Published online June 1, 2007
PEDIATRICS Vol. 119 No. 6 June 2007, pp. 1089-1094 (doi:10.1542/peds.2006-3297)
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ARTICLE

Relationship Between Angiotensin-Converting Enzyme Gene Insertion or Deletion Polymorphism and Insulin Sensitivity in Healthy Newborns

Tongyan Han, MD, PhD, Xinli Wang, MD, PhD, Yunpu Cui, MD, PhD, Hongmao Ye, MD, Xiaomei Tong, MD and Meihua Piao, MD

Department of Pediatrics, Third Hospital, Peking University, Beijing, China


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
CONTEXT. It was proposed that the association between low birth weight and adult insulin resistance is principally genetically mediated. The insertion/deletion polymorphism of the angiotensin-converting enzyme gene was associated with insulin sensitivity in adults.

OBJECTIVE. Our goal was to investigate the relationship between angiotensin-converting enzyme gene insertion/deletion polymorphism and the insulin sensitivity in healthy newborns.

PATIENTS AND METHODS. One hundred eighty healthy newborns, all of whom had a 1-minute Apgar score of >7 and gestational age >33 weeks, were enrolled in the study. Fasting glucose and insulin levels were measured on day 2 or 3 after birth, and angiotensin-converting enzyme genotype was determined.

RESULTS. The observed frequency distribution of angiotensin-converting enzyme genotypes did not deviate from that predicted by Hardy-Weinberg equilibrium in this group. There were no statistically significant differences in birth size and shape in different angiotensin-converting enzyme genotypes. Those carriers of the genotype homozygous for the deletion allele had the highest logarithmically transformed homeostasis model assessment compared with those who were heterozygous or homozygous for the insertion polymorphism. When compared with those with ≥1 insertion allele, those of the genotype homozygous for the deletion allele had significantly higher logarithmically transformed fasting insulin and logarithmically transformed homeostasis model assessment results. Regarding birth weight, birth length, ponderal index, and fasting glucose concentration, there were no significant differences between the genotype homozygous for the deletion allele and the genotypes heterozygous or homozygous for the insertion allele.

CONCLUSIONS. In this study, the deletion allele was associated with relatively impaired insulin sensitivity in healthy neonates. It may be a clue to explain the association between the deletion allele and insulin resistance in the long-term.

Key Words: ACE gene insertion/deletion polymorphism • D allele • healthy newborns • insulin sensitivity

Abbreviations: RAS—renin-angiotensin system • ACE—angiotensin-converting enzyme • I/D—insertion/deletion • ID—heterozygous for the I allele • II—homozygous for the I allele • DD—homozygous for the D allele • FI—fasting insulin • PCR—polymerase chain reaction • HOMA—homeostasis model assessment • PI—ponderal index

Impaired insulin sensitivity and insulin resistance are thought to contribute to the development of the pentad of hypertension, hyperinsulinism, dyslipidemia, obesity, and cardiovascular disease, known as metabolic syndrome.1 There is increasing evidence that insulin resistance is programmed during fetal development. In 1992, Hales and Barker2 proposed the "thrifty phenotype hypothesis," which postulates that all features of metabolic syndrome have a strong environmental basis. It suggests that fetal and early nutrition play an important role in determining the susceptibility of an individual to these diseases. Since then, most studies about low birth weight infants proved that a poor intrauterine environment starts a process of adaptation (programming) to unfavorable environments in the fetus, and this process asserts itself especially at the hormonal level, such as in adrenal medulla, the hypothalamus-pituitary axis, and the renin-angiotensin systems (RASs). Seven years later, Hattersley and Tooke3 proposed that the association between low birth weight and adult insulin resistance was principally genetically mediated. Low birth weight, measures of insulin resistance in life, and ultimately glucose intolerance, diabetes, and hypertension would all be phenotypes of the same insulin resistant genotype. Both genetics and the fetal environment are likely to be important in determining fetal growth in the same way that both genetic and environmental influences are important in adult disease susceptibility.

RASs play an important role in circulatory homeostasis. Angiotensin-converting enzyme (ACE) generates angiotensin II, a pressor, directly through vasoconstriction and indirectly through stimulation of adrenal aldosterone release and resultant salt and water retention. In addition, ACE degrades vasodilator kinins. The insertion/deletion (I/D) polymorphism of the ACE gene is characterized by the presence (I) or absence (D) of a 287-base pair alu repeat sequence within intron 16 of the ACE gene. This polymorphism accounts for nearly half the variance in serum ACE levels.4 Tissue ACE activity is similar among those heterozygous for the I allele (ID) and homozygous for the I allele (II), with homozygous for the D allele (DD) associated with an elevation in tissue ACE activity of as much as 75% in the heart and white blood cells.5, 6 The increased ACE level was suggested by some but not all studies to predispose to several common cardiovascular and renal diseases,7–9 especially in people with diabetes.9, 10 The view that the RAS is contained in the placenta and that the RAS is a factor in fetal growth as shown by the identification of receptors in trophoblast layers has gained significance.11 As in adult studies, an association between the RAS or DD carriers and insulin sensitivity was reported.12, 13 Cambien et al14 found that the ACE genotypes were associated insulin response among a group of young adults who were born small-for-gestational-age, which supported the "fetal insulin hypothesis."3 However, their results were confined to small-for-gestational-age infants. In our study, we explored whether there was an association between ACE gene I/D polymorphism and insulin sensitivity in healthy newborns to find some clues of genetic basis of insulin resistance that excluded the influences of environments (intrauterine, diet, lifestyle, and disease). Therefore, the aims of our study were to (1) measure fasting insulin (FI) and fasting glucose levels in healthy newborns, (2) determine the relation between ACE gene polymorphism and infant birth weight and shape, and (3) investigate the relation between ACE gene polymorphism and insulin sensitivity in healthy newborns.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Sample
The subjects in our study were recruited from singleton newborns who were delivered from April through December 2003 in the department of obstetrics of the Third Hospital, Peking University. Newborns were included in this study if they fulfilled the following inclusion criteria: (1) they had experienced a normal pregnancy with gestational age of >33 weeks; (2) they had a 1-minute Apgar score of >7 and a 5-minute Apgar score of 10; (3) they were breastfed during the study; and (4) there was a genomic DNA sample that could be used for genotyping. Newborns were excluded if they were born to women with diabetes, gestational diabetes, gestational hypertension, or chronic hypertension and they had intrauterine infections and congenital malformations. All studies were performed after parents gave written informed consent; the study protocol was approved by the Third Hospital Ethics Committee. The investigation conformed to the principles outlined in the Declaration of Helsinki as revised in 2000.

Measures
Birth Weight and Length
Midwives measured the birth weights and crown-to-heel lengths within 2 hours of delivery. Birth weights were recorded to the nearest gram by using a balance scale.

Fasting Glucose and Insulin Concentrations
All of the neonates were breastfed since birth. Blood was obtained by heel prick before feeding between 7:00 and 9:30 AM on day 2 or 3 of life (≥3 hours' fast) and analyzed for glucose and insulin concentration.

Glucose concentrations were measured by using the SureStep Plus System from LifeScan (Milpitas, CA). Interassay and intraassay coefficients of variation for glucose were 0.9% and 1.8%, respectively. Insulin was measured by enzyme-amplified immunoassay using active insulin ELISA Kit (DSL-10-1600; Diagnostic Systems Laboratories, Webster, TX). The detection limit of this assay was 0.26 µIU/mL (1.81 pmol/L) in our laboratory, and the intraassay and interassay coefficients of variation were 2.6% and 5.2%, respectively.

Genotype of ACE Gene
Genomic DNA was prepared from heel-prick blood (300 µL) by using a commercially available DNA isolation kit (Wizard genomic DNA purification kit; Promega, Madison, WI). The DNA concentration was adjusted to 100 ng/µL by adding distilled water. The presence of the insertion and deletion allele in intron 16 of the ACE gene was detected using the method of Rigat et al.4 The sequence of sense oligonucleotide primer was 5'-CTG GAG ACC ACT CCC ATC CTT TCT-3' and the antisense primer 5'-GAT GTG GCC ATC ACA TTC GTC AGA-3'.

The polymerase chain reaction (PCR) was performed with 200 ng of genomic DNA template in a final volume of 25 µL containing 1.5 mmol/L MgCl2, 50 mmol/L KCl, 10 mmol/L Tris-HCl, 10 pmol of each primer, 200 µmol/L of each deoxyribonucleotide triphosphate, and 1 unit of Taq DNA polymerase (Takara, Shiga, Japan). Amplification was performed by using a DNA thermal cycler (Gene Amp PCR System 9700; Perkin-Elmer, Foster City, CA) with 30 seconds denaturation at 94°C, 45 seconds annealing at 56°C, and 1-minute extension at 72°C for 35 cycles. In the last cycle, the extension step was conducted for 6 minutes. To avoid mistyping of heterozygotes as DD homozygotes,15 all DD genotype samples were confirmed by using a pair of primers that produce an amplified product only in the presence of the insertion, which was used to verify the polymorphism: sense 5'-TGG GAC CAC AGC GCC CGC CAC TAC-3' and antisense 5'-TCG CCA GCC CTC CCA TGC CCA TAA-3'.16 The PCR condition was similar to that procedure for I/D detection, except that the annealing temperature was changed to 67°C. All PCR products were visualized after electrophoresis on a 1.5% agarose gel and ethidium bromide staining. Genotyping was performed in a blinded fashion.

Statistical Analysis
The previously validated homeostasis model assessment (HOMA) was used to estimate insulin sensitivity.17 HOMA was calculated from the fasting glucose and insulin concentrations according to the equation: HOMA = [insulin (µU/mL) x glucose (mmol/L)]/22.5. Birth size and shape measures were birth weight, birth length, and ponderal index (PI = [birth weight/birth length3] x 100),18 studied as continuous variables.

The data are expressed as mean ± SD. All statistical analyses were performed by using the Statistical Package for Social Science 10.0 for Windows (SPSS Inc, Chicago, IL). Fasting insulin and HOMA were logarithmically transformed (log10) before the analysis to approach normal distribution.

The subjects were primarily divided into 3 groups according to the 3 ACE genotypes. The statistical difference in genotype distribution and allele frequencies among the groups was assessed by the Pearson {chi}2 test. One-way analysis of variance was used to test for differences in means of phenotypic characteristics between the 3 genotypes (with Bonferroni correction). We further combined the subjects of ID and II genotypes and compared with the DD carriers. The clinical characteristics of the 2 groups were compared by unpaired Student's t test. P < .05 was considered statistically significant.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
One hundred eighty newborns, including 135 term infants and 45 preterm infants, were taken into the scope of the study. All of them were Chinese and they were born at term or near term after a normal pregnancy. They had no major neonatal problems and had normal acid-base status at birth. There was no history of maternal hypertension, diabetes, or infections. Mean gestational age and birth weight of the study population were 37.65 ± 2.16 weeks and 2946.46 ± 645.75 g, respectively. The male/female ratio was 101:79.

All newborns were genotyped for the ACE I/D polymorphism. Because the ACE genotype distributions were not significantly different between term infants and preterm infants ({chi}2 = 1.090; P = .580), we combined their data and analyzed them as 1 group. The frequencies of DD, ID, and II genotypes were 18.3%, 46.7%, and 35.0%, respectively. The allele frequencies were 41.67% and 58.33% for the D and I alleles, respectively. These results were consistent with the Hardy-Weinberg equilibrium ({chi}2 = 0.188; P = .910). Demographic characteristics of gender, maternal age, gestational age, delivery method, and 1-minute Apgar score were not different between genotype groups (Table 1).


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  		TABLE 1 Comparison of Demographic Characteristics According to ACE Genotypes

 
There were no statistically significant differences in birth size and shape in different ACE genotypes (Table 2). And the fasting glucose and fasting insulin (logarithmically transformed) were not significantly different among the 3 genotypes. The individuals with DD genotype had the highest HOMA (log10HOMA = 0.21 ± 0.45) compared with individuals with the ID genotype (log10HOMA = 0.01 ± 0.38; P = 0.016) or homozygous (II) (log10HOMA = 0.01 ± 0.40; P = 0.021). After using Bonferroni correction, only the difference between DD genotype and ID genotype was significant.


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  		TABLE 2 Comparison of Birth Size and Shape and Metabolic Characteristics According to ACE Genotypes

 
As shown in Table 2, data for those of ID and II genotypes did not differ. When compared with those with ≥1 I allele, those with DD genotype had significant higher log10FI (0.93 ± 0.41 vs 0.76 ± 0.36, P = .018) and log10HOMA (0.21 ± 0.45 vs 0.01 ± 0.38, P = .010) (Fig 1). Regarding birth weight, birth length, PI, and fasting glucose concentration, there were no significant differences between DD genotype and ID+II genotypes.


Figure 1
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  		FIGURE 1 Comparison of log10FI and log10HOMA between DD genotype and ID+II genotypes. Data are expressed as the mean ± SD. Unpaired Student's t test was performed between the DD and ID+II genotypes.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
Recruits to this study were born at term or near term after a normal pregnancy, had normal acid-base status at birth, no history of maternal hypertension, and were breastfed during the study. The data were, therefore, not confounded by factors that were reported previously to be associated with serum insulin. The frequencies of ACE genotypes and the frequency of D allele in the study population were not different from those reported in our local population. Despite this relatively homogeneous study population, an evident increased fasting insulin and HOMA (logarithmically transformed) in the DD genotype infants was noted when compared with ID+II genotypes, which suggested an association between the D allele and relatively impaired insulin sensitivity.

The results of our study raise the possibility that the ACE genotype is related to insulin sensitivity. However, previous adult studies have reported conflicting results. Perticone et al19 reported that in a group of never-treated hypertensive individuals with the DD genotype were more insulin resistant as determined by the HOMA method than those individuals with either the ID or II genotype groups. Katsuya et al20 reported that normal subjects with the DD genotype were more insulin sensitive and had a lower insulin response to oral glucose administration. Panahloo et al12 found no influence of ACE genotypes on insulin sensitivity evaluated by plasma proinsulin levels and HOMA in nondiabetic subjects.

The ability of the ACE genotype to influence glucose metabolism is not understood; 1 possible mechanism explaining the link may be the elevated ACE levels that are associated with the DD genotype. Genetic analyses on I/D polymorphism of the ACE gene showed that circulating and tissue ACE levels were higher in subjects with the DD genotype than in subjects with other genotypes.21 However, because the ACE I/D polymorphism is intronic, the mechanism of ACE overexpression in subjects with DD genotype is unclear; it is possible that this relationship is the result of tight linkage to another locus involved in the regulation of ACE gene expression.22

Previous studies found that elevated ACE levels were associated with diabetes mellitus.23 As the main metabolite of serum ACE activity, angiotensin II was found to be a modulator of insulin sensitivity in both diabetic and nondiabetic subjects.24, 25 ACE inhibitors improve insulin sensitivity in noninsulin dependent diabetes mellitus patients,26 nondiabetic hypertensive patients,27 and nondiabetic normotensive subjects.28 These findings suggest the possibility that elevated ACE levels are associated with reduced insulin sensitivity and glucose intolerance, which contributes to the development of metabolic syndrome.

It was proposed that the RAS has a pivotal role in fetal development and growth, which is contained in the placenta as shown by the identification of receptors in trophoblast layers.11, 29 Studies have shown that the RAS and angiotensin II are fetal growth factors that have a significant role in the regulation of uteroplacental blood flow by means of angiotensin receptors, as well as in decidualization, placentation, and implantation.11, 29 Moreover, ACE activation was suggested to result in redistribution of the placental circulation and thus probably reduced nutrient transfer to the fetus.30 Therefore, the carrier of DD genotype, with relatively higher ACE concentration, is associated with increased risk of growth restriction. In our study, we failed to find any significant differences in birth size and shape between 3 ACE genotypes, although the carriers of DD genotype had a tendency to be lighter and smaller. This may because of the limited number of subjects examined and only healthy newborns were included in the study.


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
In this group of healthy term and near-term neonates, DD genotype carriers had a significantly increased fasting insulin and HOMA, which suggested that the D allele was associated with relatively impaired insulin sensitivity. This fact may provide genetic evidence for the clustering of metabolic syndrome or insulin resistance syndrome and may be a clue to explain the association between the D allele and insulin resistance in the long-term. Because of the limitation of the study, we believe that a larger sample size with more small-for-gestational-age infants as a control group addressing the impact of ACE genotype on insulin sensitivity could provide a more robust result.


   FOOTNOTES
 
Accepted Feb 12, 2007.

Address correspondence to Tongyan Han, MD, PhD, Department of Pediatrics, Third Hospital, Peking University, Beijing 100083, P. R. China. E-mail: tyhan66{at}yahoo.com.cn

The authors have indicated they have no financial relationships relevant to this article to disclose.


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PEDIATRICS (ISSN 1098-4275). ©2007 by the American Academy of Pediatrics




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