Esculentin-2CHa-Related Peptides Modulate Islet Cell Function and Improve Glucose Tolerance in Mice with Diet-Induced Obesity and Insulin Resistance

Article


Kanzaki, Makoto, Ojo, O., Srinivasan, Dinesh K., Owolabi, Bosede O., Vasu, Srividya, Conlon, J. Michael, Flatt, Peter R. and Abdel-Wahab, Yasser H. A. 2015. Esculentin-2CHa-Related Peptides Modulate Islet Cell Function and Improve Glucose Tolerance in Mice with Diet-Induced Obesity and Insulin Resistance. PLOS ONE. 10 (10), p. e0141549.
AuthorsKanzaki, Makoto, Ojo, O., Srinivasan, Dinesh K., Owolabi, Bosede O., Vasu, Srividya, Conlon, J. Michael, Flatt, Peter R. and Abdel-Wahab, Yasser H. A.
Abstract

The frog skin host-defense peptide esculentin-2CHa (GFSSIFRGVA10KFASKGLGK
D20LAKLGVDLVA30CKISKQC) displays antimicrobial, antitumor, and immunomodulatory
properties. This study investigated the antidiabetic actions of the peptide and selected analogues.
Esculentin-2CHa stimulated insulin secretion from rat BRIN-BD11 clonal pancreatic
β-cells at concentrations greater than 0.3 nM without cytotoxicity by a mechanism involving
membrane depolarization and increase of intracellular Ca2+. Insulinotropic activity was
attenuated by activation of KATP channels, inhibition of voltage-dependent Ca2+ channels
and chelation of extracellular Ca2+. The [L21K], [L24K], [D20K, D27K] and [C31S,C37S]
analogues were more potent but less effective than esculentin-2CHa whereas the [L28K]
and [C31K] analogues were both more potent and produced a significantly (P < 0.001)
greater maximum response. Acute administration of [L28K]esculentin-2CHa (75 nmol/kg
body weight) to high fat fed mice with obesity and insulin resistance enhanced glucose tolerance
and insulin secretion. Twice-daily administration of this dose of [L28K]esculentin-
2CHa for 28 days had no significant effect on body weight, food intake, indirect calorimetry
or body composition. However, mice exhibited decreased non-fasting plasma glucose
(P < 0.05), increased non-fasting plasma insulin (P < 0.05) as well as improved glucose tolerance
and insulin secretion (P < 0.01) following both oral and intraperitoneal glucose
loads. Impaired responses of isolated islets from high fat fed mice to established insulin
secretagogues were restored by [L28K]esculentin-2CHa treatment. Peptide treatment was
accompanied by significantly lower plasma and pancreatic glucagon levels and normalization
of α-cell mass. Circulating triglyceride concentrations were decreased but plasma cholesterol
and LDL concentrations were not significantly affected. The data encourage further
investigation of the potential of esculentin-2CHa related peptides for treatment of patients
with type 2 diabetes.

JournalPLOS ONE
Journal citation10 (10), p. e0141549
ISSN1932-6203
Year2015
PublisherPublic Library of Science
Accepted author manuscript
License
CC BY
Web address (URL)http://dx.doi.org/10.1371/journal.pone.0141549
Publication dates
Print29 Oct 2015
Publication process dates
Deposited03 Dec 2015
Accepted10 Oct 2015
FunderDiabetes UK
Copyright information© 2015 Ojo et al.
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