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 Show more
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. Show less
The antidiabetic effects and mechanisms of action of an analogue of a frog skin host-defence peptide belonging to the caerulein-precursor fragment family, [S4K]CPF-AM1 were investigated in db/db mice Show more
The antidiabetic effects and mechanisms of action of an analogue of a frog skin host-defence peptide belonging to the caerulein-precursor fragment family, [S4K]CPF-AM1 were investigated in db/db mice with a genetically inherited form of degenerative diabetes-obesity. Twice-daily treatment with the peptide (75 nmol/kg body weight) for 28 days significantly decreased blood glucose (P < 0.01) and HbA1c (P < 0.05) and increased plasma insulin (P < 0.05) concentrations with no effect on body weight, energy intake, body composition or plasma lipid profile. Peptide administration improved insulin sensitivity and intraperitoneal glucose tolerance. Elevated biomarkers of liver and kidney function associated with the db/db phenotype were significantly lowered by [S4K]CPF-AM1 administration. Peptide treatment significantly (P < 0.05) increased pancreatic insulin content and improved the responses of isolated islets to established secretagogues. Elevated expression of genes associated with insulin signalling (Slc2a4, Insr, Irs1, Akt1, Pik3ca, Ppm1b) in the skeletal muscle of db/db mice were significantly downregulated by peptide treatment. Genes associated with insulin secretion (Abcc8, Kcnj11, Slc2a2, Cacn1c, Glp1r, Gipr) were significantly upregulated by treatment with [S4K]CPF-AM1. Studies with BRIN-BD1I clonal β-cells demonstrated that the peptide evoked membrane depolarisation, increased intracellular Ca2+ and cAMP and activated the protein kinase C pathway. The data indicate that the antidiabetic properties of [S4K]CPF-AM1 mice are mediated by direct insulinotropic action and by regulation of transcription of genes involved in both the secretion and action of insulin. Show less