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JOURNAL CLUB |
1 Department of Physiology and the Centre for Excellence in Cardiovascular–Renal Research at the University of Mississippi Medical Centre, Jackson, MS 39216–4505, USA Email: jsgilbert{at}physiology.umsmed.edu
In recent years, considerable epid-emiological and experimental data have accrued which indicates that alterations in the trajectory of fetal growth and development due to suboptimal intrauterine conditions has profound, persistent effects on metabolic function in later life (Hales & Ozanne, 2003; De Blasio et al. 2007; Owens et al. 2007b). Specifically, the relationship between weight at birth and the incidence of diseases such as type 2 diabetes mellitus, hypertension, cardiovascular disease, and obesity in adulthood has received increased attention as the occurrence of this constellation of disorders has reached epidemic proportion in many parts of the world. Collectively, these disorders have come to be recognized as the metabolic syndrome X (Hales & Ozanne, 2003). Whilst remarkable progress has been made characterizing a variety of models for the developmental origins of health and disease (DOHaD), there have been relatively few studies of the fetal physiological adaptations that are likely to underlie this phenomenon.
Recently, Owens et al. (2007a) reported in the The Journal of Physiology the first evidence that impaired placental growth and function is associated with reduced glucose stimulated insulin secretion in the late gestation sheep fetus. These important findings indicate that impaired placental function (i.e. placental restriction), which is regarded as being a significant cause of intrauterine growth restriction in humans, has deleterious effects on glucose stimulated insulin secretion that begin during fetal life. Moreover, these data in concert with previous work from the same laboratory show that these effects on glucose stimulated insulin secretion and/or glucose metabolism form a continuum throughout the lifespan of the organism (i.e. fetal life, early postnatal, and adulthood).
The present study complements earlier work by making several methodological advances that permit a more thorough evaluation of fetal physiology at different gestational ages. One such advance was the administration of glucose directly to the fetus in this model of placental restriction as opposed to glucose administration to the mother (Harding et al. 1985), in which fetal glucose delivery is limited by glucose transporters 1 and 3. Thus, the authors were able to measure glucose stimulated insulin secretion in both growth-restricted and control fetuses. Furthermore, the authors show for the first time that dysregulated glucose stimulated insulin secretion presages impaired postpartum glucose stimulated insulin secretion in this model of fetal growth restriction. Another methodological advance was employing predictive fetal weight curves that were developed in the authors' laboratory for both control and placental restricted fetuses. The growth curves allowed the authors to adjust the glucose and L-arginine doses to accommodate the increased size of the fetus in later gestation (day of gestation (DG) 120 versus DG 140). Despite the observed discrepancies between predicted and observed fetal weights in the present work, this effort demonstrated excellent forethought. Further, this additional manoeuvre allowed the authors to show that there is an increase in the magnitude of the acute insulin release in response to glucose infusion from DG 120 to DG 140, which suggests an improved capacity for rapid insulin release in late gestation, an observation that is consistent with insulin being an important anabolic factor in the late gestation fetus.
Predictors of insulin secretion and glucose tolerance were also identified by Owens et al. (2007a). The authors observed that fetal plasma glucose concentration was positively correlated with placental weight rather than fetal weight, and that fetal plasma insulin concentrations correlated positively with fetal plasma glucose concentration, and fetal and placental weight. The authors suggest that these findings indicate that fetal glucose supply is the primary stimulus for basal insulin secretion and reduced anabolic stimulus from insulin may contribute to growth restriction in the placental restricted fetuses.
As expected, the authors observed evidence of accelerated maturational increase in fetal plasma cortisol concentration in the placental restricted fetuses. Interestingly, in contrast to previous studies in the rat that have implicated plasma cortisol concentrations as a programming mechanism for postnatal glucose metabolism (Nyirenda et al. 1998) the authors reported that fetal plasma cortisol concentrations were not related to outcomes in this cohort (Owens et al. 2007a). This observation may indicate that insulin has important maturational effects in late gestation that remain unrecognized, and may reveal a new direction for additional studies in the future.
The examination of the developmental origins of disease raise a variety of intriguing questions, not the least of which is that of the optimum time to intervene in an attempt to ameliorate the health concerns of both the mother and the fetus/offspring. Analysing the disruptions in fetal physiology and following the animals through to later life in a model such as the one at present employed by Owens et al. (2007a) has allowed the authors to clearly identify fetal life as an important period for prophylactic treatment of intrauterine growth restriction. Moreover, studies such as these in long gestation species allow investigators the ability to clearly identify differential effects across the discrete windows of programming. As these studies continue, it will be exciting to find out if intervention during late gestation can prevent sequelae such as metabolic syndrome X.
Another important question with regard to intervention in fetal life that is raised by the present study is whether or not the sex-dependent differences in metabolic function reported in the offspring originate during early life. Since it has been observed that the growth curves of male and female fetuses (at least in humans) diverge near mid-gestation, with male fetuses growing to be larger for any given age in the last half of gestation (Parker et al. 1984), it follows that the critical windows of sensitivity to programming insults may be shifted depending upon the sex of the fetus. The authors pursued the idea of sex differences in the response to placental restriction in a paper published earlier this year (Owens et al. 2007b). In that work they demonstrated that placental restriction was predictive of impaired glucose homeostasis and insulin secretion in males at 1 year of age, but not in age-matched placental restricted females. Nevertheless, placental restricted females that were thinner at birth became heavier at 1 year of age without a concomitant increase in frame size, suggesting an increased deposition of adipose tissue, which is predictive of impaired insulin sensitivity later in life. This previous study by Owens et al. viewed in concert with the current study suggest that these altered windows of sensitivity may exist not only in the fetus but also in the offspring. Thus, many important questions remain unanswered regarding the contributions of fetal sex to the mechanisms of programming in this and other DOHaD models.
In summary, these important observations shed further light on the mechanisms of fetal growth restriction and suggest that decreased energy substrate rather than dysregulated fetal endocrine responses may be a primary defect. Furthermore, the studies of Owens et al. (2007a,b) provide new insight into the matter of how early interventions might be required to remedy the effects of intrauterine growth restriction. The present results, viewed in concert with previous observations from clinical studies in IUGR children and adolescents (Jaquet et al. 2000) and experimental data from IUGR lambs (De Blasio et al. 2007; Owens et al. 2007b) clearly demonstrate that with respect to glucose stimulated insulin secretion, fetal size, at least during late gestation, really does matter.
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Hales CN & Ozanne SE (2003). The dangerous road of catch-up growth. J Physiol 547, 5–10.
Harding JE, Jones CT & Robinson JS (1985). Studies on experimental growth retardation in sheep. The effects of a small placenta in restricting transport to and growth of the fetus. J Dev Physiol 7, 427–442.[Medline]
Jaquet D, Gaboriau A, Czernichow P & Levy-Marchal C (2000). Insulin resistance early in adulthood in subjects born with intrauterine growth retardation. J Clin Endocrinol Metab 85, 1401–1406.
Nyirenda MJ, Lindsay RS, Kenyon CJ, Burchell A & Seckl JR (1998). Glucocorticoid exposure in late gestation permanently programs rat hepatic phosphoenolpyruvate carboxykinase and glucocorticoid receptor expression and causes glucose intolerance in adult offspring. J Clin Invest 101, 2174–2181.[Medline]
Owens JA, Gatford KL, De Blasio MJ, Edwards LJ, McMillen IC & Fowden AL (2007a). Restriction of placental growth in sheep impairs insulin secretion but not sensitivity before birth. J Physiol (in press, doi: 10.1113/jphysiol.2007.142141).
Owens JA, Thavaneswaran P, De Blasio MJ, McMillen IC, Robinson JS & Gatford KL (2007b). Sex-specific effects of placental restriction on components of the metabolic syndrome in young adult sheep. Am J Physiol Endocrinol Metab 292, E1879–E1889.
Parker AJ, Davies P, Mayho AM & Newton JR (1984). The ultrasound estimation of sex-related variations of intrauterine growth. Am J Obstet Gynecol 149, 665–669.[Medline]
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