The
antidiabetic actions of [A14K]
PGLa-AM1, an analog of
peptide glycine-leucine-amide-AM1 isolated from skin secretions of the octoploid frog Xenopus amieti, were investigated in genetically diabetic-obese db/db mice. Twice daily administration of [A14K]
PGLa-AM1 (75 nmol/kg
body weight) for 28 days significantly (P < 0.05) decreased circulating
blood glucose and HbA1c and increased plasma
insulin concentrations leading to improvements in
glucose tolerance. The elevated levels of
triglycerides,
LDL and
cholesterol associated with the db/db phenotype were significantly reduced by
peptide administration. Elevated plasma
alanine transaminase,
aspartic acid transaminase, and
alkaline phosphatase activities and
creatinine concentrations were also significantly decreased.
Peptide treatment increased pancreatic
insulin content and improved the responses of isolated islets to established
insulin secretagogues. No significant changes in islet β-cell and α-cell areas were observed in [A14K]
PGLa-AM1 treated mice but the loss of large and medium-size islets was prevented.
Peptide administration resulted in a significant (P < 0.01) increase in islet expression of the gene encoding Pdx-1, a major
transcription factor in islet cells determining β-cell survival and function, resulting in increased expression of genes involved with insulin secretion (Abcc8, Kcnj11, Slc2a2, Cacn1c) together with the genes encoding the
incretin receptors Glp1r and Gipr. In addition, the elevated expression of
insulin signalling genes (Slc2a4, Insr, Irs1, Akt1, Pik3ca, Ppm1b) in skeletal muscle associated with the db/db phenotype was downregulated by
peptide treatment These data suggest that the anti-diabetic properties of [A14K]
PGLa-AM1 are mediated by molecular changes that enhance both the secretion and action of
insulin.