Hormonal
Prolonged elevation of free fatty acids (FFA) induces skeletal muscle insulin resistance by increasing flux through the hexosamine biosynthetic pathway, leading to the accumulation of UDP-N-acetyl-hexosamines (UDP-GlcNAc), which impairs glucose uptake and glycogen synthesis.
Chronic exposure to high levels of free fatty acids (from high-fat diets or obesity) can rewire how your muscles handle glucose, not just by burning less fat, but by triggering a specific metabolic pathway (hexosamine) that actively blocks insulin's ability to move glucose into cells. This block can persist even after you lower your fat intake, suggesting that long-term dietary habits have lasting metabolic consequences beyond immediate nutrient levels.
Thus, fat-induced insulin resistance is associated with: (a) decreased skeletal muscle Glc-6-P levels indicating defective transport/phosphorylation of glucose; (b) marked accumulation of the endproducts of the hexosamine biosynthetic pathway preceding the onset of insulin resistance. Most important, the same degree of insulin resistance can be reproduced in the absence of increased FFA availability by a similar increase in skeletal muscle UDP-N-acetyl-hexosamines.
Why this rating
High-quality in vivo rat studies with rigorous clamping techniques and multiple experimental arms confirming causality.
Source
Role of the glucosamine pathway in fat-induced insulin resistance.
Meredith Hawkins et al. · Journal of Clinical Investigation · 1997
DOI 10.1172/jci119390
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