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

Elisa Vergari, Jakob G. Knudsen, Reshma Ramracheya, Albert Salehi, Quan Zhang, Julie Adam, Ingrid Wernstedt Asterholm, Anna Benrick, Linford J. B. Briant, Margarita V. Chibalina, Fiona M. Gribble, Alexander Hamilton, Benoit Hastoy, Frank Reimann, Nils J. G. Rorsman, Ioannis I. Spiliotis, Andrei Tarasov, Yanling Wu, Frances M. Ashcroft and Patrik Rorsman ()
Additional contact information
Elisa Vergari: Churchill Hospital
Jakob G. Knudsen: Churchill Hospital
Reshma Ramracheya: Churchill Hospital
Albert Salehi: University of Göteborg
Quan Zhang: Churchill Hospital
Julie Adam: Churchill Hospital
Ingrid Wernstedt Asterholm: University of Göteborg
Anna Benrick: University of Göteborg
Linford J. B. Briant: Churchill Hospital
Margarita V. Chibalina: Churchill Hospital
Fiona M. Gribble: University of Cambridge School of Clinical Medicine
Alexander Hamilton: Churchill Hospital
Benoit Hastoy: Churchill Hospital
Frank Reimann: University of Cambridge School of Clinical Medicine
Nils J. G. Rorsman: Churchill Hospital
Ioannis I. Spiliotis: Churchill Hospital
Andrei Tarasov: Churchill Hospital
Yanling Wu: University of Göteborg
Frances M. Ashcroft: University of Göteborg
Patrik Rorsman: Churchill Hospital

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-018-08193-8

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