The molecular clock maintains energy constancy by producing circadian oscillations of rate-limiting enzymes involved in tissue metabolism across the day and night1,2,3. During periods of feeding, pancreatic islets secrete insulin to maintain glucose homeostasis, and although rhythmic control of insulin release is recognized to be dysregulated in humans with diabetes4, it is not known how the circadian clock may affect this process. Here we show that pancreatic islets possess self-sustained circadian gene and protein oscillations of the transcription factors CLOCK and BMAL1. The phase of oscillation of islet genes involved in growth, glucose metabolism and insulin signalling is delayed in circadian mutant mice, and both Clock5,6 and Bmal17 (also called Arntl) mutants show impaired glucose tolerance, reduced insulin secretion and defects in size and proliferation of pancreatic islets that worsen with age. Clock disruption leads to transcriptome-wide alterations in the expression of islet genes involved in growth, survival and synaptic vesicle assembly. Notably, conditional ablation of the pancreatic clock causes diabetes mellitus due to defective β-cell function at the very latest stage of stimulus–secretion coupling. These results demonstrate a role for the β-cell clock in coordinating insulin secretion with the sleep–wake cycle, and reveal that ablation of the pancreatic clock can trigger the onset of diabetes mellitus.
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We thank F. Turek, R. Allada and G. Bell for discussions and comments on the manuscript. We thank A. Kohsaka, E. Chen, J. Doering and C. Radosevich for their technical support, as well as the Biological Imaging Facility at Northwestern University and the Islet Biology Core of the University of Chicago DRTC. We thank D. Melton for the PdxCre mice. Work was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases to K.M.R. and L.H.P.; the National Institutes of Health, Chicago Biomedical Consortium Searle Funds, and Juvenile Diabetes Research Foundation to J.B.; grant R37-ES-005703 from the National Institutes of Health to C.A.B.; and the National Institute of Mental Health to J.S.T.
Cell autonomous oscillator in pancreas.Continuous videomicroscopy monitoring of islet bioluminescence over 72 hours. Islets from Per2Luc mice were isolated via collagenase digestion and imaged as described in Supplementary Methods. The 72-hour epoch is continuously replayed.
Cell autonomous oscillator in pancreas.Islets were harvested from a separate group of Per2Luc mice and monitored under identical conditions for 72 hours. The 72-hour epoch is continuously replayed.