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Disruption of the clock components CLOCK and BMAL1 leads to hypoinsulinaemia and diabetes


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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Figure 1: Cell autonomous oscillator in pancreas.
Figure 2: Diabetic phenotypes in 8-month-old circadian mutant mice.
Figure 3: Reduced islet size, proliferation and insulin release in 8–10-month-old circadian mutant mice.
Figure 4: Impaired glucose tolerance and islet insulin secretion in 2–4-month-old pancreas-specific circadian mutant mice.


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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.

Author information

Authors and Affiliations



B.M. performed and analysed most of the experiments in this study, with technical assistance from Y.K., G.I., S.M. and C.O. E.D.B. and C.H.K. conducted and analysed real-time bioluminescence imaging experiments in isolated pancreatic islets. H.S. conducted immunostaining experiments. M.H.V. performed statistical analysis. J.P.L. conducted and analysed Ca2+ influx experiments. S.D.C. and L.J. performed statistical and gene ontogeny analysis of microarray data. C.A.B. provided Bmal1flx/flx mice. J.S.T., L.H.P., X.W., K.M.R., B.M. and J.B. provided critical intellectual input in the preparation of the manuscript. K.M.R., B.M., J.S.T. and J.B. wrote the paper.

Corresponding author

Correspondence to Joseph Bass.

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Competing interests

[Competing Interests: J.S.T. is an Investigator in the Howard Hughes Medical Institute and a co-founder of ReSet Therapeutics Inc., and J.S.T. and J.B. are members of its scientific advisory board. J.B. is also an advisor and receives support from Amylin Pharmaceuticals.]

Supplementary information

Supplementary Information

This file contains Supplementary Methods, Supplementary Descriptions 1-5, Supplementary Figures S1-S9 with legends, Supplementary Tables S1-S3 and References. (PDF 2403 kb)

Supplementary Movie 1

Cell autonomous oscillator in pancreas. (MOV 8408 kb)

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.

Supplementary Movie 2

Cell autonomous oscillator in pancreas. (MOV 8397 kb)

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.

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Marcheva, B., Ramsey, K., Buhr, E. et al. Disruption of the clock components CLOCK and BMAL1 leads to hypoinsulinaemia and diabetes. Nature 466, 627–631 (2010).

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