Insulin inhibits glucagon release by SGLT2-induced stimulation of somatostatin secretion
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Insulin inhibits glucagon release by SGLT2-induced stimulation of somatostatin secretion. / Vergari, Elisa; Knudsen, Jakob G.; Ramracheya, Reshma; Salehi, Albert; Zhang, Quan; Adam, Julie; Asterholm, Ingrid Wernstedt; Benrick, Anna; Briant, Linford J B; Chibalina, Margarita V; Gribble, Fiona M; Hamilton, Alexander; Hastoy, Benoit; Reimann, Frank; Rorsman, Nils J G; Spiliotis, Ioannis I; Tarasov, Andrei; Wu, Yanling; Ashcroft, Frances M; Rorsman, Patrik.
I: Nature Communications, Bind 10, 139, 2019.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Insulin inhibits glucagon release by SGLT2-induced stimulation of somatostatin secretion
AU - Vergari, Elisa
AU - Knudsen, Jakob G.
AU - Ramracheya, Reshma
AU - Salehi, Albert
AU - Zhang, Quan
AU - Adam, Julie
AU - Asterholm, Ingrid Wernstedt
AU - Benrick, Anna
AU - Briant, Linford J B
AU - Chibalina, Margarita V
AU - Gribble, Fiona M
AU - Hamilton, Alexander
AU - Hastoy, Benoit
AU - Reimann, Frank
AU - Rorsman, Nils J G
AU - Spiliotis, Ioannis I
AU - Tarasov, Andrei
AU - Wu, Yanling
AU - Ashcroft, Frances M
AU - Rorsman, Patrik
PY - 2019
Y1 - 2019
N2 - 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 δ-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.
AB - 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 δ-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.
KW - Animals
KW - Benzhydryl Compounds/pharmacology
KW - Blood Glucose/analysis
KW - Diabetes Mellitus/drug therapy
KW - Female
KW - Glucagon/metabolism
KW - Glucagon-Secreting Cells/drug effects
KW - Glucosides/pharmacology
KW - Humans
KW - Hypoglycemia/pathology
KW - Insulin/metabolism
KW - Male
KW - Mice
KW - Mice, Inbred C57BL
KW - Mice, Knockout
KW - Receptor, Insulin/genetics
KW - Receptors, Somatostatin/antagonists & inhibitors
KW - Sodium-Glucose Transporter 2/metabolism
KW - Sodium-Glucose Transporter 2 Inhibitors/pharmacology
KW - Somatostatin/metabolism
U2 - 10.1038/s41467-018-08193-8
DO - 10.1038/s41467-018-08193-8
M3 - Journal article
C2 - 30635569
VL - 10
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
M1 - 139
ER -
ID: 220850488