Hormonal
Increased intramyocellular lipid metabolites (fatty acyl CoAs and diacylglycerol) activate serine/threonine kinase cascades (e.g., PKC-theta), which phosphorylate IRS-1 on serine residues, thereby inhibiting insulin-stimulated glucose transport and causing skeletal muscle insulin resistance.
Insulin resistance in muscle is driven by specific lipid byproducts (like diacylglycerol) interfering with cell signaling, not just by having fat stores. Improving mitochondrial function and reducing these specific lipid intermediates can restore insulin sensitivity.
The molecular mechanism underlying defective insulin-stimulated glucose transport activity can be attributed to increases in intramyocellular lipid metabolites such as fatty acyl CoAs and diacylglycerol, which in turn activate a serine/threonine kinase cascade, thus leading to defects in insulin signaling through Ser/Thr phosphorylation of insulin receptor substrate (IRS)-1.
Why this rating
Based on multiple human studies using Magnetic Resonance Spectroscopy (MRS) and knockout mouse models, though it is a review of mechanisms rather than a single clinical trial.
Source
Molecular Mechanisms of Insulin Resistance in Humans and Their Potential Links With Mitochondrial Dysfunction
Katsutaro Morino et al. · Diabetes · 2006
DOI 10.2337/db06-s002
More from this paper
- Reduced mitochondrial density and function predispose individuals to intramyocellular lipid accumulation, which subsequently leads to insulin resistance.Good
- In the liver, increased diacylglycerol activates PKC-epsilon, which reduces IRS-2 tyrosine phosphorylation, leading to decreased glycogen synthase activation and increased gluconeogenesis, causing hepatic insulin resistance.Good
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