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Articles in PresS, published online ahead of print July 9, 2002
Am J Physiol Endocrinol Metab, 10.1152/ajpendo.00118.2002
Submitted on March 18, 2002
Accepted on July 4, 2002
1 Diabetes Biology, Novo Nordisk A/S, Bagsvaerd, Denmark
* To whom correspondence should be addressed. E-mail: gso{at}novonordisk.com.
We examined whether acute activation of AMP-activated protein kinase (AMPK) by AICAR (5'-Aminoimidazole-4-carboxamide-1-ß-D-ribonucleoside) 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 hours 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 as well as increased GS phosphorylation. When including 2mM AICAR in the last hour of the 5-hour 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 treatments affected total glycogen content. However, Glucose-6P was increased after inclusion of AICAR indicating increased influx of glucose. No effect of AICAR on the inhibited insulin stimulated glycogen synthase 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.
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