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Insulin inhibits glucagon release by SGLT2-induced stimulation of somatostatin secretion

Journal article
Authors E. Vergari
J. G. Knudsen
R. Ramracheya
Albert Salehi
Q. Zhang
J. Adam
Ingrid Wernstedt Asterholm
Anna Benrick
L. J. B. Briant
M. V. Chibalina
F. M. Gribble
A. Hamilton
B. Hastoy
F. Reimann
N. J. G. Rorsman
II Spiliotis,
A. Tarasov
Yanling Wu
Frances M. Ashcroft
Patrik Rorsman
Published in Nature Communications
Volume 10
ISSN 2041-1723
Publication year 2019
Published at Institute of Neuroscience and Physiology
Institute of Neuroscience and Physiology, Department of Physiology
Language en
Keywords pancreatic beta-cells, antagonism improves glucagon, gated ion channels, delta-cells, counterregulatory responses, cellular perfusion, alpha, receptor, dapagliflozin, hypoglycemia, Science & Technology - Other Topics, agner ji, 1988, diabetes, v37, p1715
Subject categories Endocrinology and Diabetes


Hypoglycaemia (low plasma glucose) is a serious and potentially fatal complication of insulin-treated diabetes. In healthy individuals, hypoglycaemia triggers glucagon secretion, which restores normal plasma glucose levels by stimulation of hepatic glucose production. This counterregulatory mechanism is impaired in diabetes. Here we show in mice that therapeutic concentrations of insulin inhibit glucagon secretion by an indirect (paracrine) mechanism mediated by stimulation of intra-islet somatostatin release. Insulin's capacity to inhibit glucagon secretion is lost following genetic ablation of insulin receptors in the somatostatin-secreting delta-cells, when insulin-induced somatostatin secretion is suppressed by dapagliflozin (an inhibitor of sodium-glucose co-tranporter-2; SGLT2) or when the action of secreted somatostatin is prevented by somatostatin receptor (SSTR) antagonists. Administration of these compounds in vivo antagonises insulin's hypoglycaemic effect. We extend these data to isolated human islets. We propose that SSTR or SGLT2 antagonists should be considered as adjuncts to insulin in diabetes therapy.

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