Pancreatic beta-cell insulin secretion pathways (GSIS) (GSIS)

The pancreatic beta-cell insulin secretion pathways are the integrated biological processes that enable the pancreas to release insulin in response to fluctuating blood glucose levels [KEGG hsa04911, Frontiers in Endocrinology, 2023]. The core "triggering" pathway involves glucose uptake via GLUT transporters and its metabolism by glucokinase, which increases the intracellular ATP/ADP ratio and leads to the closure of ATP-sensitive potassium (K-ATP) channels [Diabetes, 2004; PMC, 2018]. This closure causes membrane depolarization and the opening of voltage-gated calcium channels, resulting in a calcium influx that triggers the exocytosis of insulin-containing granules [PMC, 2018; Wikipedia]. Additionally, "amplifying" pathways involving incretin receptors (e.g., GLP-1R) and fatty acid receptors (e.g., GPR40) enhance this secretory response through secondary messengers like cAMP and phospholipase C [PMC, 2021; Wikipedia]. Dysregulation of these pathways is a primary driver of type 2 diabetes mellitus, making them critical targets for various antidiabetic drug classes, including sulfonylureas, GLP-1 receptor agonists, and glucokinase activators [Diabetes, 2004; ResearchGate, 2022]. Impairment in these pathways leads to chronic hyperglycemia and the progression of metabolic disease [PMC, 2021].

Other names

Glucose-stimulated insulin secretionStimulus-secretion couplingBeta-cell triggering and amplifying pathwaysInsulin secretion pathway

Drugs targeting these pathways act by closing ATP-sensitive potassium channels (sulfonylureas), activating the GLP-1 receptor (incretin mimetics), or enhancing glucose sensing via glucokinase activation, all of which increase intracellular calcium or cAMP to trigger insulin exocytosis [Diabetes, 2004; PMC, 2021; PMC, 2018].