Cholecystokinin Suppresses β-Cell Apoptosis, Including in Human Islets in a Transplant Model

Kim, H. T.; de Souza, A. H.; Umhoefer, H.; Han, J.; Anzia, L.; Sacotte, S. J.; Williams, R. A.; Blumer, J. T.; Bartosiak, J. T.; Fontaine, D. A.; Baan, M.; Kibbe, C. R.; Davis, D. B.

doi:10.1101/2021.03.02.433645

bioRxiv · 10.1101/2021.03.02.433645

Cholecystokinin Suppresses β-Cell Apoptosis, Including in Human Islets in a Transplant Model

Kim, H. T.·de Souza, A. H.·Umhoefer, H.·Han, J.·Anzia, L.·Sacotte, S. J.·Williams, R. A.·Blumer, J. T.·Bartosiak, J. T.·Fontaine, D. A.·Baan, M.·Kibbe, C. R.·Davis, D. B.

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Abstract

Loss of functional pancreatic {beta}-cell mass and increased {beta}-cell apoptosis are fundamental to the pathophysiology of both type 1 and type 2 diabetes. Pancreatic islet transplantation has the potential to cure type 1 diabetes but is often ineffective due to the death of the islet graft within the first few years after transplant. Therapeutic strategies to directly target pancreatic {beta}-cell survival are needed to prevent and treat diabetes and to improve islet transplant outcomes. Reducing {beta}-cell apoptosis is also a therapeutic strategy for type 2 diabetes. Cholecystokinin (CCK) is a peptide hormone typically produced in the gut after food intake, with positive effects on obesity and glucose metabolism in mouse models and human subjects. We have previously shown that pancreatic islets also produce CCK. The production of CCK within the islet promotes {beta}-cell survival in rodent models of diabetes and aging. Now, we demonstrate a direct effect of CCK to reduce cytokine-mediated apoptosis in a {beta}-cell line and in isolated mouse islets in a receptor-dependent manner. However, whether CCK can protect human {beta}-cells was previously unknown. Here, we report that CCK can also reduce cytokine-mediated apoptosis in isolated human islets and CCK treatment in vivo decreases {beta}-cell apoptosis in human islets transplanted into the kidney capsule of diabetic NOD/SCID mice. Collectively, these data identify CCK as a novel therapy that can directly promote {beta}-cell survival in human islets and has therapeutic potential to preserve {beta}-cell mass in diabetes and as an adjunct therapy after transplant. One Sentence SummaryCholecystokinin ameliorates pancreatic {beta}-cell death under models of stress and after transplant of human islets.

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Kim, H. T., de Souza, A. H., Umhoefer, H., Han, J., Anzia, L., Sacotte, S. J., Williams, R. A., Blumer, J. T., Bartosiak, J. T., Fontaine, D. A., Baan, M., Kibbe, C. R., Davis, D. B.. 2021-03-02. Cholecystokinin Suppresses β-Cell Apoptosis, Including in Human Islets in a Transplant Model. https://doi.org/10.1101/2021.03.02.433645

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