Disruption of the clock components CLOCK and BMAL1 leads to hypoinsulinaemia and diabetes
Open accessAbstract
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 beta-cell function at the very latest stage of stimulus-secretion coupling. These results demonstrate a role for the beta-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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CLOCK:BMAL1 transcription targets many genes in different cellular contexts across tissues.
“Because CLOCK:BMAL1-mediated transcription targets a variety of genes in different cellular contexts across tissues (Janich et al., 2011; Marcheva et al., 2010; Paschos et al., 2012; Yu et al., 2013)”
From Clock Genes Control Cortical Critical Period Timing (2015) · cites this paper as Marcheva et al., 2010
Whole-body Bmal1 knockout mice show fasting hypoglycemia, reduced plasma insulin levels and increased adiposity.
“whole-body knockout (KO) mice of Bmal1 show fasting hypoglycemia, reduced plasma insulin levels, increased adiposity [16–18].”
From Circadian control of glucose metabolism (2014) · cites this paper as [17]
The pancreatic clock regulates insulin secretion and its response to glucose.
“For example, the hepatic clock regulates fasting glycemic control and glucose clearance (8), the pancreatic clock regulates insulin secretion and its response to glucose (9-11), the adipose clock regulates lipid storage and mobilization (12,13), and the skeletal muscle clock regulates glucose uptake and metabolism (14).”
From Circadian rhythms, metabolism, and chrononutrition in rodents and humans (2016) · cites this paper as [9]
Isolated pancreatic islets from Clock mutant mice and Bmal1 null mice have profound defects in insulin secretion at basal levels and in response to glucose stimulation compared with wild-type mice.
“Examination of isolated pancreatic islets, containing the insulin-secreting b cells, from Clock mutant mice, as well as from mice carrying a null mutation of Bmal1, revealed profound defects in insulin secretion, both at basal levels and in response to glucose stimulation, compared with wild-type mice (9).”
From Circadian rhythms, metabolism, and chrononutrition in rodents and humans (2016) · cites this paper as [9]
Peripheral clocks per se can influence metabolism.
“The SCN can also influence metabolic-related factors (e.g., cortisol) via hormonal pathways (Buijs et al., 1993, 1999) and peripheral clocks per se can influence metabolism (Marcheva et al., 2010).”
From The impact of the circadian timing system on cardiovascular and metabolic function (2012) · cites this paper as Marcheva et al., 2010
Glucose-stimulated insulin secretion is reduced in isolated pancreatic islets from Clock mutants, which may explain the observed impaired glucose tolerance in these animals.
“The researchers also demonstrated that glucose-stimulated insulin secretion is reduced in isolated pancreatic islets from Clock mutants, which may explain the observed impaired glucose tolerance in these animals.”
From The impact of the circadian timing system on cardiovascular and metabolic function (2012) · cites this paper as Marcheva et al., 2010
Whole-body Clock mutation caused impaired glucose tolerance in mice.
“Marcheva et al. (2010) reported that whole-body Clock mutation caused impaired glucose tolerance in mice.”
From The impact of the circadian timing system on cardiovascular and metabolic function (2012) · cites this paper as Marcheva et al., 2010
These pancreas-specific Bmal1 mutant mice had normal body weight, activity, and feeding rhythms, suggesting that the above mentioned phenotypes are attributable to pancreatic clock disruption per se rather than to secondary changes in behavior.
“These mice had normal body weight, activity, and feeding rhythms, suggesting that the above mentioned phenotypes are attributable to pancreatic clock disruption per se rather than to secondary changes in behavior.”
From The impact of the circadian timing system on cardiovascular and metabolic function (2012) · cites this paper as Marcheva et al., 2010
Young pancreas-specific Bmal1 mutant mice showed increased ad libitum glucose levels, impaired glucose tolerance, lowered insulin secretion, and decreased insulin responsiveness to glucose.
“In recent work, young pancreas-specific Bmal1 mutant mice showed increased ad libitum glucose levels, impaired glucose tolerance, lowered insulin secretion, and decreased insulin responsiveness to glucose (Marcheva et al., 2010).”
From The impact of the circadian timing system on cardiovascular and metabolic function (2012) · cites this paper as Marcheva et al., 2010
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- Authors
- 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.
- Affiliations
- Northwestern University (US)
- University of Chicago (US)
- University of Wisconsin–Madison (US)
- Washington University in St. Louis (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Bass, Joseph
- ORCID
- Venue
- Nature
- Published
- 2010-06-18
- Volume
- 466
- Issue
- 7306
- Pages
- 627-631
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2920067
- OpenAlex
- W2162650381
- Cited by
- 1,525
- References
- 30
- Citations by year
- 2026: 61 · 2025: 88 · 2024: 86 · 2023: 89 · 2022: 109 · 2021: 97 · 2020: 116 · 2019: 93 · 2018: 92 · 2017: 91 · 2016: 116 · 2015: 109 · 2014: 106 · 2013: 103 · 2012: 73
- FWCI
- 90.99
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- Northwestern University
- National Institute on Aging (P01AG011412)
- National Heart, Lung, and Blood Institute (R01HL097817)
- National Institute of Environmental Health Sciences (R37ES005703)
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Keywords
- circadian clock, clock genes, Bmal1, pancreatic islets, beta-cell function, insulin secretion, hypoinsulinaemia, type 2 diabetes, circadian rhythm, glucose homeostasis, sleep-wake cycle, islet transcriptome, stimulus-secretion coupling, conditional gene deletion
- MeSH terms
- Insulin Secretion, Aging, Animals, Blood Glucose, Cell Survival, Circadian Rhythm, Diabetes Mellitus, Glucose Tolerance Test, Insulin, Islets of Langerhans, Phenotype, Sleep, Synaptic Vesicles, Wakefulness, Glucose Intolerance, Gene Expression Profiling, Cell Size, Cell Proliferation, Mice, CLOCK Proteins, ARNTL Transcription Factors, Period Circadian Proteins, In Vitro Techniques
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