Impaired regulation of glucose transporter 4 gene expression in insulin resistance associated with in utero undernutrition

The aim of this study was to investigate whether insulin resistance-associa ted in utero undernutrition was related to changes in insulin action on gen e expression of molecules involved in the insulin signaling pathway and per ipheral glucose metabolism in muscle and adipose tissue, Thirteen insulin-r esistant subjects born with intrauterine growth retardation (IUGR) were mat ched for age, gender, and body mass index to 13 controls. Gene expression o f insulin receptor, insulin receptor substrate-1, p85 alpha phosphatidylino sitol S-kinase, glucose transporter-4 (GLUT4), hexokinase Il, and glycogen synthase was studied in skeletal muscle at baseline and after a 3-h euglyce mic insulin stimulation. Target messenger ribonucleic acid (mRNA) levels we re quantified using the RT-competitive PCR method. Insulin-stimulated gluco se uptake was significantly lower in IUGR-born subjects than in,controls (3 6.9 +/- 12, 7 vs. 53.9 +/- 12.7 mu mol/kg min; P = 0.007), affecting both t he glucose oxidation rate and the nonoxidative glucose disposal rate. At ba seline, the expression of the six genes in muscle did not significantly dif fer between the two groups. The insulin-induced changes over baseline were comparable in both groups for all mRNAs, except GLUT4. In contrast to what observed in the control group (mean increment, 49 +/- 23%; P = 0.0009), GLU T4 expression was not stimulated by insulin in the IUGR group (8 +/- 8%; P = 0.42). Moreover, the magnitude of the defect in GLUT4 mRNA regulation by insulin was correlated to the degree of insulin resistance (r = 0.73; P = 0 .01). A similar lack of significant GLUM mRNA. stimulation by insulin was o bserved in the adipose tissue of IUGR-born subjects. In conclusion, insulin resistance in IUGR-born subjects is,associated with an impaired regulation of GLUT4 expression by insulin in muscle and adipose tissue. Our data prov ide additional information about the mechanism of insulin resistance associ ated with in utero undernutrition and strengthen the role of glucose transp ort in the control of insulin sensitivity.