Hormonal
In obese insulin-resistant individuals, elevated membrane-associated Protein Kinase C (PKC) isoforms (specifically PKC-epsilon and PKC-theta) phosphorylate the insulin receptor on serine/threonine residues, thereby reducing its tyrosine kinase activity and causing insulin resistance.
This research explains why obesity often leads to insulin resistance: excess fat leads to higher Free Fatty Acids, which activate PKC enzymes in muscle. These enzymes 'clog' the insulin receptor by adding phosphate groups to the wrong spots (serine/threonine), preventing it from working efficiently. While you cannot directly control PKC levels, reducing body fat and Free Fatty Acids through diet and exercise is the primary way to reduce this specific molecular blockage.
Thus, we postulate that the decreased tyrosine kinase activity of the insulin receptor may be caused by serine/threonine phosphorylation by PKC.
Why this rating
The study uses rigorous human tissue analysis (Western blots, enzyme assays) with appropriate controls, though it is observational/correlational regarding the specific isoforms in humans compared to prior animal models.
Source
Involvement of protein kinase C in human skeletal muscle insulin resistance and obesity.
Samar I. Itani et al. · Diabetes · 2000
DOI 10.2337/diabetes.49.8.1353
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