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

Research output: Contribution to journal › Article › peer-review

136 Citations (Scopus)

165 Downloads (Pure)

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

Funding

E.V. was supported by the Wellcome Trust OXION training programme. R.R. and Q.Z. held/holds Diabetes UK RD Lawrence Fellowships. L.J.B.B. is supported by a Sir Henry Wellcome Postdoctoral Fellowship. A.H.’s studentship was funded by Diabetes UK. J.G. K. is supported by a Novo Nordisk postdoctoral fellowship run in partnership with the University of Oxford. Supported by the Wellcome Trust (P.R., F.M.A., F.M.G. and F.R.), the European Foundation for the Study of Diabetes (P.R.), the National Institute of Health Research (P.R.), the Diabetes Research and Wellness Foundation (A.S.), the Swedish Research Council (P.R.) and the Diabetes Research and Wellness Foundation (A.S.) and the Knut och Alice Wallenbergs Stiftelse (P.R.).

UN SDGs

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

SDG 3 Good Health and Well-being

Keywords

Diabetes
Insulin signalling

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10.1038/s41467-018-08193-8Licence: CC BY

Insulin inhibits Pub VFinal published version, 985 KBLicence: CC BY

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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.",

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year = "2019",

month = jan,

day = "11",

doi = "10.1038/s41467-018-08193-8",

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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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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.

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

Abstract

Funding

UN SDGs

Keywords

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