Amino Acids

, Volume 50, Issue 6, pp 723–734 | Cite as

Insulinotropic, glucose-lowering, and beta-cell anti-apoptotic actions of peptides related to esculentin-1a(1-21).NH2

  • Vishal Musale
  • Yasser H. A. Abdel-Wahab
  • Peter R. Flatt
  • J. Michael ConlonEmail author
  • Maria Luisa Mangoni
Original Article


Long-standing Type 2 diabetes is associated with loss of both β‐cell function and β‐cell mass. Peptides derived from the frog-skin host-defense peptide esculentin-1 have been shown to exhibit potent, broad-spectrum antimicrobial activity. The aim of the present study is to determine whether such peptides also show insulinotropic and β-cell protective activities. Esculentin-1a(1-21).NH2, esculentin-1b(1-18).NH2, and esculentin-1a(1-14).NH2 produced concentration-dependent stimulations of insulin release from BRIN-BD11 rat clonal β-cells, 1.1B4 human-derived pancreatic β-cells, and isolated mouse islets with no cytotoxicity at concentrations of up to 3 μM. The mechanism of insulinotropic action involved membrane depolarization and an increase in intracellular Ca2+ concentrations. The analogue [D-Lys14, D-Ser17]esculentin-1a(1-21).NH2 (Esc(1-21)-1c) was less potent in vitro than the all L-amino acid containing peptides and esculentin-1a(9-21) was inactive indicating that helicity is an important determinant of insulinotropic activity. However, intraperitoneal injection of Esc(1-21)-1c (75 nmol/kg body weight) together with a glucose load (18 mmol/kg body weight) in C57BL6 mice improved glucose tolerance with a concomitant increase in insulin secretion, whereas administration of esculentin-1a(1-21).NH2, esculentin-1b(1-18).NH2, and esculentin-1a(1-14) was without significant effect on plasma glucose levels. Esc(1-21)-1c (1 µM) protected BRIN-BD11 cells against cytokine-induced apoptosis (P < 0.01) and augmented proliferation of the cells (P < 0.01) to a similar extent as glucagon-like peptide-1. The data demonstrate that the multifunctional peptide Esc(1-21)-1c, as well as showing therapeutic potential as an anti-infective and wound-healing agent, may constitute a template for development of compounds for treatment of patients with Type 2 diabetes.


Esculentin-1a(1-21) Type 2 diabetes Amphibian skin peptide Insulin release β-cell proliferation Anti-apoptotic peptide 



Funding for this study was provided by a project Grant from Diabetes UK (12/0004457) and by the University of Ulster Research Strategy Funding.

Compliance with ethical standards

Ethical approval

This article does not contain any studies with human participants performed by any of the authors. For this type of study, informed consent is not relevant. All animal experiments were carried out in accordance with the UK Animals (Scientific Procedures) Act 1986 and EU Directive 2010/63EU for animal experiments and approved by Ulster University Animal Ethics Review Committee. All necessary steps were taken to prevent any potential animal suffering.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

726_2018_2551_MOESM1_ESM.tif (670 kb)
Supplementary material 1 (TIFF 670 kb) Supplementary Fig. S1. Effects of Esc(1-21)-1c (1 µM) and KCl (30 mM) on (A) membrane potential in BRIN-BD11 cells expressed as relative fluorescence units, RFU and (B) the integrated response (area under the curve, AUC). Values are mean ± SEM (n = 6). *** P < 0.001 compared with 5.6 mM glucose alone
726_2018_2551_MOESM2_ESM.tif (696 kb)
Supplementary material 2 (TIFF 696 kb) Supplementary Fig. S2. Effects of Esc(1-21)-1c (1 µM) and alanine (10 mM) on (A) intracellular calcium ion concentrations [Ca2+]i in BRIN-BD11 cells expressed as relative fluorescence units, RFU and (B) the integrated response (area under the curve, AUC). Values are mean ± SEM (n = 6). ***P < 0.001 compared with 5.6 mM glucose alone


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Copyright information

© Springer-Verlag GmbH Austria, part of Springer Nature 2018

Authors and Affiliations

  • Vishal Musale
    • 1
  • Yasser H. A. Abdel-Wahab
    • 1
  • Peter R. Flatt
    • 1
  • J. Michael Conlon
    • 1
    Email author
  • Maria Luisa Mangoni
    • 2
  1. 1.SAAD Centre for Pharmacy and Diabetes, School of Biomedical SciencesUniversity of UlsterColeraineUK
  2. 2.Laboratory Affiliated To Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Department of Biochemical SciencesSapienza University of RomeRomeItaly

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