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Resistin in infants of diabetic mothers: relation to insulin and anthropometry

Hamed, Hanan M.a; Ibrahim, Hala Y.a; Moustafa, Mohamed F.b; Mohamed, Maha H.b; Ramadan, Naglaa M.a; Atef, Shereen H.c

doi: 10.1097/01.MJX.0000397206.01174.fb
ORIGINAL ARTICLES
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Objective To determine the effect of maternal diabetes on serum resistin and insulin in term neonates and to correlate their level with neonatal anthropometric measures.

Materials and methods Sixty neonates were recruited from the Obstetrics and Gynecology Hospital and Ain Shams University Hospital. These neonates were divided into three groups. Group 1 included 20 full-term macrosomic neonates of diabetic mothers. Group 2 included 20 full-term nonmacrosomic neonates of diabetic mothers. Group 3 included 20 healthy full-term nonmacrosomic neonates of nondiabetic mothers serving as a control. For all neonates, complete medical and obstetric history was taken. Thorough clinical examination and anthropometric measurements were carried out. Maternal glycosylated hemoglobin was measured. Cord blood was withdrawn to measure random blood sugar, serum insulin, and serum resistin.

Results All skin-fold thicknesses were significantly higher in infants of diabetic mothers (IDMs) than control (P<0.001). Serum insulin was significantly higher and serum resistin was significantly lower in IDMs than in the control group (P<0.001 and 0.005, respectively). Serum resistin correlated positively with cord blood glucose in IDMs of both macrosomic (r=0.522, P=0.01) and nonmacrosomic groups (r=0.462, P=0.04). A highly significant positive correlation was found between maternal glycosylated hemoglobin and neonatal birth weight, supine length, and skin-fold thickness in group 1 (macrosomic) IDM.

Conclusion It was concluded that IDMs had elevated levels of serum insulin and suppressed levels of serum resistin, suggesting that these hormones are probably operational before birth.

aMedical Division, Department of Pediatrics, National Research Centre

bDepartments of Pediatrics

cClinical Pathology, Ain Shams University, Cairo, Egypt

Correspondence to Hanan M. Hamed, Department of Pediatrics, National Research Centre, El-Bohouth Street, Dokki, PO Box 2311, Cairo, Egypt Tel: +20127171816; e-mail: hmhamed63@yahoo.com

Received January 2, 2011

Accepted March 15, 2011

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Introduction

Recent data have radically modified the concept of adipose tissue as the one solely devoted to energy storage and release. Adipose tissue is also an important endocrine organ. It can release hormones into the blood stream in response to specific extracellular stimuli or changes in metabolic status [1]. These hormones are potentially involved in the regulation of energy homeostasis, adipose tissue development, and insulin sensitivity and may be the targets for nutrient interactions relevant to the likelihood of development of obesity with adverse effects on glucose and lipid metabolism [2].

Resistin, a recently cloned adipose-secreted factor, originally named by Steppan et al. [3] for its resistance to insulin [resist+in(sulin)], is primarily involved in the modulation of insulin sensitivity and adipocyte differentiation [4].

Resistin opposes the action of insulin in peripheral tissues and has a physiologic function in the maintenance of blood glucose during fasting. It has been proposed to link obesity with diabetes [5]. Circulating resistin levels were higher in obese than in lean individuals. It has also been shown to inhibit adipogenesis in vitro [6]. Felipe et al. [2] speculated that it may be a feedback regulator of adipogenesis and a signal to restrict adipose tissue formation.

Numerous studies have explored the role of adipocytokines in intrauterine growth [7]. However, at present, no information is available with respect to resistin in intrauterine growth and very little is known with regard to the potential function of resistin in the pediatric population, especially in newborn infants.

The aim of this study was to determine the effect of maternal diabetes on serum resistin and insulin in term neonates and to correlate their level with neonatal anthropometric measures.

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Materials and methods

This is a case–control study that was conducted in 60 neonates recruited from those delivered in the Obstetrics and Gynecology Hospital and followed in the Neonatal Intensive Care Unit, Ain Shams University Hospital (Egypt). The study was approved by the Ethics Committee of both Pediatric Department (Ain Shams University) and the Ethics Committee of National Research Centre. An informative consent was taken from all mothers before recruitment.

These neonates were divided into three groups. Group 1 included 20 full-term macrosomic (birth weight: >4000 g) neonates to diabetic mothers. Group 2 included 20 full-term nonmacrosomic (birth weight: 2500–4000 g) neonates of diabetic mother who were born to mothers with pregestational type I diabetes mellitus. Group 3 included 20 healthy full-term nonmacrosomic (birth weight: 2500–4000 g) neonates of nondiabetic mothers, serving as control. Neonates with preterm delivery, low Apgar scores, congenital or perinatal infection, apparent congenital malformation along with infants whose mothers received corticosteroids or other hormonal therapy were excluded.

For all neonates, complete medical and obstetric history was taken laying stress on maternal diabetes, history of previous macrosomic neonates, mode of delivery, and Apgar score at 1 and 5 min. The gestational age of an infant was assessed by the mother's last menstrual period and/or early ultrasound dating and cross-checked with the new Ballard score examination after birth [8].

Thorough clinical examination and anthropometric measurements included the following: (i) birth weight measured by a calibrated digital scale and correlated with weight centiles, (ii) supine crown–heel length, (iii) body mass index (BMI), and (iv) skin-fold thickness (triceps, biceps, suprailiac, subscapular), measured with a skin-fold caliper (Harpenden, Slimglide, Lange).

Maternal blood was withdrawn from diabetic mothers at the time of delivery for detection of glycosylated hemoglobin (HbA1c). Cord blood was withdrawn into plain tubes for clotting, centrifugation, and serum separation. Random blood sugar was measured from the freshly separated serum using the glucose oxidase method [9]. The sera were collected in sterile tubes and then stored at −70°C until use.

Serum insulin was measured by enzyme-linked immunosorbent assay (the Biosource INS-EASIA, Europe S.A. RueDe l'Indutrie, 8-B-1400 Nivelles-Belgium) according to the manufacturer's instructions. Serum resistin was measured by ELISA (BioVendor's, Brno, Czech Republic) according to the manufacturer's instructions.

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Statistical analyses

Data were analyzed using the Statistical Package for Special Science software computer program version 13 (SPSS Inc., Chicago, Illinois, USA). Quantitative data were described using mean±standard deviation; qualitative data were described in the form of numbers and percentages. The Student's t-test of two independent samples was used for comparison of normally distributed quantitative variables, whereas the Mann–Whitney test was used for nonparametric data. The χ2 test was used for comparison of qualitative variables. Correlation between continuous variables was performed using Spearman's correlation coefficient (r). The probability of error at 0.05 was considered significant, whereas those at 0.01 and 0.001were considered to be highly significant.

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Results

Demographic and laboratory characteristics of patient and control groups are listed in Table 1. Group 1 included seven boys and 13 girls with mean birth weight of 4.44±0.44 kg (range: 4.0–5.5 kg) and mean gestational age of 37.55±0.60 weeks (range: 37–39 weeks). All of them were delivered by cesarean section. Group 2 included nine boys and 11 girls with a mean birth weight of 3.46±0.37 kg (range: 2.5–3.75 kg) and mean gestational age of 37.40±0.50 weeks (range: 37–38 weeks). Ten neonates (50%) were born by vaginal delivery and 10 neonates (50%) were delivered by cesarean section. Group 3 included 10 boys and 10 girls, with mean birth weight of 3.49±0.31 kg (range: 2.9–3.8 kg) and mean gestational age of 38.65±1.23 weeks (range: 37–42 weeks). Fourteen neonates (70%) were born by vaginal delivery and six neonates (30%) were delivered by cesarean section.

Table 1

Table 1

All skin-fold thickness was significantly higher in infants of diabetic mothers (IDMs) than control (P=0.001). Serum insulin is significantly higher in IDMs than in the control group (P<0.001) and serum resistin is significantly lower in IDMs than in the control group (P<0.005). Mothers of macrosomic IDMs had a higher history of previous macrosomic infants, significantly less strict control of diabetes, and significantly higher HbA1C than those of nonmacrosomic IDMs (Table 2). Serum glucose, insulin, and resistin were comparable in groups 1 and 2 (Table 2). Female IDMs (n=24) had significantly higher cord insulin (n=16) (44.36±45.36, 25.13±?25.81 μU/l, respectively, P=0.034) as well as significantly higher cord resistin than male IDMs (17.68±7.28, 10.0±5.46 ng/ml, respectively, P: 0.002). Levels of cord insulin and resistin were comparable in girls and boys of the control group (P=0.09 and 0.439, respectively). Mode of delivery had no effect on cord insulin and resistin in IDMs (n=40) (P=0.348 and 0.962, respectively) or control (P=0.406 and 0.130, respectively).

Table 2

Table 2

Serum resistin correlated positively with cord blood glucose in IDMs both macrosomic (r=0.522, P=0.018) and nonmacrosomic groups (r=0.462, P=0.041). Cord serum insulin correlated positively with triceps skin-fold thickness in group 1 (r=0.482, P=0.031), group 2 (r=0.484, P=0.049), and group 3 (r=0.486, P=0.03) and with maternal HbA1c in group 1 macrosomic IDMs (r=0.481, P=0.032). A highly significant positive correlation was found between maternal HbA1c and neonatal birth weight, supine length and triceps, biceps, suprailiac and subscapular skin-fold thickness in group 1 (macrosomic) IDMs.

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Discussion

Exposure to maternal diabetes in utero is associated with metabolic changes that may impact body size, glucose, and intermediary metabolism with increased adiposity at birth, as well as increases in fetal insulin [10].

In view of this, the aim of this study was to assess the influence of maternal preexisting diabetes on cord blood resistin at birth in relation to neonatal anthropometric parameters and cord blood insulin levels.

This study showed that IDMs encountered a significantly lower mean gestational age, but higher birth weight, length, triceps, biceps, suprailiac and subscapular skin-fold thickness in comparison with the control group. Similar results were also obtained by other investigators [11,12]. Maternal diabetes during pregnancy results in characteristic overgrowth of the fetus due to excess supply of nutrients, especially glucose, and consequent chronic overproduction of insulin [10].

In this study, insulin was detectable in umbilical serum of all neonates at concentrations that ranged from 5 to 150 μU/l. A significantly higher umbilical serum insulin concentration in IDMs (both macrosomic and nonmacrosomic groups) compared with the control group was observed. Fetal hyperinsulinemia has been detected in offsprings of diabetic mothers both in utero by sampling of amniotic fluid [13] and after birth by sampling of cord blood [14]. Fetal insulin production appears to be related to the extent of metabolic abnormality in the fetus and is predictive of both later-impaired glucose tolerance and obesity [10].

This study showed a significantly lower umbilical serum resistin concentration in IDMs (both macrosomic and nonmacrosomic groups) than in the control, suggesting that the regulation of metabolic pathways by this hormone is probably operational before birth. Insulin has been suggested to be a major inhibitor of resistin production, which was evident by the low resistin mRNA concentrations in insulin resistance [15]. A potential reason for suppressed resistin levels in IDMs is hyperinsulinemia encountered in them. As resistin could play a pivotal role in inhibiting adipocyte differentiation, the suppressive effect of insulin on resistin might result in eliminating the constraint on the development of new adipocytes. This mechanism might partially explain the excess accumulation of adipose tissue in utero in infants of poorly controlled diabetic mothers [5].

In accordance with these findings, Ng et al. [16] reported that infants of insulin-dependent diabetic mothers were found to have significantly lower serum resistin concentration compared with the normal control group. In addition, previous experimental studies reported that exogenous insulin treatment caused a substantial reduction of resistin mRNA in a time-dependent and dose-dependent manner in 3T3-L1 adipocytes [17,18].

With regard to sex influence on serum resistin and insulin levels, this study showed that the female IDMs had a highly significant increase in umbilical serum resistin and insulin levels than male IDMs. This confirmed the results obtained by Krishnaveni et al. [11], who reported that female offsprings of diabetic mothers had higher insulin concentrations than the male neonate [11].

In contrast, Ng et al. [16] showed no difference in circulating concentrations of resistin and insulin between male and female IDMs. A similar finding was found in adults. Increased resistin levels in females were attributed to higher fat cell mass in female than male body [19,20].

This study showed that the mode of delivery had no influence on umbilical serum resistin and insulin in both IDMs and control groups. Similar results were shown by other investigators [21]. In contrast, Ng et al. [16] found that serum resistin levels were significantly higher in infants who were born vaginally than those delivered by cesarean section. Elevated resistin level may be related to stress or inflammation induced by vaginal delivery, as resistin has been implicated to have a potential role in mediating inflammatory response and is influenced by proinflammatory stimuli or cytokines such as lipopolysaccharide or tumor necrosis factor-α [6].

To detect the association of umbilical serum resistin and serum insulin with the anthropometric indices, a comparison was made between macrosomic and nonmacrosomic IDMs. This comparison showed that the concentrations of umbilical serum resistin and insulin were comparable in the two groups. In addition, no correlation was observed between umbilical serum resistin with neonatal anthropometric indices (birth weight, length, BMI, skin-fold thickness) in both macrosomic and nonmacrosomic IDMs and control groups. Absence of correlations between umbilical resistin and neonatal anthropometric parameters is possibly due to different distribution of neonatal fat depots in neonates compared with adults. These results agreed with Ng et al. [16], who found no correlations between serum resistin and neonatal anthropometric parameters (birth weight, length, BMI, skin-fold thickness) in IDMs.

This study showed no significant correlation between umbilical serum resistin and gestational age in macrosomic and nonmacrosomic IDMs and control groups. Similarly, Cho et al. [21] detected a nonsignificant correlation between umbilical serum resistin and gestational age in a group of healthy full-term neonates. In contrast, Ng et al. [16] reported that serum resistin level is positively correlated with gestational age and its concentrations are significantly higher in term than in preterm infants, suggesting that this hormone could be gestation-related and might play an important role in regulating energy metabolism and adiposity in utero. The increase in plasma resistin concentrations with advancing gestational age might merely reflect a larger adipose tissue mass that produces a greater quantity of the hormone toward the late stages of pregnancy [5].

Several studies have reported that resistin is generated in the placenta, and human resistin gene is expressed in human placental tissue, primarily in the syncytiotrophoblasts [22]. On the basis of the fact that an increase in placental mass occurs with gestation, it is reasonable to speculate that the placental production of resistin constitutes the principle cause of the increase in levels of serum resistin with advancing gestational age [23]. Different results are attained by this study as all of the neonates included were full-term neonates.

In this study, a significant positive correlation was observed between umbilical serum resistin and glucose level in both macrosomic and nonmacrosomic IDMs. This significant correlation was not found in the control group. Functionally, resistin impairs glucose tolerance, resists insulin action, and increases hepatic glucose production. It was suggested that increased plasma resistin may be correlated with the development of insulin resistance in type II diabetes [24]. A similar positive correlation was detected in adults [25]. In discordance with these results, Ng et al. [16] determined no significant correlation between serum resistin and serum glucose in a group of IDMs and in a group of healthy full-term and preterm neonates [6]. They reported that the lack of significant correlation between resistin and glucose might suggests that resistin was not involved directly in the regulation of metabolism in utero.

In this study, no significant correlation was found between umbilical serum resistin and serum insulin. Similar finding was detected in IDMs [16] and in a group of healthy full-term neonates [6,21]. Furthermore, Lee et al. [26] reported that neither transcriptional regulation of resistin gene nor circulating resistin levels correlated with serum insulin.

Of the anthropometric parameters studied, only triceps skin-fold thickness was positively correlated with umbilical serum insulin in all studied groups. In partial accordance with these results, previous studies showed a significant association between serum insulin and birth weight and body length in normal full-term neonates [6]. Other studies reported a nonsignificant association between serum insulin and anthropometric indices in a group of IDMs [16] and in normal full-term neonates [21].

In this study, a nonsignificant correlation was observed between serum insulin and blood glucose in all the studied groups. In contrast, Ng et al. [16] stated that serum insulin was significantly associated with blood glucose in IDMs and normal neonates.

In this study, a highly significant positive correlation was observed between maternal HbA1c and neonatal birth weight, supine length and triceps, biceps, and suprailiac and subscapular skin-fold thickness in group 1 macrosomic IDMs. Glycemic control is an important variable in determining birth weight in diabetic pregnancy and this is compatible with the generally accepted maternal hyperglycemia fetal hyperinsulinemia hypothesis. In contrast, Ng et al. [16] found no significant correlation between maternal HbA1c and neonatal anthropometric parameters.

However, Penney et al. [27] and Kernaghan et al. [28] stated that there was a significant negative correlation between maternal HbA1c and neonatal birth weight. They explained that diabetic mothers with high HbA1c were more likely to have microvascular disease, which could adversely affect placental function and consequently fetal growth. Moreover, they added that a potential explanation for the negative correlation seen between HbA1c and neonatal birth weight was that inclusion of babies with congenital anomalies as a result of poor glycemic control has biased the results, as infants with congenital anomalies tend to be smaller than structurally normal infants and this is most pronounced in infants with chromosomal anomalies.

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Conclusion

It was concluded that IDMs had elevated levels of serum insulin and suppressed levels of serum resistin, suggesting that the regulation of metabolic pathways by these hormones is probably operational before birth. A lower level of circulating resistin could also be instrumental in driving an excess accumulation of adipose tissue in utero by reducing the constraint on adipogenesis in IDMs.

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Keywords:

infants of diabetic mothers; insulin; resistin

© 2011 Medical Research Journal