Research
Hormonal
Ectopic lipid accumulation (specifically diacylglycerol) in skeletal muscle and liver directly causes insulin resistance by activating specific protein kinase C (PKC) isoforms (PKCθ in muscle, PKCε in liver), which impair insulin receptor signaling.
Insulin resistance in obesity is driven by specific fat molecules (DAG) accumulating in muscle and liver, which block insulin signals. Reducing ectopic fat (via weight loss or exercise) can restore sensitivity.
StrongSupportsVERY_HIGH confidence
These studies support a mechanistic model in which muscle DAG accumulation activates PKCθ, which impairs insulin signaling.
Why this rating
Supported by multiple human studies, genetic mouse models, and lipid infusion studies.
Source
The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux
Varman T. Samuel et al. · Journal of Clinical Investigation · 2016
DOI 10.1172/jci77812
narrative_reviewCited 1,398×
Read the paper DOI resolved against Crossref · corpus check 2026-06-10
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