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

Vergari, Elisa ; Knudsen, Jakob G ; Ramracheya, Reshma ; Salehi, Albert LU orcid ; Zhang, Quan ; Adam, Julie ; Asterholm, Ingrid Wernstedt ; Benrick, Anna ; Briant, Linford J B and Chibalina, Margarita V , et al. (2019) In Nature Communications 10(1).
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... (More)

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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publication status
published
subject
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
in
Nature Communications
volume
10
issue
1
article number
139
publisher
Nature Publishing Group
external identifiers
  • scopus:85059897193
  • pmid:30635569
ISSN
2041-1723
DOI
10.1038/s41467-018-08193-8
language
English
LU publication?
yes
id
b5e5bb65-5ec5-4b88-a4f2-aef21f67ce00
date added to LUP
2019-05-22 16:50:30
date last changed
2025-04-18 00:08:24
@article{b5e5bb65-5ec5-4b88-a4f2-aef21f67ce00,
  abstract     = {{<p>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.</p>}},
  author       = {{Vergari, Elisa and Knudsen, Jakob G and Ramracheya, Reshma and Salehi, Albert and Zhang, Quan and Adam, Julie and Asterholm, Ingrid Wernstedt and Benrick, Anna and Briant, Linford J B and Chibalina, Margarita V and Gribble, Fiona M and Hamilton, Alexander and Hastoy, Benoit and Reimann, Frank and Rorsman, Nils J G and Spiliotis, Ioannis I and Tarasov, Andrei and Wu, Yanling and Ashcroft, Frances M and Rorsman, Patrik}},
  issn         = {{2041-1723}},
  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}},
  language     = {{eng}},
  month        = {{01}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{Insulin inhibits glucagon release by SGLT2-induced stimulation of somatostatin secretion}},
  url          = {{http://dx.doi.org/10.1038/s41467-018-08193-8}},
  doi          = {{10.1038/s41467-018-08193-8}},
  volume       = {{10}},
  year         = {{2019}},
}