Metabolite perturbations in type 1 diabetes associated with metabolic dysfunction-associated steatotic liver disease.

Taiwo, Merrill, Wendt, Pape, Thakkar, Maschek, Cox, Summers, Chaurasia, Pothireddy, Carlson, Sanchez, Ten Eyck, Jalal, Dokun, Taylor, Sivitz. Metabolite perturbations in type 1 diabetes associated with metabolic dysfunction-associated steatotic liver disease. Frontiers in endocrinology. 2025 Jun 3; 16:1500242, DOI: 10.3389/fendo.2025.1500242.

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Abstract:

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly called non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. Although MASLD has been widely studied in persons with Type 2 diabetes (T2D), far less in known about the pathogenesis and severity of MASLD in Type 1 diabetes (T1D). OBJECTIVES: Determine metabolic perturbations associated with MASLD in persons with T1D. STUDY DESIGN: We conducted a cross-sectional study of 30 participants with T1D. Based on the results of a FibroScan, participants were stratified as cases (MASLD) or controls. Metabolomic analyses were performed on plasma obtained from all participants after an overnight (after midnight) fast. RESULTS: 17 of 30 participants were classified as cases (MASLD) and 13 as controls. Cases had higher BMI (p = < 0.001) and were taking higher daily insulin doses than controls (p = 0.003). Metabolomic analyses revealed that those with MASLD had elevated levels of gluconeogenic substrates pyruvate (p = 0.001) and lactate (p = 0.043), gluconeogenic amino acids alanine (p < 0.001) and glutamate (p = 0.004), phenylalanine (p = 0.003), and anthranilic acid (p = 0.015). Lipidomics revealed, elevated ceramides (P = 0.02), diacylglycerols (p = 0.0009) and triacylglycerols (P = 0.0004) in MASLD group. In those with MASLD, the acylcarnitines, isovalerylcarnitine (CAR.5.0) (P = 0.002) and L-Palmitoylcarnitine (CAR.16.0) (P = 0.048), were elevated. Pathway analyses using MetaboAnalyst 5.0 Software revealed that, pathways including phenylalanine and tyrosine metabolism, tryptophan metabolism, glucose-alanine cycle, glutamate metabolism, and glutathione metabolism were significantly enriched in those with MASLD. CONCLUSION: Participants with T1D and MASLD manifest features of insulin resistance and metabolite perturbations suggesting enhanced gluconeogenesis, dysfunctional fat synthesis, and perturbed TCA cycle activity.