We examined whether acute activation of
5'-AMP-activated protein kinase (AMPK) by 5'-aminoimidazole-4-carboxamide-1-beta-D-ribonucleoside (
AICAR) ameliorates
insulin resistance in isolated rat skeletal muscle.
Insulin resistance was induced in extensor digitorum longus (EDL) muscles by prolonged exposure to 1.6 mM
palmitate, which inhibited
insulin-stimulated
glycogen synthesis to 51% of control after 5 h of incubation.
Insulin-stimulated
glucose transport was less affected (22% of control). The decrease in
glycogen synthesis was accompanied by decreased
glycogen synthase (GS) activity and increased GS phosphorylation. When including 2 mM
AICAR in the last hour of the 5-h incubation with
palmitate, the inhibitory effect of
palmitate on
insulin-stimulated
glycogen synthesis and
glucose transport was eliminated. This effect of
AICAR was accompanied by activation of AMPK. Importantly, AMPK inhibition was able to prevent this effect. Neither treatment affected total
glycogen content. However,
glucose 6-phosphate was increased after inclusion of
AICAR, indicating increased influx of
glucose. No effect of
AICAR on the inhibited
insulin-stimulated GS activity or increased GS phosphorylation by
palmitate could be detected. Thus the mechanism by which AMPK activation ameliorates the
lipid-induced
insulin resistance probably involves induction of compensatory mechanisms overriding the
insulin resistance. Our results emphasize AMPK as a promising molecular target for treatment of
insulin resistance.