Sustained metabolic benefits of ΔTRTX‐Ac1, a tarantula venom‐derived peptide, when administered together with exenatide in high‐fat fed mice

Aim: The aim of the present study was to assess the long‐term therapeutic efficacy of a recently discovered 28 amino acid peptide, Δ‐theraphotoxin‐Ac1 (Δ‐TRTX‐Ac1), originally isolated from venom of the Aphonopelma chalcodes tarantula. Δ‐TRTX‐Ac has previously been shown to improve pancreatic beta‐cell function and suppress appetite. Materials and Methods: Δ‐TRTX‐Ac1 was administered twice daily in high‐fat fed (HFF) mice with streptozotocin (STZ)‐induced insulin deficiency, namely HFF/STZ mice, for 28 days both alone and in combination with the venom‐derived glucagon‐like peptide‐1 (GLP‐1) mimetic, exenatide. Results: Initial pharmacokinetic profiling of ΔTRTX‐Ac1 revealed a plasma half‐life of 2 h in mice, with ΔTRTX‐Ac1 also evidenced in the pancreas 12 h post‐injection. Accordingly, HFF‐STZ mice received twice‐daily injections of Δ‐TRTX‐Ac1, exenatide or a combination of both peptides for 28 days. As anticipated, HFF/STZ mice presented with hyperglycaemia, impaired glucose tolerance, decreased plasma and pancreatic insulin and disturbed pancreatic islet morphology. Administration of ΔTRTX‐Ac1 reduced body weight, improved glucose tolerance and augmented pancreatic insulin content while decreasing glucagon content. Exenatide had similar benefits on body weight and pancreatic hormone content while also reducing circulating glucose. ΔTRTX‐Ac1 decreased energy expenditure on day 28 whereas exenatide had no impact. All treatment regimens restored pancreatic islet and beta‐cell area towards lean control levels, which was linked to significantly elevated beta‐cell proliferation rates. In terms of benefits of combined ΔTRTX‐Ac1 and exenatide treatment over individual agents, there was augmentation of glucose tolerance and ambulatory activity with combination therapy, and these mice presented with increased pancreatic glucagon. Conclusion: These data highlight the therapeutic promise of ΔTRTX‐Ac1 for diabetes, with suggestion that benefits could be enhanced through combined administration with exenatide.