Modeling diabetic alpha cell dysfunction using stem cell-derived alpha cells [Bulk RNA-seq]

Dysfunction of pancreatic alpha cells contributes to the pathophysiology of diabetes. Features of diabetic alpha cell dysfunction include glucagon hypersecretion, defects in proglucagon processing, and altered transcriptomic profile. The lack of an in vitro human alpha cell model has prevented the investigation, and potential correction, of these dysfunctional phenotypes. Here, we show that induction of endoplasmic reticulum stress in stem cell-derived alpha (SC-α) cells induces hypersecretion of glucagon. ER stress also increases the secretion of glicentin and expression of GLP-1, peptides produced by alternate cleavage of proglucagon by the prohormone convertase 1 (PC1/3) enzyme. Additionally, ER stress establishes a diabetic transcriptional state in SC-α cells characterized by downregulation of MAFB, as well as glycolysis and oxidative phosphorylation pathways. We show that sunitinib, a tyrosine kinase inhibitor, protects SC-α cells against the ER stress-induced glucagon hypersecretion phenotype. Thus, SC-α cell model can advance our knowledge of islets in health and diabetes. Human pluripotent stem cells were differentiated into stem cell-derived alpha cells. Stem cell-derived alpha cells underwent a 48-hour drug treatment in 30 mL bioreactors at 40 rpm with either DMSO vehicle or tunicamycin drug to induce ER-stress. Samples from the vehcile and experimental groups were analyzed using bulk RNA-seq. Samples were sequenced in two batches.