Akt2 Is Essential for the Full Effect of Calorie Restriction on Insulin-Stimulated Glucose Uptake in Skeletal Muscle

  1. Carrie E. McCurdy1 and
  2. Gregory D. Cartee2
  1. 1Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, Wisconsin
  2. 2Division of Kinesiology, University of Michigan, Ann Arbor, Michigan
  1. Address correspondence and reprint requests to Gregory D. Cartee, PhD, University of Michigan, Division of Kinesiology, Room 3040E, 401 Washtenaw Ave., Ann Arbor, MI 48109-2214. E-mail: gcartee{at}


Brief calorie restriction (CR; 20 days of 60% of ad libitum [AL] intake) improves insulin-stimulated glucose transport, concomitant with enhanced phosphorylation of Akt2. The purpose of this study was to determine whether Akt2 is essential for the calorie restriction–induced enhancement in skeletal muscle insulin sensitivity. We measured insulin-stimulated 2-deoxyglucose (2DG) uptake in isolated extensor digitorum longus (EDL) and soleus muscles from male and female wild-type (WT) and Akt2-null (knockout [KO]) mice after ad libitum or calorie-restricted (20 days at 60% of AL) feeding. In WT mice, calorie restriction significantly enhanced insulin-stimulated 2DG uptake in both muscles regardless of sex. However, in KO mice, calorie restriction did not enhance insulin-stimulated 2DG in male or female EDL or in female soleus. Only in male KO soleus did calorie restriction significantly increase insulin-stimulated 2DG through an Akt2-independent mechanism, although 2DG uptake of the KO-CR group was reduced compared with the WT-CR soleus group. Akt2 serine phosphorylation was enhanced approximately two- to threefold in insulin-stimulated WT-CR versus WT-AL muscles. Calorie restriction induced an ∼1.5- to 2-fold elevation in Akt1 phosphorylation of insulin-treated muscles, regardless of genotype, but this increase was insufficient to replace Akt2 for insulin-stimulated 2DG in Akt2-deficient muscles. These results indicate that Akt2 is essential for the full effect of brief calorie restriction on insulin-stimulated glucose uptake in skeletal muscle with physiologic insulin.


    • Accepted February 15, 2005.
    • Received October 26, 2004.
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