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Management of Diabetic Complications
through Fruit
Flavonoids as Natural Remedy
Journal:
Critical Reviews in Food Science and Nutrition
Manuscript ID:
BFSN-2014-1441.R1
Manuscript Type:
Review
Date Submitted by the Author:
12-Dec-2014
Complete List of Authors:
tanveer, amna; university of sargodha, institute of food science and
nutrition, university of sargodha
Akram, Kashif; Kyungpook National University,
Farooq, Umar; University of Sargodha, Institute of Food Science and
Nutrition
Hayat, Zafar; University college of Agriculture, University of Sargodha,
Sargodha, Pakistan, Department of Animal Science
Shafi, Afshan; University of Sargodha, Sargodha, Pakistan, Institute of
Food Science and Nutrition
Keywords:
Antidiabetic agents, Diabetes, Fruits, Flavonoids
URL: http://mc.manuscriptcentral.com/bfsn Email: fergc@foodsci.umass.edu
Critical Reviews in Food Science and Nutrition
For Peer Review Only
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Review article: Critical Reviews in Food Science and Nutrition 1
2
Management of Diabetic Complications through Fruit Flavonoids as a Natural Remedy 3
4
Running Title 5
Antidiabetic Potential of Flavonoids of Various Fruits 6
Author names: 7
Amna Tanveer, Kashif Akram, Umar Farooq*, Zafar Hayat**, Afshan Shafi 8
9
Author affiliations: 10
Institute of Food Science and Nutrition, University of Sargodha, Sargodha, Pakistan 11
** Department of Animal Sciences, University College of Agriculture, University of Sargodha, 12
Sargodha, Pakistan 13
14
*Corresponding author: Umar Farooq 15
Assistant Professor 16
Institute of Food Science and Nutrition 17
University of Sargodha, Sargodha, Pakistan. 18
Phone: +923009668293, Fax: +92489230316 19
E-mail: umarfarooq@uos.edu.pk 20
21
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Diabetes mellitus is a global disorder, and a major issue for health care systems. The current 23
review outlooks the use of fruit flavonoids as natural remedy in the prevention of diabetes 24
mellitus. The onset of diabetes mainly depends upon genetics and lifestyle issues. Currently used 25
therapeutic options for the control of diabetes, like dietary amendments, oral hypoglycemic 26
drugs, and insulin have their own limitations. Fruit flavonoids possess various anti-diabetic, 27
anti-inflammatory and antioxidant potentials and act on various cellular signaling pathways in 28
pancreas, white adipose tissue, skeletal muscle and liver function, which in result induces 29
antidiabetic effects. Recently, antidiabetic effect of fruit flavonoids has been studied using 30
various animal models and clinical trials. Research studies revealed a statistically significant 31
potential of fruit flavonoids in managing the altered glucose and oxidative metabolisms in 32
diabetes. Unlike synthetic anti-diabetic agents, fruit flavonoids manage diabetes without 33
compromising cellular homeostasis thereby posing no side effects. Further studies are required 34
in purification and characterization of different fruit flavonoids with respect to their beneficial 35
effect for diabetic patients. 36
37
Keywords: Diabetes mellitus, fruits, flavonoids, antidiabetic effect38
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INTRODUCTION 39
Diabetes mellitus is one of the most common metabolic disorders with 382 million 40
patients globally estimated till 2013 (Shi Y and Hu, 204). The personal and public health 41
problem of diabetes is continuously escalating exponentially (2.6 % annually) throughout the 42
world (Danaei et al., 2011) and according to World Health Organization, diabetes will be the 7th 43
leading cause of death in 2030 (Alwan et al., 2011). Symptomatically, diabetes mellitus is 44
characterized by chronic hyperglycaemia (elevated concentration of glucose in the blood ≥ 7.0 45
mmol/L or 126 mg/dl) (WHO, 2006). Other symptoms includes but not limited to severe thirst 46
(polydipsia), frequent urination (polyurea), increased hunger (polyphagia), unconsciousness, 47
weight loss and coma leading to death or many medical complication may occur in the absence 48
of effective treatment. This worldwide rapidly growing health threat occurs due to combination 49
of multiple genetic and environmental factors (Philippe and Raccah, 2009).
50
Diabetes has complex and various degrees of heterogeneity in its etiology. Evidently, 51
diabetes manifested when the body becomes resistant to insulin (a hormone secreted by β-cells of 52
pancreas gland) or when enough insulin is not produced to regulate glucose metabolism (DM, 53
2010; Mohan and Nandhakumar, 2014). Type 1 diabetes and type 2 diabetes are two main types 54
of this disease (Roglic and Unwin, 2010) besides other similar conditions like pre-diabetes 55
(impaired glucose regulation) and gestational diabetes (Zierath and Wallberg-Henriksson, 2002). 56
In type 1 diabetes (insulin dependent diabetes mellitus or juvenile diabetes) body cannot produce 57
insulin due to autoimmune or infectious destruction of β-cells of pancreas gland and insulin is 58
required to be externally administered (Rother, 2007). Type 2 diabetes, previously known as non 59
insulin dependent diabetes mellitus, is characterized by body’s ineffective use of insulin
and is 60
the most common and prevalent form (90-95 %) of diabetes mellitus (WHO, 1999).
61
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Exact mechanism of the development and progression of diabetes is still unclear. It is 62
postulated that diabetes occurs when the tightly controlled mechanisms have been disturbed due 63
to any reason. Notable increase has been seen in the identification of the molecular components 64
and all the signaling pathways used in the regulation of glucose absorption (Krentz and Bailey, 65
2005). Chronic hyperglycemia affects nervous system, heart, kidneys, eyes, and other systems of 66
body. Diabetes is the leading cause of many disease conditions like storkes, cardiovascular 67
disease, renal failure, visual impairment, and blindness, lower limb amputations, erectile 68
dysfunction, and insignificant wound healing (Levitan et al., 2004; Resnikoff et al., 2004; 69
Mendis et al., 2007; Boden-Albala et al., 2008; Icks et al., 2009; Akkati et al., 2011; Rizvi 70
and Mishra, 2013; Mendis and Chestnov, 2014). Sometimes diabetes is not diagnosed until the 71
development of other health problems. Stress, lethargy life style, smoking, hypertension, eating 72
habits, processing, and nutritional composition of food are some of the predisposing 73
environmental factors in the development of diabetes mellitus (Adler et al., 2000; Willi et al., 74
2007; Lee et al., 2012). On the food and nutrition fore front; refined grains, highly processed 75
food, energy dense junks, saturated fat, excessive alcohol, sugar sweetened beverages are the 76
major culprits (Riserus et al., 2009; Malik et al., 2010). 77
78
MANAGEMENT OF DIABETES 79
Diabetes is lifelong disease and no cure for diabetes is yet to be found however, different 80
pharmacological and non-pharmacological therapeutic measures have positively been employed 81
to enhance the life quality of individuals suffering from diabetes and its micro and macro-82
vascular complications (ADA, 2011). As diabetes is characterized by chronically increased 83
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levels of blood glucose thus main theme of current diabetes management is to better regulate the 84
glucose metabolism (McCrimmon and Sherwin, 2010).
26
However, this is not so simple as the 85
complex disorder needs continuous medical attention, support, and self-management education 86
of the patient to avoid serious complications and to diminish the risk of long-term complications; 87
accordingly its management is multifarious and needs many issues, beyond glycemic control, to 88
be addressed (Henriksen, 2010).
Lifestyle interventions addressing diet and physical activity are 89
considered a first-line intervention for the prevention of type 2 diabetes (Paulweber et al., 2010). 90
Insulin is routinely administered in type 1 diabetes mellitus patients due to auto-91
destruction of β-cells of pancreas and ultimately incapability of cells to secrete insulin and for 92
type 2 diabetic patients, in which cells are unable to respond the normal action of circulating 93
insulin and incapable to meet safe glycemic targets (Bodmeret al., 2008).
Some compounds 94
possessing antidiabetic properties have been extensively employed to manage disbetes (Saxena 95
and Vikram, 2004; Rother, 2007). Several surgical procedures (bariatric surgery) are adopted 96
mainly to achieve weight loss in obese persons to mange diabetes especially when the lifestyle 97
and pharmacologic interventions become unable to control type 2 diabetes or its related problems 98
(Catalan et al., 2001).
Different degrees and proportions of survival benefits are reported with 99
bariatric surgery (Robinson, 2009),
however no considerable improvement had been witnessed in 100
highly vulnerable population (Maciejewskiet al., 2011) and there are also reports of reoccurrence 101
of obesity and associated problems like obesity after surgical interventions depending upon pre-102
bariatric history of diabetes (Ramos, 2012). 103
The clinical evaluation of a patient helps to select the suitable therapy for the treatment. 104
All the above mention preventive measures fulfill their objective to some extent except bariatric 105
surgery (Zia et al., 2001) and diabetes and it related complications are not cured till now. 106
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Efficient and sustainable management of diabetes is becoming more important with rapidly 107
increasing morbidity due to this disease globally (Alwan et al., 2010). It is predicted that by year 108
2035 patients suffering from diabetes would reach to 600 million worldwide (Shi and Hu, 2014). 109
110
COMMONLY USED ANTI-DIABETES AGENTS AND THEIR RELATED PROBLEMS 111
Recently used therapeutic anti-diabetes agents are sulfonylureas, glinides, biguanides, 112
and α-glucosidase inhibitors (Kim and Egan, 2008) employed singly or in combination. In fact, 113
all anti-diabetic agents in practice work directly and indirectly by regulating the blood glucose 114
level (Fig. 1) (Molavi et al., 2007; Kim and Egan, 2008). 115
• Sulfonylureas are the antidiabetic drugs (glibenclamide and glyburide) that increase the 116
amount of insulin by acting upon the β-cells of pancreas. On β-cells membrane they 117
attached to an ATP-dependent K
+
(K
ATP
) and cause positive electric potential over the 118
membrane and open the Ca
2+
channels. This elevation of intracellular calcium ions results 119
into increased fusion of insulin granule with cell membrane, henceamplified the secretion 120
of insulin (Kim and Egan, 2008).
Incretins like exenatide and liraglutide also increase the 121
insulin production by acting on pancreas (Molavi et al., 2007). 122
• Biguanides and thiazolidinediones increase the insulin sensitivity of adipose tissue, liver, 123
and muscle by increasing the uptake of glucose in muscle and decrease the production of 124
glucose in liver. They include metformin and pioglitazone (Catalan et al., 2001; Bourron 125
et al., 2010). 126
• Acarbose and miglitol are the antidiabetic agents that slowdown the absorption of glucose 127
from gastrointestinal tract. Nutritional supplements also inhibits α-glucosidase and α-128
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amylase activity in gut and ultimately reduce the glucose uptake (Spengler et al., 2005; 129
Dixon et al., 2008). 130
Unfortunately, the treatment of diabetes through antidiabetic agents has their own flaws 131
including the increased resistance and lack of responsiveness in a large segment of the patient 132
population. In addition, no antihyperglycemic agent properly tackles the elevated lipid level that 133
is common in this disease (Chitra et al., 2010). Most of these oral antidiabetic agents impose 134
serious side effects, so diabetes management without any adverse effect is still a challenge (Liu 135
et al., 2010). Therefore, holistic exploration of more active and safer therapeutic agents in 136
eliminating diabetic syndromes is an important area of investigation (Kao et al., 2000).
137
138
FLAVONOIDS: POTENTIAL ANTI-DIABETIC AGENTS 139
Natural products from fruit and vegetable sources are becoming popular worldwide and 140
broadly accepted as an aid to conventional therapy (Yao et al., 2004). Increasing public 141
awareness and scientific interest headed the research towards the evaluation of fruits role in 142
health up-gradation and disease treatment. In recent years, great attention has been focused on 143
the health promoting roles of bioactive components known as “flavonoids” (Vessal et al., 2003). 144
Flavonoids are ubiquitously secondary metabolites present in almost all fruits and vegetables 145
(Chen et al., 2014). They comprise of two benzene rings and one heterocyclic ring (Aherne and 146
O'Brien, 2002) and include various subclasses notably flavonols (quercetin and kaempferol), 147
flavones (luteolin and apigenin), flavanols (catechins and proanthocyanidins), anthocyanidins 148
(aurantinidin, cyaniding), flavanones (naringenin and hespertine), and isoflavones (genistein and 149
daidzein) (Scalbert and Williamson, 2000)
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Flavonoids have various positive effects on complex metabolic pathologies including 151
diabetes, through multifarious modes of actions (Barone et al., 2009). It is postulated that 152
majority of the bioactivity of flavonoids is due to their α, β ketones and hydroxyl groups 153
(Veerapur et al., 2010). 154
Treatment of kaempferol (10 µM) a fruit flavonol significantly increased the viability, 155
reduced cellular apoptosis and caspase-3 activity in human beta cells and islets. Furthermore, 156
kaempferol treatment also increased the expression of anti-apoptotic proteins (Bcl-2 and Akt) 157
(Havsteen, 2002). In addition, studies also demonstrated that quercetin flavonoid increase the 158
regeneration of pancreatic islets and ultimately increase the insulin secretion in streptozotocin-159
induced diabetic rats (Vessal et al., 2003). Recently, more attention is given on research of 160
flavonoids from dietary sources, due to growing evidence of their versatile health benefits. To 161
best understand the mode of action of flavonoids as their potential role in the prevention of 162
diseases, it is important to know their biosynthesis, metabolism, and bioavailability (Hollman, 163
2004). 164
165
BIOSYNTHESIS OF FLAVONOIDS IN PLANTS 166
Flavonoids belong to the family of aromatic compounds that are derived from phenyl and 167
malonyl-coenzyme A, through the fatty acid pathway (Woo et al., 2005). In the beginning of 168
flavonoids biosynthesis, the phenylalanine (from the shikimic acid pathway) is changed to 169
coumaroyl-CoA by phenylalanine ammonia-lyase and 4-coumarate (CoA ligase, and cinnamate 170
4-hydroxylase). Coumaroyl-CoA is condensed with three molecules of malonyl-CoA (from 171
acetyl-CoA) to produce naringenin chalcone by chalcone synthase (the first enzyme for 172
flavonoid biosynthesis). Then chalcone isomerase converts naringenin chalcone to naringenin. 173
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Naringenin is further modified by glycosylation, acylation, and methylation of its three rings. All 174
these enzymatic steps result into production of substituted flavones, catechins, deoxyflavonoids, 175
flavonols, and anthocyanins. Isoflavone synthase (cytochrome P450 enzyme) form isoflavonoids 176
from naringenin or deoxyflavonoids by aryl movement of the B-ring to the 3
rd
position, then 177
hydroxylation at the 2
nd
position. The 2-hydroxyisoflavone is an unstable intermediate molecule 178
and is dehydrated to produce isoflavone (Landete, 2012). 179
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METABOLISM AND BIOAVAILABILITY OF FLAVONOIDS 181
Flavonoids are used as substrates by conjugating and hydrolyzing enzymes of small 182
intestine, liver, and colon. Then these enzymes convert the flavonoids into O-glucuronides, 183
sulfate esters, and O-methyl esters (Del-Rio et al., 2010). Flavonoids conjugation is first 184
occurred in the small intestine then in the liver. In liver, they are further metabolized to produce 185
glucuronides and sulfate derivatives which are facilitated and excreted through urine and bile 186
(Del-Rio et al., 2010). The unabsorbed compounds were further moved to colon and structurally 187
modified by colonic microflora (Scalbert et al., 2002). The flavonoid glucuronides are 188
hydrolyzed into aglycones (by microbiota) after re-entering the enterohepatic circulation 189
(Spencer et al., 2001). Then aglycones are further breakdown to low molecular compounds that 190
can easily be absorbed. 191
Spencer et al. (20018) reported that during systemic absorption of monomeric flavan-3-192
ols they are either metabolized into O-methylated forms or conjugated to form glucuronides or 193
sulphates. In addition, the monomeric flavan-3-ols (procyanidins) were split into the conjugates 194
of epicatechin. A study done by Del-Rio et al. (2010) on the absorption and metabolism of 195
flavan-3-ols in humans illustrated that epigallocatechin-O-glucuronide and methyl-epicatechin-196
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sulphate were excreted in urine hence confirmed the above statement. Another recent study done 197
by Fernandes et al. (2012) on the bioavailability of an anthocyanin derivative demonstrated the 198
transepithelial transport of flavan-3-ol-anthocyanin dimer [(+)-catechin-4, 8-malvidin-3-199
glucoside], by using Caco-2 cells. The results were compared with (+)-catechin, procyanidin B3, 200
and malvidin-3-glucoside. All the compounds under study (catechins, procyanidins B3, 201
malvidin-3-glucoside, and flavan-3-ol-anthocyanin dimer) passed the Caco-2 cell model barrier 202
and the absorption of catechin-malvidin dimer was significantly less as compared to individual 203
malvidin or catechins compounds. But the transport efficacy of the catechin-malvidin dimer was 204
more than procyanidin B3 dimer and this increased transport efficacy of catechin-malvidin dimer 205
might be due to presence of the anthocyanin and its glucose moiety in the flavan-3-ol-206
anthocyanin. Interestingly, after 2 hour of incubation only the breakdown of parent compounds 207
was observed and no catechin-malvidin dimer metabolites were found. The results of this study 208
illustrated that anthocyanins are absorbed as anthocyanin derivatives and catechin-malvidin 209
dimer is more resistant to metabolism as compared to its parent compounds. A study done on the 210
genistein (aglycone) and its glycoside genistin bioavailability showed that the bioavailability of 211
the aglycone was higher in comparison to its glycoside form (Harvey, 2008). 212
Treatment of kaempferol (10 µM) a fruit flavonol significantly increased the viability, 213
reduced cellular apoptosis and caspase-3 activity in human beta cells and islets. Furthermore, 214
kaempferol treatment also increased the expression of anti-apoptotic proteins (Bcl-2 and Akt) 215
(Havsteen, 2002). In addition, studies also demonstrated that quercetin flavonoid increase the 216
regeneration of pancreatic islets and ultimately increase the insulin secretion in streptozotocin-217
induced diabetic rats (Vessal et al., 2003). Recently, more attention is given on research of 218
flavonoids from dietary sources, due to growing evidence of their versatile health benefits. To 219
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best understand the mode of action of flavonoids as their potential role in the prevention of 220
diseases, it is important to know their biosynthesis, metabolism, and bioavailability (Hollman, 221
2004). 222
223
ANTIDIABETIC MODE OF ACTION OF FLAVONOIDS 224
Generally flavonoids exert wide range of their antidiabetic activity on various organs 225
(Fig. 2) that’s why holistic corrective actions of fruit flavonoids to combat the complexities of 226
diabetes mellitus are advantageous over the chemical antidiabetic agents which have solitary 227
actions and are notorious to disrupt metabolic equilibrium. Antidiabetic mechanism of flavonoids 228
might be mainly due to their effects on enzymes responsible for glucose metabolism or through 229
other novel mechanisms still to be explored. Importantly, flavonoids exert antidiabetic action by 230
ameliorating the insulin action on skeletal muscle and liver cells to reduce the plasma free fatty 231
acid level, hepatic gluconeogenesis, and increased glucose uptake (Aguirre et al., 2011).
In the 232
intestine, flavonoids inhibit the digestion of starch, slow down the gastric emptying and reduce 233
the absorption of glucose across the membrane (Kannappan and Anuradha, 2010). The regulation 234
of postprandial hyperglycemia is an important strategy of diabetes management. Such approach 235
is to reduce the digestion (intestinal) of complex carbohydrates (disaccharides oligosaccharides, 236
and trisaccharides) by inhibiting the activity of intestinal membrane-bound α-glucosidases (Babu 237
et al., 2013). 238
Li et al. (2009) demonstrated that flavonols such as quercetin, rutin, and isoquercetin 239
formed complexes with α- glucosidases via hydrophobic binding and inhibit its activity. Fisetin a 240
tetrahydroxy-flavone, mainly present in fruits and vegetables promoted the hexokinase, glucose-241
6-phosphate dehydrogenase, pyruvate kinase activities while reduced glucose-6-phosphatase, 242
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lactate dehydrogenase, and fructose-1,6-biphosphatase activities which results into lowered 243
blood glucose level and elevated plasma insulin concentrations in hepatic and renal tissues of 244
streptozotocin-induced diabetic rats (Prasath et al., 2010). Furthermore, fistein also improve 245
glucose homeostasis through regulation of enzymes involved in carbohydrate metabolism 246
particularly by increasing the glycogen synthase (enzyme that converts glucose in glycogen) and 247
decreasing glycogen phosphorylase (enzyme that break glycogen into glucose subunits) 248
production (Prasath and Subramanian 2011). 249
Glucose transporter type-2 is the protein, enables the transfer of glucose between liver 250
and blood and also has role in transportation of intestinal sugar. Kwon et al. (2007) reported that 251
myricetin, quercetin, and its glucoside bind the glucose transporter type-2 and prevent the 252
transport of glucose in blood stream. Flavonoids also affect glucose transporter type-4 is insulin-253
regulated glucose transporter mainly found in adipocytes and skeletal muscle. Postulated 254
mechanism is that when blood sugar concentration increases insulin translocate the glucose 255
transporter type-4, which increases the uptake of glucose from blood to adipose and skeletal 256
muscle (McCarthy and Elmendorf, 2007). Prasad et al. (2010) reported that gallic acid increased 257
glucose transporter type-4 translocation and glucose uptake in Akt-independent manner. The 258
authors also reported that glucose uptake and glucose transporter type-4 translocation is mediated 259
by protein kinase C pathway. Phosphatidylinositol (3,4,5)-trisphosphate (PIP3), the product of 260
insulin mediated protein kinase C activation, uses phosphoinsositide-depedent kinase-1 to 261
translocate in membrane where it activates protein kinase C through phosphorylation (Balendran 262
et al., 2000). 263
Fruit flavonoids can exhibit their antidiabetic activity by reduction in 264
phosphoenolpyruvate carboxykinase and glucose 6-phosphatase that are the main enzymes 265
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involved in gluconeogenesis. In diabetic condition, the levels of these enzymes raise which lead 266
to reduce utilization of glucose and elevated production of glucose (Munoz et al., 2001). Choi 267
and Ahn (2008) reported that genistein and daidzein inhibited the activities of 268
phosphoenolpyruvate carboxykinase and glucose 6-phosphatase and elevated the insulin level in 269
body. 270
Flavon-3-ol like epigallocatechin gallate conserved the β-cells viability and glucose-271
stimulated insulin secretion by regulating the expression of B-cell lymphoma 2 (anti-apoptotic 272
protein) and inhibition of Bcl-2-associated X protein (apoptotic protein) translocation (Zhang et 273
al., 2011). Epigallocatechin gallate increases the production of β-cell lymphoma 2 protein, which 274
inhibits the oxidative stress and control the mitochondrial transitional pore opening by reducing 275
the effect of Bcl-2-associated X protein and ultimately block the production of cytochrome c and 276
caspase activity. Cytochrome c and caspase are proteins involved in programmed cell death of 277
islets (Low et al., 2010; Zhang et al., 2011). 278
Certain flavonols (quercetin) use ERK1/2 (protein kinase involve in proliferation, 279
differentiation, and apoptosis) pathway and improved the glucose stimulated insulin production 280
and prevent the oxidative damage of insulin-1 cells (Youl et al., 2010). Moreover, quercetin and 281
its glycoside quercitrin also protect clonal β-cells against cytokine-induced cell death by 282
inhibiting the translocation of nuclear-factor kappa-B and suppressing nitric oxide formation 283
which consequently reduced the expression of inducible nitric oxide synthase (enzyme 284
responsible for inflammation-related insulin resistance) (Dai et al., 2013). 285
Similarly, flavones like apigenin and luteolin prevent interleukin-1β- and interferon-γ-286
induced apoptosis of β-cells, via inhibition of nuclear-factor kappa-B activation and inducible 287
nitric oxide synthase expression (Kim et al., 2007). It is reported that apigenin improved the 288
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phosphorylation of adenosine monophosphate activated protein kinase in hepatocytes (Zang et 289
al., 2006). Furthermore, apigenin also inhibited Acetyl Co-A carboxylase phosphorylation and 290
lipid accumulation in hepatocytes by improving the action of adenosine monophosphate 291
activated protein kinase (Zang et al., 2006). Adenosine monophosphate activated protein kinase 292
is an energy sensing molecule and involve in body energy homeostasis, adipocyte lipolysis 293
inhibition, and stimulate glucose uptake. It improves the glycemic level and lipid profile in 294
insulin resistant rodents (Zhang et al., 2009). Genistein (flavones) improved the production of 295
human islet β-cells by activating the cAMPK/PKA-dependent ERK1/2 signaling pathway (Fu et 296
al., 2010). Moreover, Genistein also suppressed nuclear factor kappa-B and ERK-1/2 pathway in 297
order to prevent alteration in β-cells (Kim et al., 2007). 298
299
300
PROMISING ANTIDIABETIC ROLE OF FLAVONOIDS OF VARIOUS FRUITS 301
FLAVONOIDS 302
Numerous studies demonstrated that many plants especially fruits are traditionally used 303
for the treatment of diabetes (Sabu, 2002; Steensma et al., 2006). Epidemiological studies and 304
meta-analyses described the use of fruits rich in flavonoids decrease diabetes (Arts and Hollman, 305
2005; Graf et al., 2005). Many in-vitro and animal studies support the positive effects of various 306
fruits flavonoids on glucose homeostasis (Jung et al., 2006; Cai and Lin, 2009; Fu et al., 2010; 307
Hanhineva et al., 2010; Fu et al., 2011; Zhang and Liu, 2011; Zhu et al., 2012). The fruits 308
flavonoids and their antidiabetic roles are presented in Table 1. 309
Numerous studies demonstrated that many plants especially fruits are traditionally used 310
for the treatment of diabetes (Sabu, 2002; Steensma et al., 2006). Epidemiological studies and 311
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meta-analyses described the use of fruits rich in flavonoids decrease diabetes (Graf et al., 2005; 312
Arts and Hollman, 2005). Many in-vitro and animal studies support the positive effects of 313
various fruits flavonoids on glucose homeostasis (Jung et al., 2006; Cai and Lin, 2009; Fu et al., 314
2010; Hanhineva et al., 2010; Fu et al., 2011; Zhang and Liu, 2011; Zhu et al., 2012). Generally 315
flavonoids exert wide range of their antidiabetic activity (Fig. 2) (Aguirre et al., 20111) on 316
various organs especially by ameliorating the insulin action on skeletal muscle and liver cells to 317
reduce the plasma free fatty acid level, hepatic gluconeogenesis, and increased glucose uptake.
72
318
In the intestine, flavonoids inhibit the digestion of starch, slow down the gastric emptying and 319
reduce the absorption of glucose across the membrane (Kannappan and Anuradha, 2010). The 320
fruits flavonoids and their antidiabetic roles are presented in Table 1. 321
322
Citrus Flavonoids 323
In recent years, citrus flavonoids gained much attention because of their potential 324
therapeutic properties and comparatively low toxicity to animals (Manthey et al., 2001; 325
Benavente-Garcia and Castillo, 2008; Choi and Ahn, 2008). Shen et al. (2012) reported that 326
citrus flavonoids like hesperidin, nobiletin, neohesperidin, and naringin showed antidiabetic 327
properties by binding starch and slow down its digestion. Moreover, numerous studies reported 328
that hesperidin, naringin, and nobiletin enhanced the insulin sensitivity and induced the 329
hypoglycemic effect in diabetic animals (Kobayashi et al., 2000; Akiyama et al., 2009; Akiyama 330
et al., 2010; Lee et al., 2010). Naringenin a major flavonoid found in citrus possessed 331
antidiabetic properties (Lim et al., 2008). Lim et al. (2008)
demonstrated that naringenin 332
exhibited insulin sensitive effect at a concentration of 100 M, by enhancing the uptake of 333
glucose in primary rat adipocytes (163%) as compared to insulin (130%). The studies of Huong 334
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et al. (2006) demonstrated that fruits rich in naringenin (1%) improved the oxidation of hepatic 335
fatty acid by regulating the gene that encodes the enzyme for peroxisomal β-oxidation in mice 336
and this change may account for its capability of inducing low serum lipid levels. Moreover, 337
naringenin reduced the lipid level by increasing the low density lipoprotein receptor expression 338
through phosphatidylinositol 3-kinase facilitated up regulation of sterol regulatory element-339
binding protein (Borradaile et al., 2003). Phosphoenolpyruvate carboxykinase and glucose 6-340
phosphatase are the main enzymes involved in gluconeogenesis. In diabetic condition, the levels 341
of these enzymes raise which lead to reduce utilization of glucose and elevated production of 342
glucose (Munoz et al., 2001). Naringin and hesperidin belongs to citrus flavonoids and 343
suppressed the expression of phosphoenolpyruvate carboxykinase and glucose 6-phosphatase, 344
and reduced the hepatic glucose production (Kim et al., 2012). 345
346
Berries Flavonoids 347
Procyanidin from the extract of grapes seeds increased the concentration of insulin 348
transporter: glucose transporter-4 in plasma membrane, increased the uptake of glucose in 349
adipocytes, and ultimately induced the antihyperglycemic effect in streptozotocin-induced 350
diabetic rats (Pinent et al., 2004). Glucose transporter-4 is the main insulin regulating transporter 351
which is expressed in skeletal muscle and adipose tissue. In diabetic db/db mice adipocyte, the 352
expression of glucose transpoter-4 improves the glycemic control by ameliorating insulin 353
resistance (Gibbs et al., 1995). 354
Cai et al. (2009) reported the antidiabetic effect of epigallocatechin gallate on glucose-355
induced toxicity in the pancreatic β-cells of a rat insulinoma-m5F cells. The results demonstrated 356
that 0.1 and 10 µM concentration of epigallocatechin gallate enhanced insulin secretory function 357
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and viability of β-cells in glucotoxic conditions. These properties were partially facilitated via 358
increased expression of insulin receptor substrate-2, the forkhead box protein O1, Akt (glucose 359
metabolizing protein kinase), and pancreatic duodenal homeobox1.Insulin receptors substrate 360
protein mediates the insulin action and regulates the β-cells viability and proliferation. The 361
forkhead box protein O1 regulates the cellular proliferation and protects the β-cells from 362
apoptosis (Buteau and Accili, 2007). Pancreatic duodenal homeobox1 is a transcription factor 363
that is expressed in islets of Langerhans and increase the viable count of islets (McKinnon 364
and Docherty, 2001). 365
Strawberry is a fruit of nutritional importance and now gaining attention because of 366
antidiabetic property of its flavonoids (Hannum, 2004; Aaby et al., 2005). In general α-amylase 367
and α-glucosidase are the key enzymes involved in catalytic breakdown of carbohydrates into 368
glucose. In antidiabetic analyses, IC
50
value for α-amylase and α-glucosidase activity of fruit 369
extract of strawberry was found to be 86.47 ± 1.12µg/ml and 76.83 ± 0.93µg/ml respectively. 370
Maximum inhibition of 52.35% at a concentration of 97µg/µL was done by strawberry extract 371
(rich in phytochemicals) and in comparison with standard acarbose, which exhibited maximum 372
inhibition of 72.10% at a concentration of 92µg/µL. In addition, at the concentration of 91µg/µL, 373
strawberry extract induced 58.83% of inhibition. Standard acarbose exhibited maximum 374
inhibition of 69.43% at a concentration of 96µg/µL (Mandave et al., 2013). The studies also 375
demonstrated the antidiabetic effects of bayberry fruit extract. Sun et al. (2012) reported that 376
bayberry extract (rich in cyanidin-3-glucoside) decreased the risk of oxidative stress and 377
ultimately reduced the β-cell damage. Initial treatments of β-cells with bayberry fruit extract 378
(comprising 0.5µM cyanidin-3-glucoside) stopped cell death by hydrogen peroxide, 379
mitochondrial reactive oxygen species production, and cell necrosis. 380
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The bioactive components present in the most of berries and cherries appear as 381
glycosides of anthocyanidins. Dried cherries of Cornus spp. have been traditionally used for 382
diabetes treatment in China (Yamahara et al., 1981). The cyanidin-, delphinidin-, and 383
pelargonidin glycosides are the important bioactive component of Cornus fruits (Seeram et al., 384
2002; Jayaprakasam et al., 2005). These anthocyanidins and anthocyanins components improved 385
the insulin secretion by acting on β-cells of pancreas. The pancreatic β-cells were treated with 386
cyanidin-3-glucoside and delphinidin-3-glucoside for 60 minute and they increased the glucose 387
stimulated insulin secretion. While pelargonidin-3-galactoside, cyanadin-3-galactoside, and 388
aglycones: cyanidin, pelargonidin, delphinidin, and malvidin had negligible to marginal effects 389
on glucose stimulated insulin secretion (Scazzocchio et al., 2011). Cyanidin 3-glucoside (50 µM) 390
and protocatechuic acid improved the glucose uptake and translocation of glucose transporter in 391
human and rat adipocytes (Guo et al., 2012). 392
Rostamian et al. (2011) demonstrated the antidiabetic action of hydroalcoholic extract of 393
strawberries leaves rich in flavonoids. For this purpose 24 male adult rats were selected 394
randomly and were divided into non antidiabetic control group, diabetic control, and diabetic 395
group. Diabetic group was administered with alloxan then intraperitoneally injected with extract 396
(100mg/Kg). The analysis of glucose, triglyceride, high density lipoprotein, cholesterol, and low 397
density lipoprotein content showed that the extract rich in flavonoids meaningfully reduced the 398
glucose, triglyceride, cholesterol, and elevated the level of high density lipoproteins but didnot 399
affect the low density lipoprotein content. 400
Eid et al. (2010) elucidated the mode of action of quercetin rich extract of Vaccinumvitis-401
idaea (cowberry) in the treatment of diabetes. For this purpose 10 compounds (found in berries) 402
involved in glucose absorption were analyzed in C2C12 murine skeletal myoblasts and H4IIE 403
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murine hepatocytes (main cells of liver tissue). The results revealed that quercetin-3-O-glycoside 404
and quercetin aglycone were the active components involved in glucose absorption. This effect is 405
facilitated by adenosine monophosphate activated protein kinase, which mediates the 406
translocation of glucose transporter type 4. Adenosine monophosphate activated protein kinase is 407
an energy sensing molecule and involve in body energy homeostasis. It improves the glycemic 408
level and lipid profile in insulin resistant rodents (Zhang et al., 2009). Therefore, adenosine 409
monophosphate activated protein kinase is considered as an attractive target for developing new 410
strategies to treat diabetes. 411
Bilberries are the rich source of anthocyanins (Katsube et al., 2003). Takikawa et al. 412
(2010) elucidated the metabolic properties of bilberry extract (27g bilberry extract containing 413
10g anthocyanin/Kg diet) in mice with type 2 diabetes. Bilberries extract enhanced 414
hypoglycemia and insulin sensitivity in diabetic mice by targeting adenosine monophosphate 415
activated protein kinase, glucose transporter type 4, and other metabolic enzymes. 416
417
Persimmon Flavonoids 418
The persimmon belongs to the family of Ebenaceae and inhabitant of Japan and China. 419
Several studies demonstrated the antidiabetic and antiobesity effects of persimmon flavonoids 420
(Matsumoto et al., 2006; Dewanjee et al., 2009). Proanthocyanidin; a major flavonoid obtained 421
from persimmon peel was reported to possess antidiabetic and antiobesity properties. 422
Administration of proanthocyanidin (from persimmon peel) to streptozotocin-induced diabetic 423
rats reduced the elevated level of lipid peroxidation, inhibited the reactive oxygen species 424
generation, reduced the serum glucose, glycosylation of hemoglobin, urinary protein, glycation 425
products, and serum urea nitrogen. Hence, this protective effect of proanthocyanidin showed its 426
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antidiabetic potentials (Lee et al., 2007). In addition, Dewanjee et al. (2009) reported that 427
proanthocyanidins elevated the level of super oxide dismutase, glutathione, and catalase activity 428
in the liver and kidney, and finally prevent the oxidative stress mediated diabetic complications 429
in this severe diabetic model. 430
Matsumoto et al. (2006) demonstrated that persimmon significantly reduced the elevation 431
in plasma lipids (total cholesterol, LDL cholesterol, and triglyceride) in the diet-induced obesity 432
mouse model. Moreover, Lee at al. (2008) reported that proanthocyanidin, reduced the plasma 433
glucose, glycosylation of protein, and hyperlipidemia and ultimately reduced the hyperglycemia 434
in male db/db mice (leptin receptor deficient). Proanthocyanidins polymers showed a strong 435
inhibitory effect on α-amylase, while oligomers induced a stronger protective effect against α-436
glucosidase activity and angiotensin converting enzyme formation, suggesting that oligomers 437
may have more potential as antidiabetic agents. Moreover, persimmon proanthocyanidin also 438
reduced the elevated oxidative stress in db/db mice by reducing the lipid peroxidation, reactive 439
oxygen species, protein expression of inducible nitric oxide synthase, and cyclooxygenase-2 and 440
improved the glutathione/oxidized ratio (Lee et al., 2007). Inducible nitric oxide synthase 441
mediate inflammation-related insulin resistance. Cyclooxygenase-2 is the enzyme involved in β-442
cell dysfunction. Gu et al. (2008) reported the antidiabetic effect of tannins extracted from 443
persimmon pulp. The results demonstrated that tannins exhibited their activity by scavenging the 444
hydroxyl radical and induced the antioxidant effect. Overall, the studies proposed that 445
proanthocyanidin polymerization has ability to combat the obese and diabetic phenotype, and 446
that its oligomers are the more potent and promising compounds. 447
448
Guava Flavonoids 449
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Guava is tropical fruit and rich source of natural antioxidants like, vitamin C and 450
polyphenolic compounds (Thaipong et al., 2005; Akinmoladun et al., 2010). Numerous studies 451
have demonstrated that the leaves and fruit of guava induced antidiabetic effects in alloxan- or 452
streptozotocin-induced diabetic models (Gutierrez et al., 2008); Cheng et al., 2009).
117,118
453
Wu et al. (2009) demonstrated the antiglycation activity of guava leaves extract and its 454
active compounds. The results revealed that guava leaves extract and its compounds inhibited the 455
process of glycation in albumin and their potency was compared with polyphenol 60 456
(polyphenolic compound extracted from plants) and antiglycation agent (aminoguanidine). The 457
results revealed that inhibitory effect of guava leaf extracts against α-dicarbonyl compounds 458
formation were over 95% at 50µg/mL. Guava leaf extracts also induced strong inhibition on the 459
generation of amadori product (intermediate product in advance glycation end product 460
formation) and advance glycation end products in albumin in the presence of glucose. The 461
catechins and quercetin induced 80% of the antiglycated effect. Among all the phenolic 462
compounds that were under study, quercetin showed highest activity (95%) at 100µg/mL and no 463
activity was shown by ferulic acid. 464
Cheng et al. (2009) isolated quercetin flavonoid from aqueous extract of guava leaves by 465
column chromatography and analyzed its efficacy. The results revealed that quercetin separated 466
from the guava leaves extract increased the glucose uptake in rat clone 9-hepatocytes (liver 467
cells). So quercetin contributes to mitigate hyperglycemia in diabetes as a consequence. 468
Shen et al. (2008) reported the antidiabetic effect of aqueous and ethanolic extracts of 469
guava leaves in low-dose streptozotocin and nicotinamide-induced rats. The results indicated that 470
aqueous extract increased the activities of hepatic hexokinase, phosphofructokinase, and glucose-471
6-phosphate dehydrogenase in diabetic rats as compared to the normal diabetic group. 472
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Furthermore, ethanolic extract only elevated the hepatic hexokinase and glucose-6-phosphate 473
dehydrogenase activity in diabetic rats. Due to these effects of the extracts, the assimilation of 474
glucose in glycolytic pathway and pentose monophosphate shunt was increased and resulted into 475
depression of the blood glucose level. Huang et al. (2011) demonstrated the blood glucose 476
lowering effect of guava in streptozotocin-induced diabetic rats. They reported that guava 477
induced its hypoglycemic effect by protecting the viability of β-cells from lipid peroxidation and 478
breakdown of DNA strands and ultimately improved the insulin secretion. In addition, guava 479
also inhibited the expression of pancreatic nuclear factor-kappa B protein and improved the 480
activities of superoxide dismutase, catalase, and glutathione peroxidase, which are involved in 481
antioxidant activity. Begum et al. (2004) identified more than 20 compounds in guava fruit 482
extract. In addition, studies reported the positive correlation between antihyperglycemic activity 483
and phenolic content especially flavonoids in fruits (Ramkumar et al., 2004). 484
Wang et al. (2010) reported the inhibitory activity of guava leaves extract against α-485
amylase and α-glucosidase. Seven flavonoids (quercetin, guaijaverin, avicularin, kaempferol, 486
hyperin, apigenin, and myricetin) were isolated from the ethanolic and butanolic extracts of 487
guava leaves extract. The study revealed that querticin, kaempferol, and myricetin flavonoids 488
showed highest inhibitory activity against sucrase with IC
50
values of 3.5 mM, 5.2 mM, and 489
3.0 mM, against maltase with IC
50
values of 4.8 mM, 5.6 mM, and 4.1 mM and against α-490
amylase with IC
50
values of 4.8 mM, 5.3 mM, and 4.3 mM, respectively. Among these 491
flavonoids, myricetin (1.5 mg/mL) exhibited the highest inhibition of 70% against sucrase. The 492
results suggested that hydroxyl groups play an important role in the inhibition activity. 493
494
495
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Papaya Flavonoids 496
Quercetin 3-O-rutinoside and mangiferingallate were the major flavonoids present in 497
papaya (Rivera-Pastrana et al., 2010; Andarwulan et al., 2012).
Sellamuthu et al. (2009) also 498
reported that papaya is rich source of mangiferin and the galloylated forms of mangiferin and 499
isomangiferin, xanthone glycosides. These phytochemicals were described as potent antidiabetic 500
agents. 501
Sasidharan et al. (2011) demonstrated the antidiabetic effect of ethanolic extract of 502
Carica papaya in streptozotocin-induced diabetic rats. Phytochemical screening revealed that 503
this effect was probably due to the presence of certain phytochemical especially flavonoids. The 504
phytochemicals rich extract increased the regeneration of β-cells of pancreas, improved the 505
function of liver tissue, and the recovery of cuboidal tissue of kidney. Juarez-Rojop et al. (2012) 506
reported that aqueous extract of Carica papaya increased the secretion of insulin by acting on β-507
cells. A treatment with Carica papaya significantly reduced the serum triglycerides, cholesterol, 508
and aminotransferases in diabetic rats. Aqueous extract improved the morphology of hepatocytes 509
by preventing the cells disruption and inhibition of glycogen and lipid accumulation. 510
511
Miscellaneous 512
Eugenia jambolana (jamun) is long known for its antidiabetic activities in traditional 513
medicines. Sharma et al. (2008) studied the effect of flavonoid rich extract of seeds of Eugenia 514
jambolana on streptozotocin-induced diabetic mice. The results demonstrated that flavonoid rich 515
extract improved the glucose tolerance, glycogen synthesis, glucose absorption, lipid profile, and 516
insulin release in extract treated subject. In addition, expression and regulation of glucose-6-517
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phosphatase and hexokinase also changed in response to the flavonoid rich extract. This showed 518
the hypoglycemic and hypolipidemic effect of flavonoid rich extract of Eugenia jambolana. 519
Rojo et al. (2012) studied the antidiabetic effect of standardized anthocyanin-rich 520
formulation from Maqui berry (Aristotelia chilensis) in type 2 diabetic mice model. They also 521
demonstrated the antidiabetic effect of delphinidin 3-sambubioside-5-glucoside (obtained from 522
Maqui berry). Oral administration of anthocyanin-rich formulation decreased the fasting blood 523
glucose levels and glucose tolerance in hyperglycemic obese mice (fed with high fat diet). In 524
addition, ANC decreased the glucose production by reducing the expression of glucose-6-525
phosphatase. The oral administration of delphinidin 3-sambubioside-5-glucoside in combination 526
with ANC reduced the fasting blood glucose level, increased the glucose absorption in L6 527
myotubes and lessened the glucose production in H4IIE rat liver. 528
“Punica granatum” is a traditional hypoglycemic plant, commonly known as 529
pomegranate (Vidal et al., 2003). The connection between pomegranate and its diabetic effects 530
are well discussed by Katz et al. (2007). They revealed that pomegranate extracts and their active 531
components possessed strong antidiabetic properties. Therapeutic (Jurenka, 2008) and 532
cardioprotective effect (Basu and Penugonda, 2009) of pomegranate, and its juice
were also 533
reported. Furthermore, Koren-Gluzer et al. (2011) reported that pomegranate juice in 534
combination with 50 µmol/L punicalagin, amplified the insulin production from a β-tumor cell 535
line. This property is similar to the activity of the paraoxonase 1 enzyme. Moreover, 536
administration of pomegranate fruit extract with ellagic acid (50–10µg/mL) has significantly 537
decreased the production and intracellular levels of resistin in differentiate murine 3T3-L1 538
adipocytes by encouraging its degradation at the protein level (Makino-Wakagi et al., 2012).
539
540
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CONCLUSION 541
Research on diabetes and its management has been of continued interest among the 542
scientists from last many decades. From public health perspective, diabetes is still a challenge 543
and associated with reduced life expectancy due to obscurity of its cure despite of intervening 544
research within the last two centuries. Management of diabetes through diet is a potential area of 545
research. Compelling evidence from epidemiological studies and in vitro and in vivo trials has 546
converged that several fruits possessed antidiabetic effects due to the presence of certain 547
bioactive components like flavonoids. It is encouraging that some of the flavonoids are 548
comparable in function to the clinically used antidiabetic drugs. Investigation to better 549
understand biochemical nature of antidiabetic effects of flavonoids may lead to the discovery of 550
novel natural source for the management of diabetes with minimal side effects. Antidiabetic 551
effects of flavonoids might be due to antioxidant, receptor agonist or antagonist activity, enzyme 552
inhibition or through other novel mechanisms still to be demonstrated. Further studies are needed 553
to understand the structure-activity relationships of flavonoids to find whether and how flavonoid 554
molecules interact with the cellular components. 555
Holistic corrective actions of fruit flavonoids to combat the complexities of diabetes 556
mellitus are advantageous over the chemical antidiabetic agents which have solitary actions and 557
are notorious to disrupt metabolic equilibrium. Advances in isolation, purification, and 558
characterization of bioactive compounds from fruits should be employed and flavonoids should 559
be isolated from fruits and tested for their dose dependent efficacy studies in animal and human 560
models to develop a natural and sustainable approach to mange diabetes mellitus. 561
Coherent series of experiments are needed to formulate dietary guidelines that can be 562
really helpful for people with diabetes to manage this devastating disease. Disparities among the 563
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different organizational groups should be addressed on the basis of evidence based dietary 564
recommendations to present holistic and simplified picture to diabetic patients. 565
566
ACKNOWLEDGMENTS 567
Declaration of interest. The authors have no relevant interests to declare. 568
569
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Figure Caption
Figure 1 Commonly used antidiabetic agents and their mode of action.
Figure 2 Proposed mechanism of antidiabetic action of fruits flavonoids.
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Thiazolidinedione Acarbose
Biguanides
Sulfonylurea
s
Pancreatic β-cells
Muscle
Bind to ATP
dependent
K
+
(K
ATP
)
Insulin
secretion
Glucose uptake
Insulin sensitivity
Gluconeogenesis
Glucose
uptake
Pancreatic α
amylase
Glucose
uptake
Adipogenesis
Free fatty
acid
TNFα
a
Resistin
Carbohydrate
hydrolysis
Liver
Gluconeogenesis
Adipose
tissues
Hyperglycemia
Figure 1
Commonly used antidiabetic agents and their mode of action.
a
TNFα (Tumor necrosis factor α)
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Oxidative
damage
AMPK
a
Flavonoids
Muscle Intestine
Liver Pancreas
Adipose tissue
GLUT4
b
Adipokine
Tumor necrosis
factor
Lipolysis
Glucose uptake
β-cells
Glucokinase
Glucose 6-
phosphatase
PEPCK
d
Maltase
GLUT2
c
Glucose
absorption Fat
storage
Insulin
secretion
Glucose
storage
Glucose
absorption
Hyperglycemia
Figure 2 Proposed mechanism of antidiabetic action of fruits flavonoids.
a
AMPK (Adenosine monophosphate activated protein kinase),
b
GLUT4 (Glucose transporter type 4),
c
GLUT2 (Glucose transporter type 2), and
d
PEPCK (Phosphoenolpyruvate carboxykinase).
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Flavonoids Sources Functionality Mode of action References
Quercetin Grape fruit , apple,
cranberries
Improves glucose
absorption
Act upon adenosine monophosphate-
activated protein kinase which
mediates glucose transporter 4
translocation
Eid et al. (2010)
Kaempferol Strawberries, goosebe
rries, cranberries, gra
pefruit, apple
Improves the
insulin secretion
Improves the expression of Akt and
Bcl-2
a
. Inhibit the capase-3 activity in
β-cell. So ultimately protect the β-cells
survival
Zhang and Liu,
(2011)
Myricetin Grapes, berries, waln
uts
Improves insulin
sensitivity
Improve the impaired signaling
downstream of insulin receptors Then
affect the phosphorylation of insulin
receptors:insulin receptor substrate-1,
phosphatidylinositol 3-kinase which
effects glucose transporter 4
translocation in muscles
Tzeng et al. (2011)
Table 1 Different fruits flavonoids, their sources, antidiabetic properties and underlying mode of action.
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Rutin Citrus fruits, oranges,
lemon, berries,
limes, grapefruit,peac
hes, apples
Improve the insulin
secretion
Scavenge the free radicals, inhibit the
lipid peroxidation, prevent the
oxidative stress and ultimately protect
β-cell damage through oxidative stress
Coskun et al.
(2005)
Hesperidin . Citrus fruits Ameliorates
hyperglycemia
Increasing hepatic glycolysis and
glycogen concentration or by lowering
hepatic gluconeogenesis
Jung et al. (2004)
Naringenin Citrus fruits Induce the
hypolipidemic
action
Increase in low density lipoprotein
receptor expression through
phosphatidylinositol 3-kinase mediated
upregulation of sterol regulatory
element binding protein
Kannappan and
Anuradha (2010)
Reduce the glucose
uptake from
intestine
By inhibiting the α-glycosidase activity Priscilla et al.
(2014)
Tangeritin Tangerine and citrus Improve the Increased the adenosine Kim et al. (2012)
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peels glucose uptake monophosphate-activated protein
kinase phosphorylation and altered the
secretions of adipocytokines such as
leptin, adiponectin, resistin, interleukin
6, and monocyte chemotactic protein-1
Catechins Grapes, apple juice Reduce the blood
glucose level
By inhibiting the transport of glucose
across the intestinal membrane
Kobayashi et al.
(2000)
Epigallocatechin gallate Pomegranate juice Improve the β-cells
viability
Increase the expression of insulin
receptor substrate-2, Akt, the fork head
box protein 01 and pancreatic duodenal
home box-1 and ultimately protect the
β-cell from damage
Cai and Lin (2009)
Anthocyanins and
anthocyanidins
Bilberry, raspberry,
strawberry, black
currants, peach, plum
Improve the insulin
sensitivity
Upregulated glucose transporter 4
expression, which in turn led to
downregulated theretinol binding
protein 4 expression
Takikawa et al.
(2010)
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a
Bcl-2 (B-cell lymphoma 2) are cell death regulatory proteins.
Reduce
postprandial
hyperglycemia
Inhibit the α-glucosidase activity so
inhibit the glucose liberation from
dietary carbohydratesand ultimately
delay the glucose absorption in plasma
Kumar et al. (2011)
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