Journal Article

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

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

2019

Overview

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. Impaired glucagon secretion in patients with diabetes causes hypoglycemia. Here the authors show that therapeutic concentrations of insulin inhibit alpha-cell glucagon secretion by stimulating delta-cell insulin receptor and the release of somatostatin. Blocking somatostatin secretion or action ameliorates this effect.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 14/19 / 1988 / 631/443/319/1642/137 / 631/80/86/2367 / 9/74 / 96/95 / agner ji / alpha / Animals / antagonism improves glucagon / Benzhydryl Compounds - pharmacology / Blood Glucose - analysis / cellular perfusion / Clinical Medicine / counterregulatory responses / dapagliflozin / delta-cells / Diabetes / Diabetes mellitus / Diabetes Mellitus - drug therapy / Diabetes Mellitus - pathology / Dissipation / Endocrinology and Diabetes / Endokrinologi och diabetes / Female / gated ion channels / Glucagon / Glucagon - metabolism / Glucagon-Secreting Cells - drug effects / Glucose / Glucosides - pharmacology / Humanities and Social Sciences / Humans / Hypoglycemia / Hypoglycemia - pathology / Insulin / Insulin - metabolism / Insulin receptors / Klinisk medicin / Male / Medical and Health Sciences / Medicin och hälsovetenskap / Mice / Mice, Inbred C57BL / Mice, Knockout / multidisciplinary / p1715 / pancreatic beta-cells / Paracrine signalling / receptor / Receptor, Insulin - genetics / Receptors, Somatostatin - antagonists & inhibitors / Reconstruction / Science / Science & Technology - Other Topics / Science (multidisciplinary) / Secretion / Sodium-Glucose Transporter 2 - metabolism / Sodium-Glucose Transporter 2 Inhibitors - pharmacology / Solitary waves / Somatostatin / Somatostatin - metabolism / Somatostatin receptors / Temporal resolution / v37