Bmal1 and β-Cell Clock Are Required for Adaptation to Circadian Disruption, and Their Loss of Function Leads to Oxidative Stress-Induced β-Cell Failure in Mice

Abstract

Circadian disruption has deleterious effects on metabolism. Global deletion of Bmal1, a core clock gene, results in β-cell dysfunction and diabetes. However, it is unknown if this is due to loss of cell-autonomous function of Bmal1 in β cells. To address this, we generated mice with β-cell clock disruption by deleting Bmal1 in β cells (β-Bmal1(-/-)). β-Bmal1(-/-) mice develop diabetes due to loss of glucose-stimulated insulin secretion (GSIS). This loss of GSIS is due to the accumulation of reactive oxygen species (ROS) and consequent mitochondrial uncoupling, as it is fully rescued by scavenging of the ROS or by inhibition of uncoupling protein 2. The expression of the master antioxidant regulatory factor Nrf2 (nuclear factor erythroid 2-related factor 2) and its targets, Sesn2, Prdx3, Gclc, and Gclm, was decreased in β-Bmal1(-/-) islets, which may contribute to the observed increase in ROS accumulation. In addition, by chromatin immunoprecipitation experiments, we show that Nrf2 is a direct transcriptional target of Bmal1. Interestingly, simulation of shift work-induced circadian misalignment in mice recapitulates many of the defects seen in Bmal1-deficient islets. Thus, the cell-autonomous function of Bmal1 is required for normal β-cell function by mitigating oxidative stress and serves to preserve β-cell function in the face of circadian misalignment.

Immunometabolism: Is it under the eye of the clock?

“…Genetic manipulation of the molecular clock in specific cell types demonstrates the impact of the clock on metabolism at the cellular level. The clock within beta cells is required for the rhythmic secretion of insulin and mice lacking BMAL1 exhibit beta cell dysfunction and diabetes due to a loss of glucose-stimulated insulin secretion (GSIS) [75]. BMAL1 deletion in the beta cell causes reactive oxygen species (ROS) induced oxidative damage and subsequent mitochondrial uncoupling, leading to the loss of GSIS.…”

Circadian Rhythm Disruption and Metabolic Syndrome

“…Clock 유전자 변이로 인한 Clock 기능의 소실은 식사의 일주기 리듬을 파괴하여 과식과 비만으로 고지혈증, 지방간과 함께 고혈당과 고 인슐린혈증이 발생하였다 [19]. 췌장의 베타세포에서만 Bmal1을 제거한 마우스 연구에서는 Bmal1에 의해 조 절되는 항산화 조절인자인 Nrf2 (nuclear factor erythroid 2-related factor 2)가 감소하여 활성산소 의 축적으로 미토콘드리아 호흡이상(mitochondrial uncoupling)이 일어나고, 이로 인해 포도당 자극 인슐 린 분비(glucose-stimulated insulin secretion, GSIS)가 감소하여 당뇨가 발생하였다 [20]. 간에서만 Bmal1을 제거한 연구에서는 간에서 당을 조절하는 유 전자들(glucose-6-phosphate translocase 1, g l u c o k i n a s e, p y r u v a t e k i n a s e, g l u c o s e transporter 2등)의 리듬조절이 소실되었으며 간에서 의 당 생성에 결함이 생겼다 [21].…”

Uncoupling protein‐2 mediates the protective action of berberine against oxidative stress in rat insulinoma INS‐1E cells and in diabetic mouse islets

“…Over-production of ROS impairs islet function (Koulajian et al, 2013;Lee et al, 2013) and decreases insulin secretion (Li et al, 2012;Barlow and Affourtit, 2013;Zhang et al, 2013). Thus, we measured insulin secretion in INS-1E cells.…”