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Updated: Jun 27, 2025
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Published on: February 28, 2021
Modulation of Nuclear Receptor 4A1 Expression Improves Insulin Secretion in a Mouse Model of Chronic Pancreatitis
Galande Sheethal1, Archana Verma2, Raghvendra Mall3
1From the Asian Healthcare Foundation, AIG Hospitals.
Objectives:
Diabetes secondary to chronic pancreatitis (CP) presents clinical challenges due to lack of understanding on factor(s) triggering insulin secretory defects. Therefore, we aimed to delineate the molecular mechanism of β-cell dysfunction in CP.
Materials And Methods:
Transcriptomic analysis was conducted to identify endocrine-specific receptor expression in mice and human CP on microarray. The identified receptor (NR4A1) was overexpressed in MIN6 cells using PEI linear transfection. RNA-Seq analysis of NR4A1-overexpressed (OE) MIN6 cells on NovaSeq6000 identified aberrant metabolic pathways. Upstream trigger for NR4A1OE was studied by InBio Discover and cytokine exposure, whereas downstream effect was examined by Fura2 AM-based fluorimetric and imaging studies. Mice with CP were treated with IFN-γ-neutralizing monoclonal antibodies to assess NR4A1 expression and insulin secretion.
Results:
Increased expression of NR4A1 associated with decreased insulin secretion in islets (humans: controls 9 ± 0.2, CP 3.7 ± 0.2, mice: controls 8.5 ± 0.2, CP 2.1 ± 0.1 μg/L). NR4A1OE in MIN6 cells (13.2 ± 0.1) showed reduction in insulin secretion (13 ± 5 to 0.2 ± 0.1 μg/mg protein per minute, P = 0.001) and downregulation of calcium and cAMP signaling pathways. IFN-γ was identified as upstream signal for NR4A1OE in MIN6. Mice treated with IFN-γ-neutralizing antibodies showed decreased NR4A1 expression 3.4 ± 0.11-fold ( P = 0.03), showed improved insulin secretion (4.4 ± 0.2-fold, P = 0.01), and associated with increased Ca 2+ levels (2.39 ± 0.06-fold, P = 0.009).
Conclusions:
Modulating NR4A1 expression can be a promising therapeutic strategy to improve insulin secretion in CP.
Insights
This study reveals that increased NR4A1 expression in chronic pancreatitis (CP) impairs insulin secretion by disrupting calcium and cAMP signaling. Targeting NR4A1 offers a potential therapeutic strategy for diabetes in CP patients.
Area of Science:
- Endocrinology
- Molecular Biology
- Gastroenterology
Background:
- Diabetes secondary to chronic pancreatitis (CP) poses clinical challenges due to poorly understood mechanisms of beta-cell dysfunction.
- Identifying the molecular triggers of insulin secretory defects in CP is crucial for developing effective treatments.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying beta-cell dysfunction in chronic pancreatitis.
- To investigate the role of the nuclear receptor subfamily 4 group A member 1 (NR4A1) in CP-associated diabetes.
Main Methods:
- Transcriptomic analysis (microarray, RNA-Seq) identified NR4A1 as a key receptor in CP.
- NR4A1 was overexpressed in MIN6 cells to study its downstream effects on insulin secretion and signaling pathways.
- Interferon-gamma (IFN-γ) was identified as an upstream trigger for NR4A1 overexpression.
- CP mice were treated with IFN-γ-neutralizing antibodies to assess therapeutic potential.
Main Results:
- Increased NR4A1 expression correlated with significantly reduced insulin secretion in human and mouse CP islets.
- NR4A1 overexpression in MIN6 cells led to diminished insulin secretion and downregulated calcium and cAMP signaling.
- IFN-γ was confirmed as an upstream signal inducing NR4A1 overexpression.
- Neutralization of IFN-γ in CP mice decreased NR4A1 expression, improved insulin secretion, and increased intracellular calcium levels.
Conclusions:
- NR4A1 plays a critical role in mediating beta-cell dysfunction and insulin secretory defects in chronic pancreatitis.
- Modulating NR4A1 expression presents a promising therapeutic avenue for managing diabetes in CP.
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