Hypothetical schema to explain changes in DAG, PKC, and IκB-α associated with insulin resistance in muscle of humans infused
with lipid during a euglycemic-hyperinsulinemic clamp. Key initiating events are an increase in plasma FFA, which elevates
the cytosolic concentration of long-chain fatty acyl CoA (LCCoA), and an increased uptake into muscle of glucose. The latter
enhances glycerolipid (TG, DAG) synthesis both by generating α-glycerophosphate and by enhancing the synthesis of malonyl
CoA, which inhibits fatty acid oxidation by mitochondria. It is assumed that activation of PKC sets in motion changes in IκB-α
and NFκB by one or more of the indicated mechanisms; however, direct proof that it does so in human muscle is lacking (see
text). The precise events that lead to insulin resistance remain to be determined. IKKB, IκB kinase.