The circadian timing system is programmed by an autoregulatory transcription feedback loop present in brain and peripheral tissues that coordinates metabolic processes with the sleep-wake cycle. Epidemiologic, clinical, and genetic studies indicate circadian disruption as an emerging risk factor in the development of diabetes. Our lab has demonstrated that genetic abrogation of the pancreatic ? cell clock leads to acute hypoinsulinemic diabetes, and that insulin secretion exhibits basal and incretin-stimulated circadian regulation across the sleep- wake cycle. A remaining question is: How does the core circadian transcription mechanism modulate response to glucose and insulin secretagogues over the 24-hr timescale? Evidence from clock mutant pancreatic ?-cells suggests that loss of clock activators produces impaired glucose-stimulated insulin secretion and broad changes in transcriptional activity at ?-cell enhancers. These changes in transcription include pathways that intersect with those regulated by cAMP agonists, including the incretin hormones associated with meal-related insulin secretion. Indeed, islets stimulated with a glucagon-like peptide 1/cAMP agonist exhibited pronounced time-of-day dependent transcriptional and insulin secretion responses. The scientific premise of my present proposal is that the circadian clock controls time-of-day-dependent differences in the response to nutrient and meal-associated insulin secretagogues through the rhythmic regulation of ? cell chromatin, in turn impacting glucose homeostasis throughout life. The studies in this proposal will provide new insight into the molecular pathophysiology underlying impaired glucose tolerance following circadian disruption in shiftwork and states of sleep perturbation.
/ Relevance Understanding the intersection of genetic and environmental dysregulation in the development of diabetes is a critical step towards combating the escalating epidemic of metabolic disease. While mounting evidence has implicated disruption of natural day/night circadian cycles of behavior and physiology in metabolic diseases, our knowledge of the molecular pathogenesis linking circadian disruption to metabolic disease remains in its infancy. This proposal seeks to address the role of the circadian clock in beta cell failure and metabolic disease through the integration of genomic and physiological analyses.