An intrinsic circadian clock of the pancreas is required for normal insulin release and glucose homeostasis in mice.

AIMS/HYPOTHESIS: Loss of circadian clocks from all tissues causes defective glucose homeostasis as well as loss of feeding and activity rhythms. Little is known about peripheral tissue clocks, so we tested the hypothesis that an intrinsic circadian clock of the pancreas is important for glucose homeostasis. METHODS: We monitored real-time bioluminescence of pancreas explants from circadian reporter mice and examined clock gene expression in beta cells by immunohistochemistry and in situ hybridisation. We generated mice selectively lacking the essential clock gene Bmal1 (also known as Arntl) in the pancreas and tested mutant mice and littermate controls for glucose and insulin tolerance, insulin production and behaviour. We examined islets isolated from mutants and littermate controls for glucose-stimulated insulin secretion and total insulin content. RESULTS: Pancreas explants exhibited robust circadian rhythms. Clock genes Bmal1 and Per1 were expressed in beta cells. Despite normal activity and feeding behaviour, mutant mice lacking clock function in the pancreas had severe glucose intolerance and defective insulin production; their isolated pancreatic islets had defective glucose-stimulated insulin secretion, but normal total insulin content. CONCLUSIONS/INTERPRETATION: The mouse pancreas has an autonomous clock function and beta cells are very likely to be one of the pancreatic cell types possessing an intrinsic clock. The Bmal1 circadian clock gene is required in the pancreas, probably in beta cells, for normal insulin secretion and glucose homeostasis. Our results provide evidence for a previously unrecognised molecular regulator of pancreatic glucose-sensing and/or insulin secretion.

Nuclear receptors, metabolism, and the circadian clock.

As ligand-dependent transcription factors, the nuclear receptor superfamily governs a remarkable array of rhythmic physiologic processes such as metabolism and reproduction. To provide a "molecular blueprint" for nuclear receptor function in circadian biology, we established a diurnal expression profile of all mouse nuclear receptors in critical metabolic tissues. Our finding of broad expression and tissue-specific oscillation of nuclear receptors along with their key target genes suggests that diurnal nuclear receptor expression may contribute to established rhythms in metabolic physiology and that nuclear receptors may be involved in coupling peripheral circadian clocks to divergent metabolic outputs. Conversely, nuclear receptors may serve peripheral clock input pathways, integrating signals from the light-sensing central clock in the suprachiasmatic nucleus and other environmental cues, such as nutrients and xenobiotics. Interplay between the core circadian clock and nuclear receptors may define a large-scale signaling network that links biological timing to metabolic physiology.