2038-P: The Somatostatin Analog Pasireotide Reduces Pancreatic ß-Cell Function and Survival, and Both Incretin-Based Drugs and Irisin Revert These Effects

Pasireotide is a new-generation somatostatin analog used for the treatment of acromegaly, Cushing’s disease and neuroendocrine tumors. However, due to its high affinity for somatostatin receptors (SSTR) 2 and 5, highly expressed in enteroendocrine- and pancreatic β-cells, it can reduce insulin, GLP-1 and GIP release and increase glucagonemia, causing marked hyperglycemia in some patients. The diabetogenic effects of pasireotide are significantly reduced in vivo by the co-administration of liraglutide or vildagliptin. The aim of this study was to evaluate the effects of pasireotide on β-cell survival and function, and the ability of molecules with known beneficial action on β-cells (incretin-based drugs and irisin, a myokine with β-cellular trophic properties) to prevent these effects. In INS-1E cells, both acute and chronic administration of pasireotide 10-50 nM reduced glucose-induced insulin secretion by 30% and 50% respectively and proinsulin mRNA levels by 20%, without altering cellular insulin content. Furthermore, pasireotide induced apoptosis in INS-1E cells and human pancreatic islets. Pretreatment with both incretin-based drugs (exendin-4, lixisenatide, liraglutide, saxagliptin) and irisin prevented pasireotide-induced apoptosis in INS-1E cells. In addition, pasireotide increased the protein levels of SSTR2 (2-fold) but not of SSTR5. Among the protective molecules examined, only irisin was able to prevent this increase.

In conclusion, pasireotide can induce hyperglycemia and diabetes via direct effects on β-cells, resulting in reduced insulin secretory capacity and survival. Both GLP-1 receptor agonists and DPP-4 inhibitors and irisin can reduce the proapoptotic effects of pasireotide, acting through partially different molecular mechanisms. These results demonstrate for the first time a functional antagonism between SSTR2/5 activation and incretin-based drugs or irisin in pancreatic β-cells.