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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 7 2770-2775
Copyright © 2006 by The Endocrine Society

The Insulin Gene Variable Number of Tandem Repeat: Associations and Interactions with Childhood Body Fat Mass and Insulin Secretion in Normal Children

Barbara Heude, Clive J. Petry the Avon Longitudinal Study of Parents Children (ALSPAC) study team, Marcus Pembrey, David B. Dunger, Ken K. Ong

Medical Research Council Epidemiology Unit (B.H., K.K.O.), Cambridge CB1 8RN, United Kingdom; Department of Pediatrics (C.J.P., D.B.D., K.K.O.), University of Cambridge, Cambridge CB2 2QQ, United Kingdom; Unit of Pediatric and Perinatal Epidemiology (ALSPAC study team), Department of Community Based Medicine, University of Bristol, Bristol BS8 1TQ, United Kingdom; and Clinical and Molecular Genetics Unit (M.P.), Institute of Child Health, University College London, London WC1N 1EH, United Kingdom

Address all correspondence and requests for reprints to: Dr. Ken Ong, Medical Research Council Epidemiology Unit, Strangeways Research Laboratory, Wort’s Causeway, Cambridge CB1 8RN, United Kingdom. E-mail: ken.ong{at}mrc-epid.cam.ac.uk.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Polymorphism at the insulin gene (INS) variable number of tandem repeat (VNTR) shows variable associations with childhood body mass index (BMI) in different populations.

Objective: The objective of this study was to observe INS VNTR associations with body composition and insulin secretion in children.

Design: The study was designed as a prospective birth cohort study.

Participants: A total of 947 children genotyped for the INS VNTR participated.

Main Outcome Measures: Main outcome measures were whole body dual x-ray emission absorptiometry at 9 yr to estimate height-corrected fat mass index (FMI), truncal FMI, and fat-free mass, and insulin secretion after oral glucose at 8 yr.

Results: Homozygous III/III children had higher BMI (P = 0.020), FMI (P = 0.015), and truncal FMI (P = 0.022) at 9 yr than class I bearers, but no difference in fat-free mass (P = 0.23). Gain in weight SD score between birth and 3 yr was associated positively with BMI, FMI, and truncal FMI in class I bearers, but not in III/III children (p-interaction with genotype = 0.009–0.066). INS VNTR genotype was not associated overall with insulin secretion at 8 yr (P = 0.64), but class I bearers showed a stronger positive correlation between insulin secretion and BMI at 8 yr (regression coefficient ± SE, 0.26 ± 0.05; P < 0.0001) than III/III children (–0.10 ± 0.07; P = 0.48) (p-interaction = 0.003).

Conclusion: We clarified that the overall association between INS VNTR class III/III genotype and larger BMI in this population relates to fat mass, but not fat-free mass. In contrast, among the subgroup of children who showed rapid infancy weight gain, class I bearers tended to have larger BMI and fat mass than III/III children. This genetic interaction could relate to insulin secretion, which, in class I bearers, increased more rapidly with overweight and obesity.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
HOPES OF PREVENTING childhood obesity are reliant on the early identification of children at high risk of becoming overweight or obese. Several studies have reported that rapid weight gain during early postnatal life predicts subsequent obesity risk (1, 2) and higher body fat levels (3) in children and young adults.

Rapid infancy weight gain occurs more commonly in those infants who were growth retrained in utero by factors relating to the maternal-uterine environment (4). Therefore, rapid infancy weight gain could explain the widely confirmed epidemiological associations between lower birth weight and subsequent increased risks for cardiovascular disease and type 2 diabetes (5). Such children with lower birth weight and rapid infancy weight gain also develop insulin resistance (6, 7), which has been suggested to be the key link to future metabolic disease risk (8). With the development of increasing body mass and insulin resistance, compensatory insulin hypersecretion could feedback to promote greater weight gain and body fat deposition.

We hypothesized that childhood adiposity relates to both rapidity of postnatal weight gain and genetic factors that might regulate the partitioning between lean and fat body mass. Polymorphism at the insulin gene (INS) variable number of tandem repeat (VNTR) regulates both insulin and IGF-2 gene (IGF2) expression (9, 10, 11) and is associated with risks for type 1 and possibly also type 2 diabetes (12, 13). We recently confirmed its association with size at birth in a normal population-based birth cohort (14). The class III alleles were associated recessively with larger head circumference at birth and higher cord blood levels of IGF-2, and those associations showed significant interaction with postnatal rapid weight gain, a marker of previous intrauterine growth restriction (14).

In that study, we also observed that class III/III children had greater body weight, body mass index (BMI), and waist circumference at 8 yr of age; however, those postnatal associations appeared to be reversed among the 25% of children who showed early postnatal rapid weight gain (14). Similarly, among obese French children, the INS VNTR class I alleles, rather than the class III, were associated with increased BMI gains (15). A further study in obese children reported that the INS VNTR was a quantitative trait locus for the insulin response to oral glucose, and those authors hypothesized that class I alleles could confer greater insulin secretion for the degree of BMI compared with class III alleles, and therefore, could predispose them to further weight gain (16).

Now we have reanalyzed our existing INS VNTR genotype data in the Avon Longitudinal Study of Parents and Children (ALSPAC) children (14) with new phenotype data on body composition at 9 yr of age to distinguish between genetic associations with fat mass or lean mass. We also aimed to confirm the reported interactive effects of INS VNTR genotype and BMI on insulin secretion (15, 16).


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

In the study of normal representative United Kingdom children, as part of the ALSPAC study, previously described (17), the "Children in Focus" and "Control" subcohorts were measured at 3 yr of age, in addition to the whole ALSPAC cohort measurements at birth, 7 yr, and 9 yr, when all children also had a whole body dual x-ray emission absorptiometry (DXA) scan. Analysis of body composition at 9 yr of age was based on 947 children with full data on DXA parameters, early growth phenotypes, and INS VNTR genotype. Analysis of insulin secretion at 8 yr of age was based on 750 children with complete data. The subjects analyzed in this paper did not differ from the whole ALSPAC cohort with respect to childhood growth at 9 yr of age (data not shown). Preparation of DNA and genotyping for INS VNTR were previously described (14).

Body composition

At age 9.9 (± 0.33) yr, all ALSPAC children were invited to attend a 3-h hands-on assessment. Height was measured with shoes and socks removed using a Harpenden stadiometer (Holtain Ltd., Crymych, Pembs, United Kingdom). Weight was measured using a Tanita TBF 305 body fat analyzer and weighing scales (Tanita United Kingdom Ltd., Yewsley, Middlesex, UK). Total fat, central fat, and lean mass were measured using a Lunar Prodigy DXA scanner (GE Medical Systems Lunar, Madison, WI). The scans were visually inspected and realigned where necessary. Trunk fat mass was estimated using the automatic region of interest that included chest, abdomen, and pelvis.

Body composition variables were corrected for differences in height by calculating the fat mass index (FMI) (fat mass/height2) and truncal FMI (truncal fat mass/height2) (18).

Insulin secretion

At 8 yr of age (mean ± SD: 8.2 ± 0.1, range 8.0–8.5 yr), 851 children (750 with INS VNTR genotype data) from the Children in Focus or Control subcohorts attended the research clinic in the morning after an overnight fast (6). Fasting was validated by questionnaire, and data were excluded if subjects were taking oral steroids or had any current infection. A venous blood sample was taken to measure glucose and insulin levels before and 30 min after an oral glucose load (1.75 g/kg, maximum 75 g) as a drink (Lucozade Energy Original; GlaxoSmithKline PLC, Greenford, Middlesex, UK).

Insulin sensitivity was estimated using the Homeostasis model computer program, kindly provided by Dr. Jonathan Levy (University of Oxford, Oxford, UK) (19). Insulin secretion was calculated as the corrected insulin response from 30-min insulin and glucose levels: [insulin30/(glucose30 x (glucose30 – 3.9))] (milliunits per square millimoles) (20). After oral glucose there is a dose-response relationship between glucose and insulin (20), and this correction for the attained glucose level has been shown to correlate most closely with the first-phase insulin response (21). Similar results were found when insulin secretion was estimated using the insulinogenic index (insulin30 – insulin0)/(glucose30 – glucose0) (22).

Statistical analysis

All data were explored for normality of distribution and log transformed where appropriate. The association between genotype and phenotype was analyzed using a linear regression model under both global and recessive models.

For the association with DXA, adjustment was performed on age, gender, parity, education level of the mother, and change in weight between birth and 3 yr. Interaction between genotype and postnatal weight gain was examined by introducing and testing the interactive term (genotype x weight gain) in the previous models. Adjusted regression coefficients are shown separately for each genotype group.

The association between genotype and insulin secretion at 8 yr was examined adjusting for age, gender, and BMI at 8 yr. The interaction effect between BMI and genotype was analyzed introducing and testing the interactive term (genotype x BMI). Analyses were performed using SPSS for Windows version 11.0 (SPSS, Chicago, IL).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Mean body size and body composition at 9 yr of age are displayed by genotype in Table 1Go. Overall, homozygous III/III children had larger body weight, BMI, FMI, and truncal FMI at 9 yr of age than class I bearers (P = 0.01–0.02), but there was no difference in fat-free mass (Table 1Go). At 9 yr, 12.7% of the children were obese [defined as >95th percentile for BMI according to the United Kingdom 1990 growth reference (23)]. Risk for obesity was increased in homozygous III/III children compared with class I bearers [odds ratio, 1.39; 95% confidence interval (95% CI), 1.01–1.92; P = 0.04].


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  		TABLE 1. Body size and body composition at 9 yr of age, stratified by INS VNTR genotype

 
Rate of early postnatal weight gain between birth and 3 yr was positively associated with BMI at 9 yr of age in class I/I and I/III children (P < 0.0001), but not in III/III children (P = 0.74); and the difference in regression slopes between class I bearers and homozygous III/III children was significant (p-interaction with genotype = 0.009; Table 2Go and Fig. 1Go). Similarly, rate of weight gain between birth and 3 yr was positively associated with FMI at 9 yr of age in class I bearers (P < 0.0001), but not in III/III children (P = 0.68) (p-interaction = 0.064; Table 2Go).


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  		TABLE 2. Correlations between early postnatal weight gain (change in weight SD score from birth to 3 yr) and body size and composition at 9 yr, stratified by INS VNTR genotype

 

Figure 1
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  		FIG. 1. BMI at 9 yr of age was positively related to early postnatal weight gain (change in weight SD score from birth to 3 yr) in INS VNTR class I bearers (I/I and I/III: P < 0.0001, n = 880) but not in III/III children (P = 0.74, n = 67) (p-interaction with genotype = 0.009).

 
Mean fasting insulin levels, insulin sensitivity, and parameters of insulin secretion at 8 yr of age are displayed by genotype in Table 3Go. No differences in mean values were observed between genotypes. However, in class I bearers, insulin secretion showed a much closer correlation with BMI at 8 yr than in homozygous III/III children (p-interaction = 0.003; Table 4Go and Fig. 2Go). A closer correlation between insulin secretion and insulin sensitivity was also seen in class I bearers (I/I: r = –0.22, P < 0.0001; I/III: r = –0.31, P < 0.0001) than in homozygous III/III children (III/III: r = 0.09, P = 0.6) (p-interaction = 0.01).


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  		TABLE 3. Insulin sensitivity and secretion at 8 yr, stratified by INS VNTR genotype

 

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  		TABLE 4. Correlations between BMI at 8 yr and indices of insulin sensitivity and insulin secretion at 8 yr, stratified by INSVNTR genotype

 

Figure 2
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  		FIG. 2. Insulin secretion at 8 yr of age (corrected insulin response) was positively related to BMI at 8 yr of age in INS VNTR class I bearers (I/I and I/III, P < 0.0001, n = 690) but not in III/III children (P = 0.48, n = 60) (p-interaction = 0.003).

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In this representative cohort of UK children, the INS VNTR class III/III genotype was overall associated with increased BMI and body fat mass at 9 yr of age in the whole study population. In this same group of subjects, we had previously reported association between the INS VNTR and BMI at 8 yr of age (14). Therefore, the current results do not represent an independent confirmation; however, they clarify that the association is with body fat rather than lean mass.

Furthermore, we provide significant confirmation of two recently reported genetic interactions, which may go some way toward explaining the different INS VNTR genotype associations seen in different populations or subgroups. First, as we previously observed (14), the III/III genotype association with larger size was particularly seen among those children who did not gain weight rapidly during infancy. In contrast, with increasing rate of early postnatal weight gain, class I bearers, but not III/III genotype children, had larger BMI and fat mass at 9 yr of age. Secondly, similar to another previous study (16), we found that, in class I bearers, insulin secretion increased significantly more rapidly with increasing BMI compared with class III/III children.

In childhood populations, obesity risk has been variably associated with either class III or class I INS VNTR alleles. Among French children with early onset obesity, those with the class I allele had greater BMI gains (15). Class I alleles were also associated with overweight in a further French childhood growth study of 8- to 18-yr-old adolescents (24); compared with the ALSPAC cohort, those children were older (mean age 13.5 yr) but had a similar proportion who were overweight/obese (14.2%). In contrast, a study of non-obese girls reported that the III/III homozygotes had greater fat mass by DXA (25). Recent adult population studies have found no overall association between the INS VNTR and obesity risk (26, 27). Our findings of genetic interaction with early postnatal weight gain on subsequent BMI and body composition could provide a possible explanation for these contrasting reports. Our findings could suggest two separate pathways to later obesity risk: rapid infancy weight gain associated with the INS VNTR class I allele, and nonrapid infancy weight gain associated with the III/III genotype. Genetic association studies for obesity should consider such potential interactions with early postnatal weight gain.

A further complexity is that effects of INS VNTR alleles may differ according to parent of origin (28). Among French children with early onset obesity, those who inherited a class I allele from their father (but not from their mother) had a 1.8-fold increased risk of obesity (29). Our current studies in this ALSPAC subcohort do not have sufficient power to explore parent-of-origin effects (14). Selection of children with extreme early onset obesity would also provide much greater power to detect the class I association with obesity; however, population-based studies are more generalizable and may be more likely to confirm interactive effects with the wider range of early growth trajectories.

Our studies have consistently shown apparent recessive effects of class III alleles on size at birth, childhood growth, and IGF-2 protein levels at birth (14, 30), and the mean values and regression coefficients reported in this study in I/I and I/III children were nearly identical. However, other studies have found apparent dominant effects of class III alleles (9, 16, 31). Recently, Rodriguez et al. (33) reported confirmation of associations with a haplotype in IGF2-INS-TH region tagged by INS VNTR class I alleles, together with allele A of IGF2 ApaI, and allele 9 of TH01, with both lower BMI and lower insulin secretion in adult men from two population-based UK cohorts (32, 33). Thus, the genetic associations we observed could possibly be explained by specific subtypes of INS VNTR allele class, or by linkage disequilibrium with other neighboring variants (12).

The INS VNTR has been shown to regulate INS or IGF2 transcription in utero (9, 10), and its influence on postnatal body size could be due to antenatal or postnatal gene expression. The increased type 1 diabetes risk associated with class I alleles (12, 31) has been attributed to reduced fetal thymic insulin mRNA expression leading to loss of immune tolerance to insulin (9, 34). In contrast to those studies in the thymus, in transfected pancreatic cell lines and fetal pancreas, class I alleles are associated with increased insulin mRNA expression (35, 36). Polymorphism at the INS VNTR minisatellite may alter a transcription promoter binding site (37), and transfection of class I alleles has been reported to influence alternative splicing of INS intron 1 resulting in longer, mature mRNA transcripts and higher proinsulin levels (11). In adults, class I alleles are associated with pulsatility of ß-cell insulin secretion (38).

Thus, it is possible that the class I allele could confer a greater responsiveness in insulin secretion to changes in BMI and insulin sensitivity, and therefore, a predisposition to storing adipose rather than lean tissue during periods of rapid weight gain, or in obese children (15). This could predispose to future type 2 diabetes, particularly related to the development of insulin resistance. Conversely, relatively lower insulin secretion in class III/III subjects in the face of increasing BMI or insulin resistance could also contribute to increased type 2 diabetes risk (13). Recent large studies in adults have shown no overall influence of INS VNTR genotype on type 2 diabetes risk (39). However, similar to obesity risk, we hypothesize that the pathogenesis and phenotype of type 2 diabetes could differ according to both early weight gain patterns and INS VNTR genotype.

In conclusion, in these representative children, the INS VNTR class III/III genotype was associated overall with increased adiposity. However, significant genetic interactions were seen with BMI and insulin secretion that could also support a class I allele predisposition to obesity after rapid infant weight gain. Different INS VNTR genotypes and patterns of early postnatal weight gain could underlie discrete developmental pathways to obesity and type 2 diabetes risks.


   Acknowledgments
 
We are extremely grateful to all the children and parents who took part in the study and to the midwives for their cooperation and help in recruitment.


   Footnotes
 
ALSPAC is supported by the Medical Research Council, the Wellcome Trust, the Department of Health, the Department of the Environment, the European Commission, and many others. D.B.D. is supported by the Wellcome Trust and the Juvenile Diabetes Research Foundation.

First Published Online April 11, 2006

Abbreviations: ALSPAC, Avon Longitudinal Study of Parents and Children; BMI, body mass index; CI, confidence interval; DXA, dual x-ray emission absorptiometry; FMI, fat mass index; INS, insulin gene; VNTR, variable number of tandem repeat.

Received September 13, 2005.

Accepted April 4, 2006.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals