Journal
BIOMOLECULES
Volume 11, Issue 12, Pages -Publisher
MDPI
DOI: 10.3390/biom11121892
Keywords
beta cell; islet; glucolipotoxicity (GLT); glucose stimulated insulin secretion (GSIS); unfolded protein response (UPR); type 2 diabetes (T2D)
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Trimethylamine N-oxide (TMAO), a gut microbial metabolite, accumulates in serum with high caloric intake and type 2 diabetes association. While TMAO is known to have deleterious effects in various tissues, it has been shown to protect functional beta-cell mass and may play a beneficial role in diet-induced conditions of T2D.
Serum accumulation of the gut microbial metabolite trimethylamine N-oxide (TMAO) is associated with high caloric intake and type 2 diabetes (T2D). Impaired pancreatic beta-cell function is a hallmark of diet-induced T2D, which is linked to hyperglycemia and hyperlipidemia. While TMAO production via the gut microbiome-liver axis is well defined, its molecular effects on metabolic tissues are unclear, since studies in various tissues show deleterious and beneficial TMAO effects. We investigated the molecular effects of TMAO on functional beta-cell mass. We hypothesized that TMAO may damage functional beta-cell mass by inhibiting beta-cell viability, survival, proliferation, or function to promote T2D pathogenesis. We treated INS-1 832/13 beta-cells and primary rat islets with physiological TMAO concentrations and compared functional beta-cell mass under healthy standard cell culture (SCC) and T2D-like glucolipotoxic (GLT) conditions. GLT significantly impeded beta-cell mass and function by inducing oxidative and endoplasmic reticulum (ER) stress. TMAO normalized GLT-mediated damage in beta-cells and primary islet function. Acute 40 mu M TMAO recovered insulin production, insulin granule formation, and insulin secretion by upregulating the IRE1 alpha unfolded protein response to GLT-induced ER and oxidative stress. These novel results demonstrate that TMAO protects beta-cell function and suggest that TMAO may play a beneficial molecular role in diet-induced T2D conditions.
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