Research
Hormonal
Diacylglycerol (DAG) accumulation at the plasma membrane, specifically the sn-1,2 stereoisomer, activates Protein Kinase C (PKC) isoforms (PKCε in liver, PKCθ in muscle), which inhibits insulin signaling.
Not all fat is bad for insulin signaling. It is the specific type and location of fat (DAG at the cell membrane) that blocks insulin. Reducing this specific lipid fraction improves sensitivity.
GoodSupportsHIGH confidence
The DAG hypothesis of lipid-induced insulin resistance is that interference of insulin signaling by activated protein kinase C (PKC) results from the accumulation of DAG within insulin-sensitive tissues
Why this rating
Strong evidence from animal models, human biopsies, and genetic knockouts.
Source
Insulin Resistance: From Mechanisms to Therapeutic Strategies
Shin-Hae Lee et al. · Diabetes & Metabolism Journal · 2021
DOI 10.4093/dmj.2021.0280
narrative_reviewCited 1,003×
Read the paper DOI resolved against Crossref · corpus check 2026-06-10
More from this paper
- Ectopic lipid accumulation in the liver and skeletal muscle is a primary cause of insulin resistance, mediated by lipid metabolites like diacylglycerol (DAG) and ceramides which interfere with insulin signaling pathways.Good
- Selective insulin resistance occurs in the liver where insulin fails to suppress hepatic glucose production (gluconeogenesis) but continues to stimulate lipogenesis (fat creation), leading to hyperglycemia and hepatic steatosis.Moderate
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