Mechanisms of Insulin Resistance in Humans

Insulin resistance in skeletal muscle is a characteristic abnormality in obesity and the
metabolic syndrome and a major factor responsible for the development of type 2 diabetes.
Although the mechanisms responsible for muscle insulin resistance are largely unclear, lipid
oversupply is an important factor. Among numerous potential mechanisms whereby lipid
oversupply may cause muscle insulin resistance, current evidence points towards inflammation
as being critical. Recent studies in animals, however, indicate that the inflammatory
response in skeletal muscles may require the presence of circulating pro-inflammatory
factors suggesting that the inflammation induced insulin resistance in skeletal muscles may
be a secondary event. More specifically, activation of Nuclear Factor-Kappa B(NF-kB), and
inflammatory master switch that drives the production of numerous pro-inflammatory cytokines
in fat and liver, has been implicated in causing insulin resistance in skeletal muscles by
increasing circulating pro-inflammatory cytokines. In contrast, animal studies have found
that activation of NP-KB directly in skeletal muscles has no or little effect on its insulin
sensitivity but does produce other abnormalities such as increased proteasome activity. The
study shall therefore be undertaken to determine to what extent lipid-induced inflammation
and insulin resistance in skeletal muscles requires the presence of circulating
proinflammatory factors in humans.