Dietary Chinese Quince Polyphenols Suppress Generation of Î±

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Dietary Chinese quince polyphenols suppress generation of #-dicarbonyl compounds in diabetic KK-Ay mice Nozomi Nagahora, Yoshiaki Ito, and Takashi Nagasawa J. Agric. Food Chem., Just Accepted Manuscript • DOI: 10.1021/jf401231j • Publication Date (Web): 03 Jun 2013 Downloaded from http://pubs.acs.org on June 5, 2013

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Journal of Agricultural and Food Chemistry

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Dietary Chinese quince polyphenols suppress

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generation of α-dicarbonyl compounds in

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diabetic KK-Ay mice

4 5

Nozomi Nagahora, Yoshiaki Ito, Takashi Nagasawa*

6 7

Bioresources Science, The United Graduate School of Agricultural Sciences, Iwate

8

University

9

3-18-8 Ueda, Morioka, Iwate 020-8550, Japan

10 11

*Corresponding

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E-mail address: [email protected].

13

Telephone: +81-19-621-6169.

14

Fax: +81-19-621-6262.

author: Nagasawa T.

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Key words: antidiabetic effect, green tea extract, phenols, procyanidin, Chinese quince,

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glycation, α-dicarbonyl compounds

18 19 1

ACS Paragon Plus Environment


1

ABSTRACT

2

Many dietary polyphenols can provide health benefits, such as antioxidant and antidiabetic

3

effects, and can downregulate the progression of glycation (one cause of diabetic

4

complications). Chinese quince (CQ) is rich in polyphenols, especially procyanidins. A few

5

studies have indicated that CQ has an effect on diabetes. In this study, a procyanidin-rich

6

extract was prepared from Chinese quince fruit (CQE) and its effects were investigated and

7

compared with green tea extract (GTE) in type 2 diabetes model KK-Ay mice. Mice were

8

provided one of two high fat (HF) diets for four weeks: a HF diet containing 0.5% CQE or

9

a HF diet containing 0.5% GTE. Blood glucose was suppressed in mice fed CQE and GTE

10

during the experimental period (p < 0.05), although the effect of CQE was weaker than that

11

of GTE. Intake of CQE had no effect on the blood insulin level, while GTE decreased the

12

insulin level. Body weight gain was suppressed in mice fed CQE similarly to mice fed GTE

13

(p < 0.05). Hepatic lipid content and α-dicarbonyl compounds in the kidney were reduced

14

in mice fed CQE and GTE (p < 0.05). These results suggest that intake of CQE could

15

moderate type 2 diabetes and diabetic complications.

16 17 18 19 20 21

2


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INTRODUCTION

2

About 350 million people world-wide suffer from diabetes, and type 2 diabetes (T2D)

3

affects 90% of people with diabetes.1 T2D is a lifestyle related disease that can be induced

4

by multiple factors such as overfeeding, excess body weight, physical inactivity, and

5

genetic factors. It presents with hyperglycemia as the primary symptom. Sustained

6

hyperglycemia induces insulin hypersecretion from the pancreatic islets and leads to insulin

7

resistance. The pathogenesis of T2D is aggravated by obesity, a condition in which

8

abnormal lipid accumulation disrupts secretion of adipocytokines and leads to lipid

9

peroxidation.2 Adipocytokines secreted from adipose tissue affect insulin sensitivity.3 For

10

example, a decrease in blood adiponectin decreases insulin sensitivity in adipose tissue and

11

muscle, and increases systemic inflammation.3

12

Hyperglycemia also accelerates non-enzymatic glycation, leading to accumulation of

13

advanced glycation endproducts (AGEs), which are associated with development of

14

diabetic complications such as diabetic nephropathy and retinopathy.4,5 As such the

15

complications decrease patients’ quality of life, it is important to suppress production of

16

AGEs. α-Dicarbonyl compounds; 3-deoxyglucosone (3-DG), glyoxal (GO) and

17

methylglyoxal (MG), are known to be intermediate products of glycation. They are

18

generated through the polyol pathway including the enzyme such as aldose reductase and

19

degradation of glucose.6,7 It has shown that abundance of α-dicarbonyl compounds such as

20

3-DG, GO and MG are increased in the plasma of diabetic rats and humans.8,9 These

21

compounds have higher reactivity with proteins than the reactivity of reducing sugars, and 3



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they injure proteins (the products are AGEs) and lipids (the products are advanced

2

lipoxidation endproducts; ALEs). Therefore the reaction is called carbonyl stress,10 which

3

has a vital role in the pathogenesis of diabetic nephropathy and the progression of renal

4

failure.5 Moreover, oxidative stress increases in diabetes (auto-oxidation through AGE

5

formation and low-grade inflammation induced oxidative stress). Proteins, lipids, and

6

nucleic acid are damaged by oxidative stress, and lose normal structure and function.11

7

Polyphenols exist in many plants, and have various health effects that are thought to be

8

partially due to their antioxidant activity. One of the more well known polyphenols is

9

epigallocatechin gallete (EGCG), which is known to be present mainly in green tea extract.

10

Green tea extract has many beneficial effects such as strong antioxidant activity,

11

anti-inflammatory effect, and cardiovascular protective effect.12 Green tea extract and

12

EGCG has been shown that it has antidiabetic activity which caused by the protection of β

13

cell, the improvement of insulin sensitivity.13,14 Procyanidins are a class of polyphenols and

14

consist of catechin or epicatechin polymers. Similarly to EGCG, procyanidins have been

15

reported to show antioxidant activity,15,16 anti-inflammatory activity,17 the beneficial effects

16

on lipid metabolism,18 antidiabetic effects,19 inhibition of AGE formation, and inhibition of

17

methylglyoxal-induced

18

procyanidin-rich food materials could be therapeutic agents for treatment of diabetes owing

19

to their documented antidiabetic effects.

damage

to

enzymes.20

Therefore,

it

is

expected

that

20

Chinese quince (Chaenomeles sinensis; CQ) is a popular tree in Japan and China. Its fruit

21

has been used as liquor and traditional medicines. CQ contains organic acids, vitamin C, 4


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polyphenols such as phenolic acids, flavonoids, and abundant procyanidin polymers.21

2

Extracts of CQ have been reported to show beneficial activities, such as anti-ulcer,22

3

anti-pruritic,23 anti-influenza virus,24 and antioxidant effects.24 Sancheti et al. demonstrated

4

that CQ extract had anti-diabetic effects on streptozotocin-induced diabetes,25 and

5

anti-hyperlipidemic effects.26 These activities have been considered to be responsible for

6

procyanidins which are the main components of polyphenols in CQE. However, no reports

7

have mentioned the antidiabetic effects of CQE on T2D particularly from the point of view

8

of anti-glycation. Therefore, the aims of present study were to investigate whether CQE can

9

improve hyperglycemia in type 2 diabetic model animals, and if it can influence obesity

10

and glycation (which are profoundly associated with the progress of diabetes and diabetic

11

complications). Additionally, the strength of the antidiabetic effects of CQE was compared

12

with that of GTE. In order to evaluate the effects of the extracts, type 2 diabetic model

13

animals (KK-Ay mice) were used and their blood sugar and lipid parameter were measured;

14

and in order to investigate the progression of glycation, α-dicarbonyl compounds in the

15

kidney were measured.

16 17 18

MATERIALS and METHODS

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Materials. Green tea extract (GTE) was provided from Taiyo Kagaku Co., Ltd (Mie, Japan)

20

and contained 48.8% EGCG, 17.8% epigallocatechin, 7.6% epicatechin, 7.6% epicatechin

21

gallete, 4.0% gallocatechin, 1.8% catechin, 1.5% gallocatechin gallete, and 1.4% gallic acid 5



1

(data from maker). Fresh fruit of the Chinese quince (CQ) was obtained from a farmer in

2

Iwate, Japan. 3-Deoxyglucosone detection reagents including 3-deoxyglucosone standard

3

and 2, 3-diaminonaphthalene were purchased from Dojin Laboratories (Kumamoto, Japan).

4

Methylglyoxal was obtained from Sigma Aldrich (St. Louis, MO, US). All other chemicals

5

used were of the highest quality available and purchased from Wako Pure Chemical

6

Industries. (Osaka, Japan)

7

Preparation of Chinese quince extracts (CQE). Two hundred fifty grams of fresh

8

Chinese quince fruit was washed, cut in a 5 mm squares and the seeds were removed. The

9

fruit was extracted in 10-fold by weight ethanol with stirring overnight. The extract was

10

filtered with the filter paper, and then the ethanol was removed using a vacuum evaporator.

11

The concentrated extracts were applied to a Sephadex LH-20 column (GE Healthcare

12

UK Ltd, Buckinghamshire, UK) (5 × 18 cm) to remove sugars. The column was

13

washed with 10 L of deionized water and then the polyphenols were eluted with 1 L of

14

80 % (v/v) acetone. The eluted sample was evaporated to dryness and resolved in water,

15

then lyophilized (FPU-830, Eyela, Tokyo, Japan) and stored in a freezer (–20°C) until use.

16

This series of processes were repeated to obtain a sufficient quantity of Chinese quince

17

extracts (CQE). The content of polyphenols in CQE and GTE was determined by

18

Folin-Denis method using gallic acid as the standard.27 CQE contained 0.35 g polyphenol

19

as gallic acid equivalent per 1 g dry weight, and GTE contained 1.1 g polyphenol as gallic

20

acid equivalent per 1 g dry weight. In our preliminary experiment, we confirmed that more

21

than 90% of total polyphenols were procyanidins (data not shown). A total of 1.94 ± 0.16 6


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mg (gallic acid equivalent) phenolic content was extracted from 1 g of fresh Chinese quince

2

fruit.

3

Animal experiments. Male KK-Ay mice 5 weeks of age were obtained from CLEA Japan

4

Inc. (Tokyo, Japan) and housed individually in stainless steel cages. They were maintained

5

in an

6

cycle (lights on from 6:00 to 18:00). The mice were allowed free access to water and a

7

standard chow (Rodent diet CE-2, CLEA, Tokyo, Japan) for a week, and were subsequently

8

fed an AIN93-G diet for a week. Then, the mice were randomly divided into three groups

9

(n=4-5) and then fed the experimental diet ad libitum: a high fat diet (diabetic control

10

group; DC), a high fat diet containing 0.5% CQE (diabetic Chinese quince group; DQ), or a

11

high fat diet containing 0.5% GTE (diabetic green tea group; DG) as the concentration of

12

total phenolic content (5 g gallic acid equivalent / kg diet weight). The detail of each

13

experimental diet is shown in Table 1. Blood glucose was checked weekly during the

14

experimental period for four weeks using Ascensia Breeze-2 (Bayer AG, Leverkusen,

15

Germany). The oral glucose tolerance test (OGTT) was performed on 12-h fasted mice on

16

day 27. Blood was collected from the tail vain at 0, 15, 30, 60 and 120 min after

17

administration of 2 g of glucose per kg of body weight, and was measured with an Ascensia

18

Breeze-2. On day 28, HbA1c was determined by a DCA 2000 System with a DCA 2000

19

HbA1c cartridge (Siemens AG, Munich, Germany) using blood from the tail vain. Feces

20

were collected for two days using a metabolic cage from day 28 to day 30. On day 30, after

21

1 hour of fasting, each mouse was sacrificed under anesthesia with diethylether and blood

air-conditioned room at 22±1°C at 55% relative humidity with a 12-h light/dark

7



1

was obtained from the inferior vena cava. The liver was perfused with cold saline in order

2

to remove the remaining blood. The liver, kidney, perirenal, epididymal and abdominal

3

adipose tissues were collected and the serum was immediately prepared from blood. All

4

samples were frozen in liquid N2 and stored at -80 °C until analysis. The animal care

5

protocol in this study was approved by the Iwate University Animal Research Committee

6

(A201117) under Guidelines for Animal Experiments in Iwate University.

7

Biochemical analysis of serum and liver. Serum glucose, triglyceride (TG), total

8

cholesterol (TC) and HDL-cholesterol levels were measured enzymatically with

9

commercial kits (Glucose CII-Test, Triglyceride E-Test and Cholesterol E-Test, Wako Pure

10

Chemical Industries, Osaka, Japan, respectively). Serum insulin and adiponectin

11

concentrations were measured using ELISA kits (Mouse Insulin Kit, Morinaga Institute of

12

Biological Science, Yokohama, Japan and Mouse, and Rat Adiponectin ELISA Kit, Otsuka

13

Pharmaceutical, Tokyo, Japan respectively). Liver lipids were extracted by the method of

14

Folch et al.,28 and the cholesterol and TG contents were measured with the above kits.

15

Fecal component analysis. Feces collected were lyophilized and weighed the dry weight.

16

Powdered dry feces were extracted and purified using the method described by Folch et

17

al.28 The cholesterol and TG levels in feces were measured using the same enzymatic kit

18

used in the plasma analysis.

19

Determination of α-dicarbonyl compounds in kidney. α-Dicarbonyl compounds were

20

analyzed for 2,3-diaminonaphtalene (DAN) adducts identified as fluorescing derivatives

21

according to the method of Yamada et al. using reverse-phase HPLC.8 The tissue sample 8


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(100 mg) was homogenized with 1 mL of ice-cold 10 mM sodium phosphate buffer at pH 7.4,

2

and was centrifuged at 14,000 g for 15 min. The supernatant was transferred into a new

3

tube, and proteins were precipitated by adding 50 µL of 0.005 % 2, 3-pentanedione and 1

4

mL of 6 % perchloric acid, and the sample was centrifuged at 3,350 g at 4 °C for 20 min. The

5

supernatant was neutralized with 2 mL of saturated sodium bicarbonate solution and was

6

reacted with 0.1 % (w/v) of 2, 3-diaminonaphthalene overnight at 4 °C. The derivatized

7

compounds were extracted with 4 mL of ethyl acetate three times, and the solvent was dried

8

under reduced pressure. The dried extract was dissolved with 200 µL of methanol for

9

HPLC

analysis.

Standards

(3-DG,

GO

and

MG)

were

derived

with

2,

10

3-diaminonaphthalene as described above. HPLC analysis was carried out on a

11

Lichrosphere 100RP-18e column (4.6×250 mm, Merck KGaA, Darmstadt, Germany) at

12

40 °C using PU-2089 Plus pump (JASCO Co., Tokyo, Japan). Chromatographic separation

13

was performed with isocratic elution using 10 mM sodium phosphate/acetonitrile (70/30,

14

v/v). The flow rate was 1 mL/min, and the injected volume was 5µL. The wave length used

15

for detection was 503 nm (excitation, 271 nm) on a FP-920 fluorescence spectrophotometer

16

(JASCO Co., Tokyo, Japan).

17

Statistical analysis. Data are presented as mean ± SE for each group. A computer program

18

(Graphpad InStat Software version 2.03, 1995, San Diego, CA, U.S.A) was used for

19

statistical analysis. Analysis of variance (ANOVA) was performed to determine whether

20

there were significant (p < 0.05) differences between the groups. Significant differences

21

between means identified by ANOVA were further analyzed by the Tukey multiple 9



1

comparison test.

2 3

RESULTS

4

General characteristics. Body weight gain of mice fed the high fat diets containing CQE

5

(DQ) and GTE (DG) was significantly less than that of mice fed a high fat diet (DC) (Table

6

2). Daily food intake of the DQ group was slightly decreased compared to the mice in other

7

two groups, but the difference was not significant. Dietary CQE and GTE resulted in lower

8

liver weight than mice fed a high fat diet. Moreover, intake of GTE reduced kidney weight

9

and mesenteric adipose tissue weight compared to mice fed the other experimental diets.

10

Serum analyses. Hyperglycemia observed in DC mice was lowered by ingestion of a diet

11

supplemented with GTE, and tended to improve with ingestion of a diet supplemented with

12

CQE (Table 2). Serum lipids, TG, total cholesterol (TC), and HDL-cholesterol levels were

13

unchanged after consumption of diets containing CQE and GTE. There was a trend towards

14

reduced insulin in mice DG compared with DC (p=0.079), but the variation in serum

15

insulin between animals precluded obtaining significance. Although no significant

16

differences were observed for serum adiponectin level in DQ and DG compared to DC, the

17

serum adiponectin level tended to be proportionate with the degree of suppression of serum

18

glucose level.

19

Blood glucose and HbA1c level, and blood glucose level in OGTT. Blood glucose level

20

in DC increased gradually during the experimental period (Fig.1A). The blood glucose

21

level in DQ mice was kept significantly lower than in DC mice, whereas it was kept around 10


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200 mg/dL in DG (lower than the level at the beginning of the experiment) (Fig.1A).

2

HbA1c was reduced by consumption of CQE and GTE (Fig.1B). The OGTT showed that

3

the blood glucose at 15 min in DG was also significantly lower (Fig.1C) and the area under

4

the curve (AUC) in DG mice tended to be smaller than DC mice. Although a slight

5

decrease in blood glucose and the AUC value was observed in DQ mice, this difference

6

was not significant (Fig.1D).

7

Hepatic lipids. Hepatic TG and cholesterol contents in DG mice were significantly lower

8

than those in DC mice, which was 25 – 30 % of DC (Fig.2). In DQ mice, hepatic TG levels

9

were reduced by approximately 50 % of that of DC but the difference was not significant,

10

and hepatic cholesterol levels were significantly reduced compared to that of DC mice

11

(Fig.2).

12

Fecal lipids. CQE and GTE had no effect on the weight of dried feces (Fig.3A). The

13

excretion of TG in feces was not increased by the consumption of CQE and GTE (Fig.3B).

14

Meanwhile, the excretion of cholesterol in feces in DQ and DG mice was significantly

15

greater than that of DC, and fecal total bile acid levels of DQ and DG was approximately

16

one-quarter of DC (Fig.3C and 3D).

17

α-Dicarbonyl compounds in kidney. The content of 3-DG in the kidney was not

18

significantly altered among the groups (Fig.4A). GO and MG in kidneys of mice fed the

19

high fat diet containing each polyphenol compounds were lower than that of mice fed the

20

high fat diet (Fig.4B and 4C), suggesting that the polyphenol compounds used in the

21

present study reduced carbonyl stress. 11



1 2 3

DISCUSSION

4

Polyphenols are natural products in many plants and are ingested as vegetables, fruits,

5

juices and supplements in our diets. Procyanidins, a kind of polyphenol, have been

6

observed to exert diverse protective activities against diabetes and obesity.16,17,29 The

7

Chinese quince extract (CQE) used in this study is rich in procyanidins,30 however it is not

8

yet clear whether CQE has the antidiabetic and anti-obese effects on T2D. In the present

9

study, the effect of CQE on T2D was investigated. It was revealed that ingestion of CQE is

10

valuable to treatment for T2D. The diet containing 0.5 % CQE did not appear to cause

11

hepatic damage in this preliminary study (data not shown).

12

In this study, body weight gain in KK-Ay mice was suppressed by ingestion of CQE as

13

well as GTE, and the suppression in KK-Ay mice fed the CQE and GTE extracts was

14

mainly attributed to decrease of mesenteric adipose tissue and liver weight (Table 2).

15

Several studies on the anti-obesity effect of GTE have been carried out in experimental

16

animals and humans.31-32 Rains et al. indicated that GTE reduced nutrient absorption and

17

appetite, and elevated fatty oxidation and energy expenditure,33 resulting the suppression of

18

body weight gain. Yokozawa et al. demonstrated in the rat that the administration of grape

19

seed extract containing oligomer and polymer procyanidins resulted in suppression of body

20

weight gain.34 Procyanidins in CQE might act as an inhibitor of nutrient absorption and an

21

accelerator of fatty metabolism, since it has reported that procyanidins inhibit lipase, 12


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1


α-amylase and α-glucosidase activity,35,36 and enhanced fatty acid oxidation.18

2

Ingestion of CQE was found to reduce blood glucose during the experimental period, and

3

GTE further decreased blood glucose (Fig. 1A). It was considered that absorption of

4

carbohydrate was depressed by continuous administration of CQE and GTE, since

5

procyanidins and catechins have been shown to inhibit both α-glucosidase and α-amylase.36,

6

37

7

suppressed by CQE similar to how it is suppressed by GTE after glucose loading (Fig. 1C

8

and 1D). Montagut et al. reported that grape seed procyanidins enhanced insulin

9

sensitivity by activating the insulin receptor and key proteins of the insulin signaling

10

pathway via mitogen activated protein kinase (MAPK) pathway.38 Wu et al. have shown

11

that green tea increased glucose uptake in rat adipocyte because it directly enhanced the

12

binding of insulin to the insulin receptor.14 Thus, it is possible that procyanidins in CQE

13

might play insulin like roles in diabetic mice, and the mechanisms might differ from GTE.

On the other hand, OGTT showed that blood glucose level in KK-Ay mice tends to be

14

Adiponectin is closely related to insulin sensitivity and stimulates glucose uptake in

15

adipocyte and muscle, and excess fatty accumulation in adipose tissues reduces the

16

secretion of adiponectin.2 Décordé et al. indicated that intake of grape seed procyanidin

17

extract increased plasma adiponectin level in obese hamsters induced by a high fat diet.39

18

However, in the present study, the serum adiponectin level was not significantly increased

19

by intake of CQE and GTE, but there was tendency of serum adiponectin to increase along

20

with hypoglycemic effect of CQE and GTE. It was considered that the increase of serum

21

adiponectin level by intake of GTE was induced by down-regulation of mesenteric adipose 13



1

tissue, whereas intake of CQE have no apparent effect on the suppression of mesenteric

2

adipose tissue compared to that of GTE, resulting that serum adiponectin level slightly

3

increased by intake of CQE (Table 2). Consequently, adiponectin was not observed to have

4

a conclusive involvement in the glucose-lowering effect of CQE in this experiment.

5

In KK-Ay mice fed CQE, hepatic TG and cholesterol decreased by half, which was

6

similar to the decrease seen in mice fed GTE (Fig. 2A and 2B). Intake of CQE and GTE

7

resulted in increased excretion of cholesterol in the feces, but did not change fecal TG (Fig.

8

3A and 3B), implying that the extracts inhibited absorption of cholesterol and affected lipid

9

metabolism in the liver. Oxidation and synthesis of fatty acid are regulated by many factors

10

(including sterol regulatory element binding protein-1 (SREBP-1)), and cholesterol

11

synthesis in liver is partly regulated by SREBP-2.40 It has been reported that procyanidins

12

derived from grape seed and persimmon peel suppressed SREBP-1 and SREBP-2 proteins

13

in the liver, resulting in improvement of hepatic steatosis.29,34 However, details about the

14

regulation of hepatic lipid metabolism by CQE remains uncertain, and further studies are

15

required.

16

Kidney disease caused by diabetes is called diabetic nephropathy, and is a major

17

complication of diabetes. It is known that AGEs accumulate in diabetic nephropathy,5

18

therefore AGEs are key metabolites that can be used to evaluate the degree of

19

complications of diabetic nephropathy. α-Dicarbonyl compounds are precursors of AGEs,

20

and are involved in the pathogenic mechanism of diabetic nephropathy. Thus, it is

21

important to inhibit generation of α-dicarbonyl compounds for prevention and suppression 14


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1

of diabetic complications. As shown in Fig. 4, the content of 3-DG in the kidney was

2

unchanged, but the contents of GO and MG were considerably reduced after the intake of

3

CQE and GTE. The decrease is considered to be relevant to control of blood glucose by

4

polyphenols, because it has been known that formation of α-dicarbonyl compounds

5

increases with hyperglycemia.41 Although the control of the blood glucose level with CQE

6

was not as large as compared to with GTE, the formation of GO and MG in the kidney was

7

equally suppressed by consumption of diets supplemented with both extracts. Peng et al.

8

showed that cinnamon bark procyanidins (containing catechin, epicatechin, procyanidin B2

9

etc.) scavenged reactive carbonyl compounds (such as MG),42 and inhibited formation of

10

AGEs.20 Therefore, monomeric catechins or procyanidins in CQE and GTE might prevent

11

generation of GO and MG, and result in suppression of accumulation of AGE in the kidney.

12

It is known that generation of α-dicarbonyl compounds are related to ROS,43 which are

13

elevated under chronic inflammatory diseases such as diabetes.44 Many reports have

14

demonstrated that catechin monomers and procyanidins attenuate inflammation and

15

enhance endogenous antioxidant capacity.16,17,45,46 Moreover, green tea and Chinese quince

16

have antioxidant activities,25,47 and the extracts used in the present study might have a

17

protective effect against ROS in vitro (data not shown). Therefore, it is possible that

18

antioxidant components in CQE and GTE could abolish ROS both indirectly and directly if

19

the responsible components could be absorbed from digestive tract. Taken together, these

20

results could suggest that CQE might downregulate the abundance of GO and MG in the

15



1

kidney because of attenuation of oxidative stress, resulting in decreased of the

2

accumulation of AGEs.

3

Monomeric catechins such as EGCG were reported to be absorbed from the intestine and

4

the metabolites were seen in the plasma at a quite high level (Cmax 1500 µM).48 It is

5

difficult to absorb polymer procyanidins compared to tetramer procyanidins.49 Dimer and

6

trimer procyanidins were detected in rat plasma after ingestion of procyanidin rich

7

compounds, but the concentration was considerably less than the catechin monomers (Cmax

8

1.4 µM)48. However, metabolites degraded by intestinal bacterial flora could be absorbed,

9

and in that way might exert health effects.48 Gonthier et al. showed that procyanidin B3 and

10

C2 were degraded to 3-hydroxyphenylpropionic acid, 3-hydroxyphenylacetic acid,

11

protocatechuic acid, and 4-hydroxybenzoic acid by intestinal bacterial flora, and they were

12

detected in rat urine.50 Thus, it is conceivable that the difference in absorption of CQE

13

(containing monomers and polymers) and GTE (containing all monomers: catechin,

14

epicatechin, and EGCG) affected the variation of effects in KK-A y mice.51

15

In conclusion, the present study indicates that intake of CQE in KK-Ay mice attenuated

16

both increases of blood glucose and accumulation of hepatic lipids. These effects may be

17

due to procyanidins in CQE, which regulate the absorption and metabolism of sugar and

18

lipids. Furthermore, this study demonstrated for the first time, that CQE could suppress the

19

generation of α-dicarbonyl compounds in the kidney. Therefore, the present study suggests

20

that CQE may be capable of attenuation of the pathology of type 2 diabetes and inhibition

21

of the progress of diabetic complications. 16


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Figure captions

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Figure 1. Effect of the dietary CQE and GTE supplementation on blood glucose (A) for 4

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weeks, HbA1c (B), blood glucose in OGTT (C) and AUC (D) in KK-Ay mice. DC – High

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fat diet; DQ – 0.5% CQE-High fat diet; DG – 0.5% GTE-High fat diet. Values are means ±

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SEM (n=4-5). Different letters indicate significant differences (p

Dietary Chinese Quince Polyphenols Suppress Generation of Î±

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