Hormonal
Mitochondrial overload of fatty acid oxidation in muscle, characterized by incomplete oxidation and accumulation of acylcarnitines, causes insulin resistance by depleting TCA cycle intermediates and inducing mitochondrial stress, rather than solely by the accumulation of diacylglycerols and ceramides.
When consuming high-fat diets, the body's ability to burn fat in muscle mitochondria can become overwhelmed, leading to metabolic stress and insulin resistance. This suggests that managing lipid flux and supporting mitochondrial health (e.g., through exercise which normalizes acylcarnitines) is crucial, rather than just avoiding fat entirely.
the weight of recent evidence is consistent with a model in which lipid-induced insulin resistance in muscle is explained at least in part by 'overload' of mitochondrial lipid oxidation, accumulation of incompletely oxidized fats, and depletion of TCA intermediates, leading to a condition of mitochondrial stress that activates signaling pathways (still to be defined) that interfere with insulin action.
Why this rating
The paper is a perspective/review summarizing multiple studies (animal models, cell lines, some human data) rather than a single large-scale clinical trial.
Source
Metabolomics Applied to Diabetes Research
James R. Bain et al. · Diabetes · 2009
DOI 10.2337/db09-0580
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