IAPP-induced beta cell toxicity recapitulates islet molecular pathology in type 2 diabetes

Islets in Type 2 diabetes (T2D) share many diverse abnormalities reported in neurodegenerative diseases, including the formation of toxic oligomers from amyloidogenic proteins. We evaluated the transcriptome of murine islets with beta cell-specific human IAPP (hIAPP) expression to assess the potential contribution of hIAPP toxicity to those observed in islets from T2D.Beta cell hIAPPtoxicity induced an islet transcriptome highly analogous to that in islets from humans with T2D with a prominent inflammatory signature, activation of vascular epithelium and stellate cells, cytoskeleton remodeling,and activation of cell-cycle andcellular dedifferentiation. In conclusion, many of the apparently widely disparate changes in islets in T2D may be initiated by toxic oligomers. Inhibition of expression of amyloidogenic proteins or proximal adverse consequences such as disruption of the cytoskeleton by calpain hyperactivation are rational targets for therapeutic intervention in T2D and neurodegenerative disease. RNA-seq of bulk pancreatic islets from 9-10 week old hIAPP, rIAPP, hIAPP:hCAST, hCAST and WT mice (15 samples; n = 3 per group) Treatment descriptions: hIAPP: Transgenic expression of human IAPP under insulin II promoter hIAPP_hCAST: Transgenic expression of human IAPP under insulin II promoter; transgenic expression of human CAST under insulin rIAPP: Transgenic expression of rodent IAPP under insulin II promoter hCAST: Transgenic expression of human CAST under insulin II promoter