An intrinsic circadian clock of the pancreas is required for normal insulin release and glucose homeostasis in mice
Open accessAbstract
AIMS/HYPOTHESIS: Loss of circadian clocks from all tissues causes defective glucose homeostasis as well as loss of feeding and activity rhythms. Little is known about peripheral tissue clocks, so we tested the hypothesis that an intrinsic circadian clock of the pancreas is important for glucose homeostasis. METHODS: We monitored real-time bioluminescence of pancreas explants from circadian reporter mice and examined clock gene expression in beta cells by immunohistochemistry and in situ hybridisation. We generated mice selectively lacking the essential clock gene Bmal1 (also known as Arntl) in the pancreas and tested mutant mice and littermate controls for glucose and insulin tolerance, insulin production and behaviour. We examined islets isolated from mutants and littermate controls for glucose-stimulated insulin secretion and total insulin content. RESULTS: Pancreas explants exhibited robust circadian rhythms. Clock genes Bmal1 and Per1 were expressed in beta cells. Despite normal activity and feeding behaviour, mutant mice lacking clock function in the pancreas had severe glucose intolerance and defective insulin production; their isolated pancreatic islets had defective glucose-stimulated insulin secretion, but normal total insulin content. CONCLUSIONS/INTERPRETATION: The mouse pancreas has an autonomous clock function and beta cells are very likely to be one of the pancreatic cell types possessing an intrinsic clock. The Bmal1 circadian clock gene is required in the pancreas, probably in beta cells, for normal insulin secretion and glucose homeostasis. Our results provide evidence for a previously unrecognised molecular regulator of pancreatic glucose-sensing and/or insulin secretion.
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Animal and in vitro studies with BMAL1−/− and Per1−/− show a disruption on glucose homeostasis and insulin release despite normal activity and feeding-fasting rhythms.
“Animal and in vitro studies with BMAL1−/− and Per1−/− show a disruption on glucose homeostasis and insulin release despite displaying normal activity and feeding-fasting rhythms [251,254].”
From Effects of diet, lifestyle, Chrononutrition and alternative dietary interventions on postprandial Glycemia and insulin resistance (2022) · cites this paper as [251]
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 [10]
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- Authors
- Sadacca, L. A., Lamia, K. A., deLemos, A. S., Blum, B., & Weitz, C. J.
- Affiliations
- Harvard University (US)
- Salk Institute for Biological Studies (US)
- Corresponding author
- Weitz, C. J.
- Venue
- Diabetologia
- Published
- 2010-10-03
- Volume
- 54
- Issue
- 1
- Pages
- 120-124
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- PMC
- PMC2995870
- OpenAlex
- W1987546711
- Cited by
- 314
- References
- 18
- Citations by year
- 2026: 8 · 2025: 10 · 2024: 13 · 2023: 15 · 2022: 17 · 2021: 24 · 2020: 28 · 2019: 17 · 2018: 15 · 2017: 20 · 2016: 34 · 2015: 27 · 2014: 29 · 2013: 24 · 2012: 18
- FWCI
- 18.92
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Diabetologia (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Harvard University
- Department of Neurobiology, Harvard Medical School
- Life Sciences Research Foundation
- National Institutes of Health
- National Heart, Lung, and Blood Institute (T32 HL 07901, T32HL007901)
- National Institute of Diabetes and Digestive and Kidney Diseases (T32-DK07191, T32DK007191)
- National Institute of Neurological Disorders and Stroke (R01NS060860)
- 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, pancreas, pancreatic beta cells, Bmal1, Per1, clock genes, glucose homeostasis, insulin secretion, glucose-stimulated insulin secretion, impaired glucose tolerance, pancreatic islets, circadian rhythm
- MeSH terms
- Insulin Secretion, Animals, Circadian Rhythm, Glucose, Glucose Tolerance Test, Homeostasis, Immunohistochemistry, Insulin, Pancreas, In Situ Hybridization, Mice
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