Beta-cell glucose-stimulated insulin secretion (K-ATP triggering pathway)

The triggering pathway by which the pancreatic beta cell converts a rise in blood glucose into insulin release. Glucokinase phosphorylates glucose at a rate that tracks the physiological glucose range and so sets the threshold of the pathway; glycolytic and mitochondrial oxidation of the resulting glucose 6-phosphate raises the cytosolic ATP/ADP ratio; the rise in ATP/ADP closes the ATP-sensitive potassium (K-ATP) channel formed by the Kir6.2 pore and the SUR1 regulatory subunit; the loss of K+ efflux depolarises the plasma membrane, opening L-type voltage-gated calcium channels; and the Ca2+ influx triggers exocytosis of insulin-containing dense-core granules. Glutamate dehydrogenase couples amino-acid (leucine/glutamine) oxidation into the same ATP/ADP signal, and the mitochondrial enzyme HADH restrains glutamate dehydrogenase; gain of the first and loss of the second both produce hyperinsulinism.

Scope: the K-ATP-dependent triggering pathway only. The K-ATP-independent amplifying pathway, incretin (GLP-1/GIP) and neural potentiation, insulin biosynthesis and prohormone processing (PCSK1/PCSK2/CPE), and the downstream actions of secreted insulin (modules/insulin_receptor_signaling.yaml) are outside the boundary. Steps described but not modelled as annotons, because no member has a reviewed gene record in this repository yet: beta-cell glucose uptake (GLUT2/SLC2A2 in rodents; GLUT1/SLC2A1 is the dominant human beta-cell glucose transporter), the glycolytic and mitochondrial machinery that converts glucose 6-phosphate into ATP (pyruvate carboxylase, the TCA cycle and oxidative phosphorylation), and the granule exocytosis machinery (SNAP25, syntaxin-1A, synaptotagmin-7 and VAMP2). These should be added as annotons once those genes are reviewed; the mitochondrial ATP step is represented here as a connection description rather than a part. Grounding: participants are grounded as human UniProt gene products whose ai-gene-review core functions supply the molecular-function and location terms. No PANTHER family or PAINT ancestral node is asserted: the module is deliberately a concrete human instance, and family ids were not established for every member, so they are omitted rather than guessed. The ABCC8 review is COMPLETE as of this change; its five Ensembl-projected rows, which are unrelated to the channel function used here, are resolved. The CACNA1C review is still DRAFT at the time of writing. Disease mapping: loss of K-ATP function (ABCC8, KCNJ11), gain of glucokinase function (GCK), gain of glutamate dehydrogenase function (GLUD1) and loss of HADH all cause congenital hyperinsulinism; K-ATP gain of function and glucokinase loss of function cause neonatal diabetes and GCK-MODY. Other congenital hyperinsulinism genes deliberately not modelled as parts: SLC16A1 (MCT1) and HK1 are beta-cell "disallowed" genes, silenced in normal beta cells; their hyperinsulinism is caused by ectopic de-repression (a disease state), so neither acts in the normal pathway. HNF4A and HNF1A are transcription factors that sustain the beta-cell gene program and act upstream of, not within, the triggering pathway. UCP2 restrains glucose-driven mitochondrial ATP generation by exporting C4 metabolites from the matrix, but its role in human beta-cell secretion is disputed, so it is left out until better grounded.