The circadian clock is a molecular oscillator that coordinates behavior and physiology in anticipation of the daily light cycle. Desynchrony of circadian cycles, through genetic or environmental perturbation, contributes to metabolic disorders such as cardiovascular disease, obesity, and type 2 diabetes. We previously showed that disruption of the clock transcription factors CLOCK and BMAL1 in the pancreas causes hypoinsulinemic diabetes in mice. The mechanism(s) linking clock dysfunction to pancreatic β cell failure and the means by which CLOCK and BMAL1 affect glucose metabolism in the whole organism are not well understood.

The circadian system helps to maintain glucose homeostasis across the sleep-wake cycle. This system requires cross-talk between the master clock in the central nervous system, which coordinates feeding and sleep, and peripheral tissue clocks, which synchronize behavior with the storage, mobilization, and synthesis of glucose. Although it is clear that clocks within distinct organs participate in glucose turnover, the molecular basis for time-of-day variation in organismal glucose responsiveness is still not understood. Here, we combined genome-wide analyses with gene targeting in mice to study the impact of the cell-autonomous clock on β cell function.

We found that cell-autonomous expression of CLOCK and BMAL1 in pancreatic islets isolated from wild-type mice generates robust 24-hour rhythms of glucose- and potassium chloride–stimulated insulin secretion ex vivo. About 27% of the β cell transcriptome exhibited circadian oscillation. Many of these transcripts correspond to genes coding for proteins that are involved in the assembly, trafficking, and membrane fusion of vesicles that participate in insulin secretion. Chromatin immunoprecipitation sequencing revealed that CLOCK and BMAL1 regulate cycling genes in β cells by binding at distal regulatory elements distinct from those controlling the circadian transcription of metabolic gene networks within the liver. The regulatory sites of cycling genes in the β cell resided primarily within transcriptionally active enhancers that were also bound by the pancreatic transcription factor PDX1. Finally, we found that in islets from adult mice, Bmal1 ablation either in vivo or ex vivo abrogates nutrient-responsive insulin secretion, demonstrating clock control of pancreatic β cell function throughout adult life.

Our results show that local clock-driven genomic rhythms program cell function across the light-dark cycle, including the priming of insulin secretion within limited time windows each day. Cell type–specific transcriptional regulation by the clock localizes to rhythmic enhancers that are unique to the β cell. Thus, our findings uncover a transcriptional process through which the core clock aligns physiology with the light cycle, revealing pathways that are important in both health and disease states such as type 2 diabetes.

Peripheral clocks maintain glucose homeostasis across the sleep-wake cycle by gating β cell insulin secretion through genome-wide transcriptional control of the assembly and trafficking of insulin secretory vesicles. Clock transcription factors bind within cell type–specific enhancer neighborhoods of cycling genes, revealing the mechanisms that synchronize rhythmic metabolism at transcriptional and physiologic levels across the light-dark cycle.