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Parallel Measurement of Circadian Clock Gene Expression and Hormone Secretion in Human Primary Cell Cultures
Published on: November 11, 2016
Clock Gene Dysregulation Induced by Chronic ER Stress Disrupts β-cell Function
Yasuharu Ohta1, Akihiko Taguchi2, Takuro Matsumura2
1Department of Endocrinology, Metabolism, Hematological Science and Therapeutics, Yamaguchi University, Graduate School of Medicine, 1-1-1, Minami Kogushi, Ube, Yamaguchi 755-8505, Japan; Department of Diabetes Research, Yamaguchi University, School of Medicine, 1-1-1, Minami Kogushi, Ube, Yamaguchi 755-8505, Japan.
Ebiomedicine
|April 9, 2017
Summary
Endoplasmic reticulum (ER) stress disrupts D-site-binding protein (DBP) activity in pancreatic beta cells, impairing insulin secretion and glucose tolerance. This finding offers new therapeutic targets for diabetes.
Area of Science:
- Endocrinology
- Molecular Biology
- Chronobiology
Background:
- Endoplasmic reticulum (ER) stress is implicated in beta-cell dysfunction and diabetes.
- The molecular clock transcription factor D-site-binding protein (DBP) regulates circadian rhythms and metabolic processes.
Purpose of the Study:
- To investigate the role of DBP and ER stress in beta-cell function and insulin secretion.
- To explore the impact of altered DBP/E4BP4 balance on glucose homeostasis.
Main Methods:
- Utilized Wfs1 knockout mice and transgenic mice with E4BP4 overexpression in beta-cells.
- Assessed ER stress markers, DBP and Nfil3/E4BP4 expression, and DBP transcriptional activity.
- Measured ATP/ADP ratios, intracellular Ca2+ responses, and gene expression in islets.
- Evaluated glucose tolerance and insulin secretion in vivo.
Main Results:
- ER stress in islets led to decreased DBP and increased Nfil3/E4BP4 expression, reducing DBP activity.
- Transgenic mice overexpressing E4BP4 exhibited glucose intolerance and impaired insulin secretion.
- MIP-E4BP4 islets showed elevated basal ATP/ADP ratios without circadian oscillations and blunted responses to glucose.
- Genes crucial for insulin secretion failed to upregulate in MIP-E4BP4 islets.
Conclusions:
- DBP transcriptional activity, influenced by ER stress, is critical for beta-cell priming, metabolism, and gene expression.
- ER stress-mediated disruption of DBP function contributes to beta-cell failure.
- These findings suggest novel therapeutic strategies for Type-2 diabetes by targeting ER stress-associated mechanisms.
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