Hormonal
Insulin resistance in skeletal muscle is driven by intramuscular lipid accumulation interfering with insulin signaling, rather than by increased fat oxidation inhibiting glucose metabolism via the Randle cycle.
Insulin resistance in muscle is not caused by your body's ability to burn fat. Instead, it is linked to the buildup of specific fat molecules (like diacylglycerol and ceramide) inside muscle cells that block insulin signals. This happens when lipid accumulation exceeds the muscle's ability to oxidize or store it safely, often seen in obesity and type 2 diabetes. Focus on improving metabolic flexibility and reducing intramuscular lipid accumulation rather than fearing fat oxidation.
Therefore, although the Randle cycle is a valid physiological principle, it may not explain insulin resistance in skeletal muscle... there is now evidence that in skeletal muscle from insulin-resistant subjects, fat oxidation is actually decreased under postabsorptive conditions... there is a growing body of evidence that long-chain fatty acyl-CoAs themselves may produce insulin resistance.
Why this rating
Based on a synthesis of multiple human studies (clamp techniques, indirect calorimetry, biopsies) and animal models, though direct causal proof in humans is still evolving.
Source
Fuel selection in human skeletal muscle in insulin resistance: a reexamination.
D. E. Kelley et al. · Diabetes · 2000
DOI 10.2337/diabetes.49.5.677
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