Hormonal
Nutrient excess activates the hexosamine biosynthesis pathway (HBP) and malonyl-CoA sensing, which directly cause insulin resistance and decreased energy expenditure (mitochondrial dysfunction) in peripheral tissues like skeletal muscle and adipose tissue.
To improve insulin sensitivity, you must reduce the nutrient flux that triggers these sensors. This means managing caloric intake and substrate availability (glucose and fatty acids) to prevent the activation of the hexosamine pathway and malonyl-CoA accumulation, which drive insulin resistance and reduce energy expenditure.
The experimental evidence discussed below supports the model outlined in Fig. 1A, i.e. nutrient excess activates biochemical pathways that initiate cellular responses designed to limit the oxidation of excess energy (insulin resistance) and favor weight gain.
Why this rating
This is a minireview summarizing multiple studies (transgenic models, infusion studies), not a single primary clinical trial.
Source
Minireview: Nutrient Sensing and the Regulation of Insulin Action and Energy Balance
Silvana Obici et al. · Endocrinology · 2003
DOI 10.1210/en.2003-0999
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