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1 Division of Neonatology and Developmental Biology, Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles , California, United States
2 Division of Neonatology and Developmental Biology, Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, California, United States
3 Division of Neonatology and Developmental Biology, Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, California, United States; Division of Neonatology and Developmental Biology, Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles , California, United States
4 Los Angeles, California, United States; Division of Neonatology and Developmental Biology, Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles , California, United States
5 Harbor-UCLA Medical Center; Torrance, CA; Department of Pediatrics, Harbor-UCLA Medical Center; Torrance, CA, Los Angeles, California, United States
6 Division of Neonatology and Developmental Biology, Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles , California, United States; Pediatrics, UCLA - Medical School, Los Angeles, California, United States
* To whom correspondence should be addressed. E-mail: sdevaskar{at}mednet.ucla.edu.
To determine mechanisms underlying the transgenerational presence of metabolic perturbations in the intra-uterine growth restricted second generation adult females (F2 IUGR) despite normalizing the in-utero metabolic environment, we examined in-vivo glucose kinetics and in-vitro skeletal muscle post-insulin receptor signaling after embryo transfer of first generation (F1 IUGR) to control maternal environment. Female F2 rats, procreated by F1 pre- and postnatally nutrient and growth restricted (IUGR) mothers but embryo transferred (ET) to gestate in control mothers, were compared to similarly gestating age- and sex-matched control (CON) F2 progeny. While there were no differences in birth weight or postnatal growth patterns, the F2 IUGR had increased hepatic weight, fasting hyperglycemia, hyperinsulinemia and unsuppressed hepatic glucose production (HGP), with no change in glucose futile cycling (GFC) or clearance (GC), when compared to F2 CON. These hormonal and metabolic aberrations were associated with increased skeletal muscle total GLUT4 and pAkt concentrations but decreased plasma membrane associated GLUT4, total pPKC
and PKC enzyme activity with no change in total SHP2 and PTP1B concentrations in IUGR F2 compared to F2 CON. We conclude that trans-generational presence of aberrant glucose/insulin metabolism and skeletal muscle insulin signaling of the adult F2 IUGR female offspring is independent of the immediate intra-uterine environment, supporting nutritionally induced heritable mechanisms contributing to the epidemic of type 2 diabetes mellitus.
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