Insulin Secretion Depends on Intra-islet Glucagon Signaling

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

SN - 2639-1856

VL - 25

SP - 1127-1134.E2

JO - Cell Reports

JF - Cell Reports

IS - 5

ER -