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

Kuntol Rakshit, Aleksey V. Matveyenko

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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 Bmal1 (core circadian transcription factor; β-Bmal1OV ). We subsequently examined the effects of β-Bmal1OV 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 β-Bmal1OV 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 Bmal1-dependent manner. This work suggests therapeutic targeting of the circadian system as a potential strategy to counteract β-cell failure under diabetogenic conditions.

Original languageEnglish (US)
Pages (from-to)143-154
Number of pages12
JournalDiabetes
Volume70
Issue number1
DOIs
StatePublished - Jan 1 2021

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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