Calorie restriction increases insulin-stimulated glucose transport in skeletal muscle from IRS-1 knockout mice

Calorie restriction (CR), even for brief periods (4-20 days), results in in creased whole-body insulin sensitivity, in large part due to enhanced insul in-stimulated glucose transport by skeletal muscle. Evidence suggests that the cellular alterations leading to this effect are postreceptor steps in i nsulin signaling. To determine whether insulin receptor substrate (IRS)-1 i s essential for the insulin-sensitizing effect of CR, we measured in vitro 2-deoxyglucose (2DG) uptake in the presence and absence of insulin by skele tal muscle isolated from wild-type (WT) mice and transgenic mice lacking IR S-I (knockout [KO]) after either ad libitum (AL) feeding or 20 days of CR ( 60% of ad libitum intake). Three muscles (soleus, extensor digitorum longus [EDL], and epitrochlearis) from male and female mice (4.5-6 months old) we re studied. In each muscle, insulin-stimulated 2DG uptake was not different between genotypes. For EDL and epitrochlearis, insulin-stimulated 2DG upta ke a-as greater in CR compared to AL groups, regardless of sex. Soleus insu lin-stimulated 2DG uptake was greater in CR compared with AL in males but n ot females. The diet effect on 2DG uptake was not different for WT and KO a nimals. Genotype also did not alter the CR-induced decrease in plasma const ituents (glucose, insulin, and leptin) or body composition (body weight, fa t pad/body weight ratio). Consistent sith previous studies in rats, IRS-1 p rotein expression in muscle was reduced in WT-CR compared with WT-AL mice, and muscle IRS-2 abundance was unchanged by diet. Skeletal muscle IRS-2 pro tein expression was significantly lower in WT compared with KO mice. These data demonstrate that IRS-1 is not essential for the CR-induced increase in insulin-stimulated glucose transport in skeletal muscle, and the absence o f IRS-1 does not modify any of the characteristic adaptations of CR that we re evaluated.