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FSHW Iglycin improves insulin sensitivity

 Last Update: 2022-11-14
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Introduction

Insulin resistance (IR) refers to the biological response of target tissues and organs of insulin action, such as liver, muscle, adipose tissue, etc.
, to a certain amount of insulin lower than expected
。 Insulin resistance contributes to worsening glucose tolerance in people with normal glucose tolerance and is the leading cause of type 2 diabetes, and a variety of factors have been proposed to explain the mechanisms of insulin resistance, including obesity, inflammation, mitochondrial dysfunction, hyperinsulinemia, lipidosis/hyperlipidemia, genetic background, endoplasmic reticulum stress, aging, oxidative stress, fatty liver, hypoxia, lipometabolism disorders, and pregnancy
.

Soybeans (Glycine max) are one of the most important crops, rich in high-quality protein, cholesterol-free, lower in saturated fat than animal protein, and contain all the essential amino acids
.
Consuming soy has many potential benefits for human health and can reduce many chronic diseases such as obesity, cardiovascular disease, insulin resistance/type 2 diabetes, and cancer
.
These physiological functions are attributed to soy protein, or more commonly functional bioactive peptides
from soy processing.
Soy bioactive peptides are small fragments
of soy protein produced by enzymatic hydrolysis, food processing, fermentation, or gastrointestinal digestion.

Interestingly, several soy peptides have anti-diabetic activity
in different experimental models.
For example, the soy peptides LPYP, IAVPGEVA, and IAVPTGVA increase glucose uptake
by hepatocytes through glucose transporters 1 and 4.
Similarly, soy morphine-5 (YPFVV) reduced glucose and triglyceride levels
in diabetic KKAy mice.
The soybean polypeptide vglycin normalizes fasting blood glucose levels, increases insulin sensitivity, and restores insulin signaling pathways and pancreatic function
in Wistar rats with type 2 diabetes.
In addition, it prevents liver damage, inflammation, and insulin resistance
by inhibiting fat accumulation in the liver.
Therefore, Yinghuan Wu and Yanying Zhao of Southwest University for Nationalities isolated and purified a new polypeptide iglycin from soybean seeds in this study, and explored its regulatory effect
on glucose homeostasis in C57BL/6J mice fed with a high-fat diet.

Results and Discussion

Soy peptide purification was performed using reversed-phase high performance liquid chromatography (RP-HPLC), as shown
in Figure 1.
Three peaks recovered from RP-HPLC were collected and applied to MALDI-TOF-MS analysis
.
The labeled fragment has a molecular weight of 3.
88 kDa and the amino acid sequence is ISCNG VCSPF DIPPC GTPLC RCIPA GLFVG KCRHP YG, similar
to vglycin.
Therefore, the peptide was named iglycin
.
Fig.
1 Insulin sensitivity and glucose homeostasis of iglycin C57BL/6J mice purified by reversed-phase high performance liquid chromatography Fig.
2A shows the animal experimental strategy
.
The high-fat diet significantly increased fasting blood glucose on days 28, 56, 84, 112, and 140 of C57BL/6J mice, as shown
in Figure 2B.
Long-term oral administration of iglycin at doses of 40 μg/(g·d) and 80 μg/(g·d) on days 112 and 140, respectively, had inhibitory effect
on the increase in fasting blood glucose caused by a high-fat diet, respectively.
The fasting blood glucose levels of the Iglycin-treated mice on days 112 and 140 were similar
to those in the control group.
In addition, on day 140, iglycin also reduced fasting blood glucose content in mice compared to the high-fat diet group when treated with 40 μg/(g·d) and 80 μg/(g·d) iglycin for 30 min and 60 min (Figure 2C, D).

At the same time, compared with the high-fat diet group, the serum insulin levels of mice in the insulin-resistant experimental group were also significantly reduced
at 30 min (Fig.
2E, F) at 40 μg/(g·d) and 80 μg/(g·d).
There was no clear difference
in blood glucose levels between the Iglycin treatment and feed groups in the glucose tolerance test and insulin resistance test.
It was shown that iglycin improved insulin sensitivity and glucose homeostasis
in C57BL/6J mice.
Fig.
2 Fasting blood glucose, insulin resistance and oral glucose tolerance in high-fat diet C57BL/6J mice Insulin signaling in adipose tissue is shown in Figure 3A, and insulin signaling in adipose tissue was studied by western blot, and iglycin induced phosphorylation
of IRS1 (Figure 3B) and Akt (Figure 3C).
Insulin stimulates glucose uptake
by producing IRS1 phosphorylation and altered Akt function.
Akt is a major hub in the insulin signaling network, and Akt phosphorylates many intracellular substrates, thereby coordinating the shift of GLUT4 to the plasma membrane, leading to glucose uptake
.
Therefore, iglycin's improved insulin sensitivity may be the result of
insulin signaling reconstruction.

Fig.
3 Phosphorylated glucose uptake of insulin receptor substrate 1 (IRS1) and AKT in epididymal fat depot It is well known that insulin reduces blood sugar levels
by promoting glucose uptake by fat cells and muscle cells.
To elucidate the underlying mechanism of iglycin improving insulin sensitivity and glucose homeostasis, the effect of
iglycin on insulin-stimulated glucose uptake in adipocytes under insulin resistance conditions was studied.
As shown in Figure 4, there is less
glucose remaining in normal adipocyte culture medium compared to dexamethasone-induced insulin-resistant adipocyte culture medium.
While iglycin improved insulin-stimulated glucose uptake in adipocytes under insulin resistant conditions, this may explain iglycin's normalization
of fasting blood glucose levels in C57BL/6J mice.
Fig.
4 Glucose consumption of 3T3L1 adipocytes GLUT4 translocation and insulin signaling activation in adipocytes

Under basal conditions, about 95% of the GLUT4 protein is localized within the cell, while the remaining 5% is located on the cell surface
.
Instead, insulin stimulates the shift of GLUT4 towards the plasma membrane, which leads to glucose uptake
.
Notably, impaired GLUT4 displacement toward the plasma membrane is thought to be one of
the earliest defects leading to insulin resistance and type 2 diabetes.
As shown in Figure 5B, iglycin upregulates the level of GLUT4 on the plasma membrane in a dose-dependent manner, thereby enhancing glucose uptake
by adipocytes.
In addition, iglycin also induces insulin-stimulated IRS1 (Figure 5C) and AKT phosphorylation (Figure 5D)
based on observations in adipose tissue.
It was suggested that improving GLUT4 translocation and insulin signaling activation by iglycin may help re-establish insulin-stimulated glucose uptake
in adipocytes.

Based on the fact that iglycin can reverse insulin resistance in 3T3L1 adipocytes by improving the insulin signaling pathway, it is also suggested that it can also improve oxidative stress, adipocyte apoptosis, and mitochondrial dysfunction (see main text).

Fig.
5 Effect of Iglycin on IRS1, AKT phosphorylation and translocation of insulin-responsive glucose transporter 4 (GLUT4) to the plasma membrane

Conclusion

In this study, a new soybean polypeptide iglycin was isolated and verified that it could activate insulin signaling in adipose tissue, normalize fasting blood glucose levels in high-fat diet C57BL/6J mice, and improve insulin tolerance and oral glucose tolerance
.
In addition, it can reverse the insulin resistance of 3T3L1 adipocytes by improving the insulin signaling pathway, and improve oxidative stress, adipocyte apoptosis and mitochondrial dysfunction
.

About the first author

Wu Yinghuan, female, master student of Southwest University for Nationalities, mainly engaged in molecular biology research
.

About the corresponding author

Zhao Yanying, female, Ph.
D.
(post), professor of Southwest University for Nationalities, master tutor, young and middle-aged talents of the State Ethnic Affairs Commission, director of
Sichuan Society of Biochemistry and Molecular Biology.
His research area is animal biochemistry, focusing on the effects
of biologically active substances (proteins, polysaccharides, etc.
) on human and animal health.
In recent years, he has presided over 1 National Natural Science Foundation of China, 1 Sichuan Outstanding Youth Fund project, and 1 young and middle-aged talent project of the Ethnic Affairs Committee
.
He has researched a number of national, provincial and ministerial projects
.

Novel soybean peptide iglycin ameliorates insulin resistance of high-fat diet fed C57BL/6J mice and differentiated 3T3L1 adipocytes with improvement of insulin signaling and mitochondrial function

Yinghuan Wu^a, Ran Zhao^b, Minxia Li^b, Huiyun Li^b, Zhengwang Chen^c, Yanying Zhao^a,*

^a Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization of Ministry of Education, Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization of Sichuan Province, College of Life Science and Technology, Southwest Minzu University, Chengdu 610041, China

^b Shandong Tianheng Inspection Co.
, Ltd.
, Heze 274000, China

^c Key Laboratory of Molecular Biophysics of Ministry of Education, School of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China

*Corresponding author.

E-mail address: biozyy@163.
com

Abstract

Soy consumption has been associated with potential health benefits in reducing chronic diseases.
These physiological functions have been attributed to soy proteins or more commonly to bioactive peptides.
Thus, more studies are required to identify these bioactive peptides, and elucidate their biological mechanisms of action.
In the present study, a novel peptide iglycin was purified from soybean seeds with a molecular mass of 3.
88 kDa.
Thereafter, iglycin reduced fasting blood glucose and restored insulin sensitivity of C57BL/6J mice on a high-fat diet with increased phosphorylation of insulin receptor substrate 1 (IRS1) and AKT in adipose tissue.
Furthermore, it improved glucose uptake, induced translocation of intracellular GLUT4 to plasma membrane and activation of insulin signaling in adipocytes under insulin-resistant condition .
In addition, it decreased reactive oxygen species production, lipid peroxidation and inhibited adipocyte apoptosis with improved mitochondrial function as evidenced by up-regulation of succinate dehydrogenase activity, mitochondrial membrane potential and intracellular ATP store.
These data suggested that iglycin ameliorated insulin resistance via activation of insulin signaling, which was associated with inhibition of oxidative stress, adipocyte apoptosis, and improvement of mitochondrial function.

Reference:

WU Y H, ZHAO R, LI M X, et al.
Novel soybean peptide iglycin ameliorates insulin resistance of high-fat diet fed C57BL/6J mice and differentiated 3T3L1 adipocytes with improvement of insulin signaling and mitochondrial function[J].
Food Science and Human Wellness, 2022, 11(6): 1565-1572.
DOI:10.
1016/j.
fshw.
2022.
06.
014.

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