Effect of 2 hydroxychalcone on adiponectin level in type 2 diabetes induced experimentally in rats

Effect of 2 hydroxychalcone on adiponectin level in type 2 diabetes induced experimentally in rats 1 2 4 5 6 7 8 9 10 11 1 3 14 15 16 17 18 19 20 21 22 23 24 25 2 6 47 48 49 50 51 52 53 54 55 56 57 58[.]

Trang 1

2 Full Length Article

6

7

8 Laila Ahmed Eissaa,⇑ , Nehal Mohsen Elsherbinya,b, Abdalkareem Omar Magmomaha

9 aDepartment of Biochemistry, Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia

11

1 3 a r t i c l e i n f o

14 Article history:

15 Received 19 September 2016

16 Received in revised form 15 December 2016

17 Accepted 23 December 2016

18 Available online xxxx

19 Keywords:

20 Type 2 diabetes mellitus

21 Insulin resistance

22 Adiponectin

23 PPAR-c

24 2-Hydroxychalcone

25

2 6

a b s t r a c t

27 Type 2 diabetes mellitus (T2DM) is the most common type of diabetes, accounting for 90% of diabetic

28 cases It is characterized by chronic hyperglycemia which is caused by a combination of deficiency in

29 insulin action and secretion Adipose tissue regulates insulin sensitivity via the circulating adipocytokines,

30 leptin, resistin and adiponectin Hypoadiponectinemia contributes to the development of obesity and

31 related disorders such as diabetes, hyperlipidemia and cardiovascular diseases The present study aimed

32

to evaluate the beneficial effect of flavonoid 2-hydroxychalcone in T2DM through its effect on peroxisome

33 proliferator activated receptor gamma (PPAR-c) and adiponectin T2DM was induced in male Wistar rats

34 using high fat diet and low dose of streptozotocin (STZ, 35 mg/kg, i.p.) The flavonoid 2-hydroxychalcone

35 was administered by oral tubes Levels of PPAR-cin sub abdominal adipose tissue, serum adiponectin,

36 serum tumor necrosis factor-a(TNF-a) and serum insulin levels were detected by ELISA Moreover,

37 malondialdehyde (MDA) and reduced glutathione (GSH) in sub abdominal adipose tissue, fasting serum

38 glucose, serum triglycerides and serum total cholesterol levels were measured by colorimetric methods

39 Results showed that 2-hydroxychalcone attenuated changes induced by T2DM in rats

2-Hydroxy-40 chalcone treatment increased PPAR-clevels in adipose tissue, reduced oxidative stress, restored

adiponec-41 tin levels and decreased high glucose levels in T2DM rats In conclusion, 2-hydroxychalcone reduced

42 hyperglycemia in T2DM by regulating adiponectin secretion This effect involves PPAR-c signaling

43 pathway

44

Ó 2017 Production and hosting by Elsevier B.V on behalf of Mansoura University This is an open access

45 article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

46 47

48 Introduction

49 Type 2 diabetes is referred to as non-insulin-dependent

50 diabetes or adult onset diabetes It is the most common type of

dia-51 betes, representing 90–95% of all diabetic cases in high-income

52 countries and may account for an even higher percentage in

low-53 and middle income countries [1] The hyperglycemia is caused by

54 a combination of deficiency in insulin secretion and action, leading

55 to reduced glucose uptake by peripheral tissues and increased

56 gluconeogenesis by the liver Untreated diabetes may progress to

57 loss of b-cells function in the islets of Langerhans with eventual

58 insulin deficiency b-cells destruction is not immune-mediated

59 and rarely progresses to a point where the patient became

depen-60 dent on insulin for survival Ketoacidosis is not common and is

61 usually associated with a major intercurrent illness [2,3]

62 The management of diabetes is considered a global problem, a

63 medical approach is not always sufficient for T2DM management

64 and lifestyle modification should be considered Thus, glycemic

65 control is the basis for the treatment of type-2 diabetes Existing

66 antidiabetic agents are often associated with side effects including

67 obesity, osteoporosis, sodium retention, hypoglycemia, and lactic

68 acidosis [4,5] To avoid such adverse side effects, there is a crucial

69 need for new therapies for management and treatment of T2DM

70

[6,7]

71 Adiponectin is an adipocytokine exclusively secreted by adipose

72 tissue into the blood stream [8,9] Plasma adiponectin level is

73 negatively correlated with development of insulin resistance,

74 T2DM and metabolic syndrome that are linked to obesity [10,11]

75 Indeed, plasma adiponectin levels were decreased in obesity This

76 reduction may play a causal role in the development of insulin

77 resistance [12]

78 Transcription of adiponectin was tightly controlled by

79 peroxisome proliferator-activated receptor gamma (PPAR- c ) [13]

80 PPAR- c is highly expressed in adipocytes, where it plays an

81 important role in glucose and lipid homeostasis, inflammation,

82 and adipocyte differentiation [14] A large body of evidence

83 confirmed that PPAR- c activation improves insulin sensitivity http://dx.doi.org/10.1016/j.ejbas.2016.12.002

2314-808X/Ó 2017 Production and hosting by Elsevier B.V on behalf of Mansoura University

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

⇑ Corresponding author

E-mail address:lailaeissa2002@yahoo.com(L.A Eissa)

Contents lists available at ScienceDirect

Egyptian Journal of Basic and Applied Sciences

j o u r n a l h o m e p a g e : w w w e l s e v i e r c o m / l o c a t e / e j b a s

Please cite this article in press as: Eissa LA et al Effect of 2-hydroxychalcone on adiponectin level in type 2 diabetes induced experimentally in rats Egyp

Trang 2

84 and enhances glucose disposal in adipose tissue and skeletal

mus-85 cle [15]

86 Chalcones (originally isolated from natural plant sources) are

87 considered as precursors of flavonoids Chalcones are abundant

88 in edible plants [16] In addition, they can also be synthesized in

89 laboratory [17] Hydroxychalcones have been involved in various

90 biological activities including antioxidant, inflammatory,

anti-91 cancer, anti hepatotoxic and antimalarial activities [18]

Interest-92 ingly, hydroxychalcone has been reported to mimic the effect of

93 insulin by enhancing glucose uptake and phosphorylation of

insu-94 lin receptor in adipocytes [19] In addition, various synthetic

chal-95 cone derivatives have shown inhibitory activity against diabetic

96 complications [20] Moreover, 2-hydroxy chalcone was reported

97 as a potential dietary PPAR c ligand [21] In the present study, we

98 aimed to investigate the effect of 2-hydroxychalcone on

adiponec-99 tin levels in T2DM induced experimentally in rats and the possible

100 involvement of PPAR- c

101 Materials and methods

102 Animals: experimental protocols

103 Adult male Wistar rats (8 weeks old, weighing 160–180 g) were

104 used for this study Rats were housed in stainless steel rodent cages

105 at room temperature (25 ± 2 °C) with 12 h dark/light cycle The

106 experimental protocol was approved by Research Ethics

Commit-107 tee, Faculty of Pharmacy, Mansoura University, Egypt The animals

108 were randomly divided into 3 groups (12 rats in each group):

Nor-109 mal control group, T2DM group and hydroxychalcone treated

110 group The rats (except the normal control group) were fed high

111 fat diet (HFD) for 15 days to induce T2DM HFD is composed of

112 58% fat, 25% protein and 17% carbohydrate, as a percentage of total

113 kcal and libitum, respectively [22]

114 After 15 days, the rats in second and third groups were fasted

115 for 12 h followed by a single intraperitoneal (i.p.) injection of 35

116 mg/kg STZ, (Sigma-Aldrich Co, St Louis, MO) The HFD was

contin-117 ued until the end of study STZ was freshly dissolved in (0.1 M)

118 citrate buffer (pH 4.5) and immediately injected into rats [23] To

119 overcome the hypoglycemia which follows STZ, during the first

120 24 h after their injection; diabetic rats were given 5% glucose

solu-121 tion to drink instead of tap water Animals were monitored by

peri-122 odic estimation of body weight and biochemical testing for blood

123 glucose Only animals with persistent blood glucose levels higher

124 than 300 mg/dL for 7 days after STZ administration were

consid-125 ered diabetic and selected for further pharmacological studies

126 [24] One week after the STZ injection, the third group was treated

127 by hydroxychalcone (Alfa Aesar, 26 parkridge Rd, USA) at a dose

128 25 mg/kg body weight daily by oral tube for 21 days

Hydroxychal-129 cone was dissolved in dimethylsulfoxide (DMSO) – normal saline.

130 The final concentration of DMSO in normal saline did not exceed

131 0.5%) [25] The second (T2DM) group received solvent only At

132 the end of the study, after 24 h of the last dose of treatment, all rats

133 were weighed, and then sacrificed.

134 Assessment of biochemical parameters

135 Fasting serum glucose, serum total lipid, serum triglycerides,

136 serum total cholesterol, serum high density lipoprotein (HDL),

137 serum low density lipoprotein (LDL), sub-abdominal adipose tissue

138 malondialdehyde (MDA) and sub-abdominal adipose tissue

139 reduced glutathione (GSH) concentrations were assayed using kits

140 provided by Biodiagnostic Company (Giza, Egypt), according to the

141 manufacturer’s instructions.

142 Sub abdominal adipose tissue PPAR- c , serum adiponectin,

143 serum insulin, and serum tumor necrosis factor- a (TNF- a ) levels

144 were assessed using Enzyme-Linked Immunosorbent Assay (ELISA)

145 kits provided from MyBioSource (San Diego, United States)

accord-146 ing to the manufacturer’s instructions.

147 Statistical analysis

148 The results were presented as means ± SEM The statistical

anal-149 yses were performed by one-way ANOVA followed by Turkey post

150 hoc test.

151 Results

152 Effect of 2-hydroxychalcone treatment on body weight

153

As shown in ( Fig 1 ) Hydroxychalcone treatment caused a

non-154 significant change in body weight compared to diabetic group.

155 However, diabetic rats showed significant decrease in body weight

156

by 25.25% compared to control group.

157 Effect of 2-hydroxychalcone treatment on sub abdominal adipose

158 tissue weight

159 The sub abdominal adipose tissue weight of the diabetic rats

160 was significantly decreased by 43.49% compared to that of the

con-161 trol rats The diabetic rats treated with hydroxychalcone showed

162 non-significant change in sub abdominal adipose tissue weight

163 compared to diabetic group ( Fig 2 ).

164 Effect of 2-hydroxychalcone treatment on fasting serum glucose and

165 insulin levels

166 Comparing to control group, levels of glucose and insulin in

dia-167 betic rats were significantly increased (4.48–2.05 fold

respec-168 tively) On the other hand, the diabetic rats treated with

169 hydroxychalcone showed significantly decreased serum glucose

170 and insulin levels (65.46%, 35.65% respectively) when compared

171

to diabetic group ( Figs 3 and 4 ).

172 Effect of 2-hydroxychalcone treatment on serum lipid profile

173

As depicted in Table 1 , the total cholesterol, triglyceride, total

174 lipid, low density lipoprotein and very low density lipoprotein

175 were significantly increased and high density lipoprotein was

sig-176 nificantly decreased in the diabetic group when compared to

con-177 trol group However, treatment with 2-hydroxychalcone

178 significantly attenuated diabetes induced deleterious effect on

179 lipid profile when compared to diabetic group.

0 50 100 150 200 250 300

control diabec 2-hydroxychalcone

Fig 1 Effect of 2-hydroxychalcone treatment on total body weight After induction

of T2DM, rats were treated with solvent (DMSO – normal saline) or 2-hydroxy-chalcone (25 mg/kg body weight daily by oral tube) n = 12, results are expressed as mean ± SE.*

significant compared to control group p < 0.01.#

significant compared to diabetic group p < 0.05

Trang 3

180 Effect of 2-hydroxychalcone treatment on adiponectin and PPAR- c

181 levels

182 Serum adiponectin and sub abdominal adipose tissue PPAR- c

183 levels were significantly decreased in the diabetic group compared

184

to control group (63.01% and 87.71%, respectively)

2-hydroxy-185 chalcone treatment significantly restored serum levels of

adipo-186 nectin and PPAR- c concentration (2.85 and 16.4 fold, respectively)

187 when compared to diabetic group ( Figs 5 and 6 ) Negative

188 correlation was observed between adiponectin and fasting glucose,

189 insulin and total lipid Moreover, positive correlation was observed

190 between adiponectin and PPAR- c as well as HDL-cholesterol levels.

191

In addition, Negative correlation was observed between PPAR- c

192 and fasting glucose ( Fig 10 ).

Table 1

Effect of 2-hydroxychalcone treatment on triglyceride, total cholesterol, HDL-cholesterol, LDL-cholesterol, VLDL-cholesterol and total lipids After induction of T2DM, rats were treated with solvent (DMSO – normal saline) or 2-hydroxychalcone (25 mg/kg body weight daily by oral tube) n = 12, results are expressed as mean ± SE.*

mg/d

Total cholesterol mg/d

HDL-cholesterol mg/dl

LDL-cholesterol mg/dl

VLDL-cholesterol mg/dl

Total lipids mg/dl

238 ± 8.25 26.28 ± 7.3*

110.8 ± 4.9*

73.2 ± 2.85* 1344 ± 116*

2-Hydroxychalcone 12 169.2 ± 15.34#

172 ± 13.38 79.4 ± 7.3#

65 ± 4.9#

33.8 ± 2.95#

508 ± 49.7#

*

#

0 10 20 30 40 50 60 70

Fig 5 Effect of 2-hydroxychalcone treatment on adiponectin levels After induction

of T2DM, rats were treated with solvent (DMSO – normal saline) or 2-hydroxy-chalcone (25 mg/kg body weight daily by oral tube) n = 12, results are expressed as mean ± SE.*

*

#

0

2

4

6

8 10 12 14 16 18 20

Fig 6 Effect of 2-hydroxychalcone treatment on PPAR-clevels in sub-abdominal adipose tissue After induction of T2DM, rats were treated with solvent (DMSO – normal saline) or 2-hydroxychalcone (25 mg/kg body weight daily by oral tube)

n = 12, results are expressed as mean ± SE.*

significant compared to control group

p < 0.01.#significant compared to diabetic group p < 0.05

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

*

Fig 2 Effect of 2-hydroxychalcone treatment on sub-abdominal adipose tissue

weight After induction of T2DM, rats were treated with solvent (DMSO – normal

saline) or 2-hydroxychalcone (25 mg/kg body weight daily by oral tube) n = 12,

results are expressed as mean ± SE.*

significant compared to control group p < 0.01

#

*

#

0

2

4

6

8

10

12

14

Fig 4 Effect of 2-hydroxychalcone treatment on insulin levels After induction of

T2DM, rats were treated with solvent (DMSO – normal saline) or

2-hydroxychal-cone (25 mg/kg body weight daily by oral tube) n = 12, results are expressed as

mean ± SE.*

*

#

0

100

200

300

400

500

Fig 3 Effect of 2-hydroxychalcone treatment on fasting blood glucose After

induction of T2DM, rats were treated with solvent (DMSO – normal saline) or

2-hydroxychalcone (25 mg/kg body weight daily by oral tube) n = 12, results are

expressed as mean ± SE.*

Trang 4

193 Effect of 2-hydroxychalcone treatment on serum oxidative stress

195 Our results showed that serum MDA level was significantly

196 increased (4.78 fold) but serum GSH level was markedly decreased

197 (31.3%) in diabetic group when compared to control group

How-198 ever, 2-hydroxychalcone treatment reduced MDA by (55.04%)

199 and increased GSH (2.2 fold) when compared to diabetic group

200 ( Figs 7 and 8 ) Negative correlation was observed between

adipo-201 nectin and MDA level However, adiponectin level was positively

202 correlated with GSH level ( Fig 10 ).

203 Effect of 2-hydroxychalcone treatment on serum TNF- a levels

204

Fig 9 shows that serum TNF- a concentration was significantly

205 increased (5.89 fold) in diabetic group when compared to control

206 group However, the diabetic rats treated with

2-hydroxy-207 chalcone showed significant decrease in serum TNF- a (47.55%)

208 when compared to diabetic group.

209 Discussion

210 This study used rat model of HFD feeding followed by low dose

211 STZ as model for T2DM Many researchers used the HFD-STZ model

212 showed the significant loss in body weight after STZ injection The

213 body weight reduction in the STZ-treated rats can be explained by

214 many reasons, including dehydration and excessive fats and

215 proteins catabolism [26] , which ultimately lead to muscle wasting

216

[27] On the other hand, treatment of diabetic rats with

hydroxy-217 chalcone improved body weight, which could be explained by

con-218 trol of blood glucose levels by hydroxychalcone.

219 Many previous studies have been documented the relationship

220 between diabetes mellitus and abnormalities in lipid metabolism

221

[28,29] Dyslipidemia in type 2 diabetic rats is associated with a

222 significant decrease in HDL-C and a significant increase in LDL-C,

223 total cholesterol, triglycerides and, VLDL-C [30,31] Similarly, the

224 results of our investigation revealed a significant dyslipidemia in

225 diabetic rats when compared to control group On the contrast,

226 treatment with hydroxychalcone resulted in significant

improve-227 ment of lipid profile when compared to diabetic untreated group,

228 suggesting beneficial effect of 2-hydroxychalcone on

T2DM-229 induced dyslipidemia.

230 Persistent high serum glucose is highly deleterious It is a result

231

of impaired insulin secretion and/or action [32–34] Blood glucose

232 level should be maintained in a normal range for an enhanced

233 glucose-sensing pathway and sustained insulin output [35] Firstly,

234 persistent hyperglycemia leads to hyperinsulinemia, which seems

235 likely to be an unsuccessful compensatory response of the islet

236 b-cells This is followed by decreased or absence of insulin release

237 from b-cells Indeed, the b-cell mass is reduced by 40%–60% in the

238 patients with T2DM [36] Therefore, T2DM is associated with

insu-239 lin resistance, which could be explained by accumulated fat in

dif-240 ferent body cells that disturb their response to insulin, leading to

241 insulin resistance, hyperinsulinemia, and increased blood glucose

242 levels [37,38] Insulin is a major anabolic hormone responsible for

243 lipogenesis and inhibiting lipolysis [30,39] So, Hyperinsulinemia

244

is also correlated with metabolic lipid disorders in obesity as a

245 result of decreased insulin biological activity In consistent, our

246 results showed increased blood glucose and insulin levels in

247 T2DM rats, reflecting insulin resistance status This resistance was

248 significantly attenuated by 2-hydroxychalcone treatment.

249 Several studies have documented association between elevated

250 MDA levels and the damage of b-cells in T2DM [40] Convincing

251 evidence has established a link between oxidative stress and

insu-252 lin resistance Increased free radical levels have deleterious effects

253

on b cells, including decreased insulin secretion in response to

glu-254 cose, impaired gene expression and cell death, leading ultimately

255

to hyperglycemia and diabetes [41] MDA is a reactive aldehyde

256 and the major reactive electrophilic species known to elicit stress

257

of toxic nature in cells and known to form covalent protein adducts

258 which are referred to as advanced lipoxidation end products that

259 are found to be analogous to advanced glycation end products

260

[42] It is often used to determine the oxidant/antioxidant balance

261

in diabetic patients [43] In this study, hydroxychalcone showed

262 significant reduction of the elevated MDA level in diabetic rats.

263 GSH content were significantly decreased in T2DM diabetic rats

264 when compared to non-diabetic rats [44] In this study, the rats

265 which treated with hydroxychalcone showed significant increase

*

#

0

5

10

15

20

25

30

Fig 7 Effect of 2-hydroxychalcone treatment on serum MDA levels After induction

of T2DM, rats were treated with solvent (DMSO – normal saline) or

2-hydroxy-chalcone (25 mg/kg body weight daily by oral tube) n = 12, results are expressed as

mean ± SE.*

*

#

0

0.05

0.1

0.15

0.2

0.25

Fig 8 Effect of 2-hydroxychalcone treatment on serum GSH levels After induction

of T2DM, rats were treated with solvent (DMSO – normal saline) or

2-hydroxy-chalcone (25 mg/kg body weight daily by oral tube) n = 12, results are expressed as

mean ± SE.*

*

#

0

20

40

60

80

100

120

140

160

Fig 9 Effect of 2-hydroxychalcone treatment on serum TNF-a level After

induction of T2DM, rats were treated with solvent (DMSO – normal saline) or

2-hydroxychalcone (25 mg/kg body weight daily by oral tube) n = 12, results are

expressed as mean ± SE.*significant compared to control group p < 0.01.#significant

compared to diabetic group p < 0.05

Trang 5

0

100

200

300

400

500

600

Adiponecn (pg/ml )

0

5 10 15 20 25 30

Blood glucose (mg/dl)

0

10

20

30

40

50

60

70

80

PPAR-γ (ng/g ssue)

0 10 20 30 40 50 60 70

Insulin (ng/ml)

0

10

20

30

40

50

60

70

MDA (n mol/g ssue)

0 10 20 30 40 50 60 70 80

HDL-cholesterol (mg/dl)

0

10

20

30

40

50

60

70

Total lipids (mg/dl)

0 10 20 30 40 50 60 70

TNF –alpha (Pg/ml)

0 10 20 30 40 50 60 70 80 90

GSH (n mol/g ssue)

i

Fig 10 Correlation studies (A) Significant negative correlation between blood glucose and adiponectin (r =0.3, p < 0.05) (B) Significant negative correlation between Sub abdominal adipose tissue concentration PPAR-cconcentration (ng/g tissue) and serum fasting blood glucose (mg/dl) (r =61, p < 0.05) (C) Significant positive correlation between adiponectin and PPAR-c(r = 0.847, p < 0.05) (D) Significant negative correlation between adiponectin and insulin (r =0.765, p < 0.05) (E) Significant negative correlation between adiponectin and lipid peroxide(r =0.82, p < 0.05) (F) Significant positive correlation between adiponectin and HDL-cholesterol (r = 0.77, p < 0.05) (G) Significant negative correlation between adiponectin and total lipids (r =0.86, p < 0.05) (H) Significant negative correlation between adiponectin and TNF-a(r =0.944,

p < 0.05) (I) Significant positive correlation between adiponectin and GSH levels (r = 0.869, p < 0.05)

Trang 6

266 in GSH concentration when compared to untreated diabetic rats.

267 Taken together, these results suggested which beneficial

anti-268 oxidant properties of hydroxychalcone in T2DM In addition to

269 oxidative stress, inflammation is considered an important

270 pathogenic factor for the development of insulin resistance in

271 T2DM Oxidative stress and endoplasmic reticulum stress

272 stimulate inflammatory signaling in T2DM Circulating TNF- a

273 levels are reported to be elevated in diabetic patients, as well as

274 in STZ-induced diabetic rats [45] , and this cytokine is implicated

275 in apoptosis during diabetes [46] Our results agreed with previous

276 studies which showed that hydroxychalcone treatments

signifi-277 cantly decreased T2DM-induced elevation of TNF- a level.

278 Adipose tissue is an important endocrine organ that plays a

cru-279 cial role in pathophysiology of T2DM which secretes a number of

280 biologically active adipokines such as adiponectin and TNF- a

281 [47] Adiponectin is adipokines secreted by adipose tissues [48]

282 In our study, adiponectin level showed a significant negative

corre-283 lation with glucose level These results agreed with previous study

284 [49] which reported a negative correlation between adiponectin

285 level and fasting glucose Moreover, Insulin level showed in our

286 results a significant negative correlation with adiponectin level.

287 These results could be explained by insulin resistance status

asso-288 ciated with T2DM, since adipose tissue itself serves as the site of

289 triglyceride storage and free fatty acid/glycerol release in response

290 to changing energy demands Adipose tissue also participates in

291 the regulation of energy homeostasis [50–52] These activities

292 are mediated via adipocytokines such as leptin and adiponectin.

293 Indeed, adiponectin levels is known to correlate positively with

294 insulin sensitivity [48]

295 Oxidative stress plays a critical role in obesity which associated

296 with many conditions such as diabetes [53] Some previous studies

297 have shown an association between adiponectin and antioxidant

298 markers [54,55] There is a positive correlation between

adiponec-299 tin and glutathione [56,57] and our results agreed with this On the

300 contrast, in our data, MDA showed a negative correlation with

adi-301 ponectin level, which agreed with a pervious study [58] These

302 results could be explained by antioxidant, anti-inflammatory and

303 anti-atherogenic properties of adiponectin [59]

304 Interestingly, Hydroxychalcone treatment controlled the

hyper-305 glycemic by increasing adiponectin levels which is regulated by

306 PPAR- c The activation of PPAR- c leads to increase insulin

sensitiv-307 ity, improve glucose metabolism and reduced inflammation [60]

308

In the present study, adiponectin showed a significant positive

309 correlation with PPAR- c , this could be explained by the regulated

310

of adiponectin by PPAR- c [61,62] In the present study, decreased

311 sub-abdominal adipose tissue PPAR- c was observed in diabetic rats

312 when compared to control group, which agreed with a previous study

313

[63] These adverse changes were attenuated by hydroxychalcone

314 treatment PPAR- c activation in type 2 diabetic rats leads to

improve-315 ment of insulin sensitivity [64] Moreover, PPAR- c in adipose tissue

316 increases the glucose transporter and decreases levels of cytokines

317 that induce insulin resistance in liver and muscle In addition,

318 PPAR- c acts directly on multiple tissues to redistribute fatty acids

319 away from muscle and liver and promote their storage in adipose

tis-320 sue, resulting in improved glucose utilization in muscle and liver

321

[65] In this context, our results showed that 2-hydroxychalcone

322 treatment increased PPAR- c levels in sub-abdominal adipose tissue.

323 This effect was associated with significant negative correlation with

324 blood glucose and insulin level These results suggested that

325 2-hydroxychalcone treatment resulted in PPAR- c activation with

326 subsequent improvement of insulin sensitivity.

327 Conclusion

328 The combination of HFD feeding followed by low dose STZ

329 resulted in insulin resistance associated with hyperglycemia and

"

Blood glucose level

Type 2 Diabetes Mellitus High fat diet

Inhibion of PPARγ pathway

Adiponecn

Inﬂammaon and oxidave stress

Insulin resistance

2-hydroxychalcone Treatment 2-hydroxychalcone

Treatment

Lipolysis Free fay acid

Fig 11 Proposed mechanism of action for 2-hydroxychalcone in abrogating T2DM-induced changes in experimental rats

Trang 7

330 reduced serum adiponectin concentration in rats Treatment with

331 2-hydroxychalcone is able to activate PPAR- c and to improve

332 adiponectin level in diabetic rats resulting in antihyperglycemic

333 effect ( Fig 11 ) These results suggested 2-hydroxychalcone as

334 potential therapy for disorders associated with lipid and glucose

335 metabolism.

336 Conflict of interest

337 All authors declare no potential conflict of interest including

338 any financial, personal or other relationships with other people

339 or organizations within that could inappropriately influence, or

340 be perceived to influence, this work.

342 [1] International Diabetes Federation (IDF) IDF diabetes atlas 6th ed Brussels,

343 Belgium: International Diabetes Federation; 2013.

344 [2] Skamagas M, Breen TL, LeRoith D Update on diabetes mellitus: prevention,

345 treatment, and association with oral diseases Oral Dis 2008;14(2):105–14.

346 [3] Maraschin JF Classification of diabetes In: Diabetes: an old disease, a new

347 insight New York: Springer; 2012 p 12–9.

348 [4] Hamza N, Berke B, Cheze C, Agli AN, Robinson P, Gin H, Moore N Prevention of

349 type 2 diabetes induced by high fat diet in the C57BL/6J mouse by two

350 medicinal plants used in traditional treatment of diabetes in the east of

351 Algeria J Ethnopharmacol 2010;128:513–8.

352 [5] Kobayashi M, Iwata M, Haruta T Clinical evaluation of pioglitazone Nippon

353 Rinsho 2000;58:395–400

354 [6] Ryu JK, Lee T, Kim DJ, Park IS, Yoon SM, Lee HS, Song SU, Suh JK Free

radical-355 scavenging activity of Korean red ginseng for erectile dysfunction in

non-356 insulin-dependent diabetes mellitus rats Urology 2005;65:611–5

357 [7] Gupta S, Sharma SB, Bansal SK, Prabhu KM Antihyperglycemic and

358 hypolipidemic activity of aqueous extract of Cassia auriculata L leaves in

359 experimental diabetes J Ethnopharmacol 2009;123:499–503

360 [8] Scheen AJ Pathophysiology of type 2 diabetes Acta Clin Belg 2003;58(6):

362 [9] Hotta K, Funahashi T, Arita Y, Takahashi M, Matuda M, et al Plasma

363 concentration of a novel, adipose-specific protein, adiponectin, in type 2

364 diabetic patients J Clinic Endocrinol Metab 2001;86:1930–5.

365 [10] Renaldi O, Pramono B, Sinorita H, Purnomo LB, Asdie RH, et al

Hypoadiponec-366 tinemia: a risk factor for metabolic syndrome Acta Med Indones 2009;41

368 [11] Diez JJ, Iglesias P The role of the novel adipocyte-derived hormone

369 adiponectin in human disease Eur J Endocrinol 2003;148(3):293–300.

370 [12] Fruebis J, Tsao TS, Javorschi S, Ebbets-Reed D, Erickson MR, et al Proteolytic

371 cleavage product of 30-kDa adipocyte complement-related protein increases

372 fatty acid oxidation in muscle and causes weight loss in mice Proc Natl Acad

373 Sci USA 2001;98(4):2005–10.

374 [13] Sharabi Y, Oron-Herman M, Kamari Y, Avni I, Peleg E, Shabtay Z, et al Effect of

375 PPAR-gamma agonist on adiponectin levels in the metabolic syndrome:

376 lessons from the high fructose fed rat model Am J Hypertens 2007;20

378 [14] Yamamoto Y, Hirose H, Miyashita K, Nishikai K, Saito I, Taniyama M, et al PPAR

379 gamma 2 gene Pro12Ala polymorphism may influence serum level of an

380 adipocytederived protein, adiponectin, in the Japanese population

381 Metabolism 2002;51(11):1407–9

382 [15] Lakota K, Wei J, Carns M, Hinchcliff M, Lee J, Whitfield ML, et al Levels of

383 adiponectin, a marker for PPAR-gamma activity, correlate with skin fibrosis in

384 systemic sclerosis: potential utility as biomarker? Arthritis Res There 2012;14

386 [16] Alam S, Mostahar S Studies of antimicrobial activity of two synthetic, 2,4,6,

387 trioxygenated flavones J Appl Sci 2005.

388 [17] Alan L, Miller ND Altern Med Rev 1996;1(2):103–11.

389 [18] Lim SS, Jung SH, Ji J, Shin KH, Keum SRJ Pharm Pharmacol 2001;53:653–68.

390 [19] Jarvill-Taylor KJ, Anderson RA, Graves DJ A hydroxychalcone derived from

391 cinnamon functions as a mimetic for insulin in 3T3-L1 adipocytes J Am Coll

392 Nutr 2001;20(4):327–36.

393 [20] Lim SS, Jung SH, Ji J, Shin KH, Keum SR Synthesis of flavonoids and their effects

394 on aldose reductase and sorbitol accumulation in streptozotocin-induced

395 diabetic rat tissues J Pharm Pharmacol 2001;53(5):653–68.

396 [21] Jung Sang Hoon, Park Soo Young, Kim-Pak Youngmi, Lee Hong Kyu, Park Kyong

397 Soo, Shin Kuk Hyun, Ohuchi Kazuo, Shin Hyun-Kyung, Keum Sam-Rok, Lim

398 Soon Sung Synthesis and PPAR-gamma ligand-binding activity of the new

399 series of 20-hydroxychalcone and thiazolidinedione derivatives Chem Pharm

400 Bull 2006;54(3):368–70

401 [22] Reed MJ, Meszaros K, Entes LJ, Claypool MD, Pinkett JG, Gadbois TM, et al A

402 new rat model of type 2 diabetes: the fat-fed Metabolism 2000;49(11):

404 [23] Srinivasan K, Viswanad B, Asrat L, Kaul CL, Ramarao P Combination of high-fat

405 diet-fed and low-dose streptozotocin-treated rat: a model for type 2 diabetes

406 and pharmacological screening Pharmacol Res 2005;52:313–20

407 [24] Zhang F, Ye C, Li G, Ding W, Zhou W, Zhu H, et al The rat model of type 2

408 diabetes mellitus and its glycometabolism characters Exp Anim 2003;52:

409 401–7

410 [25] Jayanthi M, Jegatheesan K, Vidhya R, Kanagavalli U Hypoglycemic effect of

2-411 hydroxychalcone on high fructose fed diabetic rat IJPSR 2012;3(2):600–4

412 [26] Hakim ZS, Patel BK, Goyal RK Effects of chronic ramipril treatment in

413 streptozotocin induced diabetic rats Indian J Physiol Pharmacol 1997;41:

414 353–60

415 [27] Rajkumar L, Srinivasan N, Balasubramanian K, Govindarajulu P Increased

416 degradation of dermal collagen in diabetic rats Indian J Exp Biol 1991;

417 29:1081–3

418 [28] Singh DP, Kondepudi KK, Bishoni M, Chopra K Altered monoamine

419 metabolism in high fat diet induced neuropsychiatric changes in rats Jobes

420 Weight Loss Ther 2014;4(4):234–9

421 [29] Kumar A, Singh V Atherogenic dyslipidemia and diabetes mellitus what’s new

422

in the management arena? Vasc Health Risk Manage 2010;6:665–9

423 [30] Vaverkova Dyslipoproteinemia and diabetes mellitus Vnitr Lek 2000;46:

424 532–8

425 [31] Taskinen Controlling lipid levels in diabetes Acta Diabetol 2002;2:29–34

426 [32] Poitout V, Robertson RP Glucolipotoxicity: fuel excess and beta-cell

427 dysfunction Endocr Rev 2008;29(3):351–66

428 [33] Del Prato S Role of glucotoxicity and lipotoxicity in the pathophysiology of

429 Type 2 diabetes mellitus and emerging treatment strategies Diabet Med 2009;

430 26(12):1185–92

431 [34] Cernea S, Dobreanu M Diabetes and beta cell function: from mechanisms to

432 evaluation and clinical implications Biochem Med 2013;23(3):266–80

433 [35] Wang Q, Jin T The role of insulin signaling in the development of beta-cell

434 dysfunction and diabetes Islets 2009;1(2):95–101

435 [36] Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC Beta-cell

436 deficit and increased beta-cell apoptosis in humans with type 2 diabetes

437 Diabetes 2003;52(1):102–10

438 [37] Leahy JL, Hirsch IB, Peterson KA, Schneider D Targeting beta-cell function early

439

in the course of therapy for type 2 diabetes mellitus J Clin Endocrinol Metab

440 2010;95(9):4206–16

441 [38] Widjaja A, Stratton IM, Horn R, Holman RR, Turner R, Brabant G Plasma leptin,

442 obesity and plasma insulin in type 2 diabetic subjects J Clin Endocrinol Metab

443 1997;82(2):654–7

444 [39] Kopecky J, Flachs P, Bardova K, Brauner P, Prazak T, Sponarova J Modulation of

445 lipid metabolism by energy status of adipocytes implications for insulin

446 sensitivity Ann N Y Acad Sci 2002;967:88–101

447 [40] Okutan H, Ozcelik N, Ramazan Yilmaz H, Uz E Effects of caffeic acid phenethyl

448 ester on lipid peroxidation and antioxidant enzymes in diabetic rat heart Clin

449 Biochem 2005;38(2):191–6

450 [41] Park K, Gross M, Lee DH, Holvoet P, Himes JH, Shikany JM, et al Oxidative

451 stress and insulin resistance: the coronary artery risk development in young

452 adults study Diabetes Care 2009;32(7):1302–7

453 [42] Farmer EE, Davoine C Reactive electrophile species Curr Opin Plant Biol

454 2007;10(4):380–6

455 [43] Pasaoglu H, Sancak B, Bukan N Lipid peroxidation and resistance to oxidation in

456 patients with type 2 diabetes mellitus Tohoku J Exp Med 2004;203(3):211–8

457 [44] Biswas M, Chan JY Role of Nrf1 in antioxidant response element-mediated

458 gene Huiression and beyond Toxicol Appl Pharm 2010;244(1):16–20

459 [45] Chen G, Goeddel DV TNF-R1 signaling: a beautiful pathway Science 2002;296

460 (5573):1634–5

461 [46] Chiarelli F, Di Marzio D Peroxisome proliferator-activated receptor-gamma

462 agonists and diabetes: current evidence and future perspectives Vasc Health

463 Risk Manage 2008;4(2):297–304

464 [47] Scheen AJ Pathophysiology of type 2 diabetes Acta Clin Belg 2003;58(6):

465 335–41

466 [48] Morigny P, Houssier M, Mouisel E, Langin D Adipocyte lipolysis and insulin

467 resistance Biochimie 2016;125:259–66

468 [49] Vandana S, Megha K, Amita Y, Anju Role of leptin and adiponectin in

469 gestational diabetes mellitus: a study in a North Indian tertiary care hospital

470 Internet J Med Update 2015;10(1):11–4

471 [50] Maeda N, Shimomura I, Kishida K, Nishizawa H, Matsuda M, Nagaretani H,

472

et al Diet-induced insulin resistance in mice lacking adiponectin/ACRP30 Nat

473 Med 2002;8(7):731–7

474 [51] Yatagaia T, Nagasaka S, Taniguchib A, Fukushimac M, Nakamuraa T, et al

475 Hypoadiponectinemia is associated with visceral fat accumulation and insulin

476 resistance in Japanese men with type 2 diabetes mellitus Metabolism 2003;52

477 (10):1274–8

478 [52] Spiegelman BM, Flier JS Adipogenesis and obesity: rounding out the big

479 picture Cell 1996;87(3):377–89

480 [53] Furukawa S, Fujita T, Shimabukuro M, et al Increased oxidative stress in

481 obesity and its impact on metabolic syndrome J Clin Invest 2004;114

482 (12):1752–61

483 [54] Nakanishi S, Yamane K, Kamei N, Nojima H, Okubo M, Kohno NA Protective

484 effect of adiponectin against oxidative stress in Japanese Americans: the

485 association between adiponectin or leptin and urinary isoprostane

486 Metabolism 2005;54(2):194–9

487 [55] Kaur S, Zilmer K, Kairane C, Kals M, Zilmer M Clear differences in adiponectin

488 level and glutathione redox status revealed in obese and normal-weight

489 patients with psoriasis Br J Dermatol 2008;159(6):1364–7

490 [56] Shin MJ, Lee JH, Jang Y, et al Insulin resistance, adipokines, and oxidative stress

491

in nondiabetic, hypercholesterolemic patients: leptin as an

8-epi-492 prostaglandin F2alpha determinant Metabolism 2006;55(7):918–22

Trang 8

493 [57] Hui X, Lam KS, Vanhoutte PM, Xu A Adiponectin and cardiovascular health: an

494 update Br J Pharmacol 2012;165(3):574–90

495 [58] Yang WS, Lee WJ, Funahashi T, Tanaka S, Matsuzawa Y, et al Weight reduction

496 increases plasma levels of an adipose-derived anti-inflammatory protein,

497 adiponectin J Clin Endocrinol Metab 2001;86(8):3815–9

498 [59] Satoh J, Yagihashi S, Toyota T The possible role of tumor necrosis factor- alpha

499 in diabetic polyneuropathy Exp Diabesity Res 2003;4(2):65–71

500 [60] Kuhad A, Chopra K Attenuation of diabetic nephropathy by tocotrienol:

501 involvement of NF-kB signaling pathway Life Sci 2009;84(9–10):296–301

502 [61] Foryst-Ludwig A, Hartge M, Clemenz M, Sprang C, Hess K, Marx N, Unger T,

503 Kintscher U PPAR gamma activation attenuates T-lymphocyte-dependent

504 inflammation of adipose tissue and development of insulin resistance in obese

505 mice Cardiovasc Diabetol 2010;9:64.

506 [62] Guo N, Woeller CF, Feldon SE, Phipps RP Peroxisome proliferatoractivated

507 receptor gamma ligands inhibit transforming growth factor-beta-induced,

508 hyaluronan-dependent, T cell adhesion to orbital fibroblasts J Biol Chem

509 2011;286(21):18856–67

510 [63] Dong X, Swaminathan S, Bachman LA, Croatt AJ, Nath KA, Doran AC, Meller N,

511 Cutchins A, Deliri H, Slayton RP, Oldham SN, Kim JB, Keller SR, McNamara CA

512 The helix-loop-helix factors Id3 and E47 are novel regulators of adiponectin

513 Circ Res 2008;103(6):624–34

514 [64] Wen-wen, Li-yong Zhong, Xiao-rong Li, Guang Li, Zhao-xia Liu, Jin feng Hu,

515 Nai-hong Chen Hyperglycemia induces the variations of 11b-hydroxysteroid

516 dehydrogenase type 1 and peroxisome proliferator-activated receptor-c

517 expression in hippocampus and hypothalamus of diabetic rats Exp Diabetes

518 Res 2012;107:130

519 [65] Rosen ED, Spiegelman BM PPAR c a nuclear regulator of metabolism,

520 differentiation, and cell growth J Biol Chem 2001;276(41):37731–4

521

Định dạng
Số trang	8
Dung lượng	878,35 KB