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

Biliana Marcheva, Kathryn M Ramsey, Ethan D. Buhr, Yumiko Kobayashi, Hong Su, Caroline H. Ko, Ganka Ivanova, Chiaki Omura, Shelley Mo, Martha Hotz Vitaterna, James P. Lopez, Louis H. Philipson, Christopher A. Bradfield, Seth D. Crosby, Lellean Jebailey, Xiaozhong Wang, Joseph S. Takahashi, Joseph Bass*

*Corresponding author for this work

Research output: Contribution to journalArticle

837 Scopus citations

Abstract

The molecular clock maintains energy constancy by producing circadian oscillations of rate-limiting enzymes involved in tissue metabolism across the day and night. 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 diabetes, 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 Clock and Bmal1 (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 2-cell function at the very latest stage of stimulusĝ€"secretion coupling. These results demonstrate a role for the 2-cell clock in coordinating insulin secretion with the sleepĝ€"wake cycle, and reveal that ablation of the pancreatic clock can trigger the onset of diabetes mellitus.

Original languageEnglish (US)
Pages (from-to)627-631
Number of pages5
JournalNature
Volume466
Issue number7306
DOIs
StatePublished - Jul 29 2010

ASJC Scopus subject areas

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    Marcheva, B., Ramsey, K. M., Buhr, E. D., Kobayashi, Y., Su, H., Ko, C. H., Ivanova, G., Omura, C., Mo, S., Vitaterna, M. H., Lopez, J. P., Philipson, L. H., Bradfield, C. A., Crosby, S. D., Jebailey, L., Wang, X., Takahashi, J. S., & Bass, J. (2010). Disruption of the clock components CLOCK and BMAL1 leads to hypoinsulinaemia and diabetes. Nature, 466(7306), 627-631. https://doi.org/10.1038/nature09253