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Home , Human placental lactogen, Resistin

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J. Perinat. Med. 35 (2007) 513–521 • Copyright by Walter de Gruyter • Berlin • New York. DOI 10.1515/JPM.2007.122

Resistin: a which induces resistance is increased in normal

Jyh Kae Nien1, Shali Mazaki-Tovi1,2, Roberto for concentration were determined for five pre- Romero1,3,*, Juan Pedro Kusanovic1, Offer specified windows of gestational age. Plasma resistin Erez1, Francesca Gotsch1, Beth L. Pineles1, concentration was determined by immunoassay. Non- Lara A. Friel1,2, Jimmy Espinoza1,2, Luis parametric statistics were used for analysis. Goncalves1, Joaquin Santolaya1, Ricardo Results: The median maternal plasma concentration of Gomez4, Joon-Seok Hong1, Samuel Edwin1, resistin between 11 to 14 weeks of gestation in women Eleazar Soto1, Karina Richani1, Moshe Mazor5 of normal weight was significantly higher than non-preg- and Sonia S. Hassan1,2 nant women; the plasma concentration of resistin increased with gestational age. 1 Perinatology Research Branch, Intramural Division, Conclusions: Normal pregnant women have a higher NICHD/NIH/DHHS, Hutzel Women’s Hospital, median plasma concentration of resistin than non-preg- Bethesda, MD, and Detroit, MI, USA nant women and the concentration of this adipokine 2 Department of Obstetrics and Gynecology, Wayne increases with advancing gestation. Alterations in the State University/Hutzel Women’s Hospital, Detroit, maternal plasma concentration of resistin during MI, USA pregnancy could contribute to metabolic changes of 3 Center for Molecular and Genetics, Wayne pregnancy. State University, Detroit, MI, USA Keywords: Adipokines; nomogram; ; pregnancy; 4 Center for Perinatal Diagnosis and Research (CEDIP), resistin. Hospital Sotero del Rio, P. Universidad Catolica de Chile, Puente Alto, Chile 5 Soroka University Medical Center, Ben Gurion University of the Negev, Beer Sheva, Israel Introduction

Abstract Pregnancy is a unique state characterized by physiolog- ical that resolves postpartum w11–13, Aims: Resistin, a newly discovered adipokine, is thought 15, 16, 28, 54, 57, 60, 74, 85, 92x. However, the mech- to play a key role in the regulation of insulin resistance. anisms responsible for insulin resistance are not well The objectives of this study were to develop a nomogram understood. By increasing availability, insulin of maternal plasma concentrations of resistin from resistance may facilitate delivery of energy to the 11 weeks of gestation to term and to determine whether w55, 74, 84x. Insulin resistance during pregnancy is com- resistin concentrations differ between normal and over- monly attributed to the increased concentration of sev- weight pregnant women. eral placental in maternal . Evidence in Methods: In this cross-sectional study, plasma concen- support of this hypothesis includes: (1) infusion of human trations of resistin were determined in normal pregnant (hPL), a hormone produced abun- women of normal body mass index (BMI 18.5–24.9; dantly by the , can induce metabolic changes in ns261), overweight pregnant women (BMI G25; non-pregnant subjects w44, 87x; (2) similar effects have ns140), and non-pregnant women of normal BMI been observed after treatment with w8, 45x, (ns40). Blood samples were collected once from each w76x or glucocorticosteroids w7, 44x; (3) insulin woman between the first trimester and term. Percentiles action on is impaired after in vitro exposure to progesterone, , , and human placental *Corresponding author: w x Roberto Romero, MD lactogen 86 ; and (4) insulin resistance during pregnancy Perinatology Research Branch rises as a function of increasing plasma concentrations Intramural Division of placental hormone secretion. NICHD/NIH/DHHS Hutzel Women’s Hospital-Box No. 4 The conventional view is that the placenta plays a key 3990 John R role in the mechanisms responsible for insulin resistance Detroit in pregnancy. However, the role of in the MI 48201, USA q pathophysiology of insulin resistance has been a subject Tel.: 1 (313) 993-2700 w x Fax: q1 (313) 993-2694 of interest 33, 39, 42, 43, 63, 69, 82, 93, 97 . Adipose E-mail: [email protected] tissue can exert its effects by several mechanisms, Article in press - uncorrected proof

514 Nien et al., Resistin in normal pregnancy

including the secretion of bioactive . These 18.5 and 24.9. A patient was considered overweight if the BMI bioactive substances, collectively termed adipokines, was G25 w24x. include w26, 29, 30x, w2, 9, 41, 64x, Written informed consent was obtained from all participants. a w38, 98x, interleukin-6 w100, 101x, The study was approved by the Institutional Review Board. Many of the samples from these patients have been employed C-reactive w10, 70x, resistin w6, 37, 49, 94x and to study the biology of , hemostasis, angiogenesis others w56, 82, 83x. Recently, adipokines have been impli- regulation, and growth factor concentrations in non-pregnant cated in the regulation of insulin resistance during preg- women, normal pregnant women and those with pregnancy nancy. Serum concentrations of tumor necrosis factor-a complications. w52, 65x, adiponectin w18, 61, 65, 81x, leptin and C-reac- w x tive protein 65 correlate with indices of insulin resis- Blood collection and resistin immunoassay tance during pregnancy. Resistin is a novel adipokine with a molecular weight Blood samples from non-pregnant women were obtained during of 12.5 kDa w37, 49, 66, 77, 94, 104x. In mice, the syn- the secretory phase of the menstrual cycle, and from pregnant thesis of resistin is restricted to adipocytes. However, in women at 11–14 weeks, 15–18 weeks, 27–30 weeks, or humans, adipocytes, muscle w56x, pancreatic islets w68x, )37 weeks of gestation. These samples were collected into mononuclear cells w47x and placenta w34, 58, 107x can vials containing ethylenediamine tetra-acetic acid and centri- synthesize this protein. Several lines of evidence support fuged for 10 min at 48C. Plasma was stored at –708C until anal- the association between resistin and insulin resistance: ysis. Plasma resistin concentrations were determined with Human Resistin ELISA (LINCO Research Inc, St Charles, MO, (1) in mice, obesity is associated with increased plasma w x USA), following the recommendations of the manufacturer. The resistin concentrations 77 ; (2) resistin mRNA expression sensitivity of the assay was 0.095 ng/mL and the inter- and in adipocytes is low during fasting but increases signifi- intra-assay coefficients of variation were 5.9% and 5.8%, cantly when fasting mice are refed with a high carbohy- respectively. drate diet (25-fold) or treated with insulin (23-fold) w49x; (3) treatment of normal mice with recombinant resistin Statistical analysis impairs glucose tolerance and insulin action; (4) admin- istration of anti-resistin antibodies potentiates insulin- Normality of the data was tested using the Shapiro-Wilk test. stimulated glucose uptake in mice with diet-induced The plasma resistin concentrations were not normally distribut- obesity w94x; (5) in vitro neutralization of resistin results in ed. Thus, non-parametric tests were used in the data analysis. enhanced insulin-stimulated glucose uptake by adipo- The relationship between maternal plasma resistin concentration cytes w94x; and (6) in humans, plasma resistin concentra- and gestational age was examined using the Spearman rank tion correlates with insulin resistance indices and obesity test. Comparisons of the median resistin concentration among groups were performed using the Kruskal-Wallis test. Post hoc w89, 95x. analyses were done with Mann-Whitney U-test, and Bonferroni The objective of this study was to generate a nomo- adjustment was applied for multiple comparisons. Analysis of gram of maternal plasma concentrations of resistin dur- covariance (ANCOVA) was performed to control for confounding ing pregnancy by determining concentrations of this factors that could affect plasma resistin concentrations during hormone during first, second and third trimesters of preg- pregnancy. nancy. In addition, we sought to determine whether BMI affects the maternal plasma concentrations of resistin. Results Materials and methods Table 1 displays the demographic characteristics and plasma resistin concentrations of the three study groups. Study design and population No significant differences in age, weight, and BMI were This retrospective, cross-sectional study compared maternal observed between pregnant women of normal weight plasma resistin concentrations among pregnant women of nor- and non-pregnant women. There was a higher proportion mal weight (ns261), overweight pregnant women (ns140) and of nulliparous women in the non-pregnant group non-pregnant women (ns40). Non-pregnant women were (P-0.05). included in the study if they had no chronic , did not use Resistin was detected in the plasma of all subjects. oral contraception, and had a body mass index (BMI) -25 Pregnant women of normal weight had a significantly kg/m2. The inclusion criteria for the pregnant group were: (1) higher median plasma resistin concentration than did singleton pregnancy; (2) no prior diabetes mellitus or other non-pregnant women (Table 1). These results did not chronic ; (3) no obstetrical, maternal, or fetal compli- change after adjusting for parity (non-pregnant nullipa- cations; (4) a normal plasma glucose concentration in the first rous median: 10.2 ng/mL, range: 5–16 vs. pregnant nul- trimester; (5) a normal oral glucose tolerance test in the third s trimester; and (6) delivery at term of a neonate with birthweight liparous median: 12.5 ng/mL, range: 5–40; P 0.04; and appropriate for gestational age. The first trimester BMI was non-pregnant multiparas median: 9.9 ng/mL, range: calculated with the following formula: BMIsweight (kg)/height 6.3–24.2 vs. pregnant multiparas median: 13.3 ng/mL, (m2). A normal BMI was defined when the values were between range: 6–81.4; Ps0.02). Article in press - uncorrected proof

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Table 1 Clinical characteristics and plasma resistin concentrations of the study population.

Non-pregnant Normal-weight Overweight (ns40) (ns261) (ns140)

Age (years) 25 (19–38) 25 (15–42) 28 (15–42) Nulliparity 21 (53%) 101 (39%)* 35 (25%)* Weight (kg) 54 (50–64) 54 (40–68) 66 (52–108)** BMI 22 (19–24.9) 22 (19–24.9) 27 (25–40)** Plasma resistin (ng/mL) 10.3 (6.5–24.2) 14.1 (1.6–159) *† 14.8 (5.1–107)*† Values are expressed as median (range) or number (percentage). BMIsbody mass index. *P-0.05 compared to non-pregnant women. **P-0.05 compared to pregnant women of normal weight. †Adjusted for parity: P-0.05 for each group.

Pregnant women between 11 and 14 weeks of ges- ma concentrations of resistin during pregnancy. Indeed, tation had significantly higher plasma concentrations of there were no significant differences in plasma resistin resistin than did non-pregnant women (Ps0.003; Figure concentrations between normal weight and overweight 1). A significant positive correlation was observed women at different gestational ages (Figure 3). between plasma resistin concentrations and gestational Table 2 presents the reference plasma resistin concen- age (rs0.22; P-0.01). Maternal plasma concentrations trations in non-pregnant women and pregnant women of of resistin at term were significantly higher than those of normal weight, including the 10th,25th,50th,75th and 90th patients in the first (11–14 weeks), second (15–18 weeks) percentiles. or early third (27–30 weeks) trimester. In contrast, there were no significant differences in the resistin concentra- tions among the first, second, and early third trimester Discussion groups (Figure 2). In order to examine the effects of confounding factors Principal findings of this study that may affect maternal plasma concentrations of resis- tin, analysis of covariance was applied, including mater- (1) Pregnant women of normal weight had a significantly nal age, parity, BMI during first trimester, and gestational higher median plasma resistin concentration compared age (categorized into -37 and G37 weeks). This model to non-pregnant women; (2) plasma resistin concentra- showed that BMI did not contribute to the maternal plas-

Figure 2 Maternal plasma resistin concentrations during preg- nancy in women of normal weight (BMI 18.5–24.9). Plasma resistin concentrations remained invariable before term Figure 1 Comparison of median plasma resistin concentra- (11–14 weeks vs. 15–18 weeks, Ps0.18; 11–14 weeks vs. tions between non-pregnant women and pregnant women in the 27–30 weeks, Ps0.44; 15–18 weeks vs. 27–30 weeks, first trimester. Ps0.66). In contrast, a significant increase of plasma resistin Pregnant women had a higher median plasma resistin concen- concentrations was observed at term (**P-0.05 for each com- tration than non-pregnant women. parison. All P-values were adjusted for multiple comparisons). Article in press - uncorrected proof

516 Nien et al., Resistin in normal pregnancy

literature regarding the changes in glucose and insulin during gestation, data regarding the specific mechanisms underlying these changes are scant. Pla- cental hormones such as hPL are thought to be the main factors in inducing gestational insulin resistance. This hypothesis was supported by the finding that placental hormones have diabetogenic effects both in vitro w86x and in vivo w7, 8, 44, 45, 76, 87x. In addition, insulin resis- tance rises with the increased maternal serum concen- trations of multiple placental hormones and resolves soon after delivery.

Adipose tissue, adipokines and insulin resistance in pregnancy

Pregnancy is characterized by insulin resistance, tradi- tionally attributed to the effect of placental hormones w7, Figure 3 Plasma resistin concentrations of normal-weight (BMI 8, 44, 45, 62, 76, 86, 87x. A single mechanism is unlikely 18.5–24.9) and overweight (BMI G25) pregnant women. No significant differences were observed in the plasma resistin to explain the link between pregnancy and insulin resis- concentrations between both groups at different gestational tance. A large body of evidence has supported the role ages. of adipose tissue in the induction and regulation of insulin resistance in non-pregnant and pregnant subjects. Indeed, during the last decade, the notion of adipose tis- tions change as a function of gestational age; (3) mater- sue as an important endocrine organ has emerged w23, nal plasma concentrations of resistin were significantly 43, 83x, and the role of adipocytes and other cellular higher at term than in the first, second, or early third tri- components of adipose tissue has been strengthened. mester; and (4) a nomogram for maternal plasma resistin Moreover, adipokines, which are -derived hor- concentration is presented. mones, have been implicated in the regulation of insulin resistance during pregnancy. Several findings support Pregnancy as a forme fruste of the metabolic the role of adipokines in the physiology and pathophy- syndrome siology of insulin resistance during pregnancy: (1) mater- A ‘‘physiological adaptation’’ of normal pregnancy nal serum concentrations of tumor necrosis factor-a w52, includes insulin resistance w11–13, 28, 60, 74, 85, 92x, 65x, adiponectin w18, 61, 65, 81x, leptin and C-reactive hyperlipidemia w17, 22, 73, 91x, increased weight and protein w65x are correlated with clinical indices of insulin deposition w14, 25, 40, 51, 75x. These changes are con- resistance; (2) in the third trimester, insulin resistance in sidered components of the w1x, obese women increased by 40% w90x, but only 25% in although physiological alterations during pregnancy do non-obese women w15x; and (3) patients with gestational not necessarily meet the threshold values for the defini- diabetes have increased maternal serum concentrations tion of the metabolic syndrome. The profound metabolic of tumor necrosis factor-a w4, 50, 52, 65, 103x, C-reactive changes are thought to be necessary for meeting the protein w65x, hyperleptinemia w4, 48, 52, 65x, and hypoa- energy demands of the rapidly growing fetus and pla- diponectinemia w4, 50, 79, 96, 102, 104, 105, 107x. The centa. Insulin resistance is the most studied metabolic insulin resistance during pregnancy is accompanied by a change during pregnancy. This is probably due to the fact remarkable increase in adipose tissue deposits, sug- that it stands out as a potential causative factor for other gesting that adipose tissue has a role in the induction metabolic changes w1x, or to the significant clinical con- and regulation of gestational insulin resistance. Our find- sequences of . While there is ample ings of elevated plasma resistin concentrations during

Table 2 Percentile ranges for plasma resistin concentrations (ng/mL) in non-pregnant and pregnant women (BMI 18.5–24.9).

5th 10th 25th 50th 75th 90th 95th Non-pregnant (ns40) 6.3 6.5 7.8 10.2 12.7 16.1 17.3 Pregnant 11–14 weeks (ns63) 6.3 7.3 9.6 12.8 16.9 25.8 49.8 15–18 weeks (ns68) 7.8 9.2 11.2 14.3 19.0 24.3 28.9 27–30 weeks (ns65) 5.8 8.1 11.1 12.8 17.9 30.3 34.5 )37 weeks (ns65) 8.6 10.9 13.6 15.7 19.9 28.5 30.9 BMIsbody mass index. Article in press - uncorrected proof

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pregnancy and further increases in the concentrations at differences among studies. In particular, our study was term support the association between adipokines and conducted using a relatively large number of patients at insulin resistance during pregnancy. gestational ages ranging from the first trimester to term, and with different BMIs. Resistin and insulin resistance in non-pregnant subjects Why do maternal serum/plasma concentrations of resistin increase during pregnancy? Resistin is a newly-discovered adipokine w37, 49, 66, 77, 94, 104x. In vivo studies in rodents confirmed the exclu- Our results indicate that pregnancy is associated with sive production of this hormone by adipose tissue. How- higher plasma concentrations of resistin than in the non- ever, studies in humans have revealed that resistin is not pregnant state and that a further elevation is observed tissue-specific and that it can be produced by muscle during the third trimester. Several explanations can w56x, pancreatic islets w68x, mononuclear cells w47x and account for this finding: w x placenta 34, 58, 107 . Preliminary studies (in vitro and in 1. Insulin resistance during pregnancy: Maternal serum animals) suggest that resistin has a role in insulin resis- resistin was associated with surrogate indices of tance and that this adipokine could be the link between insulin resistance in patients with gestational dia- w x obesity and insulin resistance 5, 94 . Indeed, exposure betes w72x. The data obtained in the present study of adipocytes to resistin impairs insulin-stimulated glu- do not allow us to discern cause-and-effect relation- cose uptake, while anti-resistin antibodies prevent this ships; however, the possibility that alterations in w x effect 94 . Hyper-resistinemia is a characteristic of maternal plasma concentrations of resistin during obese mice, and treatment with resistin induces insulin pregnancy have a role in the regulation of the meta- resistance in mice with diet-induced insulin resistance, bolic changes with advancing gestation should be while immunoneutralization of resistin reduces hypergly- considered. w x cemia 94 . Finally, resistin induces hepatic insulin resis- 2. Increased fat deposition during pregnancy: Pregnan- w x tance in 78 . cy is characterized not only by insulin resistance but There is controversy in the literature regarding the also by a remarkable increase in adipose tissue association between resistin, insulin resistance and obe- deposits. Given that resistin is produced by adipose sity in humans. Hyper-resistinemia has been documented tissue, it is plausible that plasma resistin is elevated in subjects with HIV lipodystrophy and hyperinsulinemia simply due to this increase in fat mass. w x w x 46 , patients on chronic haemodialysis 27 and subjects 3. Increased visceral fat depot during pregnancy: Some w x with Prader-Willi syndrome 71 , all conditions closely data support an increase in intra-abdominal fat dur- linked to insulin resistance. Moreover, higher plasma con- ing pregnancy w51x. Of note, visceral fat amount is centrations of resistin have been reported in obese indi- significantly higher during the third trimester, when w x viduals compared to lean subjects 32 and in patients maternal serum resistin concentrations are at their w x with diabetes compared to normal subjects 31, 106 . peak. These findings are consistent with the report However, other investigators have not found an associ- by McTernan et al., which demonstrated higher resis- ation between resistin and insulin resistance or obesity tin mRNA expression w67x and protein w66x in visceral w x 3, 35, 59, 80, 88 . fat than in peripheral fat in the thigh and the breast. Taken together, the regional alteration in fat distri- Resistin and insulin resistance in human pregnancy bution during pregnancy may be related to the increase in maternal plasma resistin. Only a handful of studies have investigated serum con- 4. Secretion by the placenta: The human placenta has centrations of resistin in human pregnancy w19–21, 34, been reported to be a site of resistin production w34, 36, 72, 99, 107x. Our finding of higher plasma resistin 58, 107x. Resistin expression in term concentrations in pregnant women compared to non- is higher than that in first trimester w107x. The hypoth- pregnant subjects are consistent with reports by Yura et esis that the placenta is a major contributor to mater- al. w107x, Cortelazzi et al. w21x and Palik et al. w72x. How- nal plasma resistin is in line with our findings of ever, Chen et al. reported that differences between serum higher plasma concentrations of resistin in the preg- resistin concentrations of non-pregnant and pregnant nant state, the dramatic increase observed during the women are significant only in the third trimester w19x. The third trimester, as well as the lack of correlation with finding that BMI does not contribute to the plasma con- maternal BMI. centrations of resistin during pregnancy is in agreement with a study by Hendler et al. w36x in which maternal serum resistin is not correlated with BMI. Herein, we report a positive correlation between maternal plasma Conclusions resistin and gestational age, which contrasts with a pre- vious report by Cortelazzi et al. w21x. However, differenc- In summary, the results presented herein indicate that es in study design and sample size may contribute to the pregnancy is associated with higher plasma concentra- Article in press - uncorrected proof

518 Nien et al., Resistin in normal pregnancy

tions of resistin than in the non-pregnant state and a w14x Butte NF, Wong WW, Treuth MS, Ellis KJ, O’Brian SE. further increase occurs during the third trimester. This Energy requirements during pregnancy based on total elevated concentration in maternal blood correlates pos- energy expenditure and energy deposition. Am J Clin Nutr. 2004;79:1078–87. itively with gestational age but not with maternal BMI. w15x Catalano PM, Tyzbir ED, Roman NM, Amini SB, Sims EA. The possibility that alterations in the maternal plasma Longitudinal changes in insulin release and insulin resis- concentration of resistin during pregnancy have a role in tance in nonobese pregnant women. Am J Obstet Gyne- the regulation of the metabolic changes during pregnan- col. 1991;165:1667–72. cy should be considered. Finally, we have presented a w16x Catalano PM, Roman-Drago NM, Amini SB, Sims EA. nomogram for plasma resistin concentrations during Longitudinal changes in body composition and energy pregnancy that may lay the groundwork for further balance in lean women with normal and abnormal glu- cose tolerance during pregnancy. Am J Obstet Gynecol. studies. 1998;179:156–65. w17x Catalano PM, Nizielski SE, Shao J, Preston L, Qiao L, Friedman JE. Downregulated IRS-1 and PPARgamma in Acknowledgements obese women with gestational diabetes: relationship to FFA during pregnancy. Am J Physiol Endocrinol Metab. Supported by the Intramural Research Program of the National 2002;282:E522–33. Institute of Child Health and Human Development, NIH, DHHS. w18x Catalano PM, Hoegh M, Minium J, Huston-Presley L, Bernard S, Kalhan S, et al. Adiponectin in human preg- nancy: implications for regulation of glucose and lipid References metabolism. 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