There are clear associations between circadian disruption (CD), induction of pancreatic β-cell failure and T2DM. However, the underlying mechanisms driving these associations remain unclear. CD is behaviorally characterized by the dysregulation of circadian feeding patterns, which play a key role in the regulation of glucose homeostasis. Therefore, we set out to test the hypothesis that disrupted circadian feeding patterns mediate CD-induced metabolic dysfunction by promoting β-cell failure and reprogramming of the circadian islet transcriptome. To address this, C57B6 mice were assigned into 3 protocols for 12 weeks: 1) LD: exposed to standard light-dark cycle on ad libitum chow; 2) CD: Constant light exposure, to disrupt endogenous circadian rhythms, on ad libitum chow; 3) CD-tRF: Constant light exposure with time-restricted access to chow (tRF) during the first 8h of the circadian “active/feeding” phase. CD led to a loss of circadian rhythmicity in feeding, activity and energy expenditure (p<0.05 vs. LD). These behavioral abnormalities corresponded with loss of circadian regulation of glucose tolerance and insulin response (p<0.05 vs. LD). Moreover, time-dependent RNA-seq of islets revealed that CD significantly altered 98% of genes that were differentially expressed under LD conditions. Restoration of circadian feeding patterns (without altering daily energy intake) in CD-tRF led to reversal of metabolic defects by enhancing circadian glucose tolerance and insulin secretory response (p<0.05 vs. CD). Importantly, CD-tRF normalized circadian expression patterns of 707 genes enriched for KEGG pathways regulating key aspects of β-cell function such as insulin secretion, protein processing in ER, and NF-kB signaling (all FDR<0.05). This study suggests that the deleterious metabolic effects of CD on the β-cell are a consequence of disrupted circadian feeding patterns and imply that tRF may attenuate β-cell failure in T2DM.


M. Brown: None. T.K. Her: None. A. Matveyenko: None.


National Institutes of Health (R01DK98468)

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