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Fat Mass Accumulation during Childhood Determines Insulin Sensitivity in Early Adulthood

Department of Paediatrics (R.W.J.L., P.O., L.K.M.H., A.A.H., A.C.S.H.-K.), Division of Endocrinology, Erasmus Medical Centre-Sophia, Children’s Hospital, 3015 GJ Rotterdam, The Netherlands; and Department of Epidemiology and Biostatistics (T.S.), Leiden University Medical Centre, 2333 ZA Leiden, The Netherlands

Address all correspondence and requests for reprints to: R. W. J. Leunissen, Erasmus MC/Sophia Children’s Hospital, Room Sb 2670, Dr. Molewaterplein 60, 3015 GJ Rotterdam, The Netherlands. E-mail: r.leunissen{at}erasmusmc.nl.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background/Objectives: Low birth weight and postnatal catch-up growth have been associated with an increased risk for diabetes mellitus type II (DMII). We evaluated the contribution of birth and adult size, body composition, and waist-to-hip ratio to DMII risk factors in young adulthood.

Methods: In a group of 136 young adults, aged 18–24 yr, insulin sensitivity and disposition index were determined by frequent sampling iv glucose tolerance test. The association of clinical parameters with these variables was analyzed with multiple regression modeling. In addition, differences in insulin sensitivity and disposition index, a measure for β-cell function, were analyzed in four subgroups, young adults either born small for gestational age SGA with short stature (n = 25) or SGA with catch-up growth (n = 23) or born appropriate for gestational age with idiopathic short stature (n = 23) or with normal stature (controls) (n = 26).

Results: Fat mass was the only significant predictor of insulin sensitivity, whereas birth length and birth weight were not significant. After correction for age, gender, and adult body size, insulin sensitivity was significantly lower in subjects born SGA with catch-up growth compared with controls. None of the variables had a significant influence on disposition index, and there was no significant difference in disposition index between the subgroups.

Conclusions: Our data show that a higher body fat mass at 21 yr is associated with reduced insulin sensitivity, independent of birth size. These findings have important implications for public health practice.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Size at birth has been inversely associated with adult diseases, such as diabetes mellitus type II (DMII) and cardiovascular diseases (1, 2, 3). A metaanalysis estimated that low birth weight was responsible for 35% of cases of DMII (4). Reduced insulin sensitivity is a well-recognized, early determinant of DMII and cardiovascular disease, and it usually precedes clinical symptoms (5, 6). Several studies found an association between low birth weight and reduced insulin sensitivity (1, 7), but these studies did not correct for adult weight.

Unfortunately, many study populations were heterogeneous with regard to gestational age, parity, ethnicity, tests used, and age at evaluation. Also, many studies did not differentiate between height and weight, either at birth or in adulthood. Often insulin sensitivity is described, whereas actually the disposition index (insulin sensitivity x insulin secretion) is a better determinant of DMII (8). The disposition index reflects how well the β-cells can compensate for a reduction in insulin sensitivity by increasing their insulin secretion (9).

At this moment, it is not clear who is most at risk for DMII, the subject born small for gestational age (SGA) with persistent short stature or the one born SGA with a normal stature after postnatal catch-up growth. We recently reported lower insulin sensitivity in 8 yr olds born SGA with persistent short stature (SGA-S) compared with age-matched short children who were born appropriate for gestational age (AGA) with idiopathic short stature (ISS) (10). Comparable results were found in another group of short prepubertal SGA children (11). Postnatal catch-up growth in weight and height is found in approximately 85% of SGA subjects (12, 13). Catch-up in height has been associated with increased insulin secretion, whereas catch-up in weight is associated with reduced insulin sensitivity (14). In young adulthood, comparison of insulin sensitivity and secretion between SGA subjects with short stature and subjects with catch-up growth has not been performed.

We hypothesized that both pre- and postnatal factors associate with insulin sensitivity. We therefore evaluated the relative contribution of birth length, birth weight, adult height, adult weight, fat mass, lean body mass, and waist-to-hip ratio to insulin sensitivity and disposition index in young adulthood. In addition, we evaluated whether there were differences with regard to insulin sensitivity and disposition index between four clinically recognizable subgroups of young adults, born SGA with short adult height (SGA-S) or normal adult height, i.e. SGA with catch-up growth (SGA-CU), or born AGA with either idiopathic short stature (ISS) or normal adult height (controls).

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Subjects

The total population consisted of 136 healthy subjects with an age between 18 and 24 yr. They were randomly selected from hospitals in The Netherlands, where they had been registered because of their being small at birth (SGA with a birth length <–2 SD) (15) or showing short stature (after being born SGA or AGA with an adult height <–2 SD) (16) or having a minor accidental health problem, but otherwise being normal. Only those born at 36 wk or more of gestation, being singleton and Caucasian, were invited to participate to exclude a potential influence of prematurity, parity, and ethnicity, respectively. All subjects fulfilled the same inclusion criteria: an uncomplicated neonatal period without signs of severe asphyxia (defined as an Apgar score < 3 after 5 min), without sepsis or long-term complications of respiratory ventilation, such as bronchopulmonary dysplasia. Subjects were excluded if they had been suffering from any serious condition or had been receiving any treatment known to interfere with growth (e.g. GH deficiency, severe chronic illness, emotional deprivation, GH treatment, treatment with glucocorticosteroids, or radiotherapy) or if they had endocrine or metabolic disorders, chromosomal defects, syndromes, or serious dysmorphic symptoms suggestive of a yet unknown syndrome. Birth data were taken from hospital records, community health services, and general practitioners. The Medical Ethics Committee of Erasmus Medical Centre, Rotterdam, The Netherlands, approved this study. Written informed consent was obtained from all the participants.

Based on SD scores (SDS) of birth length and adult height, the subjects were also assigned to one of four subgroups. To increase the statistical power for subgroup comparison, the cutoff value was set at –1 SDS (±0.1 SDS). The four subgroups were 1) born SGA (<–2 SDS) with a short adult height (<–2 SDS) (short-SGA, SGA-S), 2) born SGA (<–2 SDS) with catch-up growth resulting in a normal adult height (>–1 SDS) (SGA-CU), 3) born AGA (birth length >–1 SDS) with growth retardation resulting in a short adult height (<–2 SDS), i.e. ISS, and 4) born AGA (birth length >–1 SDS) and a normal adult height (>–1 SDS) (controls).

The number of males and females per subgroup is shown in Table 1. Of the 136 subjects, 97 were included in one of the subgroups.

All subjects were invited to the Erasmus University Medical Centre after a 12-h overnight fast and had abstained from smoking and alcohol for 16 h. At this visit, in all subjects, anthropometry was recorded, blood was drawn for fasting lipids, body composition was determined using dual-energy x-ray absorptiometry (DXA) and a frequent sampling iv glucose tolerance (FSIGT) test with tolbutamide was performed (17). All women were tested 3–5 d before their expected menstrual period. A questionnaire concerning subject’s medical history and that of their relatives, use of contraceptives, physical activity, and their substance use including smoking was completed. Adult height was measured using a Harpenden stadiometer, whereas weight in kilograms was measured to the nearest 0.1 kg on a digital scale (Servo Balance KA-20-150S). Waist and hip circumferences were measured at the level of the umbilicus and greater trochanters with a nonextendable measuring tape. One trained investigator performed all measurements according to standardized methods. Body composition was assessed on the same DXA machine (Lunar Prodigy; GE Healthcare, Chalfont St. Giles, UK), and quality assurance was performed daily. Indicators of glucose regulation were determined by the Bergman’s minimal model (MINMOD 6.01, copyright R. N. Bergman) calculating paired glucose and insulin data obtained by frequent measurements during an FSIGT (17, 18, 19) with tolbutamide (9). Values derived were insulin sensitivity (Si) index, which is the ability of insulin to increase net glucose disposal; glucose effectiveness, which is the ability of glucose to increase its own disposal and reduce its own production; acute insulin response (AIR) to glucose, which is the integrated insulin release during the first 10 min after the glucose infusion; and the disposition index, the product of insulin sensitivity and acute insulin response indicating the degree of glucose homeostasis. Blood samples were centrifuged directly after withdrawal, and serum and plasma were immediately frozen at –80 C for later analyses.

Assays

All plasma glucose levels were determined on a VITROS analyzer 750 (Orthoclinical Diagnostics, Johnson & Johnson Co., Beerse, Belgium). All plasma insulin levels were measured by immunoradiometric assay (Medgenix; Biosource Europe, Nivelles, Belgium). The intraassay coefficient of variation was 2–4.7% (19–405 pmol/liter), and the interassay coefficient of variation was 4.2–11.3% (32–375 pmol/liter). All assays were performed in one central laboratory.

Statistical analysis

SDS for birth length, birth weight, adult height, and adult weight were calculated to correct for gestational age, gender, and age (15, 16). Multiple linear regression (MR) analysis was performed to determine which variables contribute to insulin sensitivity and disposition index. First, we entered age, gender, height SDS, birth length SDS, and birth weight SDS to the model (model A). The interaction term birth length SDS x adult height SDS was added to all MR models because the study group had been selected on birth length and adult height to ensure that the effect of these variables was modeled correctly. Second, weight SDS and waist-to-hip ratio were added (model B). Third, lean body mass and fat mass were added as independent variables instead of adult weight SDS, and waist-to-hip ratio was removed (model C). Finally, we added waist-to-hip ratio again to the model (model D).

Before the study, a power analysis with a level of significance () of 0.05 and a chosen power of 80% estimated that there should be at least 17 subjects in each subgroup to enable detection of relevant differences in insulin sensitivity (10). ANOVA was used to determine whether there were differences between the subgroups with regard to the group characteristics. Bonferroni correction was used for pairwise group comparisons. To determine differences between the groups after correction for age, gender, adult size, and adult fat mass, an analysis of covariance model was used, with controls as reference group and SGA-S, SGA-CU, and ISS as dummy variables. Statistical package SPSS version 11.0 (SPSS, Inc., Chicago, IL) was used for analysis. Results were regarded statistically significant if P was <0.05.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The clinical characteristics of the study population are shown in Table 1. The total population consisted of 136 subjects with a mean (SD) age of 21 (1.5) yr. We evaluated the relative contribution of several variables to insulin sensitivity in a multiple linear regression analysis. The initial analysis with insulin sensitivity as dependent variable included age, gender, adult height SDS, birth length SDS, birth weight SDS, and the interaction term birth length SDS x adult height SDS (Table 2). Only gender and birth weight were significant determinants of insulin sensitivity (model A, adjusted R² = 0.06, P = 0.03). However, when we added adult weight SDS and waist-to-hip ratio to the regression model, gender, adult height SDS, adult weight SDS and waist-to-hip ratio were significant determinants of insulin sensitivity, whereas birth weight was no longer significant (Model B, adjusted R²= 0.17). After specification of adult weight in fat mass and lean body mass, measured by DXA, fat mass appeared to be the only significant determinant of insulin sensitivity (model C, adjusted R² = 0.23), even after adding waist-to-hip ratio to the model (model D, adjusted R² = 0.24). There were no significant interactions between birth weight or length and fat mass or lean body mass with regard to insulin sensitivity.

Comparison of the subgroups

Ninety-seven subjects were eligible for the analysis of differences between the four clinically relevant groups. There was a significant difference in gestational age between the SGA-CU group and the SGA-S and ISS group (P < 0.02) and a significant difference in birth length SDS between ISS and AGA subjects (P < 0.05) (Table 1). Other differences were due to the selection criteria. There was a tendency for a higher weight and fat mass in SGA-CU subjects, but weight and absolute or relative fat mass were not significant between groups. Physical activity, alcohol use, and smoking were not significantly different between the subgroups.

Table 3 shows the results of the FSIGT tests. The SGA-CU group had the lowest insulin sensitivity and highest insulin secretion of the four groups, but this difference was not statistically significant before correction for possible confounders. To correct for age, gender, adult height, and adult weight, we additionally performed multiple linear regression analyses. After correction, the SGA-CU group appeared to have a significantly lower insulin sensitivity compared with the controls (P = 0.01). Because fat mass is an important factor in determining insulin sensitivity, we also corrected for adult fat mass (Table 4, model 2). The explained variance rose from 0.17 to 0.30, indicating the relevance of fat mass. The difference in insulin sensitivity between the three subgroups and controls tended to become less significant, but the difference between SGA-CU and controls remained significant (P = 0.02).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Our study in 136 young adults shows that adult fat mass is the main predictor of insulin sensitivity in young adulthood, whereas birth length and birth weight were not. When data on body composition are not available, gender, adult height, adult weight, and waist-to-hip ratio appear to be significant determinants. None of these variables had a significant influence on the disposition index. Analysis in four clinically relevant subgroups showed that after correction for age, gender, adult height, and adult weight, SGA-CU subjects had significantly lower insulin sensitivity compared with controls. This difference remained significant even after an additional correction for fat mass. There were no significant differences between the subgroups with regard to disposition index.

Our data, measured by FSIGT and DXA, show a strong influence of fat mass on insulin sensitivity in young adults, whereas birth size had no influence on insulin sensitivity. These findings are in line with a previous study in 25-yr-old adults born SGA, which showed that lower insulin sensitivity coincided with weight gain rather than with birth weight (20). Due to the DXA measurements, we could specify weight gain as accumulation of fat. Our data imply that all individuals, regardless of their size at birth, should try to achieve or maintain a normal fat mass for their body size.

Our first model showed that birth weight and gender were significant determinants of insulin sensitivity. This is consistent with studies of Barker and colleagues (1, 3), who showed an inverse association between birth size and adult diseases, like DMII and cardiovascular diseases. However, when we added adult weight and waist-to-hip ratio to the model, birth weight was no longer a significant determinant of insulin sensitivity, whereas adult size (height, weight, and waist-to-hip ratio) was significant (model B). This is in line with other studies demonstrating weight gain or growth acceleration during childhood as a significant factor (14, 21, 22, 23). When we specified adult weight into fat mass and lean body mass, fat mass was the only significant determinant of insulin sensitivity (model C). The regression model shows that, given a similar birth length or birth weight, the fat mass in young adults, accumulated from birth to 21 yr, determines insulin sensitivity. Thus, an additional accumulation of 10 kg of fat will reduce insulin sensitivity by 2.42 x 10^–4/min (µU/ml). Our last model showed that waist-to-hip ratio had no additional value in determining insulin sensitivity (model D). This is probably due to the previous correction for fat mass, because in model B, waist-to-hip ratio is a significant determinant. Another reason might be the small variation of waist-to-hip ratio at this age.

The growth acceleration hypothesis, as suggested by Singhal and Lucas (24), in which fetal growth restriction relative to genetic growth potential could result in deleterious growth acceleration postnatally, can be taken a step further. In our study, we had the opportunity to correct for birth size, adult size, and adult body composition. Because fat accumulation appeared to be the only significant factor in the determination of insulin sensitivity, we therefore propose to specify growth acceleration by increased accumulation of fat mass. One may call this the fat accumulation hypothesis, indicating that an increased accumulation of fat during childhood, independent of birth size, will result in reduced insulin sensitivity. Increased fat mass is associated with changes in levels of free fatty acids and adipocytokines (e.g. adiponectin and leptin) (25), which affect insulin sensitivity and action. These changes might, in time, lead to adult diseases like DMII and cardiovascular diseases. Growth acceleration in height and weight as such is not a problem as long as a normal amount of fat is accumulated.

We analyzed whether there were differences in insulin sensitivity and disposition index between four clinically relevant groups of young adults (SGA-S, SGA-CU, ISS, and controls) because some investigators, including ourselves, described reduced insulin sensitivity in prepubertal short SGA children (10, 11, 26). We wanted to know what the insulin sensitivity would be in subjects born SGA when they had reached young adulthood. Our study revealed no difference between the SGA-S subjects compared with the other subgroups. The difference with the studies in prepubertal children might be due to puberty, when insulin sensitivity decreases in all children (27). The explanation might be that the decline in insulin sensitivity in SGA-S children is less during puberty, which would result in almost the same values as the ISS and controls in young adulthood.

After correction for age, gender, adult height, and adult weight, we found significantly lower insulin sensitivity in SGA-CU compared with controls. Because fat mass is a significant determinant of insulin sensitivity, a difference in fat mass might explain the lower insulin sensitivity in SGA-CU. This would be in line with data in 4-yr-old SGA-CU subjects who already had a higher fat mass and a lower insulin sensitivity compared with age-matched AGA subjects (23). We, therefore, performed an additional correction for fat mass. The difference in insulin sensitivity became less but remained significant, indicating that also other factors contribute to the reduced insulin sensitivity in SGA-CU subjects compared with controls. Differences in IGF-I have been described but are controversial (23, 28). Another factor that has been suggested is the amount of lean body mass. Decreased muscle mass might lead to more insulin resistance (29, 30). However, in our total study population, lean body mass had no significant association with insulin sensitivity (Table 2). Other relevant factors might be genetic factors (31), such as a higher allele frequency of polymorphism in the glucocorticoid receptor gene (32), leading to increased glucocorticoid sensitivity, which might contribute to the lower insulin sensitivity in SGA-CU subjects.

Several studies concluded that intrauterine growth retardation has an independent effect on insulin sensitivity, but they did not take adult size or weight gain into account (1, 22, 33). We have studied two SGA subgroups, with one group having lower insulin sensitivity and the other group having similar insulin sensitivity compared with controls. In our opinion, this supports our conclusion that birth size as such is not a relevant factor in determining insulin sensitivity.

ISS subjects had the same insulin sensitivity compared with controls. After correction for adult height and adult weight, their insulin sensitivity was nonsignificantly lower compared with controls, but this disappeared after correction of fat mass, indicating a relatively higher fat mass percentage in ISS subjects than controls. Insulin sensitivity of young adults with ISS has never been described.

After correction for age, gender, adult height, adult weight, and fat mass, SGA-S subjects had a significantly higher AIR compared with controls, whereas their insulin sensitivity was comparable. The reason for this is unknown, but an increased sensitivity of the β-cells for glucose might be a reason, or a reduced insulin clearance by the liver. SGA-CU subjects also had a significantly higher AIR compared with controls after the corrections, but their insulin sensitivity was significantly lower. This is a known compensation mechanism to maintain glucose tolerance (9). The significantly higher AIR in ISS subjects might be due to a difference in fat mass, because after the additional correction for fat mass, the significance disappeared.

We determined which factors influence disposition index, because the most important determinant of DMII is β-cell function (8). We applied the MR models on disposition index, but none of the variables appeared to be a significant factor. Also, our subgroups comparison showed no difference in disposition index. It has been shown that a reduction in disposition index and not reduced insulin sensitivity relates to an increased risk of DMII (34). Normally, the β-cells will increase their insulin secretion when insulin sensitivity declines. When the β-cells start to fail, the disposition index, which stands for insulin sensitivity x insulin secretion, will decline. Two studies in SGA-S and SGA subjects showed a reduced insulin sensitivity, but recalculations show that the disposition index was normal, indicating an increased insulin secretion (10, 35). Our present study shows that all four groups had a normal disposition index indicating that all groups had normal functioning β-cells at the age of 21 yr. Thus, the fear that SGA subjects might be at a higher risk of DMII at the age of 21 yr compared with those born AGA could not be substantiated by our study.

We have chosen a study population that consisted of a relatively large percentage of subjects born SGA and of short adults compared with the normal population. This results in a better statistical model because there is more contrast in the study population, so relationships between various factors can be detected with more statistical power. Another advantage of this study population is that it allows comparison between clinically relevant subgroups. Better insight could be obtained in the differences between the subgroups with regard to insulin sensitivity and disposition index, after correction for age, gender, adult size, and fat mass.

In conclusion, our study in 136 young adults shows that adult fat mass is the main predictor of insulin sensitivity in young adulthood, whereas birth length and birth weight had no significant influence on insulin sensitivity. None of these variables had a significant influence on the disposition index. SGA-CU subjects had significantly lower insulin sensitivity compared with controls, after correction for age, gender, adult height, adult weight, and fat mass. No differences in disposition index were found between the subgroups. As a result of our findings, we propose to introduce the fat accumulation hypothesis. For public health practice, this means, that parents of all children, independent of birth size or growth during childhood, should be aware of the risks of fat accumulation in their children. Children at risk for fat accumulation, like SGA-CU subjects, need to be controlled on a regular basis by primary health workers.

	Acknowledgments

 
We thank all participants. We acknowledge the support of many colleagues at the Erasmus University MC Rotterdam, MCRZ Hospital Rotterdam, University MC Nijmegen, Catharina Hospital Eindhoven, Leiden University MC, Juliana Children’s Hospital the Hague, and University Medical Centre Groningen. We thank J. P. Sluimer and P. Kooy of the Department of Nuclear Medicine, Erasmus University MC, and Dr. Hackeng for their support. We greatly acknowledge Mrs. J. Dunk and Mrs. I. van Slobbe, research nurses, for their technical assistance and support with data collection.

	Footnotes

 
This work was supported by Netherlands Organization for Scientific Research (NWO) (A.C.S.H.-K. received the ASPASIA award, Grant 015 000 088) and by grants from Revolving Fund 2001 and Vereniging Trustfonds, Erasmus University Rotterdam, and a grant by the Jan Dekkerstichting/ Dr Ludgardine Bouwmanstiching and the Stichting De Drie Lichten, The Netherlands.

Disclosure Statement: The authors have nothing to disclose.

First Published Online November 27, 2007

Abbreviations: AGA, Appropriate for gestational age; AIR, acute insulin response; DMII, diabetes mellitus type II; DXA, dual-energy x-ray absorptiometry; FSIGT, frequent sampling iv glucose tolerance; ISS, idiopathic short stature; MR, multiple linear regression; SDS, SD score; SGA, short for gestational age; SGA-CU, SGA with catch-up growth; SGA-S, SGA with short adult height; Si, insulin sensitivity.

Received July 11, 2007.

Accepted November 15, 2007.

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