BK channels affect glucose homeostasis and cell viability of murine pancreatic beta cells

Evidence is accumulating that Ca2+-regulated K+ (K-Ca) channels are important for beta cell function. We used BK channel knockout (BK-KO) mice to examine the role of these K-Ca channels for glucose homeostasis, beta cell function and viability.

Glucose and insulin tolerance were tested with male wild-type and BK-KO mice. BK channels were detected by single-cell RT-PCR, cytosolic Ca2+ concentration ([Ca2+](c)) by fura-2 fluorescence, and insulin secretion by radioimmunoassay. Electrophysiology was performed with the patch-clamp technique. Apoptosis was detected via caspase 3 or TUNEL assay.

BK channels were expressed in murine pancreatic beta cells. BK-KO mice were normoglycaemic but displayed markedly impaired glucose tolerance. Genetic or pharmacological deletion of the BK channel reduced glucose-induced insulin secretion from isolated islets. BK-KO and BK channel inhibition (with iberiotoxin, 100 nmol/l) broadened action potentials and abolished the after-hyperpolarisation in glucose-stimulated beta cells. However, BK-KO did not affect action potential frequency, the plateau potential at which action potentials start or glucose-induced elevation of [Ca2+](c). BK-KO had no direct influence on exocytosis. Importantly, in BK-KO islet cells the fraction of apoptotic cells and the rate of cell death induced by oxidative stress (H2O2, 10-100 mu mol/l) were significantly increased compared with wild-type controls. Similar effects were obtained with iberiotoxin. Determination of H2O2-induced K+ currents revealed that BK channels contribute to the hyperpolarising K+ current activated under conditions of oxidative stress.

Ablation or inhibition of BK channels impairs glucose homeostasis and insulin secretion by interfering with beta cell stimulus-secretion coupling. In addition, BK channels are part of a defence mechanism against apoptosis and oxidative stress.