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

Opeolu Ojo, DK Srinivasan, BO Owolabi, Srividya Vasu, J Michael Conlon, Peter Flatt, Yasser Abdel-Wahab

Research output: Contribution to journalArticle

8 Citations (Scopus)

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
LanguageEnglish
Pagese0141549-e0141549
JournalPLoS ONE
Volume10
Issue number10
DOIs
Publication statusPublished - 29 Oct 2015

Fingerprint

Islets of Langerhans
Insulin Resistance
Obesity
Diet
Glucose
Peptides
Insulin
Fats
Body Weight
KATP Channels
Indirect Calorimetry
Insulin-Secreting Cells
esculentin steroid
Body Composition
Glucagon
Hypoglycemic Agents
Anura
LDL Cholesterol
Type 2 Diabetes Mellitus
Triglycerides

Keywords

  • islet
  • glucose tolerance
  • high fat feeding
  • insulin resistance
  • frog skin peptides

Cite this

@article{cad56cf46f8a425b889adfdf46d96cf1,
title = "Esculentin-2CHa-Related Peptides Modulate Islet Cell Function and Improve Glucose Tolerance in Mice with Diet-Induced Obesity and Insulin Resistance.",
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",
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year = "2015",
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Esculentin-2CHa-Related Peptides Modulate Islet Cell Function and Improve Glucose Tolerance in Mice with Diet-Induced Obesity and Insulin Resistance. / Ojo, Opeolu; Srinivasan, DK; Owolabi, BO; Vasu, Srividya; Conlon, J Michael; Flatt, Peter; Abdel-Wahab, Yasser.

In: PLoS ONE, Vol. 10, No. 10, 29.10.2015, p. e0141549-e0141549.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Esculentin-2CHa-Related Peptides Modulate Islet Cell Function and Improve Glucose Tolerance in Mice with Diet-Induced Obesity and Insulin Resistance.

AU - Ojo, Opeolu

AU - Srinivasan, DK

AU - Owolabi, BO

AU - Vasu, Srividya

AU - Conlon, J Michael

AU - Flatt, Peter

AU - Abdel-Wahab, Yasser

PY - 2015/10/29

Y1 - 2015/10/29

N2 - 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

AB - 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

KW - islet

KW - glucose tolerance

KW - high fat feeding

KW - insulin resistance

KW - frog skin peptides

U2 - 10.1371/journal.pone.0141549

DO - 10.1371/journal.pone.0141549

M3 - Article

VL - 10

SP - e0141549-e0141549

JO - PLoS ONE

T2 - PLoS ONE

JF - PLoS ONE

SN - 1932-6203

IS - 10

ER -