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Pro-inflammatory Cytokine Interleukin 1β Disrupts β cell Circadian Clock Function and Regulation of Insulin Secretion.

Intrinsic β cell circadian clocks are important regulators of insulin secretion and overall glucose homeostasis. Whether the circadian clock in β cells is perturbed following exposure to pro-diabetogenic stressors such as pro-inflammatory cytokines, and whether these perturbations are featured during the development of diabetes, remains unknown. To address this, we examined the effects of cytokine-mediated inflammation common to the pathophysiology of diabetes, on the physiological and molecular regulation of the β cell circadian clock. Specifically, we provide evidence that the key diabetogenic cytokine IL-1β disrupts functionality of the β cell circadian clock and impairs circadian regulation of glucose-stimulated insulin secretion. The deleterious effects of IL-1β on the circadian clock were attributed to impaired expression of key circadian transcription factor Bmal1, and its regulator, the NAD-dependent deacetylase, Sirtuin 1 (Sirt1). Moreover, we also identified that Type 2 diabetes in humans is associated with reduced immunoreactivity of β cell BMAL1 and SIRT1, suggestive of a potential causative link between islet inflammation, circadian clock disruption, and β cell failure. These data suggest that the circadian clock in β cells is perturbed following exposure to pro-inflammatory stressors and highlights the potential for therapeutic targeting of the circadian system for treatment β cell failure in diabetes.