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1 Division of Neonatology and Developmental Biology, Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
* To whom correspondence should be addressed. E-mail: sdevaskar{at}mednet.ucla.edu.
Intra-uterine 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 lib access to nutrients (CM/SP) or nutrient restriction (SM/SP), versus postnatal nutrient restriction alone (SM/CP), on skeletal muscle and white adipose tissue (WAT) insulin responsive glucose transporter isoform (GLUT 4) expression and insulin-responsive translocation. A decline in skeletal muscle GLUT 4 expression and protein concentrations was noted only in the SM/SP and SM/CP groups. In contrast, WAT demonstrated no change in GLUT 4 expression and protein concentrations in all experimental groups. The altered in-utero hormonal/metabolic milieu was associated with a compensatory adaptation which persisted in the adult and consisted of an increase in the skeletal muscle basal plasma membrane associated GLUT 4 concentrations. This perturbation led to no further exogenous insulin-induced GLUT 4 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/post-prandial insulin. Preservation of insulin responsiveness in WAT may serve as a sink that absorbs post-prandial nutrients which can no longer efficiently access skeletal muscle. We speculate that in-utero GLUT 4 aberrations may predict type 2 diabetes mellitus, while postnatal nutrient intake may predict obesity, thereby explaining the heterogeneous phenotype of the IUGR adult offspring.
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