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GLUT4 expression and subcellular localization in the intrauterine growth-restricted adult rat female offspring

Division of Neonatology and Developmental Biology, Department of Pediatrics, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California

Submitted 29 July 2004 ; accepted in final form 23 December 2004

Intrauterine growth restriction (IUGR) leads to obesity, glucose intolerance, and type 2 diabetes mellitus in the adult. To determine the mechanism(s) behind this "metabolic imprinting" phenomenon, we examined the effect of total calorie restriction during mid- to late gestation modified by postnatal ad libitum access to nutrients (CM/SP) or nutrient restriction (SM/SP) vs. postnatal nutrient restriction alone (SM/CP) on skeletal muscle and white adipose tissue (WAT) insulin-responsive glucose transporter isoform (GLUT4) expression and insulin-responsive translocation. A decline in skeletal muscle GLUT4 expression and protein concentrations was noted only in the SM/SP and SM/CP groups. In contrast, WAT demonstrated no change in GLUT4 expression and protein concentrations in all experimental groups. The altered in utero hormonal/metabolic milieu was associated with a compensatory adaptation that persisted in the adult and consisted of an increase in the skeletal muscle basal plasma membrane-associated GLUT4 concentrations. This perturbation led to no further exogenous insulin-induced GLUT4 translocation, thereby disabling the insulin responsiveness of the skeletal muscle but retaining it in WAT. These changes, which present at birth, collectively maximize basal glucose transport to the compromised skeletal muscle with a relative resistance to exogenous/postprandial insulin. Preservation of insulin responsiveness in WAT may serve as a sink that absorbs postprandial nutrients that can no longer efficiently access skeletal muscle. We speculate that, in utero, GLUT4 aberrations may predict type 2 diabetes mellitus, whereas postnatal nutrient intake may predict obesity, thereby explaining the heterogeneous phenotype of the IUGR adult offspring.

glucose transporter 4; metabolic programming; glucose intolerance; nutrient restriction

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