Abnormal exocrine–endocrine cell cross-talk promotes β-cell dysfunction and loss in MODY8 Journal Article
| Authors: | Kahraman, S.; Dirice, E.; Basile, G.; Diegisser, D.; Alam, J.; Johansson, B. B.; Gupta, M. K.; Hu, J.; Huang, L.; Soh, C. L.; Huangfu, D.; Muthuswamy, S. K.; Raeder, H.; Molven, A.; Kulkarni, R. N. |
| Article Title: | Abnormal exocrine–endocrine cell cross-talk promotes β-cell dysfunction and loss in MODY8 |
| Abstract: | MODY8 (maturity-onset diabetes of the young, type 8) is a dominantly inherited monogenic form of diabetes associated with mutations in the carboxyl ester lipase (CEL) gene expressed by pancreatic acinar cells. MODY8 patients develop childhood-onset exocrine pancreas dysfunction followed by diabetes during adulthood. However, it is unclear how CEL mutations cause diabetes. In the present study, we report the transfer of CEL proteins from acinar cells to β-cells as a form of cross-talk between exocrine and endocrine cells. Human β-cells show a relatively higher propensity for internalizing the mutant versus the wild-type CEL protein. After internalization, the mutant protein forms stable intracellular aggregates leading to β-cell secretory dysfunction. Analysis of pancreas sections from a MODY8 patient reveals the presence of CEL protein in the few extant β-cells. The present study provides compelling evidence for the mechanism by which a mutant gene expressed specifically in acinar cells promotes dysfunction and loss of β-cells to cause diabetes. © 2022, The Author(s), under exclusive licence to Springer Nature Limited. |
| Keywords: | controlled study; gene mutation; human cell; nonhuman; flow cytometry; nuclear magnetic resonance imaging; mutant protein; animal cell; mouse; phenotype; animal tissue; cell viability; gene overexpression; apoptosis; gene expression; confocal microscopy; green fluorescent protein; animal experiment; animal model; cell differentiation; immunofluorescence; enzyme activity; enzyme linked immunosorbent assay; genetic transfection; immunocytochemistry; diabetes mellitus; exocrine cell; western blotting; lentivirus vector; histochemistry; immunoblotting; dactinomycin; pancreatectomy; glucose blood level; real time polymerase chain reaction; pluripotent stem cell; hydrocortisone; lidocaine; doxycycline; insulin dependent diabetes mellitus; endocrine cell; pancreas islet beta cell; oxygen consumption; dna extraction; fluorescence activated cell sorting; non insulin dependent diabetes mellitus; proteinase inhibitor; transcription factor sox2; glycolysis; oxidative phosphorylation; genomic dna; acinar cell; transcription factor nanog; complementary dna; rna extraction; polyacrylamide gel electrophoresis; triacylglycerol lipase; ketamine; sphingomyelin phosphodiesterase; protein aggregation; exosome; receptor cross-talk; radioimmunoprecipitation; initiation factor 2alpha; insulin treatment; lipofectamine; gastrocnemius muscle; alpha tubulin; mitophagy; induced pluripotent stem cell; sanger sequencing; dna sequencing; human; female; article; hek293 cell line; xylazine; pyroxylin; protein misfolding; internalization (cell); protein tyrosine phosphatase inhibitor; beta cell dysfunction; maturity onset diabetes of the young type 8; zonation |
| Journal Title: | Nature Metabolism |
| Volume: | 4 |
| Issue: | 1 |
| ISSN: | 2522-5812 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2022-01-01 |
| Start Page: | 76 |
| End Page: | 89 |
| Language: | English |
| DOI: | 10.1038/s42255-021-00516-2 |
| PUBMED: | 35058633 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 March 2022 -- Source: Scopus |
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