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Structure and Activity Study of IRW on Improving Insulin Sensitivity
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- Author / Creator
- Jiang, Xu
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Metabolic syndrome, a major public health challenge, is identified as a collection of impaired glucose metabolism, central obesity, elevated blood pressure and dyslipidemia. It is estimated that approximately 25% of the world’s population has metabolic syndrome. Insulin resistance, a pathologic state in which target cells fail to respond to normal levels of circulating insulin, is a common feature of most types of metabolic disorders, including type 2 diabetes.
Food protein derived bioactive peptides have attracted extensive attention during the past decades and have great potential for the development of functional foods and/or nutraceuticals for the management and prevention of metabolic syndrome. IRW (Ile-Arg-Trp) was initially identified as an inhibitor of angiotensin converting enzyme (ACE) from egg white protein ovotransferrin. For the past decade, our research group found various activities of IRW. However, the structural requirements of IRW especially which amino acid of IRW is the most important is unknown.
Two dipeptides, IR and RW, three amino acids, I, R and W, as well as eight tripeptides, ARW, IAW, IRA, IWR, RIW, RWI, WIR, and WRI were designed to understand the structure and activity relationship of IRW.
Tumour necrosis factor-α (TNF-α) induced insulin resistant skeletal muscle L6 cell was applied for the study, and IRW was used as the positive control. Among the tested peptides and amino acids, only IRA and IR showed comparable effects as that of IRW: enhanced glucose uptake, improvement in the impaired insulin signaling pathway and increased glucose transporter protein 4 (GLUT4) translocation in TNF-α treated L6 myotubes. This result demonstrated that C-terminal W is not essential to the activity of IRW.
Next, we studied the bioactivity of IR and IRA in a high-fat diet (HFD) induced insulin resistant mouse model, IRW was included as a positive control. Both IRA and IR improved fasting and decreased fasting insulin in HFD induced glucose intolerance mice. While both IRA and IR increased Akt phosphorylation and peroxisome proliferator-activated receptor gamma (PPARγ) abundance in skeletal muscle, only IRA significantly enhanced phosphorylation of 5’ AMP-activated protein kinase (AMPK). Our study also showed a reduced local renin angiotensin system (RAS) activity by peptide treatment, but only IR increased mas-receptor (Mas-R) level in skeletal muscle. Our animal study supports the cell experiment’s conclusion that C-terminal residue W of IRW is not essential for the activity of IRW, but the mechanisms of action by these two peptides are different.
This thesis supports that the C-terminal residue, W, of IRW is dispensable for regulating the activity of IRW. This result help us to understand the structure and activity relationship of IRW. -
- Subjects / Keywords
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- Graduation date
- Fall 2022
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- Type of Item
- Thesis
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- Degree
- Master of Science
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- License
- This thesis is made available by the University of Alberta Library with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.