Induction of core circadian clock transcription factor Bmal1 enhances β cell function and protects against obesity-induced glucose intolerance

Type 2 diabetes mellitus (T2DM) is characterized by β cell dysfunction due to impaired glucose-stimulated insulin secretion (GSIS). Studies show that β cell circadian clocks are important regulators of GSIS and glucose homeostasis. These observations raise the question whether enhancement of the circadian clock in β cells will confer protection against β cell dysfunction under diabetogenic conditions. To test this we employed an approach by first generating mice with β cell-specific inducible overexpression of Bmal1 (core circadian transcription factor; β-Bmal1^OV). We subsequently examined the effects of β-Bmal1^OV on the circadian clock, GSIS, islet transcriptome, and glucose metabolism in context of diet-induced obesity. We additionally tested the effects of circadian clock-enhancing small molecule Nobiletin on GSIS in mouse and human control and T2DM islets. We report that β-Bmal1^OV mice display enhanced islet circadian clock amplitude, augmented in vivo and in vitro GSIS and are protected against obesity-induced glucose intolerance. These effects were associated with increased expression of purported BMAL1-target genes mediating insulin secretion, processing, and lipid metabolism. Furthermore, exposure of isolated islets to Nobiletin enhanced β cell secretory function in Bmal1-dependent manner. This work suggests therapeutic targeting of the circadian system as a potential strategy to counteract β cell failure under diabetogenic conditions.