Insulin Secretion Depends on Intra-islet Glucagon Signaling
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Insulin Secretion Depends on Intra-islet Glucagon Signaling. / Svendsen, Berit; Larsen, Olav; Gabe, Maria Buur Nordskov; Christiansen, Charlotte Bayer; Rosenkilde, Mette M; Drucker, Daniel J; Holst, Jens Juul.
In: Cell Reports, Vol. 25, No. 5, 2018, p. 1127-1134.E2.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Insulin Secretion Depends on Intra-islet Glucagon Signaling
AU - Svendsen, Berit
AU - Larsen, Olav
AU - Gabe, Maria Buur Nordskov
AU - Christiansen, Charlotte Bayer
AU - Rosenkilde, Mette M
AU - Drucker, Daniel J
AU - Holst, Jens Juul
N1 - Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
PY - 2018
Y1 - 2018
N2 - 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, β 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 β cell GLP-1R activation results predominantly from glucagon action. Our results suggest that combined activity of glucagon and GLP-1 receptors is essential for β cell secretory responses, emphasizing a role for paracrine intra-islet glucagon actions to maintain appropriate insulin secretion. Glucose-stimulated insulin secretion can be regulated by glucagon and GLP-1 receptors on paracrine β-cells. Svendsen et al. find that complete blockade of glucagon signaling in islets severely limits insulin secretion but establish that paracrine glucagon signaling involves both the glucagon and GLP-1 receptors.
AB - 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, β 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 β cell GLP-1R activation results predominantly from glucagon action. Our results suggest that combined activity of glucagon and GLP-1 receptors is essential for β cell secretory responses, emphasizing a role for paracrine intra-islet glucagon actions to maintain appropriate insulin secretion. Glucose-stimulated insulin secretion can be regulated by glucagon and GLP-1 receptors on paracrine β-cells. Svendsen et al. find that complete blockade of glucagon signaling in islets severely limits insulin secretion but establish that paracrine glucagon signaling involves both the glucagon and GLP-1 receptors.
KW - exendin(9-39)
KW - GLP-1 receptor
KW - glucagon
KW - glucagon receptor
KW - Intra-islet communication
KW - perfused mouse pancreas
U2 - 10.1016/j.celrep.2018.10.018
DO - 10.1016/j.celrep.2018.10.018
M3 - Journal article
C2 - 30380405
VL - 25
SP - 1127-1134.E2
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 5
ER -
ID: 204461637