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; Patrik 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, Patrik Rorsman

49 Citationer (Scopus)

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.

Originalsprog	Engelsk
Artikelnummer	139
Tidsskrift	Nature Communications
Vol/bind	10
Antal sider	11
ISSN	2041-1723
DOI	https://doi.org/10.1038/s41467-018-08193-8
Status	Udgivet - 1 dec. 2019
Udgivet eksternt	Ja

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

Insulin inhibits glucagon release by SGLT2-induced stimulation of somatostatin secretionForlagets udgivne version, 985 KBLicens: CC BY

Citationsformater

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, Artikel 139. https://doi.org/10.1038/s41467-018-08193-8

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, bind 10, 139. 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'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.",

keywords = "Animals, Benzhydryl Compounds/pharmacology, Blood Glucose/analysis, Diabetes Mellitus/drug therapy, Female, Glucagon/metabolism, Glucagon-Secreting Cells/drug effects, Glucosides/pharmacology, Humans, Hypoglycemia/pathology, Insulin/metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Receptor, Insulin/genetics, Receptors, Somatostatin/antagonists & inhibitors, Sodium-Glucose Transporter 2/metabolism, Sodium-Glucose Transporter 2 Inhibitors/pharmacology, Somatostatin/metabolism",

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 Patrik Rorsman",

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

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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 - 2019/12/1

Y1 - 2019/12/1

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

SN - 2041-1723

VL - 10

JO - Nature Communications

JF - Nature Communications

M1 - 139

ER -

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

Abstract

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