Dysregulation of Glucagon Secretion in Glucagon Receptor Null Pancreatic Islets

The glucagon receptor knockout mouse (Gcgr-/-) displays high circulating glucagon levels in the fed state and increased alpha cell mass due to alpha cell hyperplasia. In order to investigate possible mechanisms for the hyperglucagonemia seen in this model, we analyzed ex vivo islet glucagon secretion in response to known secretagogues and inhibitors. In addition, we analyzed gene expression in Gcgr-/- islets by microarray technology. The goal of the analysis was to identify changes in gene expression that might account for high circulating glucagon. Our results show that Gcgr-/- islets secrete glucagon constitutively and differ from wildtype islets in their response to known modulators of pancreatic exocrine secretion. Insulin secretion is regulated similarly in wildtype and Gcgr-/- islets. Array analysis indicated changes in several genes required for glucose sensing and in genes encoding channel regulatory subunits. Transcripts involved in alpha and beta cell differentiation were also altered in the Gcgr-/- islet. MATERIALS AND METHODS