Pancreatic beta cell pathways of insulin secretion

Diagram of β-cell fuel-mediated insulin secretion showing 9 genes currently associated with congenital HI (bold and underlined). Glucose oxidation stimulates insulin secretion via a "triggering pathway" by inhibiting ATP-sensitive KATP channels, leading to plasma membrane depolarization, activation of voltage-gated calcium channels, elevation of cytosolic calcium, and release of insulin from stored granules. Insulin secretion is also promoted by various "amplification pathways" once cytosolic calcium is elevated, eg, by mitochondria-derived signals or by membrane receptors such as the GLP-1 receptor. Amino acids stimulate insulin secretion through several mechanisms, especially leucine, which allosterically activates GDH enzymatic activity to increase oxidative deamination of glutamate to α-KG; GDH activity is allosterically inhibited by GTP and by the SCHAD enzyme protein. During glucose-stimulated insulin secretion, the rise in α-KG increases flux through a gamma amino butyric acid shunt and generates γ-hydroxybutyrate (GHB), which is released as a paracrine inhibitor of glucagon secretion from α-cells. HI-associated genes include: GCK (glucokinase), MCT1 (monocarboxylate transporter 1), UCP2 (uncoupling protein 2), SCHAD (short-chain 3-hydroxyacyl-CoA dehydrogenase), GDH (glutamate dehydrogenase), HNF1A (hepatocyte nuclear factor 1A), HNF4A (hepatocyte nuclear factor 4A), SUR1 (sulfonylurea receptor 1), Kir6.2 (inwardly rectifying potassium channel 6.2).