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A Hormone Which Induces Insulin Resistance Is Increased in Normal Pregnancy

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A Hormone Which Induces Insulin Resistance Is Increased in Normal Pregnancy Article in press - uncorrected proof J. Perinat. Med. 35 (2007) 513–521 • Copyright ᮊ by Walter de Gruyter • Berlin • New York. DOI 10.1515/JPM.2007.122 Resistin: a hormone which induces insulin resistance is increased in normal pregnancy Jyh Kae Nien1, Shali Mazaki-Tovi1,2, Roberto for resistin 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 Medicine and Genetics, Wayne pregnancy. State University, Detroit, MI, USA Keywords: Adipokines; nomogram; obesity; 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 insulin resistance 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 glucose availability, insulin of maternal plasma concentrations of resistin from resistance may facilitate delivery of energy to the fetus 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 hormones in maternal serum. 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 placental lactogen (hPL), a hormone produced abun- women of normal body mass index (BMI 18.5–24.9; dantly by the placenta, 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 progesterone w8, 45x, (ns40). Blood samples were collected once from each estrogen w76x or glucocorticosteroids w7, 44x; (3) insulin woman between the first trimester and term. Percentiles action on adipocytes is impaired after in vitro exposure to progesterone, cortisol, prolactin, 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 adipose tissue 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 peptides. These 18.5 and 24.9. A patient was considered overweight if the BMI bioactive substances, collectively termed adipokines, was G25 w24x. include leptin w26, 29, 30x, adiponectin w2, 9, 41, 64x, Written informed consent was obtained from all participants. tumor necrosis factor 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 protein w10, 70x, resistin w6, 37, 49, 94x and to study the biology of inflammation, 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 disease, 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 diseases; (3) no obstetrical, maternal, or fetal compli- change after adjusting for parity (non-pregnant
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