitory activities of chebu-
lagic acid and chebulinic acid from fruit of Terminalia chebula are comparable to
that of acarbose. The Nepalese herb Pakhanbhed (Bergenia ciliata) phenolics, (-)-3-O-
galloylepicatechin and (-)-3-O-galloylcatechin, showed effective inhibition against starch
digesting enzymes. In separate studies, oral administration of starch and maltose with
persimmon (Diospyros kaki) leaf tea proanthocyanidins [containing (-)-epigallocatechin-3-
O-gallate] and black/bitter cumin (Centratherum anthelminticum) seed phenolics, respec-
tively, resulted in a significant and dose-dependent decrease in the blood glucose level in
Wistar rats. Co-application of phenolics with synthetic enzyme inhibitors may reduce the
effective dose of synthetic inhibitors required in the regulation of starch digestion. Several
phenolic compounds might be useful functional food components and could contribute to
manage both hyperglycemia and proper cellular redox status. Human dose-selecting studies
and well-controlled long-term human studies would help to optimize the beneficial effects of
phenolic compounds.

Keywords: Starch, Digestibility, Phenolic compounds, Enzyme inhibitors, Postprandial


hyperglycemia.

INTRODUCTION
Diabetes mellitus (DM) is one of the most serious and chronic diseases due to an
improper balance of glucose homeostasis. Currently, an estimated more than 220 million
people worldwide have diabetes.[1] The death toll from diabetes will increase to double
between 2005 and 2030.[1] Two types of DM are presently known, one being type 1, which
is characterized by insufficient insulin production and the other being type 2, that results
from ineffectiveness of insulin.[1,2] Worldwide, type 2 diabetes accounts for approximately
90% of the total cases.[1] A condition characterized by an abnormal postprandial increase
of blood glucose level, known as hyperglycemia or raised blood sugar, has been linked to

Received 29 April 2011; accepted 6 June 2011.


Address correspondence to Md. Ali Asgar, Department of Crop Science and Technology, University of
Rajshahi, Rajshahi 6205, Bangladesh. E-mail: maasgar@yahoo.com; maasgarbd@gmail.com
91
92 ASGAR

the onset of type 2 diabetes[2] and is the main cause of complications related with cardio-
vascular disease, renal failure, blindness, neurological complications, etc.[3] Recently, type
2 diabetes is also being found in children.[1] Thus, the increasing trend in type 2 diabetes
mellitus has become a serious medical concern worldwide.
Rapidly digested carbohydrates result in a quick increase in the post-meal blood glu-
cose level.[4] Regular consumption of rapidly digestible carbohydrates is the main cause
for the development of hyperglycemia-induced chronic diseases.[5] Chronic postprandial
hyperglycemia induces the glycosylation of proteins;[6] hyperglycemia triggers the gener-
ation of free radicals leading to oxidative stress when excessive free radicals react with
proteins and DNA[7,8] and increases plasma insulin and lipid concentrations along with
cardiovascular disease risk factors[9] (Flow Chart 1).
Starch is the most abundant storage polysaccharide in plants. Starch consists of
amylose (linear polymer of -D-glucose units linked by -1,4 glycosidic linkages) and
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amylopectin (branched polymer of -D-glucose units linked by -1,4 and -1,6 gly-
cosidic linkages). Pancreatic -amylase and intestinal -glucosidase are the two key
enzymes involved in starch digestion.[5] Starch is hydrolyzed by amylases to -dextrins
or oligosaccharides (maltose, maltotriose) that are further hydrolyzed to glucose by intesti-
nal -glucosidase before being absorbed in the duodenum and upper jejunum. Starch and
starchy food products can be classified based on their digestibility.[10] Post-meal glycaemic
control in type 2 diabetics due to ingestion of starchy food is of great interest in the context
of worldwide health concerns.
An important therapeutic approach for treating type 2 diabetes is to decrease the
post-prandial hyperglycemia by retarding the absorption of glucose through the inhibition
of the enzymes, -amylase and -glucosidase, in the digestive tract. Enzyme inhibitors
delay the rate of glucose absorption by preventing carbohydrate digestion and consequently
dulling the postprandial plasma glucose rise.[11] The inhibition of starch digestive enzymes
by synthetic agents, such as acarbose, is an important clinical strategy for controlling
postprandial glycemia.[4,10,12,13] Though acarbose (Fig. 1), which is approved by the Food

Postprandial hyperglycemia

Glycosylation High plasma Oxidative High plasma triglycerides


of proteins insulin stress and LDL-cholesterol

Increased cardiovascular risk

Flow Chart 1 Potential connections between meal-associated hyperglycemia and the increase in cardiovascular
disease risk.

Figure 1 Chemical structure of acarbose.[13]


ANTI-DIABETIC POTENTIAL OF PHENOLIC COMPOUNDS 93

and Drug Administration, reduces blood glucose levels, this inhibitor is reported to cause
critical side effects, such as liver disorders, while plant-based enzyme inhibitors are poten-
tially safer.[6,12] The natural enzyme inhibitors, the Phaseolus vulgaris -amylase inhibitor
(-AI) and wheat albumin (WA), have been known for a long time and have been well-
discussed previously.[12,14,15] Some dietary supplements used to control obesity are based
on protein concentrates from kidney bean (Phaseolus vulgaris), which are known to con-
tain significant levels of -amylase inhibitor also known as phaseolamin (-AI). -Amylase
inhibitor (-AI) is known to be effective in preventing postprandial hyperglycemia by
blocking access to the active site of the starch digestive enzyme.[12] WA can inhibit starch
digestion, resulting in improved overall glycemic status in type 2 diabetic patients with
mild hyperglycemia without the occurrence of critically adverse effects, such as hepatic
disorders.[14]
More than 80% of diabetes deaths occur in developing countries.[1] Plants continue
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to play a vital role in the treatment of type 2 diabetes, particularly in developing coun-
tries where most people do not have an access to modern treatment. The use of plant-based
enzyme inhibitors is also encouraged in developed countries because there is concern about
the critical side effects of synthetic pharmaceutical agents. To either avoid or decrease
the adverse effects of currently used synthetic agents, it is necessary to utilize naturally
occurring -amylase and -glucosidase inhibitors. Keeping this in view, the present review
mainly focuses on the possibilities of phenolic compounds as -amylase and -glucosidase
inhibitors from some underutilized plants (or only localized in a particular region) for
overcoming hyperglycemia-induced chronic diseases, such as type 2 diabetes.

METABOLIC HETEROGENEITY OF STARCH


Based on kinetics of in vitro digestion of starch (by simulating stomach and intestinal
conditions), different starch fractions are defined as:[16] (i) Rapidly digestible starch (RDS):
amount of glucose release after 20 min of in vitro digestion; (ii) Slowly digestible starch
(SDS): amount of glucose released between 20 and 120 min; (iii) Resistant starch (RS):
RS is the starch not hydrolyzed after120 min of incubation. RS is defined as that fraction
of dietary starch, which escapes digestion in the small intestine, and passes to the large
intestine for fermentation. It is measured chemically as the difference between total starch
(TS) and the sum of RDS and SDS:

RS = TS (RDS + SDS).

Of relevance to the postprandial glycemic control in type 2 diabetes, the nature


of the starch in the dietary foods is important. Structural characteristics of starch vary
among different botanical sources. Raw starches high in amylose have been shown to
digest more slowly than those high in amylopectin.[10] The ratio of amylose to amylopectin
molecules in the starchy food plays a vital role to control postprandial glucose and insulin
concentrations.[17] It was found that high amylose products induced low blood glucose
and insulin responses when compared with similar products high in amylopectin.[18]
Amylopectin is a much larger molecule than amylose. The average molecular weight of
amylopectin is between 105 and 106 , whereas the average molecular weight for amylose
is 104 . The large surface area of amylopectin makes it a suitable substrate for amylolytic
attack.[10] In addition, lower availability of amylose for amylolytic attack than amylopectin
94 ASGAR

is due to more bound glucose chains (to each other by hydrogen bonds) in amylose
polymers.[10]
High-amylose starches require high temperatures (up to 150 C) in the presence
of water to become fully gelatinized[17] and making it more easily available for enzy-
matic attack.[10] It is usually not possible to reach this temperature under normal cooking.
A higher content of amylose lowers the digestibility of starch because there is a positive cor-
relation between amylose content and the formation of RS.[19] Granfeldt et al.[20] reported
that high amylose (70%) corn flour had RS of 20 g/100 g dry matter than ordinary corn flour
(25% amylose) that had RS of 3 g/100 g dry matter. RS is highly resistant to mammalian
enzymes.

PHENOLIC COMPOUNDS
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Recently, phenolic compounds have been receiving much attention for controlling the
digestibility of starch and for having a high antioxidant activity. They are widely distributed
in plant foods, and their biological activities depend on their chemical structures, doses,
and time of consumption. Phenolic compounds belong to the families of phenolic acids,
flavonoids, and others.[21] Among them, flavonoids represent the widely distributed group
of plant phenolics. The flavonoids include the anthocyanin pigments, flavonols, flavones,
flavanols, and isoflavones. The flavanols tend to polymerize to condensed tannins, whereas
other flavonoids occur mainly as glycosides.[21]
Plant tannins are natural polyphenolic compounds of high molecular weight.
Tannins are subdivided into hydrolyzable and condensed tannins. Hydrolyzable tannins
are molecules with a polyhydroxy component.[22] It is found that the hydroxyl groups
of these molecules are esterified with phenolics, for example, ellagic acid (ellagitannins).
Condensed tannins are formed through the condensation of flavanols and are also known
as proanthocyanidins. Catechin, epicatechin, and gallocatechin are the monomeric con-
stituents of the condensed tannins.[21] Polyphenols, especially tannins, have a high
antioxidant activity.[8,23,24] Improved body antioxidant status can protect against degen-
erative diseases.

ENZYME INHIBITORS FROM PLANT ORIGINS


Pakhanbhed (Bergenia ciliata)
The Nepalese herb Bergenia ciliata is known as Pakhanbhed in the Nepali
language, and is used in traditional ayurvedic medicine as a remedy against various
diseases in an indigenous community in Nepal.[25,26] Bhandari et al.[27] have investi-
gated the anti-diabetic activity of Bergenia ciliata using an in vitro model. Investigation
of the ethyl acetate soluble extract of B. ciliata revealed that two active compounds,
(-)-3-O-galloylepicatechin and (-)-3-O-galloylcatechin, are responsible for the strong
inhibition of porcine pancreatic -amylase and rat intestinal maltase activity in a dose-
dependent manner[27] (Table 1). In addition to their antioxidant activity, catechins are also
shown to be inhibitors of starch digestive enzymes.[28,29]
The IC50 value is defined as the concentration of an inhibitor that is required for
50% inhibition of the enzyme activity and it is commonly used for the measurement of
inhibitor potency. The IC50 value for rat intestinal maltase and porcine pancreatic -amylase
were 334 and 739 M, respectively, for (-)-3-O-galloylepicatechin and 150 and 401 M,
ANTI-DIABETIC POTENTIAL OF PHENOLIC COMPOUNDS 95

Table 1 Key enzyme inhibitors from plant origins involved in starch digestion.

Plant origin Enzyme inhibitor Enzyme targets References

Pakhanbhed (-)-3-O-galloylepicatechin, Pancreatic -amylase, Bhandari et al.[27]


(B. ciliata) (-)-3-O-galloylcatechin maltase
Persimmon Proanthocyanidin [()-epigallocatechin, Pancreatic -amylase Kawakami et al.[37]
(Diospyros kaki) ()-epigallocatechin-3-O-gallate,
()-epicatechin, (+)-catechin,
()-epicatechin-3-O-gallate]
Finger millet Naringenin, kaempferol, luteolin Pancreatic -amylase, Shobana et al.[6]
(E. coracana) glycoside, apigenin, -glucosidase
(+)-catechin/()-epicatechin,
diadzein, caffeic acid, ferulic acid,
syringic acid
Raspberries Ellagic acid, catechin, -Glucosidase Zhang et al.[48]
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(Rubus idaeus) pelargonidin-3-rutinoside,


cyanidin-diglucoside
Black myrobalan Chebulanin, chebulagic acid, chebulinic Maltase Gao et al.[35]
(T. chebula) acid
Black/bitter cumin Caffeic acid, ellagic acid, ferulic acid, Maltase, sucrase, Ani and Akhilender
(C. anthelminticum) quercetin, kaempferol salivary -amylase Naidu[59]

respectively, for (-)-3-O-galloylcatechin.[27] In vivo and in vitro models, the -glucosidase


and -amylase inhibitory activities of these compounds revealed that they have a high
potential to serve as a remedy against type 2 diabetes.[2831] For catechins, their epi forms
exhibited significant inhibitory effects and the galloyl moiety also served an important
role.[5]
It is found that non-covalent interactions occur between polyphenols and enzymes
(proteins).[32] Hydroxyl groups and galloyl groups are present in the molecular structure of
polyphenols.[28] The phenolic groups can form hydrogen bonds with the polar groups of
enzyme. In contrast, there are many hydrophobic amino acids found in enzymes (protein).
Galloyl groups in polyphenols show hydrophobicity[33] and, therefore, polyphenols can
bind enzymes through hydrophobic association.[28] The galloyl moiety may play an impor-
tant role to interact with mammalian -amylase and -glucosidase[5,34] and their positions
mostly affect the effectiveness.[35] The cooperative effects of hydrophobic association and
hydrogen bond formation between polyphenols and the starch digestive enzymes could
contribute to control postprandial hyperglycemia in type 2 diabetic patients.

Persimmon (Diospyros kaki)


In addition to green tea, different kinds of tea are prepared from leaves of dietary
plants, such as persimmon, guava, and mulberry, by drying and are commercially available
as herbal teas in Japan. Based on the degree of astringency at the mature stage, Japanese
persimmon cultivars (Diospyros kaki) are classified into two groups, an astringent and
a non-astringent type.[36] Kawakami et al.[37] identified polyphenols from an astringent
cultivar of persimmon leaf tea as effective an -amylase inhibitor. Thiolysis and subse-
quent analysis revealed that the major components were proanthocyanidin, consisting of
(+)-catechin, ()-epigallocatechin, ()-epigallocatechin-3-O-gallate, ()-epicatechin, and
()-epicatechin-3-O-gallate[37] (Table 1). Similar proanthocyanidins with the same units
were also found in persimmon leaves. Like persimmon tea, green tea is also derived from
96 ASGAR

drying the fresh tea leaves and so no oxidation takes place, resulting in excellent levels of
catechins. The ()-epigallocatechin-3-O-gallate (EGCG) has been recognized as the most
beneficial component among the four other catechins isolated from green tea.[38]
The polyphenol concentrate of the persimmon leaf tea had significant -amylase
inhibitory activity in a concentration-dependent manner, but had no considerable effect
on maltase. The percentage of inhibition ratios of persimmon leaf tea against porcine pan-
creas -amylase were 24.6 3.2, and 45.2 2.8 at the concentrations 24 and 48 g/ml
of polyphenol concentrate powders, respectively.[37] The -amylase inhibitory strength of
persimmon leaves is comparable to that of green tea,[5,37] whereas, compared to green
tea,[5] maltase inhibitory potency of persimmon leaves was much less,[37] indicating
that the inhibition of -amylase by persimmon leaves proanthocyanidin appeared to be
more relatively specific than green tea proanthocyanidin. Proanthocyanidins are flavan-3-
ol polymers with high structural diversity and complexity, and the biological activities of
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proanthocyanidins depend on their structural features and doses.


When polyphenol concentrates of persimmon leaf tea were orally administered with
soluble potato starch, blood glucose levels in Wistar rats decreased in a dose-dependent
manner.[37] Eighteen overnight-starved male rats (190230 g) were divided into three
groups. Oral administration of starch (2.0 g/kg of body weight) with polyphenol concen-
trate of persimmon leaf tea at three different dosages (0, 100, and 300 mg/kg of body
weight) resulted in an increase in the blood glucose level from the values of 94 12, 112
9, and 105 15 mg/dl at 0 min to peaks of 155 24, 150 14, and 136 13 mg/dl
at 30 min, respectively, and then decreased.[37] Kao et al.[39] suggested that tea cate-
chins, particularly ()-epigallocatechin-3-O-gallate have the potential for the treatment of
hyperglycemia-induced chronic diseases, including type 2 diabetes and obesity.[39] Human
studies show anti-diabetic effects of green tea catechins, especially ()-epigallocatechin-3-
O-gallate (EGCG).[40] An epidemiological study conducted in Japan revealed that subjects
with an average consumption of more than 6 cups of green tea per day was inversely
associated with the risk for type 2 diabetes, compared to those who drank <1 cup per
week.[41] In this study, a total of 17,413 subjects were followed up for 5 years. Although, the
optimal dose of EGCG for controlling postprandial hyperglycemia has not yet been estab-
lished, a dose range of 84386 mg EGCG/day may be sufficient to support the beneficial
effects.[42,43]
Proanthocyanidins in rowanberry may contribute greatly for managing hyper-
glycemia by the inhibition of -amylase.[44] The inhibition of starch digestive enzymes by
acarbose is an important clinical strategy for controlling postprandial glycemia, but it has
adverse effects. The effect of rowanberry proanthocyanidins and acarbose were investigated
at different combinations of their IC50 values by Grussu et al.[44] Co-addition of rowanberry
proanthocyanidins with acarbose reduced the effective concentration of acarbose required
for -amylase inhibition. Although the combined effect of persimmon proanthocyanidins
and acarbose were not tested, such synergistic interactions may have implications for the
current clinical use of synthetic inhibitors for controlling starch digestion.

Finger Millet (Eleusine coracana L.)


Finger millet (Eleusine coracana L.) or ragi is cultivated in India and many of the
African countries. The millet seed coat matter is an excellent source of phenolic com-
pounds (10% w/w). Shobana et al.[6] characterized phenolic compounds from the millet
seed coat by HPLC and electrospray ionization mass spectrometry after extraction with
ANTI-DIABETIC POTENTIAL OF PHENOLIC COMPOUNDS 97

acidified methanol and then investigated the ability of phenolics in inhibiting the activities
of porcine pancreatic -amylase and rat intestinal -glucosidase.[6]
Different types of phenolic compounds, including phenolic acids and polyphenols,
such as gallic acid, protocatechuic acid, gentisic acid, caffeic acid, syringic acid, ferulic
acid, naringenin, kaempferol, luteolin glycoside, phloroglucinol, apigenin, (+)-catechin/
()-epicatechin, trans-feruloyl-malic acid, dimer of prodelphinidin (epi/gallocatechins;
2GC), daidzein, catechin gallates, and trimers and tetramers of catechin were identified
from the millet seed coat phenolics extract[6] (Table 1). The IC50 values for -glucosidase
and pancreatic amylase were 16.9 and 23.5 g of finger millet seed coat phenolics,
respectively,[6] indicating that these phenolics have the potential for managing hyper-
glycemia. Tadera et al.[45] reported that the starch digestive enzymes were inhibited by
naringenin, kaempferol, luteolin, apigenin, (+)-catechin/()-epicatechin, daidzein, and
epigallocatechin gallate and showed that there is a correlation between the potency of inhi-
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bition and the number of hydroxyl groups of flavonoids. Kinetic studies showed that the
millet seed coat phenolics non-competitively inhibited the two key enzymes involved in
starch digestion.[6] A Korean herb (Rhus chinensis) extract used as a remedy against type
2 diabetes in Korea, exhibited the same type of inhibition on -glucosidase and pancreatic
amylase.[46]

Raspberries (Rubus idaeus L.)


Raspberries (Rubus idaeus L.) are known as an excellent source of antioxidants
mainly because of their high levels of phenolics. Wolfe et al.[47] reported that a rasp-
berry extract has the highest antioxidant activity among common fruits in the USA. Zhang
et al.[48] assessed the inhibitory activities of phenolics-rich extracts from seven primo-
cane fall-bearing raspberry (Rubus idaeus L.) cultivars Nova, Dinkum, Heritage, Autumn
Britten, Josephine, Anne, and Fall Gold, against yeast -glucosidase, porcine pancreatic
-amylase, and porcine pancreatic lipase. All the raspberry extracts potently inhibit -
glucosidase but no inhibition occurred against -amylase and lipase. Among the tested
raspberry extracts, the Dinkum raspberry extract exhibited the highest -glucosidase
inhibitory activity.
Zhang et al.[48] identified four major active phenolic compounds, ellagic acid
(phenolic acids), cyanidin diglucoside (anthocyanins), pelargonidin-3-rutinoside (antho-
cyanins), and catechin (flavonoids), as the -glucosidase inhibitors by HPLC and liquid
chromatography-mass spectroscopy (LC-MS) analysis on the Dinkum raspberry extract
(Table 1). These phenolic compounds exhibited potent inhibition of -glucosidase with
IC50 from 14.7 to 64.5 g/mL.[48] McDougall et al.[49] reported that fruits rich in antho-
cyanin strongly inhibited -glucosidase activity, but the inhibitory potency of fruits
extracts against both salivary and pancreatic amylase was related to their tannin content.[49]
Diacylated anthocyanins inhibited -glucosidase activity and induced an anti-diabetic
activity in animal models.[50] Red currants inhibit -amylase more efficiently than black
currants,[51] which possess higher anthocyanin content, indicating that anthocyanins are
not crucial for amylase inhibition.[44]
It was found that the phenolic extracts of a specific raspberry (variety Glen Ample)
effectively inhibited activities of -amylase and -glucosidase.[49] The inhibitory potency
of raspberry extracts against -glucosidase was associated with their anthocyanin con-
tent. The -amylase inhibitory components in raspberry (variety Glen Ample) were
identified as ellagitannins using LC-MS.[49] Grussu et al.[44] also reported that in vitro,
98 ASGAR

extract from raspberry variety (Glen Ample) was able to inhibit porcine pancreatic
-amylase (IC50 values of 21.0 g/mL) due to the presence of ellagitannins as major active
components.[44] Purified ellagitannins from strawberry also possess -amylase inhibitory
activity.[52] Ellagitannins in raspberry (Glen Ample) have been reported to undergo
breakdown partially under simulated gastrointestinal conditions,[53] although a very recent
study[44] suggests that raspberry extracts retain amylase inhibitory activity to a high level
when subjected to in vitro digestion. The extracts of seven raspberry cultivars (Nova,
Dinkum, Heritage, Autumn Britten, Josephine, Anne, and Fall Gold) did not inhibit the
activity of pancreatic -amylase possibly because they effectively lacked ellagitannins in
these cultivars. It was found that the concentrations of the major phenolic components in
14 raspberry cultivars varied approximately 20-fold.[54,55]
In vitro results suggest that raspberry phenolics inhibit enzymes involved in starch
digestion, such as -amylase or -glucosidase, at levels easily achieved in the gastrointesti-
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nal tract through normal dietary intake of fruits. Ellagitannins in raspberry (variety Glen
Ample) were the main active components for effective inhibition of mammalian -amylase
and capable of retarding starch digestion. Although it is still not clear whether raspberry
-glucosidase inhibitors can suppress postprandial hyperglycemia, raspberry phenolics
greatly inhibited yeast -glucosidase.

Terminalia chebula Retz


The dried fruit of T. chebula Retz is known as black myrobalan in English and
Xi-Qin-Ge or Zhang-Qin-Ge in China. Gao et al.[35] investigated the inhibitory effect of the
fruits of T. chebula on mammalian -glucosidase activity. Three active ellagitannins were
identified as chebulanin, chebulagic acid, and chebulinic acid from aqueous methanolic
extract of the dried T. chebula fruits and were found to possess strong rat intestinal maltase
inhibitory activity (Table 1), with the IC50 values of 690, 97, and 36 M, respectively, but
exhibited no inhibitory effects on rat intestinal isomaltase and sucrase activities.[35] These
compounds inhibited maltase activity in a dose-dependent manner. The clove ellagitannins
were also shown to have maltase inhibitory activity.[34] The rat intestinal maltase inhibitory
activity of 1,2,3,4,6-penta-O-galloyl--D-glucose (PGG) (IC50 = 140 M) was lower than
that of chebulagic acid and chebulinic acid.[35] PGG is a potent maltase inhibitor and
inhibits the activity of maltase in response to the numbers of the galloyl group attached
to a glucose core.[34] The IC50 value of acarbose was 0.08 mM for rat intestinal maltase,[56]
indicating that chebulagic acid and chebulinic acid from dried T. chebula fruits are effective
inhibitors of maltase as acarbose. Research on the bioavailability of dietary tannins is still
limited. Binding of tannins to proteins in the gastrointestinal tract may reduce their effec-
tive concentration. Nevertheless, tannic acid and the tannin-rich nonalcoholic components
of red wine have been found to reduce post-meal blood glucose levels in a study of patients
with type 2 diabetes mellitus.[57]
One of the therapeutic approaches for preventing type 2 diabetes is to delay absorp-
tion of glucose via inhibition of -glucosidase activity. The strong enzymatic inhibitory
activity against mammalian -glucosidases shown by T. chebula fruits phenolics could help
to control blood glucose level in type 2 diabetes without any critical side effects. The inhi-
bition of -glucosidase by T. chebula fruits extracts appears to be specific as they did not
inhibit other digestive enzymes, such as intestinal sucrase and isomaltase activity, although
the inhibitory effect of the fruits of T. chebula on mammalian -amylase was not tested.
Ellagitannins from raspberry (variety Glen Ample) extract were able to inhibit -amylase
activity in vitro at low concentrations. Further studies are needed to investigate T. chebula
ANTI-DIABETIC POTENTIAL OF PHENOLIC COMPOUNDS 99

fruits phenolics activity against -amylase and to explore their potential therapeutic effects
on post-meal glycemic response by limiting carbohydrate digestion and absorption.

Black/Bitter Cumin (C. anthelminticum)


Cumin is one of the most popular spices used in chicken, beef, or mutton curry prepa-
rations in India and Bangladesh. Centratherum anthelminticum (L.) Kuntze is black in
color and bitter in taste, which possesses antioxidant and antibacterial activities.[58] Ani
et al.[59] tested the effect of phenolics of C. anthelminticum seeds extract (CA) on rat
intestinal -glucosidases, human salivary -amylase activity, and postprandial glycaemic
control in rats. Phenolic compounds of CA showed a dose dependent inhibition of rat
intestinal sucrase and maltase with an IC50 value of 34.1 3.8 and 62.2 4.5 g, respec-
tively. The phenolic compounds of C. anthelminticum seeds extracts were separated by
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HPLC and their structures were identified by LC-MS. Gallic acid, protocatechuic acid,
caffeic acid, ellagic acid, ferulic acid, quercetin, and kaempferol were the major inhibitory
components[59] (Table 1).
The IC50 value of phenolics of CA was 185.5 4.9 g for human salivary
-amylase.[59] The inhibitory potency against human salivary -amylase are expected to
be comparable to that of human pancreatic -amylase because these enzymes share a high
degree of amino acid sequence similarity with 97% identical residues overall and 92% in
catalytic domains.[60,61]
Certain naturally occurring flavonoids, such as quercetin, kaempferol, luteolin, querc-
etagetin, and scutellarein act as inhibitors of human -amylase, which makes them
promising candidates for controlling the digestion of starch.[4,45] Flavonoids are integral
parts of the human diet providing potential antioxidant benefits for managing diabetes by
also preventing the progressive impairment of pancreatic beta-cell function due to oxidative
stress.[2,24,62] They cannot be synthesized by the human body, and play beneficial roles in
human life.[62,63]
Oral administration of maltose with phenolics of CA resulted in a dose-dependent
decrease in the blood glucose level in Wistar rats.[59] Male Wistar albino rats were starved
overnight (12 h). When CA phenolics were orally administered at different dosages (0, 50,
100, and 200 mg/kg of body weight) in maltose (2.0 g/kg of body weight), blood glucose
levels increased from baseline values of 64.57 1.65, 62.82 4.04, 63.39 3.83, and
64.50 3.94 mg/dl at 0 min to 180.50 3.83, 144.62 6.49, 141.23 5.13, 139.55
2.88 mg/dl at 60 min, respectively (values are mean SEM of 5 rats in each group), and
then decreased.[59]
Mild inhibition of -amylase and strong inhibition of intestinal -glucosidase activ-
ity would be an effective strategy for type 2 diabetes management.[64] The IC50 value of
CA was lower for -glucosidase than -amylase. The inhibitory potency of CA phenolics
against -amylase and -glucosidase suggested that the potentially safer phenolic com-
pounds from C. anthelminticum seeds extract therefore may be preferred alternatives for
controlling postprandial glycemia in type 2 diabetes.

CONCLUSION
The elevated blood glucose level after a meal in type 2 diabetic patients presents a
challenge for controlling meal-associated hyperglycemia. Of relevance to the postprandial
glycemic control in type 2 diabetes, the nature of the starch in the dietary foods is important.
100 ASGAR

Postprandial glycaemic control in type 2 diabetics due to ingestion of starchy food is


of great interest in the context of worldwide health concerns. Type 2 diabetes represents
an emerging health burden for governments and health care providers, particularly in the
developing world. Although type 2 diabetes and relevant complications are on the increase
worldwide, several phenolic compounds have the potential to serve as a remedy against
these conditions. Phenolics may provide a protective effect against hyperglycemia-induced
chronic diseases through dual protection of antioxidant and inhibition of starch digestion.
Co-application of phenolics with synthetic enzyme inhibitors may reduce the effective dose
of synthetic inhibitors required for controlling prosprandial glycemia.
Human studies demonstrated the anti-diabetic effects of green tea catechins.
Nevertheless, there are several aspects of natural enzyme inhibitors that require further
research. For example, the optimal dose of phenolic compounds, including green tea cate-
chins, has not yet been established. In addition, the presence of other dietary components,
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such as proteins, may reduce the inhibitory potency of polyphenols in the gastrointesti-
nal tract, although some phenolics appear to be enzyme specific. The number of human
studies in this field is still very limited. Well-controlled, long-term human studies would
help to determine the efficacy, optimal dose, and safety of these inhibitors and ingredient
functionality of phenolics in the presence of other dietary components.
Based on the ingredient functionality of phenolic compounds in various food sys-
tems and its safer and efficacious dose for humans, it is possible to develop nutraceuticals
or functional foods for type 2 diabetic patients. Preserving the native structure of the active
molecules during functional food preparation is important. Keeping a balance between
-amylase and -glucosidase inhibitors would be useful to limit the gastrointestinal adverse
effects related to undigested starch reaching the colon. For the development of nutraceu-
ticals or functional foods, knowledge of the interaction between phenolic compounds and
digestive enzymes is desirable.

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