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; Patrick Rorsman

doi:10.1038/s41467-018-08193-8

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, Patrick Rorsman

School of Biomedical Sciences

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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.

Original language	English
Article number	139 (2019)
Number of pages	11
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-08193-8
Publication status	Published (in print/issue) - 11 Jan 2019

Keywords

Diabetes
Insulin signalling

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Vergari, E., Knudsen, J. G., Ramracheya, R., Salehi, A., Zhang, Q., Adam, J., Asterholm, I. W., Benrick, A., Briant, L. J. B., Chibalina, M. V., Gribble, F. M., Hamilton, A., Hastoy, B., Reimann, F., Rorsman, N. J. G., Spiliotis, I. I., Tarasov, A., Wu, Y., Ashcroft, F. M., & Rorsman, P. (2019). Insulin inhibits glucagon release by SGLT2-induced stimulation of somatostatin secretion. Nature Communications, 10(1), Article 139 (2019). https://doi.org/10.1038/s41467-018-08193-8

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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{\textquoteright}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{\textquoteright}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.",

keywords = "Diabetes, Insulin signalling",

author = "Elisa Vergari and Knudsen, {Jakob G.} and Reshma Ramracheya and Albert Salehi and Quan Zhang and Julie Adam and Asterholm, {Ingrid Wernstedt} and Anna Benrick and Briant, {Linford J.B.} and Chibalina, {Margarita V.} and Gribble, {Fiona M.} and Alexander Hamilton and Benoit Hastoy and Frank Reimann and Rorsman, {Nils J.G.} and Spiliotis, {Ioannis I.} and Andrei Tarasov and Yanling Wu and Ashcroft, {Frances M.} and Patrick Rorsman",

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Vergari, E, Knudsen, JG, Ramracheya, R, Salehi, A, Zhang, Q, Adam, J, Asterholm, IW, Benrick, A, Briant, LJB, Chibalina, MV, Gribble, FM, Hamilton, A, Hastoy, B, Reimann, F, Rorsman, NJG, Spiliotis, II, Tarasov, A, Wu, Y, Ashcroft, FM & Rorsman, P 2019, 'Insulin inhibits glucagon release by SGLT2-induced stimulation of somatostatin secretion', Nature Communications, vol. 10, no. 1, 139 (2019). https://doi.org/10.1038/s41467-018-08193-8

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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, Patrick

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Y1 - 2019/1/11

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 - Diabetes

KW - Insulin signalling

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AN - SCOPUS:85059897193

SN - 2041-1723

VL - 10

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 139 (2019)

ER -

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

Abstract

Keywords

UN SDGs

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