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

Abstract

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.

Developmental programming of adult hyperinsulinemia, increased proinflammatory cytokine production, and altered skeletal muscle expression of SLC2A4 (GLUT4) and uncoupling protein 3

“…Thamotharan et al (2005) demonstrated that maternal caloric restriction programmed aberrant SLC2A4 cellular distribution, but in this case skeletal muscle SLC2A4 was concentrated in the plasma membrane rather than the cytoplasm, and further translocation was not induced by insulin. These authors suggested that this aberration reflects heightened basal insulin sensitivity in the face of caloric restriction that leads to subsequent glucose intolerance when postnatal nutrition is adequate (Thamotharan et al 2005).…”

“…Similar impairment in SLC2A4 translocation occurs in adipocytes isolated from the s.c. fat of diabetic patients (Maianu et al 2001), and it has been suggested that impaired ATP synthesis in skeletal muscle of rats following intrauterine growth retardation may compromise energy-dependent SLC2A4 recruitment to the cell surface (Selak et al 2003). Thamotharan et al (2005) demonstrated that maternal caloric restriction programmed aberrant SLC2A4 cellular distribution, but in this case skeletal muscle SLC2A4 was concentrated in the plasma membrane rather than the cytoplasm, and further translocation was not induced by insulin. These authors suggested that this aberration reflects heightened basal insulin sensitivity in the face of caloric restriction that leads to subsequent glucose intolerance when postnatal nutrition is adequate (Thamotharan et al 2005).…”

“…Alterations in skeletal muscle insulin regulated Slc2a4 expression and/or function may also be central to programmed disturbances in glycemic control, since prenatal ethanol exposure in rats (Chen & Nyomba 2003) and nutrient restriction in sheep (Gardner et al 2005) both reduce Slc2a4 expression in glucose-intolerant offspring. Maternal calorie restriction has also been shown to compromise insulininduced translocation of SLC2A4 to the plasma membrane (Thamotharan et al 2005).…”

Adult Sequelae of Intrauterine Growth Restriction

“…In the rat, fetal skeletal muscle GLUT4 expression is decreased, but the amount of GLUT4 present on the plasma membrane is increased, with diminished intracellular stores, suggesting a compensatory adaptation to low glucose availability. 13 In the adult IUGR rat, skeletal muscle GLUT4 continues to be increased on the plasma membrane but there is diminished translocation of additional GLUT4 to the plasma membrane in response to insulin. Adult IUGR human subjects with insulin resistance also demonstrated a failure to upregulate muscle GLUT4 after insulin stimulation.…”

Retardo de Crecimiento Intrauterino (Rciu) y Sus Alteraciones Bioquímicas.

“…Esto podría ser el resultado de alteraciones en la placenta o del metabolismo de la glucosa fetal (9). Niveles bajos de glucosa también han sido encontrados en niños con RCIU cuyas madres presentan niveles normales, sugiriendo disminución de la transferencia de glucosa a través de la placenta, presumiblemente debido a los transportadores de glucosa (10,11).…”