Insulin resistance is associated with
nonalcoholic fatty liver disease (
NAFLD) and is a major factor in the pathogenesis of
type 2 diabetes. The development of hepatic
insulin resistance has been ascribed to multiple causes, including
inflammation, endoplasmic reticulum (ER) stress, and accumulation of hepatocellular
lipids in animal models of
NAFLD. However, it is unknown whether these same cellular mechanisms link
insulin resistance to hepatic steatosis in humans. To examine the cellular mechanisms that link hepatic steatosis to
insulin resistance, we comprehensively assessed each of these pathways by using flash-frozen liver biopsies obtained from 37 obese, nondiabetic individuals and correlating key hepatic and plasma markers of
inflammation, ER stress, and
lipids with the homeostatic model assessment of
insulin resistance index. We found that hepatic
diacylglycerol (DAG) content in cytoplasmic lipid droplets was the best predictor of
insulin resistance (R = 0.80, P < 0.001), and it was responsible for 64% of the variability in
insulin sensitivity. Hepatic DAG content was also strongly correlated with activation of hepatic PKCĪµ (R = 0.67, P < 0.001), which impairs
insulin signaling. In contrast, there was no significant association between
insulin resistance and other putative
lipid metabolites or plasma or hepatic markers of
inflammation. ER stress markers were only partly correlated with
insulin resistance. In conclusion, these data show that hepatic DAG content in lipid droplets is the best predictor of
insulin resistance in humans, and they support the hypothesis that
NAFLD-associated hepatic
insulin resistance is caused by an increase in hepatic DAG content, which results in activation of PKCĪµ.