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

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.