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

• 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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)

Nyckelord

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

pancreatic beta-cells

antagonism improves glucagon

gated ion channels

delta-cells

counterregulatory responses

cellular perfusion

alpha

receptor

dapagliflozin

hypoglycemia

Science & Technology - Other Topics

agner ji

1988

diabetes

v37

p1715

Publikations- och innehållstyp

art (ämneskategori)

ref (ämneskategori)