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2024

Diabetes. 2024 Jun 21:db230490. doi: 10.2337/db23-0490. Online ahead of print.

Trefoil factor 2 expressed by the murine pancreatic acinar cells is required for the development of islets and for beta cell function during aging

Jose A Ortiz, Nadiah Ghazalli, Kassandra Lopez, Jeffrey Rawson, Erika M McCown, Eunjin Oh, Jose M Irimia, Kevin Jou, Jacob Mares, Min-Hsuan Chen, Xiwei Wu, Heather N Zook, Janine C Quijano, Neslihan Erdem, Anahy Lizarraga, Fouad Kandeel, Patrick T Fueger, Debbie C Thurmond, Hsun Teresa Ku

Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope, Duarte, CA 91010, United States. Irell and Manella School of Biological Sciences, Beckman Research Institute, City of Hope, Duarte, CA 91010, United States. Department of Molecular & Cellular Endocrinology, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope, Duarte, CA 91010, United States. Comprehensive Metabolic Phenotyping Core, City of Hope, Duarte, CA 91010, United States. Integrative Genomics Core, City of Hope, Duarte, CA 91010, United States. Eugene and Ruth Roberts Summer Student Academy, City of Hope, Duarte, CA 91010, United States.

Service type: Knockout mice

Abstract

Exocrine-to-endocrine crosstalk in the pancreas is crucial to maintain beta cell function. However, the molecular mechanisms underlying this crosstalk are largely undefined. Trefoil factor 2 (Tff2) is a secreted factor known to promote the proliferation of beta cells in vitro, but its physiological role in vivo in the pancreas is unknown. Also, it remains unclear which pancreatic cell type expresses Tff2 protein. We therefore created a mouse model with a conditional knockout of Tff2 in the murine pancreas. We find that the Tff2 protein is preferentially expressed in acinar but not ductal or endocrine cells. Tff2 deficiency in the pancreas reduces beta cell mass on embryonic day 16.5. However, homozygous mutant mice are born without a reduction of beta cells and with acinar Tff3 compensation by day 7. When mice are aged to 1 year, both male and female homozygous and male heterozygous mutants develop impaired glucose tolerance without affected insulin sensitivity. Perifusion analysis reveals that the second phase of glucose-stimulated insulin secretion from islets is reduced in aged homozygous mutant compared to controls. Collectively, these results demonstrate a previously unknown role of Tff2 as an exocrine acinar cell-derived protein required for maintaining functional endocrine beta cells in mice.

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