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Plasma Ghrelin and Resistin Concentrations Are Suppressed in Infants of Insulin-Dependent Diabetic Mothers

Departments of Pediatrics (P.C.N., C.H.L., T.F.F.) and Chemical Pathology (C.W.K.L., I.H.S.C.) and Center of Clinical Trials and Epidemiological Research (E.W.), Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong

Address all correspondence and requests for reprints to: Dr. P. C. Ng, Department of Pediatrics, Level 6, Clinical Sciences Building, Prince of Wales Hospital, Shatin, N.T., Hong Kong. E-mail: pakcheungng{at}cuhk.edu.hk.

	Abstract

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This study aimed to investigate 1) the effect of maternal diabetes mellitus on ghrelin, resistin, leptin, and insulin in term newborns; 2) the interrelationship of these metabolic hormones in the early postnatal period; and 3) the association of the hormones with anthropometric parameters at birth. A total of 120 term newborns were prospectively enrolled and categorized into three groups: 40 were infants of nondiabetic mothers (group N), 42 were infants born to mothers with gestational diabetes on low energy dietary treatment (group D), and 38 were infants born to mothers with preexisting or severe gestational diabetes who required exogenous insulin for stabilization of blood sugar during pregnancy (group I). Plasma ghrelin and resistin were significantly lower in group I than in either group N or group D infants (P < 0.048). Plasma ghrelin and subscapular skinfold thickness were significantly higher in female than in male infants [plasma ghrelin: median (interquartile range), 3.8 (3.0–4.8) vs. 3.0 (2.4–4.0) ng/ml in females and males, respectively; P = 0.003; subscapular skinfold thickness: 4.9 (4.2–5.6) vs. 4.6 (3.9–5.2) mm; P = 0.03]. In group N, plasma ghrelin was significantly, but negatively, associated with birth weight (r = –0.31; P = 0.05) and body length (r = –0.33; P = 0.04), whereas in group I, plasma ghrelin was negatively correlated with plasma resistin (r = –0.37; P = 0.02). Plasma ghrelin and resistin are suppressed in infants of insulin-dependent diabetic mothers, suggesting that the metabolic hormonal system is probably operational in fetal and early postnatal life. A low circulating ghrelin concentration may be advantageous to these infants, because a reduction in appetite may prevent excessive weight gain postnatally and counterbalances the in utero anabolic effect of hyperinsulinism in poorly controlled diabetic mothers. The suppressive effect of insulin on resistin may partially explain the excess accumulation of adipose tissue in infants of diabetic mothers by reducing the inhibitory effect of resistin on adipogenesis. Female infants have significantly higher plasma ghrelin levels than male infants, suggesting that sexual dimorphism exists in utero. This study has also shown an association between some of the metabolic hormones in specific groups of infants and thus suggests that these hormones could have interacted in utero to regulate growth and fat storage during this critical period.

	Introduction

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UNDERSTANDING OF THE physiology of energy metabolism and appetite regulation has much progressed with the recent discovery of a number of important metabolic hormones, including ghrelin, resistin, and leptin (1, 2, 3, 4, 5). Ghrelin, a natural ligand of the GH secretagogue receptor (GHS-Rla), is a 28-amino acid peptide that shows a unique structure with an n-octanoyl ester modification at the third serine residue (1). It is produced predominantly by the stomach, but lower levels are detected in other organs, such as the intestine, pancreas, kidney, pituitary, and hypothalamus (1, 6, 7). This gut-brain peptide stimulates GH release and appetite; regulates gastric motility and acid secretion; modulates carbohydrate metabolism and insulin secretion; and ultimately influences energy balance and fat storage in the human body (8, 9, 10). In contrast, leptin is secreted by white adipocytes (5) and acts on the leptin receptor (Ob-R) of the hypothalamus to reduce food intake and increase body energy expenditure (11). Recent evidence suggests that ghrelin and leptin may act in concert to provide adiposity signals from the periphery to the central nervous system, thereby controlling appetite and body fat content (12). Resistin, another recently discovered adipose-specific secreted hormone, is also a potent regulator of glucose homeostasis that is thought to oppose the action of insulin in peripheral tissues (2). Both circulating resistin and leptin levels tend to increase in obesity, but resistin appears to impair glucose tolerance, whereas leptin has a net hypoglycemic action (13). Although knowledge of these metabolic hormones is rapidly advancing, their interaction in different categories of newborns at an early postnatal age has not been systematically evaluated. This study aimed to investigate 1) the influence of maternal preexisting and gestational diabetes on ghrelin, resistin, leptin, and insulin in term newborns; 2) the interrelationship of these hormones in the early postnatal period; and 3) the association of these hormones with anthropometric indexes at birth.

	Subjects and Methods

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Study population

A total of 120 term (37–42 wk gestation) newborns admitted to the neonatal unit at Prince of Wales Hospital, Hong Kong, were prospectively enrolled in an 18-month period. The neonatal unit admitted all newborns who were at risk of perinatal infection, including infants born to mothers who were group B streptococcus carriers, mothers with peripartum fever, and those with prolonged rupture of membranes (>24 h). These infants were routinely screened for complete blood counts and C-reactive protein soon after birth and at 24 h of life. In addition, all newborns of preexisting and gestational diabetic mothers were admitted for monitoring of blood glucose. Gestational diabetes is defined as a venous plasma glucose concentration after fasting of more than 99 mg/dl (5.5 mmol/liter) and/or more than 144 mg/dl (8.0 mmol/liter) 2 h after a 75-g oral glucose challenge (14). The gestational age of the infant was assessed by the mother’s last menstrual period, early ultrasound dating, or new Ballard score examination. Infants with chromosomal abnormalities, major or lethal congenital malformations, proven perinatal infection, and whose mothers received either inhaled and/or systemic corticosteroids or other hormonal therapy, such as T₄, during pregnancy were not studied.

Term newborns were divided into three groups. The normal group (group N) consisted of 40 term infants who were at risk of perinatal infection, but were subsequently proven to be noninfected by sterile blood, cerebrospinal fluid, urine, and surface (ear, nose, throat, and umbilicus) cultures, and had consistently normal serial C-reactive protein measurements (<10 mg/liter). The second group (group D) consisted of 42 infants born to mothers diagnosed with gestational diabetes; these mothers required only a low energy diet (1800 kcal/d) for control of blood glucose during pregnancy. The third group (group I) consisted of 38 infants born to mothers with preexisting type 1 diabetes mellitus, who required daily insulin therapy (n = 12), and with severe gestational diabetes necessitating exogenous insulin treatment (n = 26) for stabilization of blood sugar.

Blood samples

The blood samples were collected within the first 2 h of life and before milk feeding. All blood collections were scheduled to coincide with the routine clinical blood-sampling procedure to minimize any unnecessary disturbance to the infants. Venous blood was collected into 1) a prechilled plain bottle for serum leptin and insulin measurements, 2) a prechilled EDTA bottle containing aprotinin (Sigma-Aldrich Corp., St. Louis, MO; final concentration, 0.6 trypsin inhibitor unit/ml) for plasma ghrelin and resistin measurements, and 3) a fluoride bottle for plasma glucose measurements. The blood samples were immediately immersed in ice and transported to the laboratory for centrifugation at 3500 rpm for 10 min at 4 C, and the resulting plasma or serum was stored at –70 C until analysis.

Hormone assays

Serum leptin and insulin were measured by ELISA (Diagnostic Systems Laboratories, Webster, TX) and microparticle immunoassay (IMx analyzer, Abbott Laboratories, Chicago, IL), respectively. Plasma resistin and ghrelin were also measured by ELISA (Phoenix Pharmaceuticals, Inc., Belmont, CA), and glucose was determined by the hexokinase method (Hitachi 917 analyzer, Roche, Indianapolis, IN). The sensitivities and interassay coefficients of variation of ghrelin, resistin, leptin, insulin, and glucose were 1.63 ng/ml and 6.7% at 4.5 ng/ml, 0.82 ng/ml and 8.7% at 16.2 ng/ml, 0.05 ng/ml and 3.5% at 2.2 ng/ml, 1.0 µU/ml and 5.6% at 5.3 µU/ml, and 2 mg/dl and 1.59% at 90 mg/dl, respectively.

Data collection

Anthropometric measurements, including body weight and length, were performed at birth, and body mass index (BMI) was calculated as body weight (kilograms)/square of length (meters²). The birth weight was measured by a calibrated digital scale in the labor ward, and body length was measured using a Harpenden infantometer by the standard method. The tricep skinfold thickness was measured with a skinfold caliper (Holtain Ltd., Crymych, UK) halfway down the upper arm while the arm was lying in a relaxed position, and the subscapular skinfold thickness was measured laterally just below the angle of the scapula. The anthropometric and clinical data are summarized in Table 1.

Ethical approval of the study was obtained from the clinical research ethical committee of the Chinese University of Hong Kong. Informed parental consent was obtained for each patient before commencement of the test.

Statistical analysis

The clinical data, anthropometric parameters, and metabolic hormone concentrations were expressed as the median and interquartile range. The Kruskal-Wallis test was used to compare the parameters among the three groups of infants. Thereafter, the Mann-Whitney U test was used for post hoc multiple comparison of pairwise groups, and the P values were adjusted for these groups (i.e. adjusted P value = P value x 3 for comparison of three groups). Spearman’s correlation coefficient was used to evaluate the interrelationship 1) between different metabolic hormones, and 2) between the metabolic hormones and anthropometric, demographic, or clinical parameters. However, the P values of the correlations were not adjusted for multiple testing. The Mann-Whitney U test was also used to assess the difference in various metabolic hormones between the sexes. Statistically significant anthropometric parameters associated with metabolic hormones were also subjected to multivariate stepwise regression analysis. Logarithmic (Ln) transformation of metabolic hormone concentrations was required, because these values were not normally distributed. Statistical tests were performed using SPSS for Windows (release 11.5, SPSS, Inc., Chicago, IL). The level of significance was set at 5% in all comparisons.

	Results

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Overall and subgroup analysis

Tables 1 and 2 summarize the clinical and anthropometric parameters and serum/plasma hormone concentrations of the three groups of patients, respectively. Hemoglobin A_1c was only measured in insulin-dependent diabetic mothers (IDDM). There was no significant difference in clinical and anthropometric parameters at birth between the groups (Table 1). As expected, serum insulin was significantly elevated in group I compared with groups N and D (group I > group N, P < 0.001; group I > group D, P < 0.001; Table 2). In contrast, plasma ghrelin was significantly lower in group I than in group N (P = 0.021; Table 2), and plasma resistin was also significantly lower than in groups N and D (group I < group N, P = 0.039; group I < group D, P = 0.048; Table 2).

Female vs. male

There was no significant difference in anthropometric parameters (birth weight, body length, BMI, and tricep skinfold thickness), except in subscapular skinfold thickness, between female and male infants [median (interquartile range), 4.9 (4.2–5.6) vs. 4.6 (3.9–5.2) mm; P = 0.03, respectively]. Plasma ghrelin and serum leptin were also found to be significantly higher in female than in male patients [3.8 (3.0–4.8) vs. 3.0 (2.4–4.0) ng/ml (P = 0.003); and 3.7 (2.5–6.1) vs. 2.5 (1.7–3.8) ng/ml (P = 0.003), respectively]. There was, however, no significant difference in plasma resistin and serum insulin between the two sexes [resistin: 10.9 (6.8–17.5) vs. 10.2 (7.0–18.0) ng/ml; and insulin: 4.2 (2.0–7.5) vs. 5.0 (2.6–7.9) µU/ml]. These results were then cross-checked by two-way ANOVA, which confirmed that there was no significant interaction between group and sex on ghrelin, resistin (Ln), leptin (Ln), and insulin (Ln). Thus, the results were identical when analyzing group and sex separately.

In the female group, plasma ghrelin was negatively associated with serum leptin (r = –0.26; P = 0.04), whereas in the male group, plasma ghrelin was negatively associated with plasma resistin (r = –0.30; P = 0.03). Also in the latter group, serum leptin showed a borderline significant correlation with insulin, resistin, and glucose (insulin: r = 0.25; P = 0.06; resistin: r = 0.23; P = 0.08; glucose: r = –0.26; P = 0.06).

Multivariate analysis

Statistically significant anthropometric parameters, including birth weight, body length, BMI, tricep and subscapular skinfold thickness, and gender, were also subjected to multivariate stepwise regression analysis using serum leptin as the dependent variable. Subscapular skinfold thickness and gender remained significantly correlated with (Ln) serum leptin (P < 0.001 and P < 0.01, respectively; r² = 0.42).

	Discussion

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Our findings indicated that plasma ghrelin and resistin were detectable in all term infants at birth. Infants of IDDM (group I) with high circulating insulin levels were found to have significantly lower plasma ghrelin and resistin concentrations compared with the normal (group N) and/or the dietary controlled diabetic group (group D). A recent trial in adult human subjects showed that a continuous infusion of insulin for 2 h while maintaining euglycemia induced marked suppression of plasma ghrelin in all studied volunteers (15). However, another study using sc short-acting insulin analog was unable to demonstrate a suppressive effect (16). These two studies differed intrinsically in experimental design, and the most apparent disparity was the duration of increase in insulinemia. It was postulated that a sustained increase in circulating insulin was essential for inhibition of plasma ghrelin (15). Other investigators have also shown that plasma ghrelin decreased after oral or iv glucose administration and suggested that an increase in the blood glucose concentration had a potent inhibitory effect on circulating ghrelin (17, 18, 19). Thus, it is conceivable that infants of IDDM who have been chronically exposed to high levels of insulin and glucose in utero demonstrated a physiological and reciprocal change in plasma ghrelin at birth. In addition, analysis of the pooled data in our study suggested that there was a borderline negative association between ghrelin and insulin, and such an association has also been observed in adult human subjects (18, 20). Ghrelin has been shown to regulate appetite, body fat mass, and energy balance (1, 8, 9, 10). Although there were no observed anthropometric differences in the current study to indicate that infants of IDDM had increased adiposity or weight at birth, uncontrolled or poorly controlled diabetic mothers with large for gestation infants had, in general, a substantial increase in body fat mass, especially thigh fat and abdominal wall fat (21). Therefore, a low fasting ghrelin level in early postnatal life could potentially be advantageous to infants chronically exposed to high concentrations of insulin, because a reduction in appetite might counterbalance the in utero anabolic effect of hyperinsulinism by preventing excessive food intake and weight gain postnatally.

A recent animal study has shown that the administration of resistin to rodents increased insulin resistance, whereas the use of antiresistin protein could partially reverse this phenomenon (2). In humans, however, this issue remains controversial (22). Savage et al. (23) suggested that resistin mRNA expression in adipocytes was increased in obese subjects, but subsequent reports were unable to confirm an association between obesity and resistin expression (24, 25). Plasma resistin was found to be significantly lower in a high insulin environment in our patients. In accordance with our findings, Haugen and co-workers (26) showed a marked suppression of insulin, at physiological or lower concentrations, on resistin mRNA expression in 3T3-L1 adipocytes. Similarly, Kawashima et al. (22) performed a series of experiments and found that exogenous insulin treatment caused a substantial reduction of resistin mRNA in a time- and dose-dependent fashion in 3T3-L1 adipocytes. The timing of reduction in resistin mRNA at 8 h after treatment and the fact that the suppressive effect on resistin mRNA was completely blocked by cycloheximide, a protein synthesis inhibitor, suggested that the decrease in resistin mRNA was mediated through the synthesis of protein that could accelerate the degradation process, rather than through a direct influence of gene transcription by insulin (22). Because resistin could play a pivotal role in inhibiting adipocyte differentiation (3), the suppressive effect of insulin on resistin might result in eliminating the constraint on the development of new adipocytes. Thus, it raised the possibility that this mechanism might partially explain the excess accumulation of adipose tissue in infants of poorly controlled diabetic mothers.

Because our previous study as well as other reports revealed a sex difference with higher serum leptin in female than in male infants (27, 28, 29, 30), we also investigated the effect of gender on the metabolic hormones. Despite the fact that infants in both sexes have similar birth weights and BMIs, plasma ghrelin and serum leptin levels were significantly higher in female than in male infants, suggesting that sexual dimorphism for ghrelin might exist in the perinatal period. Whether this phenomenon is related to the associated finding of an increase in fat deposition in the subscapular region of female infants would require additional investigation. However, our results did not correspond with recent reports on umbilical cord blood ghrelin, where other investigators failed to demonstrate such a difference (31, 32, 33, 34). Although the exact reasons are not fully elucidated, there are a few possibilities that may account for the disparity between the observations. The discrepancy might have been related to 1) the relatively small sample size in some of the previous studies (33, 34); 2) the different categories of patients investigated, such as small for gestation or large for gestation infants vs. infants of diabetic mothers (31, 32, 33); and 3) cord blood ghrelin concentrations that were significantly lower than neonatal plasma concentrations (33). Nonetheless, a recent trial showed that female human subjects had significantly higher circulating ghrelin levels than men both in the fasting state and after lipid and glucose administration (18). This gender-related dichotomy was also consistently observed in ghrelin-regulated hormones, including GH and prolactin (35), and hormones involved in the regulation of appetite, such as leptin (27, 28, 29, 30, 31, 32, 33). Thus, it is possible that ghrelin could behave in a similar manner. In contrast, resistin and insulin did not show any difference in circulating concentrations between the two sexes. Our results suggested that plasma ghrelin correlated significantly, but negatively, with serum leptin in female infants. This negative correlation was also observed by Whatmore et al. (36), and it makes physiological sense because there is evidence to support that ghrelin interacts with the leptin hypothalamic network by activating neural pathways in the ventromedial arcuate nucleus that are inhibited by leptin (12). This reciprocal relationship represents a balance between hunger and satiety induced by the orexigenic and anorexigenic hormones (12, 36). In addition, plasma ghrelin was negatively associated with plasma resistin in the male group and in group I. This observation concurred with the findings of Asakawa et al. (37) that the administration of ghrelin reduced resistin mRNA expression in white adipose tissue. Repeated introduction of ghrelin into rodents increased adiposity and was associated with a concomitant rise in insulin levels (37). Thus, it would not be unexpected to observe a corresponding adjustment in circulating leptin and resistin, because these adipocytokines are closely linked with the regulation of fat storage and insulin resistance.

This study also confirmed the consistent relationship between serum leptin and birth weight, BMI, and other anthropometric parameters (27, 28). The strong correlation was observed in both overall and subgroup analyses. Of all the anthropometric measurements, serum leptin was the best correlated with subscapular skinfold thickness. Plasma ghrelin was also found to be negatively associated with anthropometric indexes (birth weight and body length) in normal infants (group N). The latter finding agreed with the observation of other studies that circulating ghrelin was inversely related to body weight, height, and BMI in newborns (31, 32, 33, 34), children (36, 38), and adult subjects (18, 20). Conversely, plasma resistin was not associated with any of the anthropometric parameters. Of the metabolic hormones investigated in the current study, leptin was the most consistently correlated with the anthropometric indexes. The results indicate that leptin is probably one of the most crucial hormones responsible for weight and fat regulation in utero.

In summary, plasma ghrelin and resistin are suppressed in infants of IDDM, suggesting that the regulation of metabolic pathways by these hormones is probably operational before birth. A low ghrelin level may be advantageous to these infants by blunting their appetites and preventing excessive weight gain in early postnatal life. 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 infants of diabetic mothers. In addition, sexual dimorphism for ghrelin and leptin is observed. Although this and other studies (27, 28, 31, 32, 33, 34) have provided preliminary evidence that these metabolic hormones may interact in utero and in early postnatal life, additional studies are required to delineate their exact interrelationship and regulatory mechanisms to fully understand the complex signaling network and their physiological roles in this critical period of growth and development.

	Footnotes

 
Abbreviations: BMI, Body mass index; GHS, GH secretagogue; IDDM, insulin-dependent diabetic mother; Ln, logarithmic.

Received April 20, 2004.

Accepted August 17, 2004.

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Top Abstract Introduction Subjects and Methods Results Discussion References

 

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