Saturated fatty acids such as palmitate contribute to the development of Type
2 Diabetes by reducing insulin sensitivity, increasing inflammation and potentially
contributing to anabolic resistance. We hypothesized that palmitate-induced ATP
release from skeletal muscle cells may increase inflammatory cytokine production and
contribute ...
Saturated fatty acids such as palmitate contribute to the development of Type
2 Diabetes by reducing insulin sensitivity, increasing inflammation and potentially
contributing to anabolic resistance. We hypothesized that palmitate-induced ATP
release from skeletal muscle cells may increase inflammatory cytokine production and
contribute to insulin/anabolic resistance in an autocrine/paracrine manner. In C2C12
myotubes differentiated at physiological glucose concentrations (5.5 mM), palmitate
treatment (16 h) at concentrations greater than 250 µM increased release of ATP
and inflammatory cytokines IL-6 and MIF, significantly blunted insulin and amino acidinduced signaling and reduced mitochondrial function. In contrast to our hypothesis,
degradation of extracellular ATP using apyrase, did not alter palmitate-induced insulin
resistance nor alter release of cytokines. Moreover, treatment with ATPγS (16 h), a nonhydrolysable ATP analog, in the absence of palmitate, did not diminish insulin sensitivity.
Acute treatment with ATPγS produced insulin mimetic roles; increased phosphorylation
of PKB (aka AKT), S6K1 and ERK and enhanced GLUT4-mediated glucose uptake in
the absence of exogenous insulin. The increases in PKB and S6K1 phosphorylation
were completely prevented by pre-incubation with broad spectrum purinergic receptor
(P2R) blockers PPADs and suramin but not by P2 × 4 or P2 × 7 blockers 5-BDBD or
A-438079, respectively. Moreover, ATPγS increased IL-6 yet decreased MIF release,
similar to the cytokine profile produced by exercise. Acute and chronic treatment
with ATPγS increased glycolytic rate in a manner that was differentially inhibited by
PPADs and suramin, suggesting heterogeneous P2R activation in the control of cellular
metabolism. In summary, our data suggest that the palmitate-induced increase in ATP
does not contribute to insulin/anabolic resistance in a cell autonomous manner.