In studies of gene-ablated mice, activin signaling through activin type JIB receptors (ActRIIB) and Smad2 has been shown to regulate not only pancreatic beta cell mass but also insulin secretion. However, it still remains unclear whether gain of function of activin signaling is involved in the modulation of pancreatic beta cell mass and insulin secretion. To identify distinct roles of activin signaling in pancreatic beta cells, the Cre-loxP system was used to activate signaling through activin type IB receptor (ActRIB) in pancreatic beta cells. The resultant mice (pancreatic beta cell-specific ActRIB transgenic (Tg) mice; ActRIBCA beta Tg) exhibited a defect in glucose-stimulated insulin secretion (GSIS) and a progressive impairment of glucose tolerance. Patch-clamp techniques revealed that the activity of ATP-sensitive K+ channels (K-ATP channels) was decreased in mutant 13 cells. These results indicate that an appropriate level of activin signaling may be required for GSIS in pancreatic 13 cells, and that activin signaling involves modulation of K-ATP channel activity. (C) 2014 Elsevier Inc. All rights reserved.