Inhibitory mechanism of caffeine on insulin-stimulated glucose uptake in adipose cells

Caffeine inhibits insulin-induced glucose uptake in rat adipocytes and also decreases insulin sensitivity, including whole-body glucose disposal and glucose uptake in skeletal muscle, during a euglycemic-hyperinsulinemic clamp in human. However, the mechanism by which caffeine decreases the insulin sensitivity is not still clear. We found that pre-treatment with caffeine inhibited the insulin-induced 2-deoxy-D-1-(3)H]glucose uptake in a concentration-dependent manner in mouse preadipose MC-3T3-G2/PA6 cells differentiated into mature adipose cells. Caffeine also suppressed insulin-induced GLUT4 translocation in the differentiated cells. Although caffeine did not alter insulin-induced activation of PI3K and protein kinase C-zeta (PKCzeta), an isoform of atypical PKC, which is reported to have an important role in insulin-induced GLUT4 translocation, we found that insulin-induced phosphorylation and activation of Akt were blocked by pre-treatment with caffeine. Inhibition of insulin-induced 2-deoxy-D-1-(3)H]glucose uptake by caffeine was also observed in primary cultured brown adipocytes in a concentration-dependent manner. These results may, in part, explain the ability of caffeine to decrease insulin sensitivity.