Figure 1.

Glucose regulation of insulin secretion and PHDs. In pancreatic β-cells, one important glucose-derived signal is a rise in the ATP:ADP ratio, which stimulates closure of K_ATP channels, resulting in plasma membrane depolarization, activation of voltage-dependent Ca²⁺ channels, and Ca²⁺-mediated stimulation of insulin granule exocytosis. This so-called “K_ATP channel-dependent” mechanism appears to be particularly important in ‘triggering’ exocytosis of a small number of granules from a plasma membrane-docked “readily releasable pool (RRP)” responsible for the first, acute phase of insulin release. In contrast, in the second and sustained phase of insulin secretion, ATP and Ca²⁺ may play only a permissive roles, allowing other anaplerotic-derived second messengers, such as NADPH and α-ketoglutarate, to come to the forefront. A number of glucose-derived metabolites can regulate PHDs activity. Glucose transporter 2 (GLUT2), K_ATP channel (K_ATP), voltage-dependent Ca²⁺ channels, mitochondrial pyruvate carrier (MPC), adenine nucleotide carrier (ANC), citrate carrier (CIC), α-ketoglutarate carrier (OGC), dicarboxylate carrier (DIC), malic enzyme (Me_m), pyruvate carboxylase (PC), pyruvate dehydrogenase (PDH). Figure was created with BioRender.com.