Trimethylamine N-oxide impairs β-cell function and glucose tolerance

Area of Science:

• Endocrinology
• Metabolic Diseases
• Molecular Biology

Background:

• Beta-cell dysfunction and loss are key features of type 2 diabetes (T2D).
• Elevated levels of trimethylamine N-oxide (TMAO) are observed in diabetic patients.
• The direct impact of TMAO on beta-cell function requires further elucidation.

Purpose of the Study:

• To investigate the direct effects of TMAO on beta-cell function and viability.
• To explore the mechanisms by which TMAO influences beta-cell function.
• To assess the therapeutic potential of inhibiting TMAO production in T2D.

Main Methods:

• In vitro studies using MIN6 cells and primary human/mouse islets.
• In vivo studies in male C57BL/6J mice, db/db mice, and choline diet-fed mice.
• Assessment of glucose-stimulated insulin secretion (GSIS), beta-cell proportion, glucose tolerance, calcium transients, ER stress, and apoptosis.

Main Results:

• TMAO significantly decreased GSIS and impaired beta-cell function in vitro and in vivo.
• TMAO inhibited calcium transients via NLRP3 inflammasome-related cytokines and induced Serca2 loss.
• TMAO promoted beta-cell ER stress, dedifferentiation, apoptosis, and inhibited transcriptional identity.
• Inhibition of TMAO production ameliorated beta-cell dysfunction and improved glucose tolerance.

Conclusions:

• TMAO directly impairs beta-cell function and survival, contributing to T2D pathogenesis.
• TMAO exerts its detrimental effects through mechanisms involving calcium signaling, Serca2, and ER stress.
• Inhibiting TMAO production represents a promising therapeutic avenue for T2D treatment.