Cholecystokinin Is Up-Regulated in Obese Mouse Islets and Expands β-Cell Mass by Increasing β-Cell Survival
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) was the most up-regulated gene in obese panc...
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Published in | Endocrinology (Philadelphia) Vol. 151; no. 8; pp. 3577 - 3588 |
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Main Authors | , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Endocrine Society
01.08.2010
The Endocrine Society |
Subjects | |
Online Access | Get full text |
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Summary: | 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) was the most up-regulated gene in 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.
Cholecystokinin is up-regulated in the islet by obesity. Islet CCK expression prevents obesity-induced hyperglycemia by increasing β-cell survival and expanding β-cell mass. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Address all correspondence and requests for reprints to: Alan D. Attie, 433 Babcock Drive, Madison, Wisconsin 53706. E-mail: attie@biochem.wisc.edu. J.A.L. and P.W.R. contributed equally to this work. |
ISSN: | 0013-7227 1945-7170 |
DOI: | 10.1210/en.2010-0233 |