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Anti-diabetic actions of esculentin-2CHa(1–30) and its stable analogues in a diet-induced model of obesity-diabetes

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Abstract

Actions of esculentin-2CHa(1–30) (GFSSIFRGVAKFASKGLGKDLAKLGVDLVA) and its analogues, ([d-Arg7, d-Lys15, d-Lys23]-esculentin-2CHa(1–30) and [Lys15-octanoate]-esculentin-2CHa(1–30), were evaluated in high-fat fed NIH Swiss mice with impaired glucose tolerance and insulin resistance. Twice-daily i.p. administration of the esculentin-2CHa(1–30) peptides (75 nmol/kg body weight) or exendin-4 (25 nmol/kg) for 28 days reduced body weight, without altering cumulative energy intake. All peptides reduced blood glucose levels by 6–12 mmol/l concomitant with lower plasma insulin levels, with significance evident from day 6. All peptides improved glucose tolerance, insulin sensitivity, blood glucose profile over 24 h and decreased HbA1c to a similar extent as exendin-4. The peptides also reduced high fat diet-induced increases in plasma GLP-1 and glucagon. None of the peptides altered bone mineral density/content or lean mass but decreased fat mass. Islets isolated from peptide-treated mice exhibited improved glucose-, alanine- and GLP-1-stimulated insulin secretion. Islet morphometric analyses revealed that exendin-4 and the esculentin-2CHa(1–30) peptides significantly reduced islet, beta and alpha cell areas compared to high-fat controls. Esculentin-2CHa(1–30) peptides markedly reduced high fat diet-induced increase in beta cell proliferation and apoptosis. Peptide treatments had beneficial effects on expression of islet genes (Ins1, Slc2a2, Pdx1) and skeletal muscle genes involved in insulin action (Slc2a4, Pdk1, Irs1, Akt1). High-fat diet significantly increased LDL cholesterol which was reduced by the acylated esculentin-2CHa(1–30) analogue. Peptide treatments did not alter circulating concentrations of amylase and marker enzymes of liver function, indicating a lack of toxicity. These data indicate that esculentin-2CHa(1–30) and its analogues may be useful for improvement of blood glucose control and weight loss in type 2 diabetes.

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Author notes

  1. Yasser H. A. Abdel-Wahab

    Present address: Cell Growth and Metabolism Section, Diabetes, Endocrinology, and Obesity Branch, NIDDK, National Institutes of Health, Bethesda, MD, 20892, USA

  2. Opeolu O. Ojo

    Present address: School of Health, Sport and Bioscience, University of East London, Stratford Campus, London, E15 4LZ, UK

Authors and Affiliations

  1. SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, BT52 1SA, UK

    Srividya Vasu, Opeolu O. Ojo, R. Charlotte Moffett, J. Michael Conlon, Peter R. Flatt & Yasser H. A. Abdel-Wahab

  2. Cell Growth and Metabolism Section, Diabetes, Endocrinology, and Obesity Branch, NIDDK, National Institutes of Health, Bethesda, MD, 20892, USA

    Srividya Vasu

Authors
  1. Srividya Vasu
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  2. Opeolu O. Ojo
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  3. R. Charlotte Moffett
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  4. J. Michael Conlon
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  5. Peter R. Flatt
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  6. Yasser H. A. Abdel-Wahab
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Contributions

SV and RCM performed the experiments, analysed data and prepared the manuscript. OO, YHAA, JMC and PRF conceived and designed the study and prepared the manuscript.

Corresponding author

Correspondence to Srividya Vasu.

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Conflict of interest

The authors declare that they have no conflict of interest. Funding for this study was provided by a proof of concept project grant from Invest NI (Grant Number POC 418) and project grant from Diabetes UK. Ulster University has patent filings in the area of frog skin peptides and diabetes.

Research involving humans and/or animals

All procedures performed in studies involving animals were in accordance with UK Animals (Scientific Procedures) Act 1986 and ‘Principles of laboratory animal care’ (NIH publication no. 86–23, revised 1985). This article does not contain any studies with human participants performed by any of the authors.

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Handling Editor: T. Langer.

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Vasu, S., Ojo, O.O., Moffett, R.C. et al. Anti-diabetic actions of esculentin-2CHa(1–30) and its stable analogues in a diet-induced model of obesity-diabetes. Amino Acids 49, 1705–1717 (2017). https://doi.org/10.1007/s00726-017-2469-3

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  • DOI: https://doi.org/10.1007/s00726-017-2469-3

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