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Muscle Adaptation to Short-Term Fasting in Healthy Lean Humans

Departments of Endocrinology and Metabolism (M.R.S., H.P.S., E.F., M.J.S.), of Medical Biochemistry (P.F.D., J.E.G., J.M.A.), and of Clinical Chemistry (M.T.A.), Laboratory of Endocrinology, Academic Medical Center, University of Amsterdam, 1100 DD Amsterdam, The Netherlands

Address all correspondence and requests for reprints to: M. R. Soeters, M.D., Department of Endocrinology and Metabolism, Academic Medical Center, P.O. Box 22660, 1100 DD Amsterdam, The Netherlands. E-mail: m.r.soeters{at}amc.uva.nl.

Context: It has been demonstrated repeatedly that short-term fasting induces insulin resistance, although the exact mechanism in humans is unknown to date. Intramyocellular sphingolipids (i.e. ceramide) have been suggested to induce insulin resistance by interfering with the insulin signaling cascade in obesity.

Objective: Our objective was to study peripheral insulin sensitivity together with muscle ceramide concentrations and protein kinase B/AKT phosphorylation after short-term fasting.

Main Outcome Measures and Design: After 14- and 62-h fasting, glucose fluxes were measured before and after a hyperinsulinemic euglycemic clamp. Muscle biopsies were performed in the basal state and during the clamp to assess muscle ceramide and protein kinase B/AKT.

Results: Insulin-mediated peripheral glucose uptake was significantly lower after 62-h fasting compared with 14-h fasting. Intramuscular ceramide concentrations tended to increase during fasting. During the clamp the phosphorylation of protein kinase B/AKT at serine⁴⁷³ in proportion to the total amount of protein kinase B/AKT was significantly lower. Muscle ceramide did not correlate with plasma free fatty acids.

Conclusions: Fasting for 62 h decreases insulin-mediated peripheral glucose uptake with lower phosphorylation of AKT at serine⁴⁷³. AKT may play a regulatory role in fasting-induced insulin resistance. Whether the decrease in AKT can be attributed to the trend to higher muscle ceramide remains unanswered.

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