Davies Iona, Adriaenssens Alice E, Scott William R, Carling David, Murphy Kevin G, Minnion James S, Bloom Stephen R, Jones Ben, Tan Tricia M-M
Section of Endocrinology and Investigative Medicine, Imperial College London, United Kingdom.
Department of Neuroscience, Physiology, and Pharmacology, University College London, London, United Kingdom.
Mol Metab. 2025 Feb;92:102094. doi: 10.1016/j.molmet.2025.102094. Epub 2025 Jan 7.
There is renewed interest in targeting the glucose-dependent insulinotropic polypeptide receptor (GIPR) for treatment of obesity and type 2 diabetes. G-protein coupled receptor desensitisation is suggested to reduce the long-term efficacy of glucagon-like-peptide 1 receptor (GLP-1R) agonists and may similarly affect the efficacy of GIPR agonists. We explored the extent of pancreatic GIPR functional desensitisation with sustained agonist exposure.
A long-acting GIPR agonist, GIP108, was used to probe the effect of sustained agonist exposure on cAMP responses in dispersed pancreatic islets using live cell imaging, with rechallenge cAMP responses after prior agonist treatment used to quantify functional desensitisation. Receptor internalisation and β-arrestin-2 activation were investigated in vitro using imaging-based assays. Pancreatic mouse GIPR desensitisation was assessed in vivo via intraperitoneal glucose tolerance testing.
GIP108 treatment led to weight loss and improved glucose homeostasis in mice. Prolonged exposure to GIPR agonists produced homologous functional GIPR desensitisation in isolated islets. GIP108 pre-treatment in vivo also reduced the subsequent anti-hyperglycaemic response to GIP re-challenge. GIPR showed minimal agonist-induced internalisation or β-arrestin-2 activation.
Although GIP108 chronic treatment improved glucose tolerance, it also resulted in partial desensitisation of the pancreatic islet GIPR. This suggests that ligands with reduced desensitisation tendency might lead to improved in vivo efficacy. Understanding whether pancreatic GIPR desensitisation affects the long-term benefits of GIPR agonists in humans is vital to design effective metabolic pharmacotherapies.
靶向葡萄糖依赖性促胰岛素多肽受体（GIPR）治疗肥胖症和2型糖尿病再次引起了人们的关注。G蛋白偶联受体脱敏被认为会降低胰高血糖素样肽1受体（GLP-1R）激动剂的长期疗效，并且可能同样影响GIPR激动剂的疗效。我们探讨了持续暴露于激动剂下胰腺GIPR功能脱敏的程度。
使用长效GIPR激动剂GIP108，通过活细胞成像来探究持续暴露于激动剂对分散的胰岛中cAMP反应的影响，使用先前激动剂处理后的再次激发cAMP反应来量化功能脱敏。使用基于成像的分析方法在体外研究受体内化和β-抑制蛋白2的激活。通过腹腔葡萄糖耐量试验在体内评估胰腺小鼠GIPR脱敏情况。
GIP108治疗导致小鼠体重减轻并改善了葡萄糖稳态。长时间暴露于GIPR激动剂会在分离的胰岛中产生同源功能性GIPR脱敏。体内GIP108预处理也降低了随后对GIP再次激发的抗高血糖反应。GIPR显示出最小的激动剂诱导的内化或β-抑制蛋白2激活。
尽管GIP108长期治疗改善了葡萄糖耐量，但也导致胰岛GIPR部分脱敏。这表明脱敏倾向降低的配体可能会提高体内疗效。了解胰腺GIPR脱敏是否会影响GIPR激动剂对人类的长期益处对于设计有效的代谢药物疗法至关重要。
