Preventing the calorie restriction-induced increase in insulin-stimulated Akt2 phosphorylation eliminates calorie restriction's effect on glucose uptake in skeletal muscle

► Greater insulin sensitivity leads to improved health with calorie restriction (CR). ► Enhanced insulin effects on Akt2 and glucose uptake in muscle are hallmarks of CR. ► Akt inhibitor MK-2206 eliminated these CR effects in isolated rat skeletal muscle. ► MK-2206 also eliminated CR effects on Akt2 substrates in insulin-stimulated muscle. ► CR effect on Akt2 in insulin-activated muscle is likely a key for health benefits.