Induction of Core Circadian Clock Transcription Factor Bmal1 Enhances β-Cell Function and Protects Against Obesity-Induced Glucose Intolerance.

Abstract

Type 2 diabetes mellitus (T2DM) is characterized by β-cell dysfunction as a result of 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 about whether enhancement of the circadian clock in β-cells will confer protection against β-cell dysfunction under diabetogenic conditions. To test this, we used an approach by first generating mice with β-cell-specific inducible overexpression of <i>Bmal1</i> (core circadian transcription factor; <i>β-Bmal1</i> ^<i>OV</i> ). We subsequently examined the effects of <i>β-Bmal1</i> ^<i>OV</i> on the circadian clock, GSIS, islet transcriptome, and glucose metabolism in the context of diet-induced obesity. We also 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</i> ^<i>OV</i> mice display enhanced islet circadian clock amplitude and 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 a <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.