Academia Journal of Medicinal Plants 1(2): 031-036, February 2013

DOI: http://dx.doi.org/10.15413/ajmp.2012.0111
ISSN: 2315-7720
2013 Academia Publishing

Review

Flavonoids as alternatives in treatment of type 2 diabetes mellitus

Accepted 21th January, 2013
ABSTRACT

Saad Abdulrahman Hussain1* and Bushra Hasan

Marouf2
1Department

of Pharmacology and Toxicology,

College of Pharmacy, University of Baghdad,
Baghdad, Iraq.
2Department of Pharmacology and Toxicology,
Faculty of Medical Sciences, University of
Sulaimani, Kurdistan, Iraq.
*Corresponding author. E-mail:
saad_alzaidi@yahoo.com.

The global pandemic of type 2 diabetes mellitus (T2DM) places an incalculable

burden on health care systems. It is estimated that ~ 40% of the population will
have diabetes or pre-diabetes in 2020, conditions that already cost the health
care providing systems billions of US $ a year in health care spending. Currently
available therapeutic options for T2DM, such as dietary modification, oral
hypoglycemics, and insulin, have limitations of their own. Many natural products
and herbal medicines have been recommended for the treatment of DM.
Amelioration of T2DM risk usually targets lifestyle and diet, primarily with the
aim of reducing obesity, the foremost risk factor in the development of insulin
resistance and ultimately T2DM. However, particular dietary components, such
as flavonoids, may assist in T2DM prevention in ways other than those already
followed by the currently available therapeutic approaches.
Key words: Flavonoids, glycemic control, type 2 diabetes mellitus,
phytotherapy.

INTRODUCTION
Diabetes mellitus is a metabolic disorder which arises from
complex interactions between multiple genetic and
environmental or lifestyle factors. This chronic disease is
characterized by the presence of hyperglycemia due to
defective insulin secretion, insulin action, or both. Longterm diabetes is associated with several comorbidities, such
as erectile dysfunction, blindness, poor wound healing,
kidney failure, heart disease, etc; as a result of considerable
damage, dysfunction, and failure of various organs that
develop as the disease progresses (Nathan et al., 2009). The
incidence of diabetes worldwide is now estimated to be
around 366 million, far beyond the 285 million projected by
the World Health Organization (WHO) for 2010 from global
statistics gathered in 2008 (Danaei et al., 1980). This means
that there may have been more than 4 million deaths or
6.8% of global mortality in 2010 that could be attributed
directly or indirectly to diabetes (Roglic and Unwin, 2010),
and explains why global diabetes health expenditure in
2010 was estimated around $320 billion or 12% of total
global health care costs (Shaw et al., 2010). The two major

forms of the syndrome result from either lack of the

metabolism regulatory hormone, insulin (type 1 diabetes,
T1D), or because body tissues fail to respond to the
hormone (type 2 diabetes, T2D). The majority or 90% of
patients with diabetes have T2DM. As insulin is crucial for
the maintenance of life, T1DM patients depend on
externally administered insulin, while for T2DM patients
who do not respond to diet and exercise regimes, oral antidiabetes drugs (OADs) and sometimes external insulin are
administered to help keep their blood glucose as normal as
possible (Roglic and Unwin, 2010). According to the data
from WHO, the highest increases in diabetes prevalence are
amongst low- and middle-income countries, predominantly
within the 40-59 years age group, although a tendency is
seen for onset at a younger age (Colagiuri et al., 2005).
Thus, apart from the expected global health care costs
involved in treating and managing DM, this disease imposes
additional social economic burdens from lost productivity
and slow economic growth. Therefore, there is a need for
the development of more effective preventive and thera-

Academia Journal of Medicinal Plants; Hussain and Marouf

peutic approaches that address and abolish the reduction in

life expectancy and life quality imposed by DM and its
complications or comorbidities (Hu, 2011).
While obesity and lack of exercise are the primary
environmental factors known to be closely associated with
the global T2DM upsurge, advances in genome wide
screenings have only revealed a few genes that increase the
risk of developing the illness. For example, the gene IFIH1,
which codes for interferon induced with helicase C domain
1, has been implicated in the etiology of T1DM (Nejentsev
et al., 2009). Some variants of the 3-adrenergic receptor
gene (Silver et al., 1997), PPAR- gene in both Caucasian
(Caramori et al., 2003) and Chinese (Liu et al., 2010)
patients, PPAR- co-activator 1- gene (PCG-1) (Mootha et
al., 2003), and the gene coding for the T-cell specific
transcription factor, TCF7L2 (Jin and Liu, 2008), have been
linked to higher risks of developing T2DM. However, it is
not clear how environmental factors interact with the gene
products to cause the disease. Concerning the current
understanding of T2DM Pathophysiology, several factors
underlie the disease development and progression into
tissue degenerations and the diabetic complications like
cardiovascular diseases, amputation, poor wound healing,
and others. Among these factors are pancreatic -cell and bcell dysfunction, increased hepatic glucose production,
decreased insulin-sensitivity in muscle, adipocytes and
central nervous system, reduced gastrointestinal incretin
secretion/sensitivity and enhanced glucose reabsorption in
kidneys (De Fronzo, 2009).
CURRENTLY
PROBLEMS

USED

THERAPY

AND

ASSOCIATED

Although there is no cure for this disease, new

pharmacological and non-pharmacological approaches to
treatment have certainly improved the prognosis for
individuals with DM and their quality of life, morbidity and
increased mortality from micro- and macro-vascular
complications remain. Diabetes is a chronic illness that
requires continuing medical care and on-going patient selfmanagement education and support to prevent acute
complications and to reduce the risk of long-term
complications; accordingly its management is complex and
requires that many issues, beyond glycemic control, be
addressed (ADA, 2011). As diabetes is commonly regarded
as a disorder involving chronically elevated blood sugar
levels, anti-diabetic therapy has to a large extent been
glucose fixated. This means that the therapeutic agents
that are currently used to treat or manage diabetes work
directly or indirectly by regularizing/normalizing blood
glucose levels. They include:
1. Insulin for T1DM patients who lack the hormone, and for
T2DM patients who exhibit poor blood glucose
management and are unable to meet or keep within safe
glycemic goals.

032

2. Agents that increase the amount of insulin secreted by

the pancreas, sulfonylureas (glibenclamide, gliburide) and
new generation incretins and glucagon-like peptide analogs
and agonists (e.g., exenatide and liraglutide).
3. Agents which increase the sensitivity of target tissues like
skeletal muscle to insulin, e.g., biguanides and thiazolidinediones (includes metformin and pioglitazone).
4. Agents that decrease the rate at which glucose is
absorbed from the gastrointestinal tract, (e.g., acarbose and
miglitol). Inhibition of -glucosidase and -amylase in the
gut by nutritional supplements also decrease glucose
uptake.
5. Bariatric surgery for adults with BMI 35 kg/m 2 and
T2DM, especially where the diabetes or associated
comorbidities are difficult to control with lifestyle and
pharmacologic interventions.
The choice of anti-diabetic therapy is therefore highly
dependent on the clinical assessment of the individual
patients. All the above measures serve their purpose to
some extent, and apart from bariatric surgery (as indicated
in small trials) (Dixon et al., 2008), the disease is neither
cured nor is the development of the adverse complications
associated with long-term diabetes prevented.
The available treatments for T2DM have their own
drawbacks ranging from development of resistance and
adverse effects to lack of responsiveness in a large segment
of patient population. Moreover, none of the glucose
lowering agents adequately control the hyperlipidemia that
frequently met with the disease (Zia et al., 2001). The
limitation of currently available oral anti-diabetic agents
either in terms of efficacy/safety coupled with the
emergence of the disease into global epidemic have
encouraged alternative therapy that can manage diabetes
more efficiently and safely. Diet plays an important role in
the etiology and prevention of several obesity-associated
chronic diseases, most notably of diabetes and
cardiovascular diseases. Dietary pattern characterized by
higher consumption of vegetables, fruits and whole grains
is associated with reduced risk of T2DM (van Dam et al.,
2002). The evidence for individual dietary components is
limited, but phytochemicals, a large group of non-nutrient
secondary metabolites in plants which provide much of the
color and taste in fresh or processed fruits and vegetables,
are thought to play a significant role in the health effects of
plant-based diets. Especially the antioxidant effects of
phytochemicals such as polyphenols or carotenoids have
been studied extensively, but less is known of the other
possible biological mechanisms linking phytochemicals to
the prevention of T2DM.
Since time immemorial, plant extracts have been used to
treat patients with DM in various parts of the world.
Currently, especially in developing countries, many plants
were listed to be used for the management of diabetes
(Bnouham et al., 2006; Aissaoui et al., 2011). A large
number of these plants or their preparation have been
evaluated and confirmed to have hypoglycemic effects in

Academia Journal of Medicinal Plants; Hussain and Marouf

animal models (Gupta et al., 2005; Kesari et al., 2006). Some

have also been evaluated in human beings (HerreraArellano et al., 2004; Jayawardena et al., 2005). Most of
these plants contain glycosides, alkaloids, terpenoids,
flavonoids, polysaccharides, and saponins, which are
frequently implicated to having anti-diabetic effect (Jung et
al., 2006; Fahey et al., 2001). However, much is not known
about the specific mechanism of action of these plants,
although insulin-mimetic activity has been proposed for
some (Patel et al., 2012). The World Health Organization
Expert Committee on diabetes recommended that
traditional medicinal herbs be further investigated as they
are frequently considered to be less toxic and free from side
effects (Halberstein, 2005). Therefore, search for safe and
more effective agents has continued to be an important
area of active research.
A large number of studies have emphasized the potential
health-promoting and disease- preventing effects of fruits
and vegetables in the diet. Fruits and vegetables contain a
multitude of flavonoids and related phenolic compounds
that also act as natural antioxidants. Primarily recognized
as the pigments responsible for the autumnal burst of hues
and the many shades of yellow, orange, and red in flowers
and food, the flavonoids are found in fruits, vegetables,
nuts, seeds, herbs, spices, stems, flowers, as well as tea and
red wine. Flavonoids are low molecular weight bioactive
polyphenols (Fernandez et al., 2006; Heim et al., 2002)
which play a vital role in photosynthesizing cells
(Timberlake and Henry, 1986). Flavonoids, which are
poorly soluble in water, are polyphenolic molecules
containing 15 carbon atoms and they can be visualized as
two benzene rings which are joined together with a short
three carbon chain. One of the carbons of the short chain is
always connected to a carbon of one of the benzene rings,
either directly or through an oxygen bridge, thereby
forming a third middle ring. This class consists of 5 major
subgroups: flavones, flavonols, flavanones, flavanols and
anthocyanidins.
FLAVONOIDS AS ALTERNATIVE THERAPY FOR T2DM
Many conventional drugs have been derived from
prototypic molecules in medicinal plants. Development of
metformin was based on the use of Galega officinalis to
treat diabetes (Bailey and Day, 1989). G. officinalis is rich in
guanidine, and because guanidine is too toxic for clinical
use, the alkyl biguanides synthalin A and synthalin B were
introduced as oral anti-diabetic agents in Europe in the
1920s but were discontinued after insulin became more
widely available. However, experience with guanidine and
biguanides prompted the development of metformin
(Bailey, 1988). Over 400 traditional plant treatments for
diabetes have been reported, though only a small number
of these have received scientific and medical evaluation to
assess their efficacy. The hypoglycemic effect of some herbal

033

extracts has been confirmed in human and animal models

of T2DM. The World Health Organization Expert Committee
on diabetes has recommended that traditional treatment to
be further investigated (Bailey and Day, 1989).
Regulation of the postprandial glucose by inhibiting
starch digestion, delaying the gastric emptying rate and
reducing active transport of glucose across intestinal brush
border membrane is one of the mechanisms by which diet
can reduce the risk of T2DM. Thus inhibition of intestine
sodiumglucose cotransporter-1 (Na-Glut-1) along with
inhibition of -amylase and -glucosidase activity by plant
phenols makes them a potential candidate in the
management of hyperglycemia (Heilbronn et al., 2004).
Several plant polyphenols were reported to inhibit amylase and sucrase activity, decreasing postprandial
glycaemia (Kobayashi et al., 2000). Individual polyphenols,
such as catechin, epicatechin, epigallocatechin, epicatechin
gallate, and isoavones from soya beans also decrease SGlut-1 mediated intestinal transport of glucose (Tiwari and
Rao, 2002). Anthocyanins, a significant group of
polyphenols in bilberries and other berries, may also
prevent T2DM and obesity. Anthocyanins from different
sources have been shown to affect glucose absorption and
insulin level/secretion/action and lipid metabolism in vitro
and in vivo (Jayaprakasam et al., 2005; Martineau et al.,
2006). Many in vitro studies suggest that the anthocyanins
may decrease the intestinal absorption of glucose by
retarding the release of glucose during digestion (Tsuda et
al., 2006; Xia et al., 2006). Recently, Ganugapati et al. (2012)
reported that flavonoids isolated from banana flowers have
the potential to activate the insulin receptor tyrosine
kinase, and may represent an alternative choice for
treatment if T2DM patients with insulin resistance
(Ganugapati et al., 2012; Kemertelidze et al., 2012).
Flavonoids, especially quercetin have been reported to
possess antidiabetic activity. Vessal et al. (2003) reported
that quercetin brings about the regeneration of pancreatic
islets and probably increases insulin release in
streptozotocin-induced diabetic. Also in another study, Hii
and Howell reported that quercetin stimulate insulin
release and enhanced Ca2+ uptake from isolated islets cell
which suggest a place for flavonoids in T2DM (Hii and
Howell, 1985).
Dietary polyphenols are chemicals of plant origin that are
abundant in fruit, vegetables, chocolate, and nuts, as well as
in beverages such as tea, coffee, wine, and soy milk (Manach
et al., 2004; Torabian et al., 2009). In tea leaves for example,
polyphenols can account for up to 30% of their dry weight
(Mukhtar and Ahmad, 2000). As such, polyphenols are the
most abundant antioxidants in the diet of human beings
(Scalbert et al., 2005a). Dietary polyphenol consumption is
of interest because it is associated with lower rates of
diabetes and cardiovascular disease (Scalbert et al., 2005b;
Crozier et al., 2009). There are thousands of natural
polyphenols in the plant kingdom (and in derived foods), all
of which share the basic structure of an aromatic ring with

Academia Journal of Medicinal Plants; Hussain and Marouf

attached hydroxyl groups. Variations in this structure led to

individual classifications of polyphenols, with at least 10
separate classes identified (Perez-Jimenez et al., 2011), four
of which are important in the diet of human beings:
phenolic acids, flavonoids, stilbenes, and lignans (PerezJimenez et al., 2010; de Bock et al., 2012). Currently, there is
a major imbalance between the published clinical studies
on the benefits of polyphenols to human health and the
marketing of these products. There is mounting evidence
that polyphenols can reduce insulin resistance in in vitro
and animal studies (Hanhineva et al., 2010; Verma et al.,
2012), but data from studies in human beings remains
limited. A good example in this respect is the polyphenol
content in red wine, which may explain the so called French
paradox, where there is a low incidence of cardiovascular
disease in France despite a relatively high intake of
saturated fat. Since Renaud and de Lorgerils original article
(Renaud and de Lorgeril, 1992), the subsequent literature
has focused on the antioxidant effect and lipid-lowering
properties of red wine polyphenols, whereas some trials
have investigated the effect of grape and wine products on
glucose homeostasis (Kar et al., 2009; Hollis et al., 2009).
Yet these studies have yielded contradictory results: two
studies showed no improvement (Hollis et al., 2009;
Naissides et al., 2006), one showed lowered fructosamine
but no change in insulin sensitivity (Kar et al., 2009),
another demonstrated acute amelioration of glucose
excursion when wine was taken with a meal (Gin et al.,
1999), but only Banini and colleagues (Banini et al., 2006)
found a clinically significant reduction in glycosylated
hemoglobin (7.4 to 6.8%) in T2DM patients after 28 days of
wine supplementation. However, the use of pure
standardized silibinin as adjuvant for treatment of patients
with T2DM (Hussain, 2007; Huseini et al., 2006)
demonstrates promising clinical and biochemical outcomes.
The other consideration in this respect is whether total
dietary polyphenol intake is more important in regulating
glucose homeostasis, in comparison to the intake of a single
polyphenol in large quantities. In this respect, many animal
and human studies indicated the significance of
pharmacological doses of standardized pure single
flavonoids in improving glycemic control, both in
experimental animal models of DM and in patients with
T2DM; most of the studied flavonoids act through
interference with digestion of complex sugars and
absorption of glucose (Hussain et al., 2012a; Hussain et al.,
2012b; Brasnyo et al., 2011; Fu et al., 2012). Inhibition of
carbohydrate digestive enzymes may be of use to patients
with T2DM as well as the growing pre-diabetic population
around the world (Kamiyama et al., 2010; Li et al., 2009).
Many previous researches have demonstrated that orally
administered green tea extract, which contains many
monomeric flavan-3-ols, including epigallocatechin gallate
and epicatechin gallate, may inhibit glucose absorption
from the lumen of the intestine (Park et al., 2009; Johnston
et al., 2005). Therefore, it is conceivable that natural,

034

dietary inhibitors of glucosidases that likely pose fewer

adverse side effects than synthetic compounds could be
useful in the prevention or treatment of T2DM and prediabetes. Moreover, in a randomized clinical study,
Sattanathan and others demonstrated that administration
of the flavonoid rutin, as adjuvant with oral hypoglycemic
agents, improves glycemic control and lipid profile in T2DM
patients (Sattanathan et al., 2011).
CONCLUSIONS
Despite promising data from in vitro and animal studies, the
effects of polyphenols on glucose homeostasis in humans
have not been consistently declared. Further research in
human beings should adopt robust randomized placebocontrolled study designs, and standard techniques to
evaluate insulin sensitivity should be utilized where
possible. Moreover, scientists should investigate molecular
pathways involved in glucose homeostasis that may
translate into long-term health benefits, which are not
observed in short-term studies. Despite the paucity of
robust data showing beneficial health outcomes associated
with flavonoids in humans, these compounds already have
a large commercial value. Further research in this area is
urgently needed because prescribable flavonoids to manage
the diabetes pandemic are an exciting prospect.
ACKNOWLEDGEMENT
The authors thank Baghdad University and Sulaimani
University for support.
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Cite this article as:

Saad AH and Bushra HM (2013). Flavonoids as alternatives
in treatment of type 2 diabetes mellitus. Acad. J. Med.
Plants. 1(2): 031-036.
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