Disruption of the Clock Components CLOCK and BMAL1 Leads to Hypoinsulinemia and Diabetes

By Biliana Marcheva, Kathryn Moynihan Ramsey, Ethan D. Buhr, Yumiko Kobayashi, Hong Su, C. H. Ko, Ganka Ivanova, Chiaki Omura, Shelley Mo, M. Vitaterna and 8 more. Nature, 2010

1,472 citations recorded by the source corpus.

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 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.

Subfields: Endocrine and Autonomic Systems, Endocrinology, Diabetes and Metabolism, Surgery

View Paper: https://www.semanticscholar.org/paper/9d05e70dabaa889e785891b2daace981dd846c44

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In Endocrine and Autonomic Systems

Citations in the corpus

Molecular components of the Mammalian circadian clock. (2013, background): “For example, loss of function of the clock gene, Bmal1, in pancreatic beta cells can lead to hypoinsulinemia and diabetes (Marcheva et al. 2010).”
Time restricted feeding without reducing caloric intake prevents metabolic diseases in mice fed a high fat diet (2012, neutral): “A number of mouse genetic models carrying wholebody- or tissue-specific perturbation of circadian oscillators (Cho et al., 2012; Kornmann et al., 2007; Lamia et al., 2008; Marcheva et al., 2010; Preitner et al., 2002; Turek et al., 2005) or key metabolic regulators (Andreelli et al.”
Light at night increases body mass by shifting the time of food intake (2010, background): “Moreover, mice with mutations in either Clock or Brain and muscle Arnt-like protein-1 (Bmal1) show impaired glucose tolerance, reduced insulin secretion, and defects in the proliferation and size of pancreatic islets (30).”
Timing to perfection: the biology of central and peripheral circadian clocks. (2012, background): “For example, Clockmutant mice exhibit a reduced metabolic rate and obesity (Turek et al., 2005) and further show impaired glucose tolerance, reduced insulin secretion, and defects in size and proliferation of pancreatic islets (Marcheva et al., 2010).”
A circadian gene expression atlas in mammals: Implications for biology and medicine (2014, methodology): “Disruption of normal circadian rhythms leads to clinically relevant disorders including neurodegeneration and metabolic disorders (3, 4).”
Reprogramming of the Circadian Clock by Nutritional Challenge (2013, neutral): “Metabolic homeostasis is not maintained when components of the circadian clock are missing or functioning improperly (Kondratov et al., 2006; Lee et al., 2011; Marcheva et al., 2010; Rudic et al., 2004; Sadacca et al., 2011; Shi et al., 2013; Turek et al., 2005; Zhang et al., 2010) and circadian dis”