The role of glucagon : GCGR axis in pancreatic neuroendocrine

• Autor(a) principal: Ferreira, Bárbara Carina de Poeiras
• Data de Publicação: 2023
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10362/162617
• topic: glucagon; GCGR axis; pancreatic neuroendocrine; Ciências Médicas

Abstract Cancer metabolism research has studied the relationship between cellular bioenergetics, biosynthesis, and tumour progression. However, the impact of systemic metabolism and diet on tumour evolution is less understood. This thesis delves into the role of glucagon, a key hormone in systemic metabolism, particularly its influence on pancreatic neuroendocrine tumours (pNETs). Glucagon ability to bind to its natural receptor, GCGR, and its regulator, GLP-1R, introduces intricate dynamics to cancer biology. Our research focused on the role of glucagon in the regulation of cancer cell features and the metabolic remodelling in the presence and absence of glucose. To fulfil the experiments pNETs cell lines (BON-1 and QGP-1) and non-malignant pancreatic α-TC1 cell line were used as models. Results showed pNETs cells responded differently to glucose deprivation than α-TC1 cells. Specifically, pNETs cells upregulated GCGR in the absence of glucose, while α-TC1 cells did so in high-glucose conditions. Glucagon activated the MAPK/ERK pathway, especially in pNETs cells without glucose and α-TC1 cells with high glucose. Tests revealed that glucagon enhanced metabolic viability, proliferation, and migration in pNETs cells under glucose deprived conditions and hyperglucagonemia. Meanwhile, in α-TC1 cell line, glucagon modulated these features under high-glucose conditions and physiological glucagon levels. The study also explored the effects of blocking GCGR using an inhibitor, LGD-6972. The results varied across cell lines and glucagon conditions. Metabolic analysis using NMR revealed differences in amino acid levels and metabolic processes based on glucose availability between cell lines. Interestingly, QGP-1 and α-TC1 produced glucose in no-glucose conditions, and glucagon upregulated glucose production in α-TC1. Furthermore, gene expression analysis showed that glucose conditions largely influenced gene expression patterns in both pNETs and non-malignant α-cells. The increased levels of alanine, and the ability of QGP-1 and α-TC1 cells to produce glucose together with the upregulation of gluconeogenesis related genes it was clear that the synthesis of glucose is a core pathway in α-TC1 cell biology and QGP-1 cells. Hence gluconeogenesis may be beneficial for some pNETs subsets and its open new perspectives to novel metabolism-based strategies to clinically manage pNETs. Furthermore, the production of glucose by α-cells was not described so far and is a step forward in endocrinology and systemic metabolism. Lastly, the study examined the association between GCGR and disease parameters in pNETs cases. Findings revealed a negative correlation between GCGR expression and tumour grading. Additionally, GLP-1R expression was lower in pNETs than in healthy tissue. This underscores the significant, yet not fully understood, role of glucagon signalling in pNETs progression. The complex relationship between glucose conditions, glucagon signalling, and cellular characteristics warrants further exploration for future therapeutic strategies for pNETs and related diseases.