Cholecystokinin is up-regulated in obese mouse islets and expands β-cell mass by increasing β-cell survival

Jeremy A. Lavine, Philipp W. Raess, Donald S. Stapleton, Mary E. Rabaglia, Joshua I. Suhonen, Kathryn L. Schueler, James E. Koltes, John A. Dawson, Brian S. Yandell, Linda C. Samuelson, Margery C. Beinfeld, Dawn Belt Davis, Marc K. Hellerstein, Mark P. Keller, Alan D. Attie

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Abstract

An absolute or functional deficit in β-cell mass is a key factor in the pathogenesis of diabetes. We model obesity-driven β-cell mass expansion by studying the diabetes-resistant C57BL/6-Leptinob/ob mouse. We previously reported that cholecystokinin (Cck)wasthe most up-regulatedgenein obese pancreatic islets. We now show that islet cholecystokinin (CCK) is up-regulated 500-fold by obesity and expressed in both α- and β-cells. We bred a null Cck allele into the C57BL/6-Leptinob/ob background and investigated β-cell mass and metabolic parameters of Cck-deficient obese mice. Loss of CCK resulted in decreased islet size and reduced β-cell mass through increased β-cell death. CCK deficiency and decreased β-cell mass exacerbated fasting hyperglycemia and reduced hyperinsulinemia. We further investigated whether CCK can directly affect β-cell death in cell culture and isolated islets. CCK was able to directly reduce cytokine- and endoplasmic reticulum stress-induced cell death. In summary, CCK is up-regulated by islet cells during obesity and functions as a paracrine or autocrine factor to increase β-cell survival and expand β-cell mass to compensate for obesity-induced insulin resistance.

Original languageEnglish (US)
Pages (from-to)3577-3588
Number of pages12
JournalEndocrinology
Volume151
Issue number8
DOIs
StatePublished - Aug 1 2010

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ASJC Scopus subject areas

  • Endocrinology

Cite this

Lavine, J. A., Raess, P. W., Stapleton, D. S., Rabaglia, M. E., Suhonen, J. I., Schueler, K. L., Koltes, J. E., Dawson, J. A., Yandell, B. S., Samuelson, L. C., Beinfeld, M. C., Belt Davis, D., Hellerstein, M. K., Keller, M. P., & Attie, A. D. (2010). Cholecystokinin is up-regulated in obese mouse islets and expands β-cell mass by increasing β-cell survival. Endocrinology, 151(8), 3577-3588. https://doi.org/10.1210/en.2010-0233