Steen Bønløkke Pedersen

Insulin Resistance after a 72 hour Fast is Associated with Impaired AS160 Phosphorylation and Accumulation of Lipid and Glycogen in Human Skeletal Muscle

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During fasting human skeletal muscle depends on lipid oxidation for its energy substrate metabolism. This is associated with the development of insulin resistance and a subsequent reduction of insulin-stimulated glucose uptake. The underlying mechanisms controlling insulin action on skeletal muscle under these conditions are unresolved. In a randomized design, we investigated 8 healthy subjects after a 72 hour fast as compared to a 10 hour overnight fast. Insulin action on skeletal muscle was assessed by a hyperinsulinemic-euglycemic clamp and by determining insulin signaling to glucose transport. In addition, substrate oxidation, skeletal muscle lipid content, regulation of glycogen synthesis, and AMPK signaling were assessed. Skeletal muscle insulin sensitivity was profoundly reduced in response to a 72 hour fast and substrate oxidation shifted to predominantly lipid oxidation. This was associated with accumulation of both lipid and glycogen in skeletal muscle. Intracellular insulin signaling to glucose transport was impaired by regulation of phosphorylation at specific sites on AS160, a key regulator of glucose uptake. In contrast, fasting did not impact phosphorylation of AMPK and insulin regulation of Akt, both established upstream kinases of AS160. These findings show that insulin resistance in muscles from healthy individuals is associated with suppression of site-specific phosphorylation of AS160 without affecting Akt and AMPK. This impairment of AS160 phosphorylation, in combination with glycogen accumulation and increased intramuscular lipid content, may provide the underlying mechanisms for resistance to insulin in skeletal muscle after a prolonged fast.
OriginalsprogEngelsk
TidsskriftAmerican Journal of Physiology: Endocrinology and Metabolism
Vol/bind95
Nummer2
Sider (fra-til)283-289
Antal sider7
ISSN0193-1849
DOI
StatusUdgivet - feb. 2012

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