Insulinostatic activity of cerebellin--evidence from in vivo and in vitro studies in rats

Cerebellin (CER) is a neuromodulatory hexadecapeptide that originates from the precursor protein precerebellin (Cbln1). Four highly homologous isoforms of Cbln are known (Cbln1-Cbln4), which are expressed in the central nervous system (CNS) and in peripheral tissues. CER modulates synaptic structure formation in the CNS, whereas in the peripheral tissues CER regulates Catecholamine secretion. Cbln is also expressed in the pancreas; however, its function in the pancreas is unknown. Here, we demonstrate the role of CER in regulating Insulin secretion in vivo and in vitro. We identified Cbln1 and Cbln3 transcripts in rat pancreatic islets and detected Cbln-immunoreactivity, predominantly located in the periphery of the rat endocrine pancreas. In vivo, CER reduced plasma Insulin levels in rats after 1 and 2 h. CER decreased Insulin secretion from isolated rat pancreatic islets at high (11 mM), but not at low (3.33 mM) glucose concentration. CER inhibited stimulated Insulin secretion from clonal rat insulinoma (INS-1) cells, reduced forskolin-induced production of cAMP and intracellular calcium concentration. Our study demonstrates for the first time that Cbln1 and Cbln3 are expressed in the rat endocrine pancreas. Furthermore, we identify CER as an insulinostatic factor, which decreases intracellular cAMP production and calcium in INS-1 cells.