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

Abstract

Calorie restriction (CR), even for brief periods (4-20 days), results in increased whole-body insulin sensitivity, in large part due to enhanced insulin-stimulated glucose transport by skeletal muscle. Evidence suggests that the cellular alterations leading to this effect are postreceptor steps in insulin signaling. To determine whether insulin receptor substrate (IRS)-1 is essential for the insulin-sensitizing effect of CR, we measured in vitro 2-deoxyglucose (2DG) uptake in the presence and absence of insulin by skeletal muscle isolated from wild-type (WT) mice and transgenic mice lacking IRS-1 (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) were studied. In each muscle, insulin-stimulated 2DG uptake was not different between genotypes. For EDL and epitrochlearis, insulin-stimulated 2DG uptake was greater in CR compared to AL groups, regardless of sex. Soleus insulin-stimulated 2DG uptake was greater in CR compared with AL in males but not females. The diet effect on 2DG uptake was not different for WT and KO animals. Genotype also did not alter the CR-induced decrease in plasma constituents (glucose, insulin, and leptin) or body composition (body weight, fat pad/body weight ratio). Consistent with previous studies in rats, IRS-1 protein 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 protein 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 of IRS-1 does not modify any of the characteristic adaptations of CR that were evaluated.

Low replacement doses of thyroxine during food restriction restores type 1 deiodinase activity in rats and promotes body protein loss

“…The changes in metabolism created by the association of two inverse energy conditions: food deprivation (decreased energy) and T 4 administration (increased energy) led to a significant decrease in body protein compartment, showing that the reduction in RMR during FR could represent a mechanism of physiological protection against body protein loss, as previously suggested (Gardner et al 1979). The effects of food restriction on serum TSH, leptin, and thyroid hormones were strikingly similar to those previously described by other authors (Salih et al 1993, Gazdag et al 1999, Davidson et al 2002. The mechanisms that explain T 4 reduction during calorific restriction have been partially defined.…”

Proprotein convertase furin regulates osteocalcin and bone endocrine function

“…Collectively, these observations suggest that Furin osb-/-mice do not develop insulin resistance as robustly as do Ocn -/-mice, in part because of a reduction in calorie intake, a condition shown previously to improve insulin sensitivity in mice (36).…”

“…Because reduced calorie intake was shown to improve insulin sensitivity (36), this could explain why glucose intolerance and insulin sensitivity phenotypes are milder in Furin osb-/-mice than in Ocn -/-mice. Accordingly, pair feeding revealed a more severe glucose intolerance and insulin sensitivity phenotype in the Furin osb-/-mice.…”

Sirt1 enhances skeletal muscle insulin sensitivity in mice during caloric restriction

“…In contrast, CR does not appear to augment insulin action upstream of PI3K at the level of the IR or Irs1 in response to submaximal insulin (9) but has been shown to enhance IR-Irs1 activation in response to supraphysiological insulin stimulation (8,9,11,23), although this is not a universal finding (24,25). In addition, mice with KO of Irs1 exhibit the expected increase in skeletal muscle insulin sensitivity after CR (26). In this study, CR augmented insulin-stimulated PI3K-AktAs160 signaling and 2DOGU in skeletal muscle from WT mice but not in that from mKO mice.…”