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 <i>Bmal1</i> (core
circadian transcription factor; <i>β-Bmal1<sup>OV</sup></i>). We subsequently
examined the effects of <i>β-Bmal1<sup>OV</sup>
</i>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 <i>β-Bmal1<sup>OV</sup>
</i>mice display<i> </i>enhanced islet
circadian clock amplitude, augmented <i>in
vivo</i> and <i>in vitro</i> 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 <i>Bmal1</i>-dependent manner. This work suggests therapeutic targeting of
the circadian system as a potential strategy to counteract β cell failure under
diabetogenic conditions.