Glucose-stimulated insulin secretion pathway (GSIS)

The glucose-stimulated insulin secretion (GSIS) pathway is the primary physiological mechanism by which pancreatic beta cells release insulin in response to rising blood glucose levels (StatPearls: NBK534806). Glucose enters the beta cell via GLUT transporters and undergoes glycolysis, increasing the intracellular ATP/ADP ratio, which leads to the closure of ATP-sensitive potassium (KATP) channels (PubMed: 28814421). This closure causes membrane depolarization, opening voltage-gated calcium channels and triggering the exocytosis of insulin-containing granules (UniProt: P48346). Dysregulation of this pathway is a hallmark of Type 2 Diabetes Mellitus, where beta-cell sensitivity to glucose is impaired, leading to chronic hyperglycemia (NIH: PMC4459260). Pharmacological interventions often target specific components of this pathway, such as KATP channels or incretin receptors, to restore or enhance insulin release and maintain glycemic control (PubChem: SID 472386361).

Other names

Glucose-responsive insulin secretionPancreatic beta-cell glucose signalingGlucose-induced insulin secretion

Drugs modulate this pathway by closing ATP-sensitive potassium (KATP) channels to induce membrane depolarization (sulfonylureas/meglitinides) or by activating GLP-1 receptors to increase intracellular cAMP, which potentiates glucose-dependent insulin release (GLP-1 agonists/DPP-4 inhibitors) (PubMed: 19049586, StatPearls: NBK534806).