GPRC6A mediates responses to osteocalcin in β‐cells in vitro and pancreas in vivo

A bone‐pancreas endocrine loop has been identified recently that involves insulin secreted from β‐cells in the pancreas stimulating insulin receptors in osteoblasts, leading to osteoblastic differentiation and increased secretion of osteocalcin (Ocn), a bone‐derived hormone that regulates insulin secretion in β‐cells. The identity of the Ocn‐sensing receptor in β‐cells is a missing component of this endocrine loop. The abnormalities in glucose homeostasis in Gprc6a null mice suggests that this pertussis toxin–sensitive G protein–coupled receptor is a candidate for mediating the effects of Ocn on insulin secretion in the pancreas. In support of this possibility, we found that transfection of non‐ Gprc6a‐ expressing HEK‐293 cells with a full‐length Gprc6a cDNA imparted a dose‐dependent response to Ocn (5 to 60 ng/mL), as measured by PKD1 and ERK phosphorylation. In addition, Gprc6a is highly expressed in mouse pancreatic tissue and in the mouse TC‐6 pancreatic β‐cell line. Ocn also stimulated ERK activity in TC‐6 pancreatic β‐cells. Finally, intraperitoneal injection of Ocn stimulated ERK activity in the pancreas and increased serum insulin levels in wild‐type mice, but these responses were markedly attenuated in Gprc6a −/− mice. These findings suggest that GPRC6A is a candidate for mediating the response to Ocn in the bone‐pancreas endocrine loop regulating insulin signaling. © 2011 American Society for Bone and Mineral Research.