Abstract
Tigerinin-1R (Arg–Val–Cys–Ser–Ala–Ile–Pro–Leu–Pro–Ile–Cys–His–NH2), a cationic 12-mer peptide containing a disulfide bond extracted from frog skin secretions, lacks antibacterial activity, but has the ability to stimulate insulin release both in vitro and in vivo. To study the structure–function relationships of tigerinin-1R, we designed and synthesized five analogs, including tigerinin-cyclic, tigerinin-1R-L4, tigerinin-linear, [C3K]tigerinin-1R, and [C11K]tigerinin-1R. Tigerinin-1R promoted insulin secretion in a concentration-dependent manner in INS-1 cells without obvious cytotoxicity. At a concentration of 10−5 M, [C11K]tigerinin-1R exhibited the highest stimulation ability, suggesting that the positive charge at the C-terminus may contribute to the in vitro insulin-releasing activity of tigerinin-1R. Tigerinin-1R peptides stimulated insulin release in INS-1 cells through a universal mechanism that involves mobilization of intracellular calcium without disrupting the cell membrane. In vivo experiments showed that both tigerinin-1R and [C11K]tigerinin-1R improved glucose tolerance in overnight-fasted mice. Due to its structural stability, tigerinin-1R showed superior hypoglycemic activity to [C11K]tigerinin-1R, which suggested a critical role of the disulfide bonds. In addition, we also identified a protective effect of tigerinin-1R peptides in apoptosis induced by oxidative stress. These results further confirm the potential for the development of tigerinin-1R as an anti-diabetic therapeutic agent in clinical practice.
Highlights
Diabetes mellitus (DM) is a group of metabolic diseases characterized by chronic hyperglycemia [1,2]
Another is the use of agents to protect pancreatic β-cells from damage caused by oxidative stress, as the expression of various enzymes of the anti-oxidation defense system is low in type 2 diabetes patients [7,8,9]
The insulinotropic activity of tigerinin-cyclic was lower than that of tigerinin-1R, indicating that positively charged amino acid “tail” outside the disulfide ring structure contributes to the activity of tigerinin-1R. [C3K]tigerinin-1R has a similar structure to [C11K]tigerinin-1R, that is, one cysteine residue participating in the formation of disulfide bond was replaced by a positively charged lysine
Summary
Diabetes mellitus (DM) is a group of metabolic diseases characterized by chronic hyperglycemia [1,2]. Exenatide and liraglutide are two peptide drugs that have been commercialized for clinical treatment, and have been shown to benefit many patients with diabetes [12,13,14,15] In addition to these peptides, skin secretions of anurans as a natural peptide library have recently received increasing attention [16,17]. Several peptides, such as temporin-Vb [18], esculentins-1, esculentins-1B, brevinins-1E, and brevinins-2EC [19], which were isolated as antimicrobial agents, were shown to promote the secretion of insulin in vitro or in vivo Peptides such as tigerinin-1R [20] and alyteserin-2a [21], which are partially deficient in antimicrobial activity, are able to promote the secretion of insulin, showing a potential for use in the treatment to type 2 diabetes. It seems that there is no relation between their insulin-releasing activity and antimicrobial activity
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
