Inhibition of voltage-gated potassium channels mediates uncarboxylated osteocalcin-regulated insulin secretion in rat pancreatic β cells

Insulin secretion from pancreatic beta cells is important to maintain glucose homeostasis and is regulated by electrical activities. Uncarboxylated osteocalcin, a bone-derived protein, has been reported to regulate glucose metabolism by increasing insulin secretion, stimulating beta cell proliferation and improving insulin sensitivity. But the underlying mechanisms of uncarboxylated osteocalcin-modulated insulin secretion remain unclear. In the present study, we investigated the relationship of uncarboxylated osteocalcin-regulated insulin secretion and voltage-gated potassium (K-v) channels, voltage-gated calcium channels in rat beta cells. Insulin secretion was measured by radioimmunoassay. Channel currents and membrane action potentials were recorded using the conventional whole-cell patch-clamp technique. Calcium imaging system was used to analyze intracellular Ca2+ concentration ([Ca2+](i)). The data show that under 16.7 mmol/l glucose conditions uncarboxylated osteocalcin alone increased insulin secretion and [Ca2+](i), but with no such effects on insulin secretion and [Ca2+](i) in the presence of a K-v channel blocker, tetraethylammonium chloride. In the patch-clamp experiments, uncarboxylated osteocalcin lengthened action potential duration and significantly inhibited K-v currents, but had no influence on the characteristics of voltage-gated calcium channels. These results indicate that K-v channels are involved in uncarboxylated osteocalcin-regulated insulin secretion in rat pancreatic beta cells. By inhibiting K-v channels, uncarboxylated osteocalcin prolongs action potential duration, increases intracellular Ca2+ concentration and finally promotes insulin secretion. This finding provides new insight into the mechanisms of osteocalcin-modulated insulin secretion. (C) 2016 Elsevier B.V. All rights reserved.