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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 11 5738-5741
Copyright © 2004 by The Endocrine Society

The Effects of the ACE Gene Insertion/Deletion Polymorphism on Glucose Tolerance and Insulin Secretion in Elderly People Are Modified by Birth Weight

Eero Kajantie, Anna Rautanen, Juha Kere, Sture Andersson, Hilkka Ylihärsilä, Clive Osmond, David J. P. Barker, Tom Forsén and Johan Eriksson

National Public Health Institute (E.K., H.Y., T.F., J.E.), 00300 Helsinki, Finland; Hospital for Children and Adolescents (E.K., S.A.), Helsinki University Central Hospital, 00029 HUS, Helsinki, Finland; Finnish Genome Centre (A.R., J.K.), University of Helsinki, Helsinki, Finland; Department of Biosciences at Novum and Clinical Research Centre (J.K.), Karolinska Institute, 141 86 Stockholm, Sweden; and Medical Research Council Environmental Epidemiology Unit (E.K., C.O., D.J.P.B.), Southampton General Hospital, Southampton SO16 6YD, United Kingdom

Address all correspondence and requests for reprints to: Dr. Eero Kajantie, National Public Health Institute, Mannerheimintie 166, 00300 Helsinki, Finland. E-mail: eero.kajantie{at}helsinki.fi.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
The I allele of an insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme gene (ACE) appears to be protective against the complications of type 2 diabetes. Low birth weight, a marker of an adverse intrauterine environment, is associated with higher rates of type 2 diabetes. We examined whether the ACE I/D polymorphism could explain or modify the association between low birth weight and adulthood glucose tolerance.

We measured plasma glucose and insulin concentrations after an oral glucose challenge in a group of 423 men and women, ages 65–75 yr, with measurements at birth recorded. The presence of the I allele was associated with shorter duration of gestation (P = 0.006) and, relative to gestational age, higher birth weight (P = 0.008) and length (P = 0.02). The I allele was associated with lower glucose at 120 min (P = 0.04) and a greater insulin response (P = 0.03 for insulin at 30 min and P = 0.06 for insulin area under the curve) to a standard oral glucose tolerance test. However, the associations between the ACE genotype and adulthood insulin secretion were only present in people with low birth weight (P for interaction birth weight * ACE genotype on insulin at 30 min = 0.003 and on insulin area under the curve = 0.05).

The ACE I allele is associated with shorter duration of gestation and higher birth weight. The association between the presence of the ACE I allele and increased indices of adult insulin secretion is confined to subjects with low birth weight. We suggest that these findings reflect interactions between genotype and intrauterine environment with resulting changes in gene expression.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
SMALL BODY SIZE at birth is associated with higher rates of type 2 diabetes, insulin resistance, and the metabolic syndrome (1, 2, 3, 4, 5). A large body of experimental evidence attributes this association to developmental plasticity, the phenomenon whereby one genotype can give rise to a range of different structures and functions in response to conditions during development (6, 7). If conditions are adverse, as indicated in humans by low birth weight (8), there are permanent alterations in the expression of genes, which lead to metabolic and morphological changes that predispose to disease in later life. This being so, one would expect associations between genetic polymorphisms and later disease to be conditioned by birth weight or other markers of the early environment (9, 10, 11).

Angiotensin-converting enzyme (ACE) is a key enzyme in the renin-angiotensin system. Its effects include catalyzation of the conversion of angiotensin I to angiotensin II and inactivation of the vasodilatory peptide bradykinin. The ACE gene has an insertion/deletion (I/D) polymorphism, which is due to the presence or absence of a 287-bp fragment inside intron 16. The D allele is associated with higher circulating and tissue ACE levels (12, 13). It has also been associated with increased risk of micro- and macrovascular complications of type 2 diabetes (14, 15, 16). These findings have, however, been inconsistent, and the studies have been criticized because the effect on some outcomes has been more modest in larger studies, suggesting publication bias (17). One possibility is that size at birth could modify the risk associated with the I/D polymorphism. Evidence for this comes from a group of young adults, within whom the I allele was related to greater insulin secretion only in those born small but not in those born appropriate for gestational age (9). However, whether a similar effect is seen across the normal range of birth weights has not been reported. We have therefore examined interactions between the ACE gene I/D polymorphism and size at birth on glucose and insulin metabolism in a group of elderly men and women around 70 yr of age, whose body size at birth was recorded.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Study population

The original study cohort consisted of 7086 men and women who were born as singletons at Helsinki University Central Hospital (Helsinki, Finland) during 1924–1933 (18). Their birth records included gestational age, weight, length, and head circumference. Ponderal index at birth was calculated as weight (kilograms)/[length (meters)]3.

From this cohort, 465 subjects with known birth weight and gestational age attended a clinical study and had their ACE genotype determined. The clinical study, which included standard anthropometry, blood pressure, and a 75-g oral glucose tolerance test, has been described (5). The study protocol was approved by the Ethics Committee, and informed consent was obtained from all participants. Homeostasis model of assessment (HOMA) insulin resistance index was calculated as fasting glucose * fasting insulin/22.5 (19), insulin area under the curve (AUC) as [logAUC = (logins0min + 4 * logins30min + 3 * logins120min)/8]. There were 15 sibling pairs among the study population. To ensure that possible associations are attributable to the ACE gene locus, one randomly chosen subject from each sibling pair was excluded. In addition, because medication for diabetes may affect glucose and insulin concentrations, the 27 subjects receiving this medication were excluded, leaving us with 423 subjects (155 men and 268 women). Their mean birth weight was 3350 g (SD 461), length 49.9 cm (SD 1.7), head circumference 34.5 cm (SD 1.3), and gestational age at birth 276 d (SD 15). At the clinical examination, their mean age was 69.5 yr (SD 2.8) and body mass index (BMI) 27.3 kg/m2 (SD 4.2). One hundred twenty-five subjects (30%) had impaired glucose tolerance, and 68 subjects (16%) type 2 diabetes according to World Health Organization 1998 criteria (20).

Genotyping of the ACE I/D polymorphism

The region of the ACE I/D polymorphism was amplified by the forward PCR primer 5'-CTCCCATCCTTTCTCCCATT-3' and reverse primer 5'-GGCGAAACCACATAAAAGTGA-3'. The 5' end of the forward primer was labeled with HEX fluorescent dye. PCRs were performed in a total volume of 5 µl containing 20 ng of human genomic DNA, 250 µM of each deoxynucleotide triphosphate (Applied Biosystems, Foster City, CA), 3.0 mM MgCl2 (Applied Biosystems), 1x PCR buffer (Applied Biosystems), 0.2 U Ampli-Taq Gold DNA-polymerase (Applied Biosystems), and 0.1 mM of each primer (Sigma-Genosys, Cambridge, UK). The thermal cycling conditions were 95 C for 10 min and 30 cycles at 95 C for 30 s, 60 C for 30 s, and 72 C for 30 s, followed by a final extension at 72 C for 7 min. PCR products were separated with the ABI PRISM 377 (Applied Biosystems) DNA sequencer, with the data analyzed by Genescan 3.1 and Genotyper 2.5 software (Applied Biosystems). The I/D alleles were discriminated based on the sizes of amplified fragments (353 or 65 bp, respectively).

Data analysis

Plasma glucose and insulin concentrations were log-transformed to normality. Linear regression was used to assess correlation between continuous variables, as well as with the ACE I/D polymorphism, because previous studies (9, 21) have suggested an allele-dosage effect of this polymorphism on adult phenotype. Logistic regression was used with binary outcome variables. Interactions between the effects of size at birth and the ACE genotype on adult phenotype were assessed by adding an interaction term (ACE genotype * birth measurement) to the regression equation. Birth measurements were adjusted for gestational age and sex by linear regression. Regression analyses with an adult phenotype variable as the dependent variable were, in addition, adjusted for sex, current age, and BMI.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
There were 69 subjects homozygous for the I allele (II), 210 heterozygous subjects (ID), and 144 subjects homozygous for the D allele (DD). The genotypes were in Hardy-Weinberg equilibrium. Because no interaction was observed between the effects of sex and ACE genotype on birth or clinical characteristics, we present a pooled analysis adjusted for sex.

We first assessed the relationship between ACE genotype and glucose and insulin metabolism. In a standard oral glucose tolerance test, the presence of the I allele was associated with higher indices of ß-cell function and lower glucose at 120 min (Table 1Go). This relationship appeared to show an allele-dosage relationship, with highest values in II homozygotes, followed by ID heterozygotes and thereafter DD homozygotes. The ACE genotype was not associated with fasting glucose or insulin concentration, BMI, waist circumference, blood pressure, or the presence of impaired glucose tolerance or diabetes.


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  		TABLE 1. Results of the oral glucose tolerance test with calculated indices of insulin secretion and insulin resistance, in relation to ACE I/D genotype

 
Measurements and gestational age at birth according to ACE genotype are shown in Table 2Go. The mean gestational age of subjects with II genotype was 38 wk 6 d, of those with ID genotype 39 wk 3 d, and of those with DD genotype 39 wk 5 d (P for trend = 0.006). Adjusted for gestational age and sex, ACE genotype was associated with size at birth: weight (P for trend = 0.008), length (P = 0.02), and head circumference (P = 0.007) were all highest in II individuals, followed by ID and thereafter DD individuals.


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  		TABLE 2. Birth data according to ACE I/D genotype

 
The relationship between ACE genotype and indices of insulin secretion in adulthood was dependent on size at birth. This is shown by interactions between the effects of birth weight and ACE genotype. The rows of Table 3Go demonstrate this interaction by showing that, within subjects with relative birth weight in the lowest third, the highest mean insulin at 30 min and insulin AUC, as well as the lowest glucose at 120 min, is seen in II individuals. By contrast, in subjects with relative birth weight in the highest third, there is no relationship with ACE genotype. The columns of Table 3Go exhibit the other aspect of this interaction: low birth weight is associated with higher indices of insulin secretion in individuals with II and ID genotype but not in those with DD genotype.


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  		TABLE 3. Indices of insulin secretion and glucose tolerance according to ACE I/D genotype and birth weight

 
There was no interaction between the effects of ACE I/D genotype and relative birth weight on indices of insulin sensitivity including fasting insulin, glucose, or HOMA insulin resistance index. Based on findings by Cambien et al. (9), we searched also for two-way interactions, i.e. gestational age * ACE I/D genotype. Such interactions were not found.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
We have shown that the ACE I allele is associated with a larger body size at birth and shorter duration of gestation. Moreover, the effects of this polymorphism on an adulthood trait, insulin secretion, are dependent on size at birth, a proxy of intrauterine environment.

These associations between the I/D polymorphisms of the ACE gene and glucose tolerance and insulin secretion are consistent with previous studies in that the D allele has been associated with increased risk of complications of type 2 diabetes (14, 15, 16). The associations between birth weight and these parameters are also consistent with previous findings (1, 2, 3, 4, 5). Our study was carried out on a sample of elderly people belonging to an epidemiological cohort (5). We have previously shown that the associations between size at birth and metabolic outcome are not affected by elderly age (5). Therefore, we think that the interactions between the I/D polymorphisms and birth weight are not the results of confounding factors.

Cambien et al. (9) found that the I allele was associated with a greater insulin response among a group of young adults, being however confined to those born small for gestational age. We have now found this association in elderly people whose birth weights extended across the normal range. It was strongest among those whose relative birth weights were in the lowest third and was not present in those with higher birth weights. One suggested explanation for the high insulin secretion of low-birth-weight people with the I allele is that it indicates insulin resistance (9). This seems unlikely, however, because the I allele is protective against complications of diabetes (14, 15, 16), and we found no similar relationships with fasting insulin concentration or HOMA, commonly used indicators of insulin resistance. Another possibility is that small body size at birth is associated with insulin resistance (2), whereas the I allele confers an increased capacity of the pancreatic ß-cells to respond to the increased insulin demand, or intrauterine growth failure is known to be associated with a reduction in the number and function of the pancreatic ß-cells, and the presence of the I allele could protect against this (22). These ideas remain speculative because little is known about the effects of the renin-angiotensin system on ß-cells.

ACE is active in the placenta. Its activity is increased in preeclampsia, a common pregnancy disorder frequently complicated by inadequate fetal substrate supply and growth restriction. ACE activation has been suggested to result in redistribution of the placental circulation (23) and thus probably reduced nutrient transfer to the fetus. Interestingly, the presence of a maternal D allele, a prerequisite for the fetus to carry a DD genotype, is associated with increased risk of preeclampsia or fetal growth restriction and abnormal uteroplacental circulation (21). One might thus speculate that such alterations, even if not manifesting as frank preeclampsia, could affect fetal growth and perhaps regulation of parturition. They thus constitute a conceivable mechanism explaining the link between ACE D allele, longer gestation, and smaller size at birth.

A limitation of this study is that our gestational age data were based on the date of the mother’s last menstrual period. Although this method has been validated against dating by ultrasound measurement of fetal biparietal diameter (24), this may still be another source of inaccuracy. However, such inaccuracies would only weaken our ability to detect existing effects.

Only a small number of genetic polymorphisms have consistently been associated with insulin resistance and type 2 diabetes. One reason may be that few genetic association studies with late-life outcomes have been able to incorporate data describing environment early in life. We suggest that our findings reflect interactions between genotype and intrauterine environment, occurring as manifestations of developmental plasticity in response to, for example, adverse nutritional and hormonal conditions the fetus experiences before birth. These findings underline the importance of thorough assessment of such interactions in the search for susceptibility genes for common complex disorders.


   Acknowledgments
 
We thank Paula Nyholm, Terttu Nopanen, and Liisa Toivanen for coordination of the study and Sigrid Rosten for data management. Genotyping was performed at the Finnish Genome Center, whose skillful personnel are gratefully acknowledged.


   Footnotes
 
This work was supported by grants from the Academy of Finland, British Heart Foundation, Finnish Diabetes Foundation, Finnish Heart Foundation, Finnish Medical Society Duodecim, Finska Läkaresällskapet, Foundation for Pediatric Research, Jalmari and Rauha Ahokas Foundation, Päivikki and Sakari Sohlberg Foundation, Sigrid Jusélius Foundation, Royal Society, and Yrjö Jahnsson Foundation.

Abbreviations: ACE, Angiotensin-converting enzyme; BMI, body mass index; HOMA, homeostasis model of assessment; I/D, insertion/deletion.

Received March 15, 2004.

Accepted July 19, 2004.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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  7. Barker DJP 2002 Components in the interpretation of the high mortality in the county of Finnmark. Int J Epidemiol 31:309–310[Free Full Text]
  8. Harding JE 2001 The nutritional basis of the fetal origins of adult disease. Int J Epidemiol 30:15–23[Free Full Text]
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  12. Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol B, Soubrier F 1990 An insertion-deletion polymorphism in the angiotensin I converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest 86:1343–1346
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  16. Huang XH, Rantalaiho V, Wirta O, Pasternack A, Koivula T, Hiltunen TP, Nikkari T, Lehtimaki T 1998 Angiotensin-converting enzyme gene polymorphism is associated with coronary heart disease in non-insulin-dependent diabetic patients evaluated for 9 years. Metabolism 47:1258–1262[CrossRef][Medline]
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