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

Oct 22, 2020Diabetes

Increasing the Core Body Clock Protein Bmal1 Improves Insulin-Producing Cell Function and Helps Prevent Obesity-Related Blood Sugar Problems

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Abstract

Mice with enhanced β-cell circadian clock function display increased insulin secretion and protection against obesity-induced glucose intolerance.

Enhanced β-cell circadian clock amplitude was observed in genetically modified mice.
In vivo and in vitro glucose-stimulated insulin secretion (GSIS) was augmented in these mice.
Increased expression of certain genes related to insulin secretion and metabolism was noted.
The small molecule nobiletin improved β-cell secretory function in isolated islets from both mice and humans.
Therapeutic targeting of the circadian system may offer a strategy to address β-cell dysfunction in diabetes.

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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(core circadian transcription factor;). We subsequently examined the effects ofon 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 thatmice 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-dependent manner. This work suggests therapeutic targeting of the circadian system as a potential strategy to counteract β-cell failure under diabetogenic conditions. Bmal1 β-Bmal1 β-Bmal1 β-Bmal1Bmal1OV OV OV

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

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