CARD9 mediates glucose-stimulated insulin secretion in pancreatic beta cells

Area of Science:

• Immunology
• Metabolic disease research
• Cellular signaling

Background:

• Caspase recruitment domain containing protein 9 (CARD9) is crucial for immune responses and implicated in metabolic diseases like insulin resistance.
• The role of CARD9 in glucose-stimulated insulin secretion (GSIS) is currently unknown.
• Understanding CARD9's function in GSIS is vital for metabolic disease research.

Purpose of the Study:

• To investigate the role of CARD9 in glucose-stimulated insulin secretion (GSIS).
• To elucidate the signaling pathways through which CARD9 may regulate insulin secretion.
• To determine if CARD9's effect on GSIS is Rac1-dependent.

Main Methods:

• CARD9 expression analysis in human, rat, and mouse islets, and INS-1 832/13 cells.
• siRNA-mediated CARD9 depletion in INS-1 832/13 cells to assess GSIS.
• Assessment of Rac1 activation, KCl/mastoparan-stimulated insulin secretion, and p38/ERK1/2 phosphorylation.
• Pharmacological inhibition of CARD9-TRIM62 interaction.

Main Results:

• CARD9 is expressed in various islet cells and predominantly localized in the cytosol of INS-1 832/13 cells.
• CARD9 depletion significantly suppressed GSIS (~50%) in INS-1 832/13 cells.
• GSIS was impaired independently of Rac1 activation, and insulin secretion stimulated by KCl or mastoparan was unaffected by CARD9 depletion.
• CARD9 depletion inhibited glucose-induced p38 phosphorylation but not ERK1/2 phosphorylation in beta cells.

Conclusions:

• CARD9 plays a significant role in regulating glucose-stimulated insulin secretion (GSIS).
• CARD9 appears to mediate GSIS through a Rac1-independent pathway.
• The findings suggest CARD9 regulates GSIS via p38-dependent signaling in beta cells, offering potential therapeutic targets for metabolic diseases.