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PEDIATRICS Vol. 113 No. 1 January 2004, pp. 82-86

Girls at Five Are Intrinsically More Insulin Resistant Than Boys: The Programming Hypotheses Revisited—The EarlyBird Study (EarlyBird 6)

Michael J. Murphy, MRCPath*, Brad S. Metcalf, BSc{ddagger}, Linda D. Voss, PhD{ddagger}, Alison N. Jeffery, RGN{ddagger}, Joanne Kirkby, BSc{ddagger}, Katie M. Mallam, MRCPCH{ddagger} and Terence J. Wilkin, MD{ddagger}

* Department of Molecular and Cellular Pathology, University of Dundee, Dundee, United Kingdom
{ddagger} Peninsula Medical School, Plymouth, United Kingdom


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Objective. Recent studies of type 2 diabetes in young populations consistently show a predominance of affected girls over boys. Girls are more insulin resistant than boys. We aimed in the present report to establish how much of the sex difference in insulin resistance is intrinsic.

Methods. EarlyBird is a community-based, nonintervention cohort study of 307 healthy children from school entry at age 5 years. It asks the question: which children are insulin resistant and why? Anthropometric measures, physical activity, resting energy expenditure, and insulin resistance and its metabolic correlates were measured.

Results. At 5 years, insulin resistance was 35% higher in girls than in boys. Girls carried 26% more subcutaneous fat despite similar body weights. However, after correcting for anthropometric variables and physical activity, girls remained 33% more insulin resistant than boys. Triglycerides were significantly higher in girls, and high-density lipoprotein cholesterol and sex hormone-binding globulin were significantly lower.

Conclusions. Sex-linked genes may account for the intrinsic sex difference observed. These genes may have an important impact on the development of insulin resistance and the metabolic syndrome and may help to explain the female preponderance of type 2 diabetes in children. Their identification may also help in understanding the pathogenesis of insulin resistance.

Key Words: type 2 diabetes • insulin resistance • sex difference • programming • sex-linked genes

Abbreviations: BMI, body mass index • SD, standard deviation • REE, resting energy expenditure • HOMA-IR, homeostasis model assessment, insulin resistance • SHBG, sex hormone-binding globulin • HDL, high-density lipoprotein

Type 2 diabetes is becoming a global public health problem.1 The World Health Organization predicts a rise in prevalence of type 2 diabetes during the 30 years 1995–2025 of 40% (from 51 million to 72 million) among industrialized nations and of 170% (from 84 million to 228 million) in the industrializing world.2 A key issue surrounding the rising prevalence of type 2 diabetes is its progressively younger age at presentation. A disease that, a generation ago, was considered as "adult," "late," or "maturity" onset diabetes is now presenting in children.3,4 The emergence of type 2 diabetes in recent years in youths has paralleled a rising prevalence of obesity and of insulin resistance and its associated risk factors during childhood and adolescence.5–8

A consistent feature of recent studies of type 2 diabetes in young populations is the predominance of affected girls over boys9–17 (Table 1). Several studies have shown that girls are more insulin resistant than boys during puberty and adolescence,18–20 and there are recent reports of similar findings in overweight children aged between 5 and 10 years.21 In some of these studies, the observed sex difference in insulin resistance can be explained partly by sex differences in adiposity or pubertal stage,18,19,21 but a residual difference remains after correction for these factors. In a study of school children in Taiwan (age range: 12–16 years), fasting insulin was lower in boys despite their greater body mass index (BMI).20 Such observations are consistent with the possibility that girls may be intrinsically more insulin resistant than boys, although the basis of such a difference is unclear. In the present study of healthy 5-year-old children in the United Kingdom, we sought to investigate this possibility by correcting for factors that influence insulin resistance.


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  		TABLE 1. Reported Sex Ratios in Studies of Type 2 Diabetes in Children and Adolescents

 

   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Study Design and Recruitment
EarlyBird is a nonintervention prospective cohort study that aims to establish which children are insulin resistant and why. It is monitoring 307 healthy children from school entry at age 4/5 years to the age of 16. All Plymouth primary schools were identified, and their head teachers were asked for agreement to participate in the study. The 56 schools that consented were stratified into quartiles according to the proportion of pupils entitled to free school meals as a socioeconomic proxy, and a random selection of each was made. Registration into the study was invited during parent induction meetings for school entry, and parents who expressed interest were given a full written explanation of the study. Exclusion criteria were diabetes, pathologic states likely to affect growth or body composition, moderate or severe physical disability, and long-term use of oral steroids. With the parents’ written consent, a total of 307 children became the EarlyBird cohort. The study was approved by the Local Research Ethics Committee in 1999.

Study Population
The 137 girls and 170 boys were matched for age by their school entry status (mean age ± standard deviation [SD]: girls, 4.9 ± 0.30 years; boys, 4.9 ± 0.27 years; P = .46) and for socioeconomic status by their randomization: the proportion of girls drawn from the 4 school socioeconomic status groupings (lowest to highest) was 23%, 25%, 33%, and 20%, respectively, and the proportion of boys was 20%, 23%, 32%, and 25%, respectively (P ≥ .40 for each comparison).

Procedures
All measurements were made by the same team of researchers. Anthropometry is repeated on the children at 6 months and all other assessments annually. The baseline studies reported here began in January 2000 and were completed in June 2001.

Baseline assessments incorporated anthropometry, physical activity, and resting energy expenditure (REE), as well as insulin resistance and its metabolic correlates. DNA was archived. Anthropometric measures included height and weight (BMI), waist circumference, and subcutaneous fat mass as the sum of skinfold thickness measured by caliper at 5 sites (supra-iliac, biceps, triceps, subscapular, and para-umbilical). Indirect calorimetry was used to measure REE by gas exchange monitor (Nutrem, Manchester, UK). Test-retest correlations over 12 months (r = .54, P < .001) suggest metabolic stability in individual children. Physical activity was assessed by piezo-electric accelerometers (Computer Science & Applications Inc, Shalimar, FL). Each device measures changes in acceleration 10 times per second and was worn by the child continuously during waking hours for 7 consecutive days. Data were downloaded onto a PC for storage and analysis. Physical activity was deduced from the area under the curve over a specified time period. Test-retest correlations 12 months apart were high (r = .44, P < .001) suggesting that, as with REE, children are consistent in their physical activity over long periods. Standardized food frequency questionnaires were completed. Precision data were obtained for all measures. The height, weight, and BMI standards used throughout are those set for the United Kingdom in 1990.

Laboratory Measurements
Insulin resistance was assessed by the homeostasis model method (HOMA-IR),22 based on fasting glucose and insulin concentrations. The use of this method in epidemiologic studies has been validated.23,24 Insulin and sex hormone-binding globulin (SHBG) were measured by immunometric assay on a Diagnostic Products Corp Immulite analyser (Los Angeles, CA). Glucose, cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, and uric acid were measured on a Cobas Integra 700 analyzer (Roche Diagnostics, Lewes, East Sussex, UK).


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Anthropometry
Baseline anthropometric data are shown in Table 2. The mean weights of girls and boys were similar, but girls were of slightly greater BMI. Girls had gained significantly more excess weight since birth (crossed more centiles) than boys (weight at 5 years: 0.38 SD score for girls; 0.03 SD score for boys). Girls also carried more subcutaneous fat, the difference persisting after correction for height. Waist circumference corrected for height was significantly greater in girls.


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  		TABLE 2. Subject Characteristics by Sex

 
Anthropometry and Insulin Resistance
Insulin resistance (log-transformed HOMA-IR) was 34.6% greater in the girls than in the boys. Significant correlations between HOMA-IR and anthropometric variables were observed in both sexes and are summarized in Table 3. Height, weight, and waist circumference correlated significantly with HOMA-IR in girls and in boys, and BMI correlated significantly with HOMA-IR in girls only.


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  		TABLE 3. Correlations of Anthropometric Measures With Insulin Resistance (Log HOMA-IR)

 
Physical Activity and Insulin Resistance
Physical activity was categorized into high, medium, and low intensities according to cutpoints representing sedentary activity, walking, and running. Compared with girls, boys took more medium- and high-intensity physical activity but less low-intensity physical activity. However, no significant correlation was observed in either sex between any category or combination of categories of physical activity and insulin resistance (Table 2).

REE and Insulin Resistance
There were clear positive correlations between REE and current weight in both sexes (girls: r = .57, P < .01; boys: r = .50, P < .01) and between REE and BMI (girls: r = .46, P < .01; boys: r = .39, P < .01). Although their BMI was significantly higher, the REE of girls was significantly lower than that of boys (Table 2). REE did not significantly correlate with insulin resistance, independent of current weight, in either sex (girls: r = –.05, P = .66; boys: r = –.14, P = .15).

Covariate Analysis
We added each of the measures in turn to the analysis of covariance model to establish the residual difference that might remain in insulin resistance between the sexes as a result (Table 4). Subcutaneous fat, BMI, waist circumference, and weight all were higher in the girls, and inclusion of each in the equation reduced the sex difference in insulin resistance. REE, physical activity, and height all were lower in the girls. The first 2 had little effect, but after height was included, the adjusted sex difference (33.2%) was similar to what it had been before adjustment (34.6%). In short, the combined impact of all covariates on the difference in insulin resistance between 5-year-old girls and boys was negligible.


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  		TABLE 4. Impact of Anthropometric Variables and PA Levels on the Sex Difference in Insulin Resistance

 
Impact of Insulin Resistance on Its Metabolic Correlates
Baseline laboratory data are shown in Table 2. Fasting concentrations of insulin were higher in the girls. Triglycerides were significantly higher in the girls, and HDL cholesterol and SHBG were lower. No other significant sex differences were observed in the metabolic correlates of insulin resistance or in glucose concentrations.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
We used EarlyBird, a prospective cohort study of healthy prepubertal children, to investigate more fully previous suggestions of sex diversity in insulin resistance in young populations.18–21 We examined factors that might influence insulin resistance, as well as the impact of insulin resistance on metabolic health. We found important differences between the sexes. Girls were substantially more insulin resistant than boys. Moreover, they had higher concentrations of triglycerides and lower concentrations of HDL cholesterol and SHBG, suggesting that the metabolic disturbances are more advanced in girls even at this early age. The difference in insulin resistance may help to account for the predominance of affected girls over boys in recent studies of type 2 diabetes in young populations.

The sex difference in insulin resistance could be explained partly by differences in individual anthropometric variables. Compared with boys, girls had significantly greater BMI, waist circumference, and subcutaneous fat. When introduced as a covariate, each of these measures reduced the sex difference in insulin resistance. Most were co-correlated, however, so that their inclusion together added little to the dominant effect of subcutaneous fat. By contrast, height in girls correlated positively with insulin resistance independent of measures of fatness. The girls were shorter than the boys, and when height was included in the analysis of covariance, the adjusted sex difference in insulin resistance was similar to what it had been before adjustment (Table 4).

Physical activity reduces insulin resistance independent of body fatness in adults25 but did not seem to influence insulin resistance in our children despite a 2.6-fold variation in the levels of activity observed. The boys were significantly more active than the girls, but correction for physical activity had no impact on the sex difference in insulin resistance. There are 3 possible explanations. First, the accelerometers may not record whatever aspect of physical activity most influences insulin resistance. This seems unlikely in light of the published validation data26; comparison of energy expenditure scores recorded by the Computer Science and Applications monitor and indirect calorimetry gives impressive correlation, with coefficients ranging from 0.82 to 0.94.27,28 Second, it may be that the activity undertaken by the children was simply not sufficient to influence insulin resistance. The EarlyBird children, like many in the modern industrialized world, are sedentary for long periods of the day. Finally, we sampled only 7 days of activity, which may not be a representative sample. However, the year-on-year reproducibility of 7-day accelerometer recordings in the same children is good, with a test-retest correlation of r = .47 (P < .01).

We found no association between insulin resistance and REE, independent of current weight. REE was strongly and positively correlated with body mass in the EarlyBird children, as it is in adults, reflecting the metabolic activity of the greater muscle mass that heavier individuals develop. However, the REE of girls was significantly lower than that of boys, despite their significantly higher BMI. This is consistent with the higher proportion of fat known to contribute to the body composition of girls.29

In the absence of other known covariates, these findings suggest that girls at 5 years are intrinsically more insulin resistant than boys. "Intrinsic" in this context suggests programming, either gestational or genetic, and metabolic programming has been a focus of intense interest for more than a decade. The gestational programming hypotheses30,31 propose that undernutrition in fetal life results in permanent alterations in the structure and function of ß cells and/or other cells and tissues. Low birth weight acts as a marker of interference with fetal growth. The fetal insulin hypothesis32 proposes instead that insulin resistance is genetically programmed, and low birth weight is seen as evidence of reduced fetal response to insulin. According to the thrifty genotype hypothesis,33 insulin resistance is a secondary phenomenon, resulting from excessive production of insulin antagonists in response to genetically programmed overproduction of insulin. Low birth weight is not a feature.

Although observations suggest that poor fetal growth and low birth weight were undoubtedly associated with insulin resistance in the past, it is increasingly difficult to reconcile this explanation with the rise of both insulin resistance and birth weight in contemporary populations. We have reported elsewhere the relationships between insulin resistance, current weight, "catch-up" weight, and birth weight in the EarlyBird cohort and find that current weight best explains the variance of insulin resistance in contemporary children in both sexes; birth weight has no detectable influence on insulin resistance, and "catch-up" weight is merely a co-correlate of current weight.34 There is, furthermore, a specific difficulty in attempting to reconcile the existence of an intrinsic sex difference in insulin resistance with gestational hypotheses. Why should the undernutrition, which leads to gestational programming, discriminate between the sexes or be associated per se with sex differences in either birth weight or insulin resistance? Of course, sex differences may exist in the response to undernutrition, but such differences would themselves be programmed—by genes.

We propose that young girls are intrinsically more insulin resistant than boys for genetic reasons and that the gene(s) in question is/are sex linked. Genetic data that are consistent with this version of the fetal insulin hypothesis are already emerging. The GENNID (Genetics of NIDDM) study, a genome-wide search for type 2 diabetes susceptibility genes, has identified several chromosomal regions linked to diabetes and impaired glucose tolerance.35 One of the regions identified was on the X chromosome (X-chromosome map position 130 cM, LOD score 2.99). Insulin resistance genes of the kind we envisage could affect the mother or her female offspring or both—but not her male offspring. Fetal growth is controlled largely by the fetal insulin response to maternal glucose. Mildly hyperglycemic insulin-resistant mothers will confer higher birth weight on their genetically unaffected male offspring, which may have offered a survival advantage during evolution, and pass on insulin resistance to their genetically affected female offspring, perpetuating the insulin-resistant state—and with it the tendency to be born lighter.

In conclusion, we present evidence that prepubertal girls are intrinsically more insulin resistant than boys. The programming hypotheses were formulated primarily to explain differences in insulin resistance within the sexes but in light of the present findings must also be able to explain differences between the sexes. We suggest that sex-linked genes may explain this intrinsic difference. The nature of these genes is unclear, but they may have an important impact on the development of insulin resistance and the metabolic syndrome.


   ACKNOWLEDGMENTS
 
We are grateful to Roche Products, Smith’s Charity, Child Growth Foundation, London Law Trust, and Eli Lilly for generous support of this study.


   FOOTNOTES
 
Received for publication Dec 4, 2002; Accepted Mar 24, 2003.

Address correspondence to Terence J. Wilkin, MD, University Medicine, Level 7, Derriford Hospital, Plymouth PL6 8DH, United Kingdom. E-mail: t.wilkin{at}pms.ac.uk


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PEDIATRICS (ISSN 1098-4275). ©2004 by the American Academy of Pediatrics



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