Molecular clock as a regulator of β-cell function

Type 2 diabetes mellitus is characterized by the loss of β‐cell function and mass, resulting from interactions between genetic predisposition and various environmental factors1. One environmental condition identified as a risk factor for type 2 diabetes mellitus is circadian rhythm disruption, which is induced by shift work or sleep disturbance. However, the mechanism whereby circadian disruption leads to impaired glucose metabolism is not well understood. A circadian rhythm is an approximately 24‐h cycle in the physiological processes of living beings, including cyanobacteria. The circadian clock system is based on transcriptional–translational regulation of ‘core clock genes’ in mammals. Clock genes are expressed throughout mammalian organ systems, and they play an important role by generating both behavioral and physiological rhythms, and synchronizing metabolism in anticipation of the sleep/wake and fasting/feeding cycle. The circadian clock is encoded by the heterodimeric basic helix‐loop‐helix Per‐Arnt‐Sim (bHLH‐PAS) transcription factors CLOCK, and brain and muscle Arnt‐like 1 (BMAL1), which trigger the expressions of period (PER)/cryptochrome (CRY) repressors that inhibit CLOCK/BMAL1 in a cycle that repeats itself every 24 h. According to genetic studies, Clock mutant mice show altered expressions of genes known to regulate islet growth, survival, maturation and proliferation2. Bmal1 deletion in β‐cells also results in failed metabolic adaptation to a high‐fat diet, characterized by hyperglycemia, glucose intolerance and loss of glucose‐stimulated insulin secretion3. These results suggest that circadian disruption‐induced metabolic disorder is, at least in part, attributable to β‐cell failure, though the mechanisms remain largely unknown. The Wfs1 −/− A y/a mouse is an animal model of Wolfram syndrome with mild obesity4. These mice develop diabetes with severe insulin deficiency as a result of endoplasmic reticulum (ER) stress‐induced β‐cell failure. The precise mechanism whereby Wolfram syndrome 1 (WFS1) mutation induces ER stress, followed by β‐cell failure, is not fully understood. However, various studies have shown that the WFS1 protein localizes to the ER membrane, and exerts a protective effect against ER stress5. In gene expression studies, we showed alteration of clock‐related gene expressions in Wfs1 −/− A y/a mice islets, as compared with those in A y/a mice; D site of albumin promoter (Dbp) messenger ribonucleic acid (RNA) levels of Wfs1 −/− A y/a mice islets were decreased by 50%, whereas their E4 promoter‐binding protein 4 (E4bp4) messenger RNA levels were increased by 50% at Zeitgeber Time 12. Notably, similar alterations were observed with chemically‐induced ER stress in in vitro experiments using MIN6 cells.