Gut Metabolite Trimethylamine N-Oxide Protects INS-1 β-Cell and Rat Islet Function under Diabetic Glucolipotoxic Conditions

• Published in: Biomolecules (Basel, Switzerland) Vol. 11; no. 12; p. 1892
• Main Authors: Krueger, Emily S, Beales, Joseph L, Russon, Kacie B, Elison, Weston S, Davis, Jordan R, Hansen, Jackson M, Neilson, Andrew P, Hansen, Jason M, Tessem, Jeffery S
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 17.12.2021; MDPI
• Subjects: Acids; Animals; Apoptosis; beta cell; Beta cells; Cell culture; Cell Proliferation - drug effects; Cell survival; Cell Survival - drug effects; Cell viability; Cells, Cultured; Chronic illnesses; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - prevention & control; Diet; Disease; Endoplasmic reticulum; Endoplasmic Reticulum Stress; Endoribonucleases - metabolism; Female; Gastrointestinal Microbiome; Gene Expression Regulation - drug effects; glucolipotoxicity (GLT); Glucose; glucose stimulated insulin secretion (GSIS); Hyperglycemia; Hyperlipidemia; Insulin; Insulin - metabolism; Insulin resistance; Insulin secretion; Insulin-Secreting Cells - cytology; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Intestinal microflora; islet; Laboratory animals; Metabolic disorders; Metabolites; Methylamines - pharmacology; Microbiomes; Microscopy; Models, Biological; Multienzyme Complexes - metabolism; Oxidative Stress; Pathogenesis; Primary Cell Culture; Protein folding; Protein Serine-Threonine Kinases - metabolism; Rats; Trimethylamine; type 2 diabetes (T2D); unfolded protein response (UPR); United States > US; beta cell; glucose stimulated insulin secretion (GSIS); islet; type 2 diabetes (T2D); unfolded protein response (UPR); glucolipotoxicity (GLT)
• ISSN: 2218-273X; 2218-273X
• DOI: 10.3390/biom11121892

Serum accumulation of the gut microbial metabolite trimethylamine N-oxide (TMAO) is associated with high caloric intake and type 2 diabetes (T2D). Impaired pancreatic β-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 β-cell mass. We hypothesized that TMAO may damage functional β-cell mass by inhibiting β-cell viability, survival, proliferation, or function to promote T2D pathogenesis. We treated INS-1 832/13 β-cells and primary rat islets with physiological TMAO concentrations and compared functional β-cell mass under healthy standard cell culture (SCC) and T2D-like glucolipotoxic (GLT) conditions. GLT significantly impeded β-cell mass and function by inducing oxidative and endoplasmic reticulum (ER) stress. TMAO normalized GLT-mediated damage in β-cells and primary islet function. Acute 40µM TMAO recovered insulin production, insulin granule formation, and insulin secretion by upregulating the IRE1α unfolded protein response to GLT-induced ER and oxidative stress. These novel results demonstrate that TMAO protects β-cell function and suggest that TMAO may play a beneficial molecular role in diet-induced T2D conditions.