Circadian control of β-cell function and stress responses

J. Lee, R. Liu, D. de Jesus, B. S. Kim, K. Ma, M. Moulik, V. Yechoor

Research output: Contribution to journalReview article

15 Scopus citations

Abstract

Circadian disruption is the bane of modern existence and its deleterious effects on health; in particular, diabetes and metabolic syndrome have been well recognized in shift workers. Recent human studies strongly implicate a 'dose-dependent' relationship between circadian disruption and diabetes. Genetic and environmental disruption of the circadian clock in rodents leads to diabetes secondary to β-cell failure. Deletion of Bmal1, a non-redundant core clock gene, leads to defects in β-cell stimulus-secretion coupling, decreased glucose-stimulated ATP production, uncoupling of OXPHOS and impaired glucose-stimulated insulin secretion. Both genetic and environmental circadian disruptions are sufficient to induce oxidative stress and this is mediated by a disruption of the direct transcriptional control of the core molecular clock and Bmal1 on Nrf2, the master antioxidant transcription factor in the β-cell. In addition, circadian disruption also leads to a dysregulation of the unfolded protein response and leads to endoplasmic reticulum stress in β-cells. Both the oxidative and endoplasmic reticulum (ER) stress contribute to an impairment of mitochondrial function and β-cell failure. Understanding the basis of the circadian control of these adaptive stress responses offers hope to target them for pharmacological modulation to prevent and mitigate the deleterious metabolic consequences of circadian disruption.

Original languageEnglish (US)
Pages (from-to)123-133
Number of pages11
JournalDiabetes, Obesity and Metabolism
Volume17
Issue numberS1
DOIs
StatePublished - Sep 1 2015

Keywords

  • Bmal1
  • Circadian
  • Clock
  • Diabetes
  • ER stress
  • Insulin
  • Islet
  • Mitochondria
  • OXPHOS
  • Oxidative stress
  • Rev-erb
  • Shift work
  • UPR
  • β-cell

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

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