Insulin secretion (revision 3)

Insulin secretion is the regulated release of insulin from the beta cells of the pancreatic islets. It is triggered by glucose metabolism within the beta cell rather than by glucose binding to a receptor, and it is amplified by a second set of signals — among them the incretin hormones — that have no effect in the absence of the trigger.^[1]

The distinction between triggering and amplifying pathways is the single most important idea for understanding why GLP-1 receptor agonists rarely cause hypoglycaemia while sulfonylureas frequently do. Sulfonylureas act on the triggering pathway and initiate secretion regardless of glucose; incretins act on the amplifying pathway and can only enlarge a response that glucose has already begun.^[2]

Glucose enters the beta cell through GLUT1 and GLUT3 transporters and is phosphorylated by glucokinase, whose kinetics — a high K_m near 8 mM and no product inhibition — make it the rate-limiting step and the cell's effective glucose sensor. Subsequent glycolysis and mitochondrial oxidation raise the cytosolic ATP:ADP ratio.^[1]

The rise in ATP:ADP closes ATP-sensitive potassium channels. The membrane depolarises, voltage-gated calcium channels open, cytosolic calcium rises, and the calcium rise triggers exocytosis of insulin granules. Sulfonylureas close the same potassium channel pharmacologically, which is why their action is glucose-independent, and loss-of-function mutations in the channel produce congenital hyperinsulinism.^[1]