Review article: Nutrition Reviews

The Potential of Fruits Flavonoids as Antidiabetic Agents

Institute of Food Science and Nutrition, University of Sargodha, Sargodha, Pakistan

*Corresponding author: Umar Farooq

Assistant Professor

Institute of Food Science and Nutrition

University of Sargodha, Sargodha, Pakistan.

Phone: +923227149412, Fax: +92489230316

E-mail: umarfarooq@uos.edu.pk

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Diabetes mellitus is a global disorder, and major issue for health care systems. The onset of

diabetes mainly depends upon genetics and lifestyle. Currently used therapeutic options for

diabetes mellitus, like dietary amendments, oral hypoglycemic drugs, and insulin have their own

limitations. Recently, antidiabetic effect of fruits flavonoids has been studied due to their

property of managing the altered glucose and oxidative metabolisms of in diabetic state. The

current review outlooks the use of fruits flavonoids as an alternative in the prevention of diabetes

mellitus.

Keywords: Diabetes mellitus, fruits, flavonoids, antidiabetic

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INTRODUCTION

DIABETES: PREVALENCE, ETIOLOGY AND CONSEQUENCES

Diabetes mellitus is one of the most common metabolic disorders with 382 million patients

globally estimated till 2013.N -1 The personal and public health problem of diabetes is

continuously escalating exponentially (2.6 % annually) throughout the world N-2, and according to

World Health Organization, diabetes will be the 7th leading cause of death in 2030. N - 3

Symptomatically, diabetes mellitus is characterized by chronic hyperglycaemia (elevated

concentration of glucose in the blood ≥ 7.0 mmol/L or 126 mg/dl). N - 4 Other symptoms includes

but not limited to severe thirst (polydipsia), frequent urination (polyurea), increased hunger

(polyphagia), unconsciousness, weight loss and coma leading to death or many medical

complication may occur in the absence of effective treatment. This worldwide rapidly growing

health threat occurs due to multiple interaction and combination of multiple genetic and

environmental factors Diabetes mellitus (metabolic disorder) occurs because of complex

interactions between multiple genetic and environmental factors.1

Diabetes has complex and various degrees of heterogeneity in its etiology. Evidently, diabetes

manifested when the body becomes resistant to insulin (a hormone secreted by β-cells of

pancreas gland) or when enough insulin is not produced to regulate glucose metabolism.N-5 Type

1 diabetes and type 2 diabetes are two main types of this disease 4,5 besides other similar

conditions like pre-diabetes (impaired glucose regulation) and gestational diabetes. In type 1

diabetes (insulin dependent diabetes mellitus or juvenile diabetes) body cannot produce insulin

due to autoimmune or infectious destruction of β-cells of pancreas gland and insulin is required

to be externally administered.N - 6 Type 2 diabetes, previously known as non insulin dependent

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diabetes mellitus, is characterized by body’s ineffective use of insulin N - 7 and is the most common

and prevalent form (90-95 %) of diabetes mellitus.

Exact mechanism of the development and progression of diabetes is still unclear. It is postulated

that diabetes occurs when the tightly controlled mechanisms have been disturbed due to any

reason. Notable increase has been seen in the identification of the molecular components and all

the signaling pathways used in the regulation of glucose absorption.6 Chronic hyperglycaeima

affects nerves system, heart, kidneys, eyes and other systems of body. Diabetes is the leading

cause of many disease conditions like storkes, cardiovascular disease, renal failure, visual

impairment and blindness, lower limb amputations, erectile dysfunction, insignificant wound

healing.2,3, N - 8 , N - 9 , N - 10 , N - 11 , N - 12 , N - 13 Sometimes diabetes is not diagnosed until the development of

other health problems. Stress, lethargy life style, smoking, hypertension, eating habits,

processing and nutritional composition of food are some of the predisposing environmental

factors in the development of diabetes mellitus. N - 14 , N - 15 , N - 1 6 On the food and nutrition fore front;

refined grains, highly processed food, energy dense junks, saturated fat, excessive alcohol, sugar

sweetened beverages are major culprits.N-1 7 , N-1 8

This metabolic disorder is described as the high level of blood sugar due to defects in insulin

secretion or insulin action.

Erectile dysfunction, insignificant wound healing, blindness, kidney failure, and heart diseases

are the main problems related to long-term diabetes and these problems increases as the disease

progresses.2,3 The two main types of this disease are: type 1 diabetes (insulin is externally

administered) and type 2 diabetes (use of oral antihyperglycemic drugs and externally

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administered insulin).4,5 Notable increase has been seen in the identification of the molecular

components and all the signaling pathways used in the regulation of glucose absorption.6

MANAGEMENT OF DIABETES

Diabetes is life long disease and no cure for diabetes is yet to be found however, different

pharmacological and non-pharmacological therapeutic measures have positively been employed

to enhance the life quality of individuals suffering from diabetes and its micro and macro-

vascular complications.15 As diabetes is characterized by chronically increased levels of blood

glucose thus main theme of current diabetes management is to better regulate the glucose

metabolism.N-19 However, this is not so simple, this complex disorder needs continuous medical

attention, support, and self-management education of the patient to avoid serious complications

and to diminish the risk of long-term complications; accordingly its management is multifarious

and needs many issues, beyond glycemic control, to be addressed.16 Lifestyle interventions

addressing diet and physical activity are considered a first-line intervention for the prevention of

type 2 diabetes.N-20

Insulin is routinely administered in type 1 diabetes mellitus patients due to auto-destruction of β-

cells of pancreas and ultimately incapability of cells to secrete insulin and for type 2 diabetic

patients, in which cells are unable to respond the normal action of circulating insulin and

incapable to meet safe glycemic targets.17 Some compounds possessing antidiabetic properties

have been extensively employed to manage disbetes.N-6, 7 Several surgical procedures (bariatric

surgery) are adopted mainly to achieve weight loss in obese persons to mange diabetes especially

when the lifestyle and pharmacologic interventions become unable to control type 2 diabetes or

its related problems.24 Different degrees and proportions of survival benefits are reported with

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bariatric surgery,N-21 however no considerable improvement had been witnessed in highly

vulnerable population N-22 and there are also reports of reoccurrence of obesity and associated

problems like obesity after surgical interventions depending upon pre-bariatric history of

diabetes.N-23

The clinical evaluation of a patient helps to select the suitable therapy for the treatment. All the

above mention preventive measures fulfill their objective to some extent except bariatric

surgery24 and diabetes and it related complications are not cured till now. Efficient and

sustainable management of diabetes is becoming more important with rapidly increasing

morbidity due to this disease globally.N-3 It is predicted that by year 2035 patients suffering from

diabetes would reach to 600 million worldwide. N-1

COMMONLY USED ANTI-DIABETES AGENTS AND THEIR RELATED PROBLEMS

Recently used therapeutic anti-diabetes agents measures for diabetes comprise of insulin

and several other oral antidiabetic agents likeare sulfonylureas, glinides, biguanides, and α-

glucosidase inhibitors.7 They are used asemployed singly or in combine form. to attain better

glucose regulation. Most of these oral antidiabetic agents impose serious side effects so, diabetes

management without any adverse effect is still a challenge.8 Therefore, the exploration of more

active and safer therapeutic agents in eliminating diabetic syndromes is an important area of

investigation.9

Natural products from fruit and vegetable sources are becoming popular worldwide and

broadly accepted as an aide to conventional therapy.10 Increasing public awareness and scientific

interest headed the research towards the evaluation of fruits role in health up-gradation and

disease treatment. In recent years, great attention has been focused on the antidiabetic role of

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bioactive components of fruits known as “flavonoids”.11 Flavonoids are secondary metabolites of

plants; share a common carbon skeleton of two benzene rings, linked by a 3-carbon bridge (C6–

C3–C6).12 Flavonoids include various subclasses, among them flavonols (quercetin and

kaempferol), flavones (luteolin and apigenin), flavanols (catechins and proanthocyanidins),

anthocyanidins, flavanones (naringenin and hespertine), and isoflavones (genistein and daidzein)

are commonly found in different foods especially fruits.13

Treatment of kaempferol (10 μM) a fruit flavonol significantly increased the viability,

reduced cellular apoptosis and caspase-3 activity in human beta cells and islets. Furthermore,

kaempferol treatment also increased the expression of anti-apoptotic proteins (Bcl-2 and

Akt) (Zhang and Liu, 2011)14. In addition, studies also demonstrated that quercetin flavonoid

increase the regeneration of pancreatic islets and ultimately increase the insulin secretion in

streptozotocin-induced diabetic rats.11

COMMONLY USED THERAPIES AGAINST DIABETES AND THEIR RELATED

PROBLEMS

No cure for diabetes is yet to be found, but currently use pharmacological and non-

pharmacological therapeutic measures have positively enhanced the life quality of individuals

suffering from diabetes and its micro and macro-vascular complications.15 Diabetes is a disorder

that needs continuous medical attention, support, and self-management education of the patient

to avoid serious complications and to diminish the risk of long-term complications; accordingly

its management is complex and needs many issues, beyond glycemic control, to be addressed.16

As diabetes is a disorder characterized by chronically increased levels of blood glucose. The

currently used antidiabetic treatments have largely fixed the glucose problem. In fact, all

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currently used anti-diabetic agents in practice work directly and indirectly by regulating the

blood glucose level (Figure 1). They include:

Insulin administration in type 1 diabetes mellitus patients due to auto-destruction of β-

cells of pancreas and ultimately incapability of cells to secrete insulin and for type 2

diabetic patients, in which cells are unable to respond the normal action of circulating

insulin and incapable to meet safe glycemic targets.17

Sulfonylureas are the antidiabetic drugs (glibenclamide and glyburide) that increase the

amount of insulin by acting upon the β-cells of pancreas. On β-cells membrane they

attached to an ATP-dependent K+(KATP) and cause positive electric potential over the

membrane and open the Ca2+ channels. This elevation of intracellular calcium ions results

into increased fusion of insulin granule with cell membrane, henceamplifiedthe secretion

of insulin.18 Incretins like exenatide and liraglutide also increase the insulin production by

acting on pancreas.19

Biguanides and thiazolidinediones increase the insulin sensitivity of adipose tissue, liver,

and muscle by increasing the uptake of glucose in muscle and decrease the production of

glucose in liver. They include metformin and pioglitazone.20,21

Acarbose and miglitol are the antidiabetic agents that slowdown the absorption of glucose

from gastrointestinal tract. Nutritional supplements also inhibits α-glucosidase and α-

amylase activity in gut and ultimately reduce the glucose uptake.22,23

Bariatric surgery, especially when the lifestyle and pharmacologic interventions become

unable to control diabetes or its related problems.24

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The clinical evaluation of a patient helps to select the suitable therapy for the treatment. All the

above mention preventive measures fulfill their objective to some extent except bariatric

surgery.24 Diabetes and it related complications are not cured till now.

Unfortunately, Tthe present treatments of for diabetes through anti-diabetic agents have their

own flaws including the increased resistance and lack of responsiveness in a large segment of the

patient population. In addition, not any antihyperglycemic agent properly controlstackles the

elevated lipid level that is common in this disease.25

The above mention antidiabetic drugs impose serious side effects on human heath, so the need of

antidiabetic agent primarily from natural source is of prime importance.26 Most of these oral

antidiabetic agents impose serious side effects so, diabetes management without any adverse

effect is still a challenge.8 Therefore, holistic exploration of more active and safer therapeutic

agents in eliminating diabetic syndromes is an important area of investigation.9

FLAVONOIDS: POTENTIAL ANTI-DIABETIC AGENTS

Recently, more attention is given on research of flavonoids from dietary sources, due to growing

evidence of their versatile health benefits. To best understand the mode of action of flavonoids as

their potential role in the prevention of diseases, it is important to know their biosynthesis,

metabolism, and bioavailability.27

Natural products from fruit and vegetable sources are becoming popular worldwide and

broadly accepted as an aid to conventional therapy.10 Increasing public awareness and scientific

interest headed the research towards the evaluation of fruits role in health up-gradation and

disease treatment. In recent years, great attention has been focused on the health promoting roles

of bioactive components known as “flavonoids”.11 Flavonoids are ubiquitously secondary

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metabolites present in almost all fruits and vegetables.N - 23 They share a similar carbon skeleton of

two benzene rings, linked by a 3-carbon bridge (C6–C3–C6)12 and include various subclasses

(table 1), notably flavonols (quercetin and kaempferol), flavones (luteolin and apigenin),

flavanols (catechins and proanthocyanidins), anthocyanidins (aurantinidin, cyaniding),

flavanones (naringenin and hespertine), and isoflavones (genistein and daidzein).13

Please make a table

Class of Flavonoid General Structure Different members with their

sources

Flavonoids have various positive effects on complex metabolic pathologies including

diabetes, through multifarious modes of actions.N-24 It is postulated that majority of the

bioactivity of flavonoids is due to their α,β ketones and hydroxyl groups. N - 25

Treatment of kaempferol (10 μM) a fruit flavonol significantly increased the viability,

reduced cellular apoptosis and caspase-3 activity in human beta cells and islets. Furthermore,

kaempferol treatment also increased the expression of anti-apoptotic proteins (Bcl-2 and

Akt) (Zhang and Liu, 2011)14 . In addition, studies also demonstrated that quercetin flavonoid

increase the regeneration of pancreatic islets and ultimately increase the insulin secretion in

streptozotocin-induced diabetic rats.11

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Recently, more attention is given on research of flavonoids from dietary sources, due to growing

evidence of their versatile health benefits. To best understand the mode of action of flavonoids as

their potential role in the prevention of diseases, it is important to know their biosynthesis,

metabolism, and bioavailability.27

BIOSYNTHESIS OF FLAVONOIDS IN PLANTS

Flavonoids belong to the family of aromatic compounds that are derived from phenyl and

malonyl-coenzyme A, through the fatty acid pathway.28 In the beginning of flavonoids

biosynthesis, the phenylalanine (from the shikimic acid pathway) is changed to coumaroyl-CoA

by phenylalanine ammonia-lyase and 4-coumarate (CoA ligase, and cinnamate 4-hydroxylase).

Coumaroyl-CoA is condensed with three molecules of malonyl-CoA (from acetyl-CoA) to

produce naringenin chalcone by chalcone synthase (the first enzyme for flavonoid biosynthesis).

Then chalcone isomerase converts naringenin chalcone to naringenin. Naringenin is further

modified by glycosylation, acylation, and methylation of its three rings. All these enzymatic

steps result into production of substituted flavones, catechins, deoxyflavonoids, flavonols, and

anthocyanins. Isoflavone synthase (cytochrome P450 enzyme) form isoflavonoids from

naringenin or deoxyflavonoids by aryl movement of the B-ring to the 3rd position, then

hydroxylation at the 2nd position. The 2-hydroxyisoflavone is an unstable intermediate molecule

and is dehydrated to produce isoflavone.29

METABOLISM AND BIOAVAILABILITY OF FLAVONOIDS

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Flavonoids are used as substrates by conjugating and hydrolyzing enzymes of small intestine,

liver, and colon. Then these enzymes convert the flavonoids into O-glucuronides, sulfate esters,

and O-methyl esters.30 Flavonoids conjugation is first occurred happened in the small intestine

then in the liver. In liver, they are further metabolized to produce glucuronides and sulfate

derivatives which are then facilitated and excreted through urine and bile.30 The unabsorbed

compounds were further moved to colon and structurally modified by colonic microflora.31 The

flavonoid glucuronides are hydrolyzed into aglycones (by microbiota) after re-entering the

enterohepatic circulation.32 Then aglycones are further breakdown to low molecular compounds

that can easily be absorbed.

Spencer et al.33 reported that during systemic absorption of monomeric flavan-3-ols they

are either metabolized into O-methylated forms or conjugated to form glucuronides or sulphates.

In addition, the monomeric flavan-3-ols (procyanidins) were split into the conjugates of

epicatechin. A study done by Del-Rio et al.31 on the absorption and metabolism of flavan-3-ols in

humans illustrated that epigallocatechin-O-glucuronide and methyl-epicatechin-sulphate were

excreted in urine hence confirmed the above statement. Another recent study done by Fernandes

et al.34 on the bioavailability of an anthocyanin derivative demonstrated the transepithelial

transport of flavan-3-ol-anthocyanin dimer [(+)-catechin-4, 8-malvidin-3-glucoside], by using

Caco-2 cells. The results were compared with (+)-catechin, procyanidin B3 (dimer), and

malvidin-3-glucoside. All the compounds under consideration passed the Caco-2 cell model

barrier and the absorption of catechin-malvidin dimer was significantly less as compared to

individual malvidin or catechins compounds. But the transport efficacy of the catechin-malvidin

dimer was more than procyanidin B3 dimer and this increased transport efficacy of catechin-

malvidin dimer might be due to presence of the anthocyanin and its glucose moiety in the flavan-

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3-ol-anthocyanin. Interestingly, after 2 hour of incubation only the breakdown of parent

compounds was observed and no catechin-malvidin dimer metabolites were found. The results of

this study illustrated that anthocyanins are absorbed as anthocyanin derivatives and catechin-

malvidin dimer is more resistant to metabolism as compared to its parent compounds. A study

done on the genistein (aglycone) and its glycoside genistin bioavailability showed that the

bioavailability of the aglycone was higher in comparison to its glycoside form.35

PROMISING ANTIDIABETIC ROLE OF FRUITS FLAVONOIDS

Numerous studies demonstrated that many plants especially fruits are traditionally used for the

treatment of diabetes.36,37 Epidemiological studies and meta- analyses described that use of fruits

rich in flavonoids (found in fruits) utilization decreased the age related disorder especially

diabetes.38,39 Plenty ofMany in- vitro and animal studies support the worthy positive effects of

various fruits flavonoids on glucose homeostasis.40-46 These Generally flavonoids exert wide

range of their antidiabetic activity on various organs especially work as antidiabetic agents by

ameliorating the insulin action on skeletal muscle and liver cells. They to reduce the plasma free

fatty acid level, hepatic gluconeogenesis, and increased glucose uptake.47 In the intestine,

flavonoids inhibit the digestion of starch, slow down the gastric emptying and reduce the

absorption of glucose across the membrane.48 The proposed antidiabetic mechanism of fruits

flavonoids is presented in Figure 2. The fruits flavonoids and their antidiabetic roles are

presented in Table 1.

Citrus flavonoids as antidiabetic agent

In recent years, citrus flavonoids gained much attention because of their potential therapeutic

properties and comparatively low toxicity to animals.49-51 Shen et al.52 reported that citrus

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flavonoids like hesperidin, nobiletin, neohesperidin, and naringin showed antidiabetic properties

by binding starch and slow down its digestion. Numerous studies reported that hesperidin,

naringin, and nobiletin enhanced the insulin sensitivity and induced the hypoglycemic effect in

diabetic animals.46,53-56 Naringenin a major flavonoid found in citrus possessed antidiabetic

properties. Lim et al.57 demonstrated that naringenin exhibited insulin sensitive effect at a

concentration of 100 µM, by enhancing the uptake of glucose in primary rat adipocytes (163%)

as compared to insulin (130%). The studies of Huong et al.58 demonstrated that fruits rich in

naringenin (1%) improved the oxidation of hepatic fatty acid by regulating the gene that encodes

the enzyme for peroxisomal β-oxidation in mice and this change may account for its capability of

inducing low serum lipid levels. Moreover, naringenin reduced the lipid level by increasing the

low density lipoprotein receptor expression through phosphatidylinositol 3-kinase facilitated up

regulation of sterol regulatory element-binding protein.59

Phosphoenolpyruvate carboxykinase and glucose 6-phosphatase are the main enzymes

involved in gluconeogenesis. In diabetic condition, the levels of these enzymes raise which lead

to reduce utilization of glucose and elevated production of glucose.60 Naringin and hesperidin

belongs to citrus flavonoids and suppressed the expression of phosphoenolpyruvate

carboxykinase and glucose 6-phosphatase, and reduced the hepatic glucose production.46

Berries flavonoids as antidiabetic agent

Procyanidin extract of grapes seeds increased the concentration of insulin transporter:

glucose transporter-4 in plasma membrane, increased the uptake of glucose in adipocytes, and

ultimately induced the antihyperglycemic effect in streptozotocin-induced diabetic rats.61 Glucose

transporter-4 is the main insulin regulating transporter which is expressed in skeletal muscle and

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adipose tissue. In diabetic db/db mice adipocyte, the expression of glucose transpoter-4 improves

the glycemic control by ameliorating insulin resistance.62

Cai et al. 41 reported the antidiabetic effect of epigallocatechin gallate on glucose-induced

toxicity in the pancreatic β-cells of a rat insulinoma-m5F cells. The results demonstrated that 0.1

and 10 μM concentration of epigallocatechin gallate enhanced insulin secretory function and

viability of β-cells in glucotoxic conditions. These properties were partially facilitated via

increased expression of insulin receptor substrate-2, the forkhead box protein O1, Akt (glucose

metabolizing protein kinase), and pancreatic duodenal homeobox1.Insulin receptors substrate

protein mediates the insulin action and regulates the β-cells viability and proliferation. The

forkhead box protein O1 regulates the cellular proliferation and protects the β-cells from

apoptosis.63 Pancreatic duodenal homeobox1 is a transcription factor that is expressed in islets of

Langerhans and increase the viable count of islets.64

Strawberry is a fruit of nutritional importance and now gaining attention because of

antidiabetic property of its flavonoids.65,66 In general α-amylase and α-glucosidase are the key

enzymes involved in catalytic breakdown of carbohydrates into glucose. In antidiabetic analyses,

IC50 value for α-amylase and α-glucosidase activity of fruit extract of strawberry was found to be

86.47 ± 1.12μg/ml and 76.83 ± 0.93μg/ml respectively. Maximum inhibition of 52.35% at a

concentration of 97μg/μL was done by strawberry extract (rich in phytochemicals) and in

comparison with standard acarbose, which exhibited maximum inhibition of 72.10% at a

concentration of 92μg/μL. In addition, at the concentration of 91μg/μL, strawberry extract

induced 58.83% of inhibition. Standard acarbose exhibited maximum inhibition of 69.43% at a

concentration of 96μg/μL.67 The studies also demonstrated the antidiabetic effects of bayberry

fruit extract. Sun et al.68 reported that bayberry extract (rich in cyanidin-3-glucoside) decreased

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the risk of oxidative stress and ultimately reduced the β-cell damage. Initial treatments of β-cells

with bayberry fruit extract (comprising 0.5μM cyanidin-3-glucoside) stopped cell death by

hydrogen peroxide, mitochondrial reactive oxygen species production, and cell necrosis.

The bioactive components present in the most of berries and cherries appear as

glycosides of anthocyanidins. Dried cherries of Cornus spp. have been traditionally used for

diabetes treatment in China.69 The cyanidin-, delphinidin-, and pelargonidin glycosides are the

important bioactive component of Cornus fruits.70,71 These anthocyanidins and anthocyanins

components improved the insulin secretion by acting on β-cells of pancreas. The pancreatic β-

cells were treated with cyanidin-3-glucoside and delphinidin-3-glucoside for 60 minute and they

increased the glucose stimulated insulin secretion. While pelargonidin-3-galactoside, cyanadin-3-

galactoside, and aglycones: cyanidin, pelargonidin, delphinidin, and malvidin had negligible to

marginal effects on glucose stimulated insulin secretion.72 Cyanidin 3-glucoside (50 μM) and

protocatechuic acid improved the glucose uptake and translocation of glucose transporter in

human and rat adipocytes.73

Rostamian et al.74 demonstrated the antidiabetic action of hydroalcoholic extract of

strawberries leaves rich in flavonoids. For this purpose 24 male adult rats were selected

randomly and were divided into non antidiabetic control group, diabetic control, and diabetic

group. Diabetic group was administered with alloxan then intraperitoneally injected with extract

(100mg/Kg). The analysis of glucose, triglyceride, high density lipoprotein, cholesterol, and low

density lipoprotein content showed that the extract rich in flavonoids meaningfully reduced the

glucose, triglyceride, cholesterol, and elevated the level of high density lipoproteins but didn’t

affect the low density lipoprotein content.

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Eid et al.75 elucidated the mode of action of quercetin rich extract of Vaccinumvitis-idaea

(cowberry) in the treatment of diabetes. For this purpose 10 compounds (found in berries)

involved in glucose absorption were analyzed in C2C12 murine skeletal myoblasts and H4IIE

murine hepatocytes (main cells of liver tissue). The results revealed that quercetin-3-O-glycoside

and quercetin aglycone were the active components involved in glucose absorption. This effect is

facilitated by adenosine monophosphate activated protein kinase, which mediates the

translocation of glucose transporter type 4. Adenosine monophosphate activated protein kinase is

an energy sensing molecule and involve in body energy homeostasis. It improves the glycemic

level and lipid profile in insulin resistant rodents.76 Therefore, adenosine monophosphate

activated protein kinase is considered as an attractive target for developing new strategies to treat

diabetes.

Bilberries are the rich source of anthocyanins.77,78 Takikawa et al.78 elucidated the

metabolic properties of bilberry extract (27g bilberry extract containing 10g anthocyanin/Kg

diet) in mice with type 2 diabetes. Bilberries extract enhanced hypoglycemia and insulin

sensitivity in diabetic mice by targeting adenosine monophosphate activated protein kinase,

glucose transporter type 4, and other metabolic enzymes.

Persimmon flavonoids as antidiabetic agent

The persimmon belongs to the family of Ebenaceae and inhabitant of Japan and China. Several

studies demonstrated the antidiabetic and antiobesity effects of persimmon flavonoids.79,80

Proanthocyanidin, a major flavonoid obtained from persimmon peel was reported to possess

antidiabetic and antiobesity properties. Administration of proanthocyanidin (from persimmon

peel) to streptozotocin-induced diabetic rats reduced the elevated level of lipid peroxidation,

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inhibited the reactive oxygen species generation, reduced the serum glucose, glycosylation of

hemoglobin, urinary protein, glycation products, and serum urea nitrogen. Hence, this protective

effect of proanthocyanidin showed its antidiabetic potentials.81 In addition, Dewanjee et al.79

reported that proanthocyanidin elevated the level of super oxide dismutase, glutathione, and

catalase activity in the liver and kidney, and finally prevent the oxidative stress mediated diabetic

complications in this severe diabetic model.

Matsumoto et al.80 demonstrated that persimmon significantly reduced the elevation in

plasma lipids (total cholesterol, LDL cholesterol, and triglyceride) in the diet-induced obesity

mouse model. Moreover, Lee at al.82 reported that proanthocyanidin, reduced the plasma glucose,

glycosylation of protein, and hyperlipidemia and ultimately reduced the hyperglycemia in male

db/db mice (leptin receptor deficient). Proanthocyanidins polymers showed a strong inhibitory

effect on α-amylase, while oligomers induced a stronger protective effect against α-glucosidase

activity and angiotensin converting enzyme formation, suggesting that oligomers may have more

potential as anti-diabetic agents. Moreover, persimmon proanthocyanidin also reduced the

elevated oxidative stress in db/db mice by reducing the lipid peroxidation, reactive oxygen

species, protein expression of inducible nitric oxide synthase, and cyclooxygenase-2 and

improved the glutathione/oxidized ratio.81 Inducible nitric oxide synthase mediate inflammation-

related insulin resistance. Cyclooxygenase-2 is the enzyme involved in β-cell dysfunction. Gu et

al.83 reported the antidiabetic effect of tannins extracted from persimmon pulp. The results

demonstrated that tannins exhibited their activity by scavenging the hydroxyl radical and induced

the antioxidant effect. Overall, the studies proposed that proanthocyanidin polymerization has

ability to combat the obese and diabetic phenotype, and that its oligomers are the more potent

and promising compounds.

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Guava flavonoids as antidiabetic agent

Guava is tropical fruit and rich source of natural antioxidants like, vitamin C and polyphenolic

compounds.84,85 Numerous studies have demonstrated that the leaves and fruit of guava induced

antidiabetic effects in alloxan- or streptozotocin-induced diabetic models.86,87

Wu et al.88 demonstrated the antiglycation activity of guava leaves extract and its active

compounds. The results revealed that guava leaves extract and its compounds inhibited the

process of glycation in albumin and their potency was compared with polyphenol 60

(polyphenolic compound extracted from plants) and antiglycation agent (aminoguanidine). The

results revealed that inhibitory effect of guava leaf extracts against α-dicarbonyl compounds

formation were over 95% at 50μg/mL. The guava leaf extracts also induced strong inhibition on

the generation of amadori product (intermediate product in advance glycation end product

formation) and advance glycation end products in albumin in the presence of glucose. The

catechins and quercetin induced 80% of the antiglycated effect. Among all the phenolic

compounds that were under study, quercetin showed highest activity (95%) at 100μg/mL and no

activity was shown by ferulic acid.

Cheng et al.86 isolated quercetin flavonoid from aqueous extract of guava leaves by

column chromatography and analyzed its efficacy. The results revealed that quercetin separated

from the guava leaves extract increased the glucose uptake in rat clone 9-hepatocytes (liver

cells). So quercetin contributes to mitigate hyperglycemia in diabetes as a consequence.

Shen et al.89 reported the antidiabetic effect of aqueous and ethanolic extracts of guava

leaves in low-dose streptozotocin and nicotinamide-induced rats. The results indicated that

aqueous extract increased the activities of hepatic hexokinase, phosphofructokinase, and glucose-

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6-phosphate dehydrogenase in diabetic rats as compared to the normal diabetic group.

Furthermore, ethanolic extract only elevated the hepatic hexokinase and glucose-6-phosphate

dehydrogenase activity in diabetic rats. Due to these effects of the extracts, the assimilation of

glucose in glycolytic pathway and pentose monophosphate shunt was increased and resulted into

depression of the blood glucose level. Huang et al.90 demonstrated the blood glucose lowering

effect of guava in streptozotocin-induced diabetic rats. They reported that guava induced its

hypoglycemic effect by protecting the viability of β-cells from lipid peroxidation and breakdown

of DNA strands and ultimately improved the insulin secretion. In addition, guava also inhibited

the expression of pancreatic nuclear factor-kappa B protein and improved the activities of

superoxide dismutase, catalase, and glutathione peroxidase, which are involved in antioxidant

activity. Begum et al.91 identified more than 20 compounds in guava fruit extract. In addition,

studies reported the positive correlation between antihyperglycemic activity and phenolic content

especially flavonoids in fruits.92

Wang et al.93 reported the inhibitory activity of guava leaves extract against α-amylase

and α-glucosidase. Seven flavonoids (quercetin, guaijaverin, avicularin, kaempferol, hyperin,

apigenin, and myricetin) were isolated from the ethanolic and butanolic extracts of guava leaves

extract. The study revealed that querticin, kaempferol, and myricetin flavonoids showed highest

inhibitory activity against sucrase with IC50 values of 3.5 mM, 5.2 mM, and 3.0 mM, against

maltase with IC50 values of 4.8 mM, 5.6 mM, and 4.1 mM and against α-amylase with

IC50 values of 4.8 mM, 5.3 mM, and 4.3 mM, respectively. Among these flavonoids, myricetin

(1.5 mg/mL) exhibited the highest inhibition of 70% against sucrase. The results suggested that

hydroxyl groups play an important role in the inhibition activity.

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Papaya Flavonoids as Antidiabetic Agents

Quercetin 3-O-rutinoside and mangiferingallate were the major flavonoids present in papaya.94,95

Sellamuthu et al.96 also reported that papaya is rich source of mangiferin and the galloylated

forms of mangiferin and isomangiferin, xanthone glycosides. These phytochemicals were

described as potent antidiabetic agents.

Sasidharan et al.97 demonstrated the antidiabetic effect of ethanolic extract of Carica

papaya in streptozotocin-induced diabetic rats. Phytochemical screening revealed that this effect

was probably due to the presence of certain phytochemical especially flavonoids. The

phytochemicals rich extract increased the regeneration of β-cells of pancreas, improved the

function of liver tissue, and the recovery of cuboidal tissue of kidney.

Juarez-Rojop et al.98 reported that aqueous extract of Carica papaya increased the

secretion of insulin by acting on β-cells. A treatment with Carica papaya significantly reduced

the serum triglycerides, cholesterol, and aminotransferases in diabetic rats. Aqueous extract

improved the morphology of hepatocytes by preventing the cells disruption and inhibition of

glycogen and lipid accumulation.

Miscellaneous

Eugenia jambolana (jamun) is long known for its antidiabetic activities in traditional medicines.

Sharma et al.99 study the effect of flavonoid rich extract of seeds of Eugenia jambolana on

streptozotocin-induced diabetic mice. The results demonstrated that flavonoid rich extract

improved the glucose tolerance, glycogen synthesis, glucose absorption, lipid profile, and insulin

release in extract treated subject. In addition, expression and regulation of glucose-6-phosphatase

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and hexokinase also changed in response to the flavonoid rich extract. This showed the

hypoglycemic and hypolipidemic effect of flavonoid rich extract of Eugenia jambolana.

Rojo et al.100 studied the antidiabetic effect of standardized anthocyanin-rich formulation

from Maqui Berry (Aristotelia chilensis) in type 2 diabetic mice model. They also demonstrated

the antidiabetic effect of delphinidin 3-sambubioside-5-glucoside (obtained from Maqui Berry).

Oral administration of anthocyanin-rich formulation decreased the fasting blood glucose levels

and glucose tolerance in hyperglycemic obese mice (fed with high fat diet). In addition, ANC

decreased the glucose production by reducing the expression of glucose-6-phosphatase. The oral

administration of delphinidin 3-sambubioside-5-glucoside in combination with ANC reduced the

fasting blood glucose level, increased the glucose absorption in L6 myotubes and lessened the

glucose production in H4IIE rat liver.

“Punica granatum” is a traditional hypoglycemic plant, commonly known as

pomegranate.101 The connection between pomegranate and its diabetic effects are well discussed

by Katz et al.102 They revealed that pomegranate extracts and their active components possessed

strong antidiabetic properties. Therapeutic103 and cardioprotective effect104 of pomegranate, and

its juice were also reported. Furthermore, Koren-Gluzer et al.105 reported that pomegranate juice

in combination with 50 μmol/L punicalagin, amplified the insulin production from a β-tumor cell

line. This property is similar to the activity of the paraoxonase 1 enzyme. Moreover,

administration of pomegranate fruit extract with ellagic acid (50–10μg/mL) to differentiated

murine 3T3-L1 adipocytes has significantly decreased the production and intracellular levels of

resistin by encouraging its degradation at the protein level.106

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CONCLUDING THOUGHTS AND FUTURE RESEARCH

TRENDSCHALLENGES

Research on diabetes and its management has been of continued interest among the scientists for

the last many decades. Importance of research on diabetes is evident from the fact that 7 Nobel

prizes to 10 scientists have been awarded on various ground breaking discoveries related to

diabetes. Ironically, from public health perspective, diabetes is still a challenge and associated

with reduced life expectancy due to obscurity of its cure despite of intervening research within

the last two centuries.

Management of diabetes through diet is a potential area of research. Compelling evidence from

epidemiological studies and in vitro and vivo trials has converged that several fruits possessed

antidiabetic effects due to the presence of certain bioactive components like flavonoids. It is

encouraging that some of the flavonoids are comparable in function to the clinically used

antidiabetic drugs. Investigation to better understand biochemical nature of antidiabetic effects of

flavonoids may lead to the discovery of novel natural source for the management of diabetes

with minimal side effects. Fruit flavonoids possess various anti-diabetic, anti-inflammatory and

antioxidant potentials and act on various cellular signaling pathways in pancreas, white adipose

tissue, skeletal muscle, and liver and induce antidiabetic effects. Antidiabetic effects of these

flavonoids might be due to antioxidant, receptor agonist or antagonist activity, enzyme inhibition

or through other novel mechanisms still to be demonstrated. Unlike synthetic anti-diabetic

agents, fruit flavonoids manage diabetes without compromising cellular homeostasis thereby

posing no side effects. Further studies are needed to understand the structure-activity

relationships of flavonoids to find whether and how flavonoid molecules interact with the

cellular components.

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Holistic corrective actions of fruit flavonoids to combat the complexities of diabetes mellitus are

advantageous over the chemical antidiabetic agents which have solitary actions and are notorious

to disrupt metabolic equilibrium. Advances in isolation, purification and characterization of

bioactive compounds from fruits should be employed and flavonoids should be isolated from

fruits and tested for their dose dependent efficacy studies in animal and human models to

develop a natural and sustainable approach to mange diabetes mellitus. pharmaceutical

treatments for diabetes.

Large clinical trials on humans are required to validate the plant based therapies for diabetes.

(MORE ELABORATION NEEDED) Coherent series of experiments are needed to formulate

dietary guidelines that can be really helpful for people with diabetes to manage this devastating

disease. Disparities among the different organizations groups should be addressed on the basis of

evidence based dietary recommendations to present holistic and simplified picture to diabetic

patients.

CONCLUSION

Epidemiological studies in vitro and vivo revealed that several fruits possessed antidiabetic effect

due to the presence of certain bioactive components like flavonoids. Flavonoids act on various

cellular signaling pathways in pancreas, white adipose tissue, skeletal muscle, and liver and

induce antidiabetic effects. Antidiabetic effects of these flavonoids might be due to antioxidant,

receptor agonist or antagonist activity, enzyme inhibition or through other novel mechanisms

still to be demonstrated. It is encouraging that some of the flavonoids are comparable in function

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to the clinically used antidiabetic drugs and their antidiabetic effect is further evaluated for

generation of novel natural antidiabetic drug.

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