1. Induction of Core Circadian Clock Transcription Factor Bmal1 Enhances β-Cell Function and Protects Against Obesity-Induced Glucose Intolerance
- Author
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Aleksey V. Matveyenko and Kuntol Rakshit
- Subjects
Blood Glucose ,Male ,0301 basic medicine ,endocrine system ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Circadian clock ,Mice, Transgenic ,030209 endocrinology & metabolism ,Context (language use) ,Motor Activity ,Carbohydrate metabolism ,Biology ,Nobiletin ,Islets of Langerhans ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Circadian Clocks ,Insulin-Secreting Cells ,Internal medicine ,Glucose Intolerance ,Internal Medicine ,medicine ,Animals ,Humans ,Insulin ,Glucose homeostasis ,Obesity ,Circadian rhythm ,Transcription factor ,geography ,geography.geographical_feature_category ,ARNTL Transcription Factors ,Flavones ,Islet ,Circadian Rhythm ,Glucose ,030104 developmental biology ,Endocrinology ,Islet Studies ,chemistry ,Insulin Resistance - 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.
- Published
- 2020