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

ABSTRACT: β-Cell dysfunction, manifested as impaired glucose-stimulated insulin secretion (GSIS), and β-cell loss, which presents as dedifferentiation, inhibited transcriptional identity and death, are the hallmarks of type 2 diabetes. Trimethylamine N-oxide (TMAO), a gut microbiota metabolite, has been shown to play a role in cardiovascular disease. Here, we found that plasma TMAO levels are elevated in both diabetic mice and human subjects and that TMAO at a similar concentration to that found in diabetes could directly decrease β-cell GSIS in both MIN6 cells and primary islets from mice or humans. Elevation of TMAO levels through choline diet feeding impairs GSIS, the β-cell proportion, and glucose tolerance. TMAO inhibits calcium transients through NLRP3 inflammasome-related inflammatory cytokines and induced Serca2 loss, and a Serca2 agonist reversed the effect of TMAO on β-cell function in vitro and in vivo. Additionally, long-term TMAO exposure promotes β-cell ER stress, dedifferentiation, and apoptosis and inhibits β-cell transcriptional identity. Inhibition of TMAO production through either genetic knockdown or antisense oligomers of Fmo3, the TMAO-producing enzyme, improves β-cell GSIS, the β-cell proportion, and glucose tolerance in both db/db and choline diet-fed mice. These observations elucidate a novel role for TMAO in β-cell dysfunction and maintenance, and inhibition of TMAO could be a new approach for the treatment of type 2 diabetes.

ORGANISM(S): Mus musculus

PROVIDER: GSE243083 | GEO | 2024/02/23

REPOSITORIES: GEO

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β-cell Jagged1 is sufficient but not necessary for islet Notch activity and insulin secretory defects.

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2014-04-01 | E-GEOD-48815 | biostudies-arrayexpress

VGF-derived peptide attenuates development of type 2 diabetes via enhancement of islet beta cell survival and function survival and function

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Glucagon regulates Hepatic Kisspeptin1 to Impair Insulin Secretion in Diabetes Mellitus

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Progenitor Cell Marker Aldehyde Dehydrogenase 1a3 Defines a Subset of Failing Pancreatic Beta Cells in Diabetic Mice

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