83-OR: Pancreatic Exocrine to Endocrine Cell Cross Talk Mediates Endoplasmic Reticulum Stress and Beta-Cell Dysfunction in MODY8

Abstract

MODY8 (maturity onset diabetes of the young, type 8) is a dominantly inherited monogenic form of diabetes. This disease is associated with frameshift mutations in the carboxyl ester lipase (CEL) gene expressed by pancreatic acinar tissue. Patients with the mutation develop childhood-onset exocrine pancreas dysfunction followed by diabetes during adulthood. However, it is unclear how CEL mutations cause diabetes in MODY8 patients. In this study, we investigated the potential crosstalk between exocrine acinar cells and endocrine beta cells in vitro. Co-culture of beta cells (EndoC-bH1 beta cells) with donor cells (HEK293 embryonic kidney cells or 266-6 acinar cells) overexpressing mutant or wild type CEL gene in an in vitro transwell system demonstrated transfer of mutant protein from donor cells to beta cells. While both the wild type and mutant CEL proteins were observed to be taken up by the beta cells there was a significantly higher amount of the mutant (11.4±2.3% cells) compared to the wild type protein (1.8±0.7% cells) (n=3, p<0.01 mutant vs. wild type). The mutant protein formed intracellular aggregates represented as punctuate structures within the cytoplasm of beta cells. Culturing beta cells in mutant donor cell-conditioned media for 12 days activated the unfolded protein response, and increased endoplasmic reticulum stress by promoting the gene expression of BiP, spliced XBP1, and caused beta cell secretory dysfunction (insulin stimulation index 16.7 mM/3.3 mM: 1.3±0.1 (mutant) vs. 2.1±0.3 fold (wild type), n=8, p=0.05). Our data indicate a unique crosstalk between pancreatic acinar and beta cells, which adversely affects the latter by increasing ER stress and impairing insulin secretion. This study provides one possible explanation of how a mutant gene expressed specifically in acinar cells causes endocrine cell dysfunction and diabetes in MODY8 patients. Disclosure S. Kahraman: None. D. Diegisser: None. B.B. Johansson: None. A. Molven: None. R. Kulkarni: None. Funding National Institutes of Health (R01DK67536)