Abnormal exocrine-endocrine cell crosstalk promotes ß-cell dysfunction and loss in MODY8

MODY8 (maturity-onset diabetes of the young, type 8) is a dominantly inherited monogenic form of diabetes associated with frameshift mutations in the carboxyl ester lipase (CEL) gene expressed by pancreatic acinar cells. Patients carrying the mutation develop childhood-onset exocrine pancreas dysfunction followed by the manifestation of diabetes during adulthood. However, it is unclear how CEL mutations cause diabetes. Here we report the transfer of proteins from acinar cells to ß-cells as a form of crosstalk between exocrine and endocrine cells. Human ß-cells showed a relatively higher propensity for internalizing the mutant versus the wild-type CEL protein. Following internalization, the mutant protein formed stable intracellular aggregates leading to ß-cell secretory dysfunction. To investigate the effects in vivo, we transplanted stem cell-derived wild-type or mutant pancreatic progenitors into independent mice and generated insulin-secreting ß-like cells and CEL-expressing acinar-like cells. While the ß-like cells derived from wild-type stem cells responded to glucose, the ß-like cells derived from mutant stem cells were dysfunctional secondary to the accumulation of intracellular mutant CEL protein. Analysis of pancreas sections from a MODY8 patient also revealed the presence of CEL protein in the few extant ß-cells. This study provides compelling evidence for the mechanism by which a mutant gene expressed specifically in acinar cells promotes dysfunction and loss of ß-cells to cause diabetes. Overall design: EndoC-ßH1 cells were cultured in conditioned media collected from HEK293 cells overexpressing either the empty vector (EV), wild-type CEL gene (WT) or mutant CEL gene (MUT) for 10 days. Conditioned media was refreshed every day. Cells were lysed in RLT buffer and then RNA was extracted using Qiagen RNeasy kit according to the manufacturer's instructions. RNAseq was performed on an Illumina NovaSeq 6000 according to the manufacturer's instructions.