Proinflammatory Cytokine Interleukin 1β Disrupts β-cell Circadian Clock Function and Regulation of Insulin Secretion

Abstract

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 prodiabetogenic stressors such as proinflammatory 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 proinflammatory stressors and highlights the potential for therapeutic targeting of the circadian system for treatment for β-cell failure in diabetes.