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 μmol/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.