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Actions of PGLa-AM1 and its [A14K] and [A20K] analogues and their therapeutic potential as anti-diabetic agents
- Owolabi, Bosede O., Musale, Vishal, Ojo, Opeolu O., Moffett, R. Charlotte, McGahon, Mary K., Curtis, Tim M., Conlon, J. Michael, Flatt, Peter R., Abdel-Wahab, Yasser H.A.
- Biochimie 2017 v.138 pp. 1-12
- Xenopus, antimicrobial properties, apoptosis, body weight, cAMP-dependent protein kinase, calcium, cyclic AMP, cytotoxicity, forskolin, frogs, glucagon-like peptide 1, glucose tolerance, hypoglycemic agents, insulin, insulin resistance, insulin secretion, intraperitoneal injection, islets of Langerhans, mice, noninsulin-dependent diabetes mellitus, patients, peptides, rats
- PGLa-AM1 (GMASKAGSVL10GKVAKVALKA20AL.NH2) was first identified in skin secretions of the frog Xenopus amieti (Pipidae) on the basis of its antimicrobial properties. PGLa-AM1 and its [A14K] and [A20K] analogues produced a concentration-dependent stimulation of insulin release from BRIN-BD11 rat clonal β-cells without cytotoxicity at concentrations up to 3 μM. In contrast, the [A3K] analogue was cytotoxic at concentrations ≥ 30 nM. The potency and maximum rate of insulin release produced by the [A14K] and [A20K] peptides were significantly greater than produced by PGLa-AM1. [A14K]PGLa-AM1 also stimulated insulin release from mouse islets at concentrations ≥ 1 nM and from the 1.1B4 human-derived pancreatic β-cell line at concentrations > 30 pM. PGLa-AM1 (1 μM) produced membrane depolarization in BRIN-BD11 cells with a small, but significant (P < 0.05), increase in intracellular Ca2+ concentrations but the peptide had no direct effect on KATP channels. The [A14K] analogue (1 μM) produced a significant increase in cAMP concentration in BRIN-BD11 cells and down-regulation of the protein kinase A pathway by overnight incubation with forskolin completely abolished the insulin-releasing effects of the peptide. [A14K]PGLa-AM1 (1 μM) protected against cytokine-induced apoptosis (p < 0.001) in BRIN-BD11 cells and augmented (p < 0.001) proliferation of the cells to a similar extent as GLP-1. Intraperitoneal administration of the [A14K] and [A20K] analogues (75 nmol/kg body weight) to both lean mice and high fat-fed mice with insulin resistance improved glucose tolerance with a concomitant increase in insulin secretion. The data provide further support for the assertion that host defense peptides from frogs belonging to the Pipidae family show potential for development into agents for the treatment of patients with Type 2 diabetes.