Despina D. Briana

Intrauterine growth restriction and adult disease: the role of adipocytokines.

Intrauterine growth restriction (IUGR) is the failure of the fetus to achieve his/her intrinsic growth potential, due to anatomical and/or functional disorders and diseases in the feto-placental-maternal unit. IUGR results in significant perinatal and long-term complications, including the development of insulin resistance/metabolic syndrome in adulthood. The thrifty phenotype hypothesis holds that intrauterine malnutrition leads to an adaptive response that alters the fetal metabolic and hormonal milieu designed for intrauterine survival. This fetal programming predisposes to an increased susceptibility for chronic diseases. Although the mechanisms controlling intrauterine growth are poorly understood, adipose tissue may play an important role in linking poor fetal growth to the subsequent development of adult diseases. Adipose tissue secretes a number of hormones, called adipocytokines, important in modulating metabolism and recently involved in intrauterine growth. This review aims to summarize reported findings concerning the role of adipocytokines (leptin, adiponectin, ghrelin, tumor necrosis factor (TNF), interleukin-6 (IL6), visfatin, resistin, apelin) in early life, while attempting to speculate mechanisms through which differential regulation of adipocytokines in IUGR may influence the risk for development of chronic diseases in later life.

Reviews: Adipocytokines in Normal and Complicated Pregnancies

Human pregnancy is characterized by insulin resistance, traditionally attributed to the effects of placental hormones. Normal pregnancy—induced insulin resistance is further enhanced in pregnancy complications, associated with disturbed placental function, such as gestational diabetes mellitus, preeclampsia, and intrauterine growth restriction. Compelling evidence suggests that these pregnancy disorders are associated with future development of maternal metabolic syndrome. However, the pathogenetic mechanisms underlying the association between abnormal placental development, insulin resistance, and maternal metabolic syndrome are not fully understood. A large body of evidence has recently supported the role of adipose tissue in the regulation of insulin resistance in both nonpregnant and pregnant participants. In this respect, adipocytokines, which are adipocyte-derived hormones, have been implicated in the regulation of maternal metabolism and gestational insulin resistance. Adipocytokines, including leptin, adiponectin, tumor necrosis factor α, interleukin 6, as well as the newly discovered resistin, visfatin, and apelin, are also known to be produced within the intrauterine environment. However, data concerning the pattern of adipocytokines secretion in normal and complicated pregnancies are still limited and partially contradictory. Given the importance of adipose tissue and its hormones in terms of adequate metabolic control and energy homeostasis, we present a review of published data related to the role of adipocytokines in pregnancy, especially in relation to pregnancy complications. Focus will be placed on the functions and other potential roles of the novel adipocytokines resistin, visfatin, and apelin.

Perinatal Circulating Visfatin Levels in Intrauterine Growth Restriction

OBJECTIVE. The objective of this study was to investigate possible alterations in circulating levels of the adipocytokine visfatin in intrauterine growth-restricted and normal pregnancies, given that these groups differ considerably in fetal nutrition, body fat mass, and metabolic/endocrine mechanisms. METHODS. Serum visfatin levels were prospectively measured by enzyme immunoassay in 40 mothers and their 40 singleton term fetuses and neonates on postnatal days 1 and 4. Twenty neonates had intrauterine growth restriction (birth weight ≤3rd customized centile, adjusted for parameters that influence growth potential), and 20 were appropriate for gestational age. RESULTS. Circulating maternal visfatin levels were significantly elevated in pregnancies with intrauterine growth restriction compared with control pregnancies with appropriate-for-gestational-age infants and negatively correlated with customized centiles in the group with intrauterine growth restriction. Postnatal day-1 and -4 visfatin levels were significantly higher in neonates with intrauterine growth restriction compared with neonates who were appropriate for gestational age. Postnatal-day-1 prefeeding insulin levels were significantly lower in neonates with intrauterine growth restriction. CONCLUSIONS. Pathologic conditions in pregnancy that lead to intrauterine growth restriction could be responsible for elevated maternal visfatin levels. Higher visfatin levels in neonates with intrauterine growth restriction may serve as an early marker with prognostic value for later development of insulin resistance or type 2 diabetes, whereas lower insulin levels may indicate reduced β-cell mass and/or impaired β-cell function.

Perinatal changes of plasma resistin concentrations in pregnancies with normal and restricted fetal growth.

Background:The adipocytokine resistin inhibits adipogenesis and induces insulin resistance. Intrauterine growth-restricted (IUGR) neonates have reduced fat mass and changes of endocrine/metabolic mechanisms, predisposing to insulin resistance and metabolic syndrome in adult life. Objectives: To investigate plasma resistin concentrations in maternal, fetal and neonatal samples from IUGR and appropriate-for-gestational-age (AGA) pregnancies and correlate them with respective insulin concentrations. Methods: Plasma resistin and insulin concentrations were determined in 40 mothers and their 20 IUGR and 20 AGA singleton full-term fetuses and neonates on postnatal day 1 (N1) and day 4 (N4). Results: No significant differences in resistin concentrations were observed between AGA and IUGR groups. In the AGA group, maternal resistin concentrations were significantly lower compared to fetal, N1 and N4 ones (p = 0.003, p = 0.017 and p = 0.039, respectively). Maternal resistin concentrations positively correlated with fetal ones (r = 0.527, p = 0.02). In the IUGR group, maternal resistin concentrations were significantly lower compared to N1 (p < 0.001) and positively correlated with N4 concentrations (r = 0.626, p = 0.007). In both groups, the effect of gender, mode of delivery, parity and adjusted birth weight (customized centiles) on resistin concentrations was not significant. No correlation between resistin and insulin concentrations was documented. Conclusions: Lack of difference in resistin concentrations between IUGR and AGA groups, and lack of correlation between resistin and insulin concentrations as well as customized centiles, possibly suggests that resistin may not be directly involved in the regulation of insulin sensitivity and adipogenesis in the perinatal period. Mode of delivery and parity are not associated with circulating resistin concentrations.

Enteral L-Arginine Supplementation for Prevention of Necrotizing Enterocolitis in Very Low Birth Weight Neonates A Double-Blind Randomized Pilot Study of Efficacy and Safety

BACKGROUND Necrotizing enterocolitis (NEC) is the most common acquired gastrointestinal disease in premature infants and has high mortality and morbidity. Endothelial nitric oxide is an important regulator of vascular perfusion and is synthetized from the amino acid L-arginine. Hypoargininemia is frequently observed in preterm neonates and may predispose them to NEC. Our objective was to determine the effect of enteral L-arginine supplementation on the incidence and severity of NEC in very low birth weight (VLBW) neonates. MATERIALS AND METHODS We conducted a parallel blind randomized pilot study, comprising VLBW neonates with birth weight ≤1500 g and gestational age ≤34 weeks. VLBW neonates were randomly assigned to receive enteral L-arginine supplementation (1.5 mmol/kg/d bid) between the 3rd and 28th day of life or placebo. Diagnosis and classification of NEC were done according to modified Bells criteria. RESULTS Eighty-three neonates were randomized to the arginine (n = 40) or placebo (n = 43) group. No adverse effects were observed in neonates receiving L-arginine supplementation. The incidence of NEC stage III was significantly lower in the arginine-supplemented group (2.5% vs 18.6%, P = .030). CONCLUSIONS Enteral L-arginine supplementation of 1.5 mmol/kg/d bid can be safely administered in VLBW neonates from the 3rd to the 28th day of life. Enteral L-arginine supplementation appears to reduce the incidence of stage III NEC in VLBW infants. Larger studies are needed to further evaluate the effect of L-arginine supplementation in preventing NEC in VLBW infants.

The impact of oral glutamine supplementation on the intestinal permeability and incidence of necrotizing enterocolitis/septicemia in premature neonates

Objective. To examine the impact of oral glutamine (Gln) supplementation on gut integrity and on the incidence of necrotizing enterocolitis (NEC)/septicemia of premature neonates. Methods. Preterm neonates (n = 101, gestational age <34 weeks, birth weight <2000 g) were randomly allocated to receive from day 3 to day 30 postpartum, either oral Gln (0.3 g/kg/day, n = 51-Gln group) or placebo (caloreen-isocaloric, n = 50-control group). Intestinal permeability was determined from the urinary lactulose/mannitol recovery (L/M ratio) following their oral administration and assessed at three time points: day 2 (before first administration), day 7 and day 30 of life. The incidence of NEC and septicemia over the study period was also recorded. Results. A decrease of lactulose recovery at days 7 (p = 0.001) and 30 (p < 0.001) and a decrease of L/M ratio at day 7 (p = 0.002) were observed only in the Gln group. Lactulose recovery and L/M ratio at day 7 (p = 0.022 and p = 0.004, respectively), as well as lactulose recovery (p = 0.001), mannitol recovery (p = 0.042), and L/M ratio (p = 0.001) at day 30, were decreased in the Gln group as compared to controls. NEC and septicemia were lower in the Gln group at the end of the first week (p = 0.009 and p = 0.041, respectively) and up to the end of the study (p < 0.001 and p = 0.048, respectively). Conclusion. Oral Gln administration may have beneficial effects on intestinal integrity and the overall incidence of NEC/septicemia in preterm infants.

Cord Blood Ischemia-Modified Albumin Levels in Normal and Intrauterine Growth Restricted Pregnancies

Ischemia-modified albumin (IMA) is a sensitive biomarker of cardiac ischemia. Intrauterine growth restriction (IUGR) may imply fetal hypoxia, resulting in blood flow centralization in favour of vital organs (brain, heart, adrenals—“brain sparing effect”). Based on the latter, we hypothesized that cord blood IMA levels should not differ between IUGR and appropriate-for-gestational-age (AGA) full-term pregnancies. IMA was measured in blood samples from doubly-clamped umbilical cords of 110 AGA and 57 asymmetric IUGR pregnancies. No significant differences in IMA levels were documented between AGA and IUGR groups. IMA levels were elevated in cases of elective cesarean section (P = .035), and offspring of multigravidas (P = .021). In conclusion, “brain sparing effect” is possibly responsible for the lack of differences in cord blood IMA levels at term, between IUGR and AGA groups. Furthermore, higher oxidative stress could account for the elevated IMA levels in cases of elective cesarean section, and offspring of multigravidas.

Role of visfatin, insulin-like growth factor-I and insulin in fetal growth.

Abstract Objective: IGF-I and insulin are the main regulators of intrauterine and postnatal growth. Adipose tissue secreted cytokines are implicated in intrauterine growth. The relevant function of the adipocytokine visfatin is unknown. Materials and methods: Serum visfatin, IGF-I and insulin levels were measured by enzyme immunoassays in 40 singleton full-term fetuses and neonates on postnatal days 1(N1) and 4 (N4). Results: No significant correlations exist between visfatin and IGF-I or insulin. N1 and N4 visfatin positively correlated with customized (adjusted) birth weight centiles (r=0.511, P=0.021, and r=0.597, P=0.005, respectively). Fetal and N1 IGF-I positively correlated with customized centiles (r=0.608, P<0.001 and r=0.485, P=0.006, respectively). Fetal insulin positively correlated with customized centiles (r=0.654, P=0.021). Conclusions: Potential implication of visfatin in fetal growth is probably not mediated by IGF-I or insulin. Although a more active role cannot be excluded, visfatin may simply represent a marker of fat accumulation.

Circulating Osteoprotegerin and sRANKL Concentrations in the Perinatal Period at Term

Background: Intrauterine growth restriction (IUGR) has been associated with low bone mass in infancy and increased risk for osteoporosis development in adult life. Osteoprotegerin (OPG) and receptor activator of nuclear factor-κB ligand (RANKL) are main determinants of bone resorption. Objectives: To investigate OPG and soluble RANKL (sRANKL) concentrations in maternal, fetal and neonatal serum of IUGR patients and appropriate for gestational age (AGA) pregnancies. Additionally, plasma intact parathormone (PTH) concentrations were evaluated. Methods: Circulating OPG, sRANKL and PTH concentrations were measured in 40 mothers and their singleton full-term fetuses-neonates (AGA: n = 20, and IUGR: n =20) on postnatal days 1 (N1) and 4 (N4). Results: No significant differences in OPG, sRANKL or PTH concentrations were observed between AGA and IUGR groups. In both groups, maternal OPG concentrations were elevated compared with fetal, and N1 and N4 concentrations (p ≤ 0.045 in all cases). N4 sRANKL concentrations were elevated compared with maternal, fetal and N1 ones (p ≤ 0.01 in all cases). Fetal and N1 sRANKL concentrations correlated positively with PTH levels (r = 0.642, p = 0.024 and r = 0.584, p = 0.046, respectively). Conclusions: The lack of a difference in circulating OPG, sRANKL or PTH concentrations between IUGR cases and AGA controls suggests that the low bone mass of IUGR infants may not be related to higher bone resorption rates. The increased maternal, compared with fetal/neonatal, OPG concentrations may suggest their placental origin. The lower OPG and higher sRANKL concentrations in fetuses and neonates could represent high bone resorption rates.

Perinatal Changes of Cardiac Troponin-I in Normal and Intrauterine Growth-Restricted Pregnancies

Intrauterine growth restriction (IUGR) implies fetal hypoxia, resulting in blood flow redistribution and sparing of vital organs (brain, heart). Serum cardiac Troponin-I (cTnI), a well-established marker of myocardial ischaemia, was measured in 40 mothers prior to delivery, the doubly clamped umbilical cords (representing fetal state), and their 20 IUGR and 20 appropriate-forgestational-age (AGA) neonates on day 1 and 4 postpartum. At all time points, no differences in cTnI levels were observed between the AGA and IUGR groups. Strong positive correlations were documented between maternal and fetal/neonatal values (r ≥ .498, P ≤ .025 in all cases in the AGA and r ≥ .615, P ≤ .009 in all cases in the IUGR group). These results may indicate (a) normal heart function, due to heart sparing, in the IUGR group (b) potential crossing of the placental barrier by cTnI in both groups.