Insulin-releasing properties of the frog skin peptide pseudin-2 and its [Lys18]-substituted analogue |
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Authors: | Abdel-Wahab Yasser H A Power Gavin J Ng Ming T Flatt Peter R Conlon J Michael |
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Institution: | School of Biomedical Sciences, University of Ulster, Cromore Road, Coleraine BT52 1SA, UK. |
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Abstract: | Abstract Pseudin-2 is a cationic alpha-helical peptide that was first isolated from the skin of the paradoxical frog Pseudis paradoxa on the basis of its antimicrobial activity. We have investigated the insulin-releasing properties and cytotoxicity of the peptide, together with selected analogues with increased cationicity and hydrophobicity. At concentrations in the range 10(-9)-10(-6) m, pseudin-2, and its Lys18], Phe8], and d-Lys3,d-Lys10,d-Lys14] derivatives, stimulated insulin release from the BRIN-BD11 clonal beta-cell line without increasing release of lactate dehydrogenase. The Lys18] analogue was the most potent (46% increase in insulin release at 10(-9) m) and the most effective (215% increase in insulin release at 10(-6) m). The more cationic Lys3,Lys10,Lys14] and Lys3,Lys10,Lys14,Lys21] analogues lacked insulinotropic action and the more hydrophobic Phe16] analogue was cytotoxic at concentrations > or =10(-7) m. Pseudin-2 and Lys18]-pseudin-2 had no effect on intracellular calcium concentrations and stimulated insulin release in the absence of external calcium. Lys18]-pseudin-2 (10(-8) m) stimulated insulin release in the presence of diazoxide and verapamil. Our results demonstrate that pseudin-2 stimulates insulin secretion from BRIN-BD11 cells by a mechanism involving Ca2+-independent pathways and identify Lys18]-pseudin-2 as a peptide that may have potential for development as a therapeutically valuable insulinotropic agent for the treatment of type 2 diabetes. |
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