| Abstract | Type 2 diabetes (T2D) represents one of the major disease challenges worldwide, with epidemic proportions of more than 400 million affected across the globe.
Therapeutic agents for disease management are often met by challenges such as the inability to restore long-term glucose homeostasis; highlighting the need for novel agents with increased potency or better therapeutic efficacy. The discovery of exendin-4, a compound isolated from venom of the Gila monster lizard (Heloderma suspectum) and developed into a potent anti-diabetic drug, further motivated interests in the search animal sources for novel therapeutic agents.
Over the last decade, much attention has been drawn towards amphibian skin peptides, which have uncovered their previously unexplored anti-diabetic actions. Among many other peptides, tigerinin-1R (isolated from Hoplobatracus rugulosus) and magainin-AM2 (isolated from Xenopus amieti) have been extensively characterised for their anti-diabetic actions both in vitro and in vivo, showing promise for further investigations. In the context of T2D, a recently explored approach yielding pre-clinical success is based on the creation of hybrid peptides with established anti-diabetic components into a single molecular entity. The rationale for this concept is the generation of hybrids presenting features of their individual components, while introducing additional beneficial effects.
This study characterised the in vitro potential of novel hybrid peptides, designed by combining established anti-diabetic agents, exendin-4 and d-Ala2-GIP, with the amphibian peptides tigerinin-1R and magainin-AM2. After assessing their insulinotropic actions in the clonal pancreatic cells, BRIN-BD11, and in isolated primary islets, specific modulators of insulin secretion were employed to elucidate the mechanism of action of the peptides. This screening revealed that combining magainin-AM2 with exendin-4 produced the best augmented and non-toxic actions on insulin secretion from BRIN-BD11 cells and isolated islets through the activation of the ATP-dependent pathway of insulin secretion. Metabolomic analysis under hyperglycaemic conditions, using 1H-NMR and GC-MS, along with gene expression studies further highlighted the anti-diabetic actions of these peptides. A reduction in lipid abundance as well as an increase in glucose metabolism were observed. Gene expression studies revealed increase in the genes encoding for insulin and beta-cell proliferation, further expanding on the anti-diabetic potential of these compounds.
Finally, by considering the inflammatory component associated with T2D, characterisation of the peptides’ actions on bone-marrow derived dendritic cells (BM-DCs) revealed, for the first time in this model, reduction of perpetuating inflammatory signals, in favour of an anti-inflammatory environment.
Taken together, these studies revealed that combining the selected amphibian skin peptides with exendin-4 significantly enhanced the therapeutic promise of these peptides and encourage further analysis of their in vivo actions as well as further development into a clinically available therapy for type 2 diabetes. |
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