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, Meihua Piao, MD
Department of Pediatrics, Third Hospital, Peking University, Beijing, China
The authors have indicated they have no ﬁnancial relationships relevant to this article to disclose.
CONTEXT.It was proposed that the association between low birth weight and adult insulin resistance is principally genetically mediated. The insertion/deletion poly-morphism of the angiotensin-converting enzyme gene was associated with insulin sensitivity in adults.
OBJECTIVE.Our goal was to investigate the relationship between angiotensin-con-verting 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 ge-notype homozygous for the deletion allele had the highest logarithmically trans-formed homeostasis model assessment compared with those who were heterozy-gous or homozyheterozy-gous for the insertion polymorphism. When compared with those
withⱖ1 insertion allele, those of the genotype homozygous for the deletion allele
had significantly higher logarithmically transformed fasting insulin and logarith-mically 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.
ACE gene insertion/deletion
polymorphism, D allele, healthy newborns, insulin sensitivity
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
Accepted for publication Feb 12, 2007
Address correspondence to Tongyan Han, MD, PhD, Department of Pediatrics, Third Hospital, Peking University, Beijing 100083, P. R. China. E-mail: email@example.com
IMPAIRED INSULIN SENSITIVITYand insulin resistance are thought to contribute to the development of the pen-tad of hypertension, hyperinsulinism, dyslipidemia, obe-sity, and cardiovascular disease, known as metabolic
syndrome.1There is increasing evidence that insulin
re-sistance is programmed during fetal development. In
1992, Hales and Barker2proposed the “thrifty phenotype
hypothesis,” which postulates that all features of meta-bolic 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 environ-ment 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 Tooke3proposed that the association
be-tween low birth weight and adult insulin resistance was principally genetically mediated. Low birth weight, mea-sures 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 im-portant in determining fetal growth in the same way that both genetic and environmental influences are im-portant in adult disease susceptibility.
RASs play an important role in circulatory homeosta-sis. Angiotensin-converting enzyme (ACE) generates an-giotensin II, a pressor, directly through vasoconstriction and indirectly through stimulation of adrenal aldoste-rone release and resultant salt and water retention. In addition, ACE degrades vasodilator kinins. The inser-tion/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.4Tissue ACE
ac-tivity is similar among those heterozygous for the I allele (ID) and homozygous for the I allele (II), with homozy-gous 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
sug-gested by some but not all studies to predispose to
sev-eral common cardiovascular and renal diseases,7–9
espe-cially in people with diabetes.9,10The 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
recep-tors in trophoblast layers has gained significance.11As in
adult studies, an association between the RAS or DD
carriers and insulin sensitivity was reported.12,13
Cam-bien et al14found that the ACE genotypes were
associ-ated insulin response among a group of young adults who were born small-for-gestational-age, which
sup-ported the “fetal insulin hypothesis.”3 However, their
results were confined to small-for-gestational-age in-fants. 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, life-style, 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
be-tweenACEgene polymorphism and insulin sensitivity in
The subjects in our study were recruited from singleton newborns who were delivered from April through De-cember 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
ges-tational 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 genotyp-ing. 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.
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 (ⱖ3 hours’ fast) and
analyzed for glucose and insulin concentration.
assay was 0.26IU/mL (1.81 pmol/L) in our laboratory, and the intraassay and interassay coefficients of varia-tion were 2.6% and 5.2%, respectively.
Genotype of ACE Gene
Genomic DNA was prepared from heel-prick blood (300
L) by using a commercially available DNA isolation kit
(Wizard genomic DNA purification kit; Promega, Madi-son, WI). The DNA concentration was adjusted to 100
ng/L 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.4The
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 25L containing 1.5 mmol/L MgCl2, 50 mmol/L KCl,
10 mmol/L Tris-HCl, 10 pmol of each primer, 200
mol/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, Fos-ter 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⬘.16The PCR condition was similar to that
proce-dure for I/D detection, except that the annealing tem-perature was changed to 67°C. All PCR products were visualized after electrophoresis on a 1.5% agarose gel and ethidium bromide staining. Genotyping was per-formed in a blinded fashion.
The previously validated homeostasis model assessment
(HOMA) was used to estimate insulin sensitivity.17
HOMA was calculated from the fasting glucose and in-sulin concentrations according to the equation: HOMA
⫽ [insulin (U/mL) ⫻ glucose (mmol/L)]/22.5. Birth
size and shape measures were birth weight, birth length,
and ponderal index (PI⫽[birth weight/birth length3]⫻
100),18studied 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
The subjects were primarily divided into 3 groups
according to the 3 ACE genotypes. The statistical differ-ence in genotype distribution and allele frequencies
among the groups was assessed by the Pearson 2test.
One-way analysis of variance was used to test for differ-ences in means of phenotypic characteristics between the 3 genotypes (with Bonferroni correction). We fur-ther combined the subjects of ID and II genotypes and compared with the DD carriers. The clinical characteris-tics of the 2 groups were compared by unpaired
Stu-dent’sttest.P⬍.05 was considered statistically
One hundred eighty newborns, including 135 term in-fants and 45 preterm inin-fants, 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 mater-nal hypertension, diabetes, or infections. Mean gesta-tional age and birth weight of the study population were
37.65 ⫾ 2.16 weeks and 2946.46 ⫾ 645.75 g,
respec-tively. The male/female ratio was 101:79.
All newborns were genotyped for the ACE I/D poly-morphism. Because the ACE genotype distributions were not significantly different between term infants
and preterm infants (2 ⫽ 1.090;P ⫽ .580), we
com-bined 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, respec-tively. These results were consistent with the
Hardy-Weinberg equilibrium (2⫽ 0.188; P ⫽ .910).
Demo-graphic characteristics of gender, maternal age,
gestational age, delivery method, and 1-minute Apgar score were not different between genotype groups (Ta-ble 1).
There were no statistically significant differences in birth size and shape in different ACE genotypes (Table 2). And the fasting glucose and fasting insulin (logarith-mically transformed) were not significantly different among the 3 genotypes. The individuals with DD
geno-type 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.
As shown in Table 2, data for those of ID and II genotypes did not differ. When compared with those
withⱖ1 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
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
ge-notype 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 al19reported 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 sen-sitive 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 sub-jects.
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
geno-types.21However, because the ACE I/D polymorphism is
intronic, the mechanism of ACE overexpression in sub-jects with DD genotype is unclear; it is possible that this relationship is the result of tight linkage to another locus
involved in the regulation ofACEgene expression.22
Previous studies found that elevated ACE levels were
associated with diabetes mellitus.23As the main
metab-TABLE 1 Comparison of Demographic Characteristics According to ACE Genotypes
ACE Genotypes 2/F P
DD (n⫽33) ID (n⫽84) II (n⫽63)
Male,n(%)a 21 (63.6) 40 (47.6) 40 (63.5) 4.612 .100
Maternal age, mean⫾SD, yb 28.79⫾5.04 28.49⫾5.05 28.84⫾4.04 0.114 .892
Vaginal delivery,n(%)a 22 (67.3) 62 (73.8) 44 (69.8) 9.446 .150
Gestational age, mean⫾SD, wkb 37.51⫾2.08 37.96⫾2.15 37.31⫾2.18 1.694 .187
Apgar score at 1 min, mean⫾SDb 9.73⫾0.63 9.74⫾0.64 9.78⫾0.58 0.101 .904
Comparisons were performed withaPearson’s2orbanalysis of variance.
TABLE 2 Comparison of Birth Size and Shape and Metabolic Characteristics According to ACE Genotypes
ACE Genotypes F P
DD (n⫽33) ID (n⫽84) II (n⫽63)
Birth weight, g 2858.18⫾616.70 2982.50⫾638.95 2944.63⫾674.64 0.437 .647
Birth length, cm 48.09⫾3.46 48.67⫾2.77 48.29⫾3.10 0.538 .585
PI 2.54⫾0.26 2.55⫾0.29 2.57⫾0.25 0.160 .852
Fasting glucose, mmol/L 4.44⫾1.40 4.14⫾0.94 4.10⫾1.08 1.168 .313
FI, mIU/L 13.22⫾14.52 7.99⫾8.09 7.85⫾5.10 — —
Log10FI 0.93⫾0.41 0.75⫾0.37 0.77⫾0.38 2.865 0.060
HOMA 3.03⫾5.34 1.46⫾1.46 1.46⫾1.05 — —
Log10HOMA 0.21⫾0.45 0.01⫾0.38 0.01⫾0.40 3.377 0.036
Data are expressed as mean⫾SD. Fasting insulin and HOMA were logarithmically transformed (log10) before the analysis to approach normal distribution. All statistical comparisons were performed with analysis of variance. — indicates not applicable.
Comparison of log10FI and log10HOMA between DD genotype and ID⫹II genotypes.
olite of serum ACE activity, angiotensin II was found to be a modulator of insulin sensitivity in both diabetic and
nondiabetic subjects.24,25ACE inhibitors improve insulin
sensitivity in noninsulin dependent diabetes mellitus
pa-tients,26nondiabetic hypertensive patients,27and
nondi-abetic 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 syn-drome.
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.11,29Studies 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
prob-ably reduced nutrient transfer to the fetus.30Therefore,
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.
In this group of healthy term and near-term neonates, DD genotype carriers had a significantly increased fast-ing insulin and HOMA, which suggested that the D allele was associated with relatively impaired insulin sensitiv-ity. This fact may provide genetic evidence for the clus-tering of metabolic syndrome or insulin resistance syn-drome 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-gestation-al-age infants as a control group addressing the impact of ACE genotype on insulin sensitivity could provide a more robust result.
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Tongyan Han, Xinli Wang, Yunpu Cui, Hongmao Ye, Xiaomei Tong and Meihua
Deletion Polymorphism and Insulin Sensitivity in Healthy Newborns
Relationship Between Angiotensin-Converting Enzyme Gene Insertion or
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