Utilising spider venom for diabetes drug recovery

Abstract

Type 2 diabetes (T2D) is a metabolic disorder characterised by hyperglycaemia, impaired insulin secretion and sensitivity, resulting in a dysregulation of glucose homeostasis. There is a plethora of drugs available to manage T2D, however, these have a high failure rate meaning new effective therapies are required. This thesis explored the antidiabetic promise of peptides from tarantula venom, namely Jingzhaotoxin IX and Jingzhaotoxin XI, from the Chinese earth tarantula, Chilobrachys jingzhao, the novel peptide ΔTRTX-Ac1 originally isolated from the Mexican Blonde tarantula Aphonopelma chalcodes venom by Moore and colleagues at Ulster University, and the crude venom of Psalmopoeus cambridgei and Grammostola porteri. Jingzhaotoxin peptides displayed remarkable insulin secretory effects in BRIN-BD11 cells with positive actions on beta-cell health. The peptides were hypothesised to have increased stability, however, were shown to be degraded within 30 min in murine plasma. When exploring ΔTRTX-Ac1 peptides, these remained stable for up to 12 h and had insulinotropic activity in BRIN-BD11 cells and in C57Bl/6. Mass spectrometry imaging was able to characterise the distribution of this peptide within the pancreas, kidney, liver, and brain of mice. The antidiabetic efficacy of ΔTRTX-Ac1 was investigated alongside exenatide in high fat-fed (HFF)mice with specific beta-cell toxin streptozotocin (STZ). Combination therapy withΔTRTX-Ac1 and exenatide resulted in clear benefits on glucose homeostasis, satiety and body weight in HFF/STZ mice. To further support the antidiabetic potential of tarantula venom peptides, crude venom from Psalmopoeus cambridgei and Grammostola porteri was assessed. One fraction from the Grammostola porteri caused a significant increase of insulin release at 5.6- and 16.7-mM glucose, with no cytotoxicity. This thesis has demonstrated the positive metabolic actions of tarantula venom-derived peptides both alone and in combination with GLP-1 analogue exenatide. Together, these findings reinforce further development of tarantula venom derived peptides for the treatment of diabetes and obesity.

Date of Award	May 2023
Original language	English
Sponsors	Diabetes UK
Supervisor	Stephen McClean (Supervisor), Nigel Irwin (Supervisor) & Victor Gault (Supervisor)