Journal
CELL REPORTS
Volume 25, Issue 5, Pages 1127-+Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2018.10.018
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Funding
- Novo Nordisk Foundation
- Lundbeck Foundation [2011-9560, 2016-2394]
- Carlsberg Foundation [CF16-0996]
- Danish Council for Independent Research [6110-00660]
- Canada Research Chairs Program
- BBDC-Novo Nordisk Chair in Incretin Biology
- CIHR [136942, 154321]
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The intra-islet theory states that glucagon secretion is suppressed when insulin secretion is stimulated, but glucagon's role in intra-islet paracrine regulation is controversial. This study investigated intra-islet functions of glucagon in mice. We examined glucagon-induced insulin secretion using isolated perfused pancreata from wild-type, GLP-1 receptor (GLP-1R) knockout, diphtheria toxin-induced proglucagon knockdown, beta cell-specific glucagon receptor (Gcgr) knockout, and global Gcgr knockout (Gcgr(-/-)) mice. We found that glucagon stimulates insulin secretion through both Gcgr and GLP-1R. Moreover, loss of either Gcgr or GLP-1R does not change insulin responses, whereas combined blockage of both receptors significantly reduces insulin secretion. Active GLP-1 is identified in pancreatic perfusate from Gcgr(-/-) but not wild-type mice, suggesting that b cell GLP-1R activation results predominantly from glucagon action. Our results suggest that combined activity of glucagon and GLP-1 receptors is essential for beta cell secretory responses, emphasizing a role for paracrine intra-islet glucagon actions to maintain appropriate insulin secretion.
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