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Insulin resistance is a well-known physiological adaptation to prolonged
fasting in healthy skeletal muscle. Obesity is associated with insulin
resistance and metabolic inflexibility in skeletal muscle, and a
pronounced increase in the risk of metabolic complications. Under the
hypothesis that the metabolic traits of insulin resistance associated with
prolonged fasting are different from insulin resistance associated with
obesity, we examined nine obese and nine lean participants during 12 and
72h of fasting, respectively. Insulin resistance in obese participants was
associated with impaired insulin signaling, and reduced levels of
glucose-6-phosphate and TCA-cycle intermediates. 72h of fasting in lean
participants reduced insulin-stimulated glucose uptake to levels similar
to obese participants fasted for 12h. This was associated with increased
lipid oxidation, but not accumulation of diacylglycerol or acylcarnitines
and impairment of insulin signaling. Prolonged fasting was associated with
pronounced increases in β-hydroxybutyrate and β- hydroxybutyrylcarnitine
levels in skeletal muscle suggesting augmented ketone body metabolism.
Fasting induced insulin resistance may be a consequence of substrate
competition. The underlying mechanism behind insulin resistance in obesity
is thus not comparable to the physiological adaptations in skeletal muscle
induced by prolonged fasting in lean participants.
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