Hypoglycemic and hypolipidemic effects of glucomannan extracted

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Hypoglycemic and hypolipidemic effects of glucomannan extracted from konjac on type 2 diabetic rats Haihong Chen, Qixing Nie, Jielun Hu, Xiaojun Huang, Ke Zhang, Shijie Pan, and Shao-Ping Nie J. Agric. Food Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jafc.9b01192 • Publication Date (Web): 09 Apr 2019 Downloaded from http://pubs.acs.org on April 10, 2019

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Hypoglycemic and hypolipidemic effects of glucomannan extracted from konjac on type 2 diabetic rats

Haihong Chen, Qixing Nie, Jielun Hu, Xiaojun Huang, Ke Zhang, Shijie Pan, Shaoping Nie* State Key Laboratory of Food Science and Technology, China-Canada Joint Lab of Food Science and Technology (Nanchang), Nanchang University, 235 Nanjing East Road, Nanchang 330047, China

* Corresponding author: Professor Shao-Ping Nie, PhD Tel & Fax: +86-791-88304452 (S. P. NIE) E-mail address: [email protected]

1

1

SKGM, soluble glucomannan from konjac, PCA, principal component analysis,

PLS-DA, partial least-square-discrimination analysis, VIP, variable importance in the projection, PC, polysaccharide control.

1


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Abstract: Diabetes and its complications is one of the most concerned metabolic

2

diseases

3

Hypoglycemic and hypolipidemic effects of glucomannan extracted from konjac on

4

high-fat diet and streptozocin-induced type 2 diabetic rats were evaluated in this study.

5

Administration of konjac glucomannan significantly decreased the levels of fasting

6

blood glucose, serum insulin, glucagon-like peptide 1 and glycated serum protein. The

7

concentrations of serum lipids including total cholesterol, triacylglycerols,

8

low-density lipoprotein cholesterol, and non-esterified fatty acid were notably reduced

9

by konjac glucomannan treated. In addition, antioxidant capacity, pancreatic injury

10

and adipose cell hypertrophy were ameliorated by konjac glucomannan administration

11

in type 2 diabetic rats. Besides, UPLC-QTOF MS based lipidomics analysis was used

12

to explore the improvement of lipid metabolic by konjac glucomannan treatment. The

13

disturbance of glycerolipids (diacylglycerol, monoacylglycerol, and triacylglycerol),

14

fatty

15

sphingomyelin) and glycerophospholipids (phosphatidylcholines) metabolism were

16

attenuated for the glucomannan treatment. This study provided a new insight for

17

investigating the anti-diabetic effects of konjac glucomannan and suggest that konjac

18

glucomannan may be a promising nutraceutical for treating type 2 diabetes.

19

Keywords: type 2 diabetes, konjac glucomannan, hypoglycemic, hypolipidemic,

20

lipidomics.

in

acyls

the

worldwide

(acylcarnitine,

and

hydroxyl

threaten

fatty

acid),

21 2


human

health

sphingolipids

severely.

(ceramide,


22

Introduction

23

Diabetes is one of the most common chronic metabolic disease characterized by

24

disturbance of glucose, lipid metabolism and insulin efficacy, eventually the disorder

25

of host systemic homeostasis including hyperlipidemia, hyperglycemia, etc. 1, 2

26

Nowadays, lots of anti-diabetic drugs including biguanides, a-glucosidase

27

inhibitor, and thiazolidinediones, have been synthesized for the pharmacotherapy of

28

diabetes. However, the side-effects such as flatulence, discomfort, as well as diarrhea

29

occurred in patients for the long-term medication.3 The use of phytochemicals (e.g.,

30

polysaccharide, polyphenol) from natural herbs either as pharmaceutical or dietary

31

supplements are being explored. Amounts of plant polysaccharides have been

32

identified to have anti-diabetic functions with low side-effects through various

33

mechanisms, including ameliorating β-cell dysfunctions, decreasing α-glucosidase

34

activities, increasing insulin efficacy, balancing hepatic glucose metabolism,

35

etc.4,5,6,7,8

36

Glucomannan is one type of polysaccharides belongs to the mannans family

37

possessed structural and storage functions in plants. Glucomannan obtained from

38

tuber, bulb, softwood, and root of many herbs are composed of a linear chain of

39

mixed residues of -1, 4 linked D-mannose and D-glucose monomers arranged in

40

blocks.9,10,11 Previous studies reported that glucomannan had different bioactivities

41

including controlling cholesterol, maintaining the body weight, preventing cancer,

42

promoting wound healing, relieving constipation, regulating immunity and managing 3


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diabetes, etc.12 Among which konjac glucomannan is one of the most widely studied

44

glucomannan, with β-(1→4) linked D-glucosyl and D-mannosyl residues as the main

45

chain with branches through β-(1→6)-glucosyl units.13,14,15 Nowadays, it has been

46

used as a food additive and dietary supplement primarily for the management of

47

obesity, constipation, and indigestion,16,17 but the hypoglycemic and hypolipidemic

48

effects of glucomannan extracted from konjac on type 2 diabetes was rarely reported.

49

Lipids dysregulation was closely related to the onset and development of type 2

50

diabetes. Disorder of lipid metabolism closely related to the inflammation and

51

oxidative stress that significantly associated with the risk of type 2 diabetes. In recent

52

decades, lipidomics was becoming more and more popular for it efficiently increasing

53

the prediction of future disease risk. In contrast to explore total cholesterol, total

54

triglyceride or lipoproteins (LDL-c, HDL-c, etc.), whole serum lipidomics analysis

55

explores a more comprehensive view of lipid metabolism and could provide a detailed

56

picture of the disorders of lipid metabolism related to type 2 diabetes.18

57

Accordingly, we adopted the biochemical analysis and lipidomics methods to

58

explore the anti-hyperglycemia and anti-hyperlipoidemia activities of the konjac

59

glucomannan on a high-fat diet and streptozocin (HFD-STZ)-induced type 2 diabetic

60

rats.

61

Materials and methods

62

Glucomannan preparation

4



63

The fresh tuber of herbaceous perennial konjac was purchased from Sichuan yi

64

planting konjac plant co., Ltd. (Sichuan China). Soluble glucomannan from konjac

65

(SKGM) was extracted and purified according to our previous method.19

66

Animals and experimental design

67

Seven weeks old male inbred Wistar rat (200 ± 20 g) was purchased from Vital

68

River Laboratories (VRL, Beijing, China). The animal experiment was performed

69

according to our previous method.20 After the diabetic model was established (fasting

70

blood glucose (FBG) concentration more than 16.7 mmol/L), all the rats were grouped

71

into normal control group (NC), polysaccharides control group (treated with 80 mg/kg

72

SKGM, PC) and diabetic groups. Diabetic group was randomly grouped into 5 groups

73

(Figure 1A): untreated diabetic group (Model); metformin treated group (Met); 40, 80

74

and 160 mg/kg SKGM treatment groups (SKGM-40, SKGM-80 and SKGM-160 in

75

respectively).

76

OGTT test

77

Oral glucose tolerance test (OGTT) and the calculated areas under the curve

78

(AUC) were conducted according to our previous method after 4 weeks of SKGM or

79

Met treatment.21

80

Measurement of serum BG, GSP, GLP-1, insulin level, and HOMA-IR

81

Determination of serum BG, glycated serum protein (GSP), insulin, as well as

82

the calculated of homeostatic measurement assessment insulin resistance (HOMA-IR) 5


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was based on our previous method.21 Glucagon-like peptide1 (GLP-1) was measured

84

according to commercial available kits (Nanjing Jiancheng Bioengineering Institute,

85

Jiangsu, China).

86

Determination of serum lipid and NEFA

87

Concentrations of serum lipid parameters including total cholesterol (TC),

88

triacylglycerols (TG), high-density lipoprotein cholesterol (HDL-c) and low-density

89

lipoprotein cholesterol (LDL-c), as well as levels of non-esterified fatty acid (NEFA)

90

were determined according to our previous methods.21

91

Evaluation of oxidative stress

92

Level of serum malondialdehyde (MDA) was determined following the

93

instructions on the kits. MDA kit was obtained from Nanjing Jiancheng

94

Bioengineering Institute (Nanjing, China). Superoxide dismutase (SOD) and 2,

95

2'-azino-bis (3-ethylbenzothiazoline -6- sulphonic acid) (ABTS) kits were purchased

96

from Beyotime (Shanghai, China) and determined following the instructions.

97

Histopathological analysis

98 99

Histopathological analysis of pancreas and fat samples was performed according to our previous method.21

100

Serum lipidomics analysis

101

Sample preparation

6



102

For serum lipid extraction, 8 replicate serum samples (25 μL for each) were

103

extracted in 10 mL tubes by addition of the following solvents: 975 μL H2O (sit on ice

104

for 10 min), 2.0 mL MeOH, 0.9 mL CH2Cl2. Then, samples were vortex for 1 min and

105

make sure the mixture has a monophasic at this stage. Mixture sits on ice for 30 min.

106

Add 1 mL H2O and 0.9 mL CH2Cl2, invert tubes 10 times. Centrifuge at 1200 rpm for

107

10 min, collect lower layer and put into a fresh tube. Repeated the extraction by

108

adding 2 mL CH2Cl2 to the remains in extraction tube, collect lower layer and add to

109

the first extract. Evaporate solvent under a stream of nitrogen. Finally, resuspended

110

lipids in 50:50 (MeOH: CH2Cl2) containing 5 mM ammonium.

111

UPLC Q-TOF/MS analysis

112

Liquid chromatographic (LC) separation and MS/MS2 data acquisition were

113

based on our previous method.21

114

Statistical analysis

115

Statistics analysis was performed by using SPSS 17.0 and the pictures were

116

drawn via GraphPad Prism 6.01 (GraphPad, American). Homogeneous subsets was

117

evaluated using Turkey HSD test, p < 0.05 was considered as significant.

118

For lipidomics analysis, LipidView (AB SCIEX) and MS DIAL 2.94 software

119

were used for data processing, coupling with MS and MS/MS spectra lipidblast for

120

lipids identification. Multivariate and univariate analysis were performed by using

121

MetaboAnalyst 4.0 (http://www.metaboanalyst.ca.). 7


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Results

123

Effects of SKGM on body weight, food intake and water consumption in diabetic

124

rats

125

The changes of body weight was presented in Figure 1B, there was no

126

significant difference among all of the groups before STZ injection (p > 0.05), but rats

127

showed gradual emaciation by injection of STZ, (body weights were decreased 30-50

128

g after STZ injection for 3 days, Figure 1B). Besides, during the whole of the

129

experiment period, the average body weight of NC group showed steadily increased

130

(from 399.67 ± 31.74 g to 483.50 ± 29.03 g) whereas the model group was showed

131

the opposite trend (from 399.33 ± 16.59 g to 288.70 ± 14.53 g). Compared with the

132

NC group, increased food intake and water consumption were observed in the model

133

group (Table 1). These symptoms were alleviated by SKGM treatment. On the one

134

hand, the body weight loss was attenuated by SKGM treatment, and the body weight

135

of SKGM treated groups were increased at the secondary week (Figure 1B). On the

136

other hand, SKGM treatment significantly decreased food intake and water

137

consumption compared with untreated diabetic rats (Table 1). Furthermore,

138

SKGM-80 group exhibited more efficient effects on body weight attenuation and

139

polydipsia symptom alleviation on type 2 diabetic rats.

140

Results of OGTT

141

OGTT and AUC were used to evaluate the glucose response to SKGM treatment.

142

Compared with the NC group rats, a higher concentration of blood glucose was 8



143

observed in diabetic rats from 0 min up to 180 min (Figure 1C), suggesting the

144

damaged glucose tolerance in diabetes.22 The decreased blood glucose was observed

145

in SKGM treated group in the OGTT test (Figure 1C). The calculated AUC values in

146

model group (96.16 ± 7.08 mmol L−1·h) was notably higher than that of the NC group

147

(20.08 ± 1.26 mmol L−1·h) (p < 0.0001, Figure 1D). SKGM treatment showed a

148

significant reduction in AUC compared with model group, especially in the

149

SKGM-80 treated group (p < 0.001).

150

Effects of SKGM on BG, GSP, GLP-1, insulin level, and HOMA-IR

151

Serum BG, GSP, GLP-1 and insulin levels in each group was determined to

152

evaluate the hypoglycemic effects of SKGM (Figure 2). The concentration of BG in

153

model group (38.20 ± 4.03 mmol/L) was notably higher than that of the NC group

154

(4.65 ± 0.59 mmol/L), and SKGM treatment significantly decreased the level of

155

serum BG (Figure 2A). Compared the three SKGM treatment groups, SKGM-80

156

treated group exhibited the lowest glucose level, which was 17.96 ± 3.73 mmol/L.

157

GSP is an effective indicator of the blood glucose level in the first two weeks, which

158

was significantly reduced by SKGM treatment (2.21 ± 0.23, 2.02 ± 0.16, 2.27 ± 0.21

159

mmol/L in SKGM-40, SKGM-80 and SKGM-160 group, respectively) compared with

160

model group (5.508 ±2.024 mmol/L) (p < 0.0001) (Figure 2B). The concentration of

161

GLP-1 in model group was lower than that of the NC and glucomannan treated groups

162

(Figure 2C). Insulin in this study was remarkably enhanced (283.03%) in model

163

group (compared with the NC group) (Figure 2D), suggesting insulin resistance. 9


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Compared with the model group, SKGM administration resulted in 54.39%, 61.03%

165

and 56.61% reductions of insulin levels in SKGM-40, SKGM-80 and SKGM-160

166

groups respectively (p < 0.0001). HOMA-IR is a commonly used parameter of insulin

167

resistance in diabetes studies.23 In this study, severe insulin resistance was observed in

168

the model group rats, which HOMA-IR was (181.49 ± 24.00), significantly higher

169

than that of the NC group (7.80 ± 2.03) (Figure 2E). HOMA-IR in SKGM groups

170

were notably lower than that of the model group (Figure 2E).

171

Effects of SKGM on serum lipid function parameters and NEFA

172

Concentrations of NEFA, TC, TG, HDL-c, and LDL-c were measured to

173

investigate the hypolipidemic effects of SKGM on type 2 diabetic rats. Compared

174

with the NC group, a significant increase in serum NEFA levels was observed in

175

model group (1.85 ± 0.26, 0.82 ± 0.26 mmol/L in the model and NC group

176

respectively, Table 2). A remarkable decrease of NEFA level in serum were observed

177

in SKGM treatment groups which were 0.96 ± 0.12, 0.82 ± 0.20, 0.86 ± 0.16 mmol/L

178

in SKGM-40, 80 and160 treated group, respectively. In addition, a significant

179

increase of serum TC, TG, LDL-c, and a decrease of HDL-c were observed in the

180

model group compared with the NC group (Table 2). However, treatment with

181

SKGM significantly decrease the concentrations of serum TC, TG, LDL-c, and

182

increase the levels of HDL-c in diabetic rats. Among all of these SKGM treated

183

groups, SKGM-80 group exhibited the best hypolipidemic effects in type 2 diabetic

184

rats. 10



185

Evaluation of oxidative stress

186

In this study, SOD, ABTS, and MDA were determined to evaluate the

187

antioxidant effects of SKGM on type 2 diabetic rats. Enzymatic activity of SOD in

188

model group was significantly lower than that of NC and SKGM treatment groups

189

(Figure 3A). Compared with the NC group, a decreased concentration of ABTS was

190

observed in the model group. SKGM treatment notably increasing the level of ABTS

191

in diabetic rats (Figure 3B). Furthermore, compared with the NC group, a

192

significantly increased level of MDA in model group was observed (175.40 ± 33.45,

193

25.38 ± 12.95 µmol/L in the model, NC group respectively). However, it was

194

decreased by the SKGM treatment (63.69 ± 27.54, 40.95 ± 17.05, 54.20 ± 15.04

195

µmol/L, in SKGM-40, SKGM-80 and SKGM-160 group respectively (Figure 3C).

196

Histological analysis

197

STZ injection directly caused pancreatic β-cell toxicity, thus the necrotic islets

198

with the destruction of cell populations were exhibited in diabetic rats, and

199

intracellular degranulation and inflammation also occurred at the cellular level.24 On

200

the contrary, the islets structure of normal rats were integrity, pancreatic β-cell was

201

clearly visible. And SKGM treatment attenuated the islets necrotic and pancreatic

202

β-cell damage visibly (Figure 4A).

203

Light photomicrographs of fat tissue sections from different experimental groups

204

were displayed in Figure 4B. The fat cells of NC and PC group were evenly arranged

205

in size, while the model group rats exhibited serious cellular proliferation and 11


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inflammatory infiltration. Increased not the uniform size of visceral adipocytes cells,

207

glycoprotein deposits on the vessel and capillary basilar membrane, etc. were

208

observed in model group rats (Figure 4B). The symptom was significantly improved

209

for the SKGM treatment, adipose tissue cells arranged in size and slightly cellular

210

proliferation or inflammatory infiltration were observed in SKGM treated groups

211

(Figure 4B).

212

Serum lipidomics analysis

213

UPLC/Q-TOF-MS based method was carried out to explore the lipid metabolic

214

fingerprints of serum samples. 180 and 275 lipid species were identified in the

215

positive and negative model, respectively. These lipids are mainly belonging to fatty

216

esters, sphingolipids, glycerophospholipids, and glycerolipids (classified according to

217

LipidMaps, http://www.lipidmaps.org/). Firstly, PLS-DA and t-test analysis were

218

performed to explore the potential lipids that closely associated with lipid metabolism

219

disorder on type 2 diabetes (PLS-DA for model and NC group). A total of 40 lipids (6

220

fatty acyls, 7 sphingolipids, 2 glycerophospholipids, and 25 glycerolipids) were

221

identified with VIP > 1, p < 0.05 and FDR < 0.05, the detailed information of these

222

lipids were shown in Table 3 and Figure 5A. Results showed that most of the

223

unsaturated triglycerides concentration was decreased (63%), while all of the

224

saturated triglycerides were increased. All of the acylcarnitine (Acar, belongs to fatty

225

acyls) were increased, while fatty acid ester of hydroxyl fatty acid (FAHFA, belongs

226

to

fatty

acyls)

was

decreased.

Level

of

glycerophospholipids

12


including


227

phosphatidylcholines 36:4 (PC 18:2-18:2), phosphatidylcholines 36:5 (PC 16:1-20:4)

228

were increased. Sphingolipids including ceramide alpha-hydroxy fatty acid-

229

phytosphingosine t37:3 (Cer-AP t17:1/20:2), ceramide non-hydroxy fatty acid-

230

dihydrosphingosine d34:2 (Cer-NDS d16:0/18:2), sphingomyelins d30:0 (SM

231

d14:0/16:0), sphingomyelins (d40:2; SM d14:0/26:2) were increased, while ceramide

232

beta-hydroxy fatty acid-dihydrosphingosine d47:7 (Cer-BS d16:3/31:4), ceramide

233

non-hydroxy fatty acid-sphingosine d31:4 (Cer-NS d15:3/16:1), ceramide non-

234

hydroxy fatty acid-sphingosine d39:4 (Cer-NS d15:3/24:1) were decreased Table 3

235

and Figure 5A. Concentration comparison of the individual lipids was performed and

236

displayed in Figure 6I.

237

To explore the effects of SKGM treatment on lipids metabolism. PCA was firstly

238

carried out to characterize the clustering features among the model, NC, Met, and

239

SKGM treated groups (Figure 5B and C). A clear separation was exhibited among

240

the model, NC, and SKGM treatment groups and it was in agreement with the results

241

of clustering analysis (Figure S1 C and D were clustering analysis in the positive and

242

negative model, respectively). The separation trend indicated that diabetes notably

243

altered the pattern of endogenous serum lipids metabolism in diabetic rats and SKGM

244

treatment could change the perturbed lipid metabolism. The average intensity of fatty

245

acyls, sphingolipids, glycerophospholipids, sterol lipids and glycerolipids (classified

246

according to LipidMaps, http://www.lipidmaps.org/) were calculated to explore the

247

effects of SKGM treatment on type 2 diabetic rats serum lipid metabolism. Figure 5I 13


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showed that total amounts of fatty acyls, sphingolipids, glycerophospholipids, sterol

249

lipids, and glycerolipids were notably increased in model group compared with NC,

250

Met and SKGM treatment groups (p < 0.0001). Furthermore, expected fatty acid ester

251

of hydroxyl fatty acid (FAHFA) all the other lipids including acylcarnitine (Acar),

252

ceramide

253

phosphatidylcholine

254

monoacylglycerol (MAG), triacylglycerol (TAG) were significantly increased

255

(Figure 5D, Figure 5E, Figure 5F, Figure 5G, Figure 5H). However, SKGM

256

treatment could balance the disturbance of type 2 diabetic rats serum lipid metabolism,

257

especially of the 80 mg/kg SKGM treatment (Figure 5D, Figure 5E, Figure 5F,

258

Figure 5G, Figure 5H).

259

Discussion

(Cer),

sphingomyelin (PC)

(SM),

cholesteryl

ester

lysophosphatidylcholine (CE),

diacylglycerol

(LPC), (DAG),

260

Diabetes and its complications are becoming more and more popular worldwide

261

and seriously influence the quality of human life. It is a common chronic metabolic

262

disorder characterized by dysglycemia and dyslipidemia, etc. Hyperglycemia and

263

hyperlipidemia always leading to a series of the health problem, including eyes,

264

kidney, heart and hepatic dysfunction. So blood glucose and lipids control were the

265

most vital problems in diabetes treatment and prevention.25 In this study, the

266

anti-hyperglycemic, anti-hyperlipidemic effects of glucomannan extracted from

267

konjac on HFD-STZ induced type 2 diabetes were evaluated.

268

Generally, gradual emaciation was a problem which troubled the diabetic 14



269

patients seriously. STZ-induced diabetic rats were also accompanied with gradually

270

body weight loss and serious polydipsia symptoms.20 Disturbance of lipid and glucose

271

metabolism results in the excessive catabolism of nutrients may be a contributing

272

factor to gradual emaciation in diabetes.26 In this study, we found that SKGM

273

treatment could maintain the body weight (Figure 1B), which may attribute to the

274

amelioration of insulin sensitivity and glycemic regulation in diabetic rats.2 In the

275

present study, levels of serum FBG and insulin were determined, as well as the

276

HOMA-IR was calculated. Compared with the model group, an observably lower

277

levels of BG and deceased of HOMA-IR were obtained by SKGM treatment. The

278

concentration of GSP, an effective indicator of glycemic control, was also decreased

279

by the SKGM and metformin treatments (compared with the model group), which

280

was in agreement with the results of FBG. Furthermore, the pancreas is the most

281

important organs for the regulation of blood glucose. In this study, histopathological

282

observation showed an obviously lighten of lesions in pancreatic tissues were

283

obtained in diabetic rats treated with SKGM, which may indicate that maintain the

284

pancreatic structure integrity from damage was one of the mechanisms for SKGM

285

regulating the glucose homeostasis in type 2 diabetic rats (Figure 4A).

286

In addition, persistent hyperglycemia would induce chronic oxidative stress

287

through glyceraldehyde autoxidation, oxidative phosphorylation, hexosamine

288

metabolism, protein kinase C activation, methylglyoxal and sorbitol formation

289

pathways (lead to ROS formation).27 The increased level of ROS would cause cell 15


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structure damage and dysfunction, subsequently leading to tissue injury.27

291

Furthermore, ROS was especially relevant and dangerous for islets, which was one of

292

the organs that have the lowest intrinsic antioxidant capacity.27 CAT, GSH-Px and

293

SOD were important non-enzymatic and enzymatic antioxidants in vivo. An increased

294

level of ABTS, SOD and decreased the level of MDA was observed by SKGM

295

treatment, suggesting the increased antioxidant capacity on attenuation of lipids

296

peroxidation and beta islets injury.

297

Dyslipidemia, characterized by abnormal levels of lipids (eg: TG, TC and/or fat

298

phospholipids) in the blood.28 Dyslipidemia characterized by elevated of lipids had

299

been reported to be associated with insulin resistance and oxidant stress-induced

300

tissue injury on type 2 diabetes.29,30 Pearson correlation analysis showed lipid

301

parameters including TC, TG, LDL-c and NEFA were positively correlated with

302

insulin, HOMA-IR and MDA (p 1, p < 0.05 and FDR < 0.05 (Table 3). Fatty acyls including FAHFAs and

313

Acars were identified closely associated with lipid metabolism disorder in type 2

314

diabetes rats. FAHFAs has been reported to have metabolic benefits and

315

anti-inflammatory effects and could be synthesized in both humans, animals, and

316

plants.31 Serum FAHFAs levels were reported to closely associated with insulin

317

resistance, and oral administration with FAHFAs could improve glucose tolerance

318

and stimulate insulin and GLP-1 secretion for appetite control.31 Pearson correlation

319

analysis showed FAHFAs were negatively associated with HOMA-IR but positively

320

associated with GLP-1 (Figure 6B). Compared with model group, a significantly (p

Hypoglycemic and hypolipidemic effects of glucomannan extracted

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