GLP-1 receptor agonists counteract the detrimental effects of pasireotide on pancreatic beta-cell function and survival

Pasireotide is a somatostatin analogue used to treat acromegaly, Cushing’s disease, and neuroendocrine tumors. Due to its high affinity for somatostatin receptors 5 and 2, highly expressed in pancreatic beta-cells and enteroendocrine cells, pasireotide may reduce the secretion of insulin, GLP-1, and GIP, causing hyperglycemia in some patients. The diabetogenic effects of pasireotide appear to be hampered in vivo by co-administration of incretin-based drugs. This study investigated the effects of pasireotide on beta-cell function and survival, the protective role of different GLP-1 receptor agonists (GLP-1RAs), and the underlying mechanisms. INS-1E cells and human pancreatic islets were exposed to pasireotide without or with pretreatment with a GLP-1RA (exendin-4, lixisenatide, or liraglutide). Glucose-stimulated insulin secretion (GSIS), insulin content, and apoptosis were assessed using ELISA and fluorescence microscopy, while intracellular signaling, calcium and cAMP levels by immunoblotting and fluorimetric or luminescent assays. Pasireotide reduced GSIS without altering insulin content and induced apoptosis in both models. Exendin-4 and liraglutide prevented pasireotide-induced secretory dysfunction by modulating cAMP, PKA and calcium levels. All investigated GLP-1RAs prevented pasireotide-induced apoptosis via AKT pathway activation. Overall, these findings demonstrate that pasireotide impairs beta-cell function and survival, and support the co-administration of GLP-1RAs with pasireotide to mitigate its diabetogenic action.