Hyperinsulinism of infancy - The regulated release of insulin by K-ATP channel-independent pathways

Hyperinsulinism of infancy (HI) is a congenital defect in the regulated rel ease of insulin from pancreatic beta -cells. Here we describe stimulus-secr etion coupling mechanisms in beta -cells and intact islets of Langerhans is olated from three patients with a novel SUR1 gene defect. 2154+3 A to G SUR 1 (GenBank accession number L78207) is the first report of familial HI amon g nonconsanguineous Caucasians identified in the U.K. Using patch-clamp met hodologies, we have shown that this mutation is associated with both a decr ease in the number of operational ATP-sensitive K+ channels (K-ATP channels ) in beta -cells and impaired ADP-dependent regulation, There were no appar ent defects in the regulation of Ca2+- and voltage-gated K+ channels or del ayed rectifier K+ channels. Intact HI beta -cells were spontaneously electr ically active and generating Ca2+ action currents that were largely insensi tive to diazoxide and somatostatin. As a consequence, when intact HI islets were challenged with glucose and tolbutamide, there was no rise in intrace llular free calcium ion concentration ([Ca2+](i)) over basal values. Capaci tance measurements used to monitor exocytosis in control and HI beta -cells revealed that there were no defects in Ca2+-dependent exocytotic events. F inally insulin release studies documented that whereas tolbutamide failed t o cause insulin secretion as a consequence of impaired [Ca2+](i) signaling, glucose readily promoted insulin release, Glucose was also found to augmen t the actions of protein kinase C- and protein kinase A-dependent agonists in the absence of extracellular Ca2+. These findings document the relations hip between SUR1 gene defects and insulin secretion in vivo and in vitro an d describe for the first time K-ATP channel-independent pathways of regulat ed insulin secretion in diseased human beta -cells.