Research
Hormonal
In humans, insulin resistance in muscle is primarily caused by intracellular accumulation of fatty acid metabolites (diacylglycerol, ceramides) which activate serine/threonine kinases (e.g., PKC-theta), leading to impaired insulin signaling and reduced glucose transport, rather than by the Randle glucose-fatty acid cycle mechanism.
Insulin resistance in muscle is driven by lipid intermediates like diacylglycerol interfering with insulin signaling, not just by fat oxidation. Managing this involves improving how the body partitions fat away from muscle and liver, potentially through agents that promote adipocyte differentiation or improve mitochondrial fatty acid metabolism.
GoodRefutesHIGH confidence
This model holds that increasing intracellular fatty acid metabolites, such as diacylglycerol, fatty acyl CoA’s, or ceramides activates a serine/threonine kinase cascade (possibly initiated by protein kinase Cq ), leading to phosphorylation of serine/threonine sites on insulin receptor substrates... resulting in decreased activation of glucose transport and other downstream events.
Why this rating
Based on multiple NMR studies, lipid infusion protocols, and transgenic mouse models cited by the author.
Source
Cellular mechanisms of insulin resistance
Gerald I. Shulman · Journal of Clinical Investigation · 2000
DOI 10.1172/jci10583
narrative_reviewCited 2,703×
Read the paper DOI resolved against Crossref · corpus check 2026-06-10
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