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

Area of Science:

• Endocrinology
• Diabetes Research
• Metabolic Regulation

Background:

• Hypoglycaemia is a critical complication of insulin therapy in diabetes.
• Normally, glucagon secretion counteracts low blood glucose by stimulating hepatic glucose production.
• This vital counterregulatory mechanism is compromised in diabetic individuals.

Purpose of the Study:

• To investigate the mechanism by which insulin affects glucagon secretion in the context of diabetes.
• To explore the role of somatostatin in mediating insulin's effect on glucagon.
• To assess the potential of targeting the somatostatin pathway to improve glucose control in diabetes.

Main Methods:

• Experiments were conducted using mouse models and isolated human islets.
• Genetic ablation of insulin receptors in δ-cells was performed.
• The effects of dapagliflozin (a sodium-glucose co-transporter-2 inhibitor) and somatostatin receptor antagonists were evaluated.
• Insulin's hypoglycaemic effect was assessed in vivo.

Main Results:

• Therapeutic insulin concentrations inhibit glucagon secretion indirectly via somatostatin release from δ-cells.
• This inhibitory effect is abolished by removing insulin receptors from δ-cells or by using SGLT2 inhibitors or SSTR antagonists.
• These interventions counteract insulin's glucose-lowering effect in vivo.
• The findings were replicated in isolated human islets.

Conclusions:

• Insulin suppresses glucagon secretion through a paracrine mechanism involving somatostatin.
• This pathway is a key mediator of insulin's impact on glucose counterregulation.
• Somatostatin receptor or SGLT2 antagonists could serve as valuable adjuncts to insulin therapy for managing diabetes.