Figure 2.

Current working hypothesis depicting mechanisms regulating insulin secretion from pancreatic β-cells and proposed sites for interference by agmatine. ATP generated by glucose metabolism shuts down K⁺-channels, resulting in depolarization and subsequent influx of Ca²⁺ through voltage-activated Ca²⁺-channels. This influx of Ca²⁺ increases cytosolic Ca²⁺ concentration, which is accompanied by mobilization of Ca²⁺ from the endoplasmic reticulum (ER), an event triggering secretory granule translocation and exocytotic release of insulin. The respective binding of imidazolines (such as efaroxan) and sulphonylurea derivatives (such as glibenclamide) to I₃-binding sites and the sulphonylurea receptor, also closes the K⁺-channels. Agmatine does not bind to I₃-binding sites. However, agmatine may enhance insulin secretion via its metabolites, after it is taken up by specific transporters. Putrescine, spermidine are necessary for proinsulin biosynthesis, whereas spermine may exert a stimulatory or permissive role in RNA transcription and long-term insulin release. Polyamines are also probably involved in regulation of cytosolic Ca²⁺-concentration by blocking Ca²⁺-influx and its release from intracellular stores. Abbreviations: …▪quot; : stimulation; …•: inhibition.