NYMC Faculty Publications

Abnormal Exocrine-Endocrine Cell Cross-Talk Promotes Β-Cell Dysfunction and Loss in MODY8

Authors

Sevim Kahraman, Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA, USA.
Ercument Dirice, Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA, USA.Follow
Giorgio Basile, Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA, USA.
Danielle Diegisser, Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA, USA.
Jahedul Alam, Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, Bergen, Norway.
Bente B. Johansson, Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway.
Manoj K. Gupta, Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA, USA.
Jiang Hu, Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA, USA.
Ling Huang, Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Chew-Li Soh, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Danwei Huangfu, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Senthil K. Muthuswamy, Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Helge Raeder, Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway.
Anders Molven, Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, Bergen, Norway.
Rohit N. Kulkarni, Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA, USA. Rohit.Kulkarni@joslin.harvard.edu.

Author Type(s)

Faculty

DOI

10.1038/s42255-021-00516-2

Journal Title

Nature Metabolism

First Page

76

Last Page

89

Document Type

Article

Publication Date

1-1-2022

Department

Pharmacology

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.

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