Birth weight of offspring and insulin resistance in late adulthood: cross sectional survey

Introduction

Low birth weight is associated with cardiovascular disease and type 2 diabetes in adulthood, but the mechanisms underlying these associations are unclear.1Poor intrauterine nutrition leads to babies with low birth weight and may programme“ selective changes in body composition, hormonal axes, and metabolism, leading to increased risk of cardiovascular disease in later life.1 Alternatively, the fetal insulinhypothesis suggests that the specific genetic polymorphisms lead to increased insulin resistanceand impaired growth and that these polymorphisms underlie the association between birth weight andcardiovascular disease.2 Studies have shown that low birthweight of offspring is related to an increased risk of cardiovascular disease and diabetes in the parents.3^–10

The relation between low birth weight and later risk of disease in the individual may be explained by a programming effect of the intrauterine environment,1 but the relation between a baby's low birth weight and its parents' risk must have a different explanation: a plausible explanation for these transgenerational associations is that birth weight and cardiovascular disease are linked by a common genetic factor.

No previous study has directly assessed the fetal insulin hypothesis by looking at the association between birth weight of offspring and parental insulin resistance. Mothers with gestational glucose intolerance tend to have heavier babies,10 and since these mothers are more likely to be insulin resistant and to develop diabetes later in life,11 the expectation is of a positive correlation between birth weight of offspring and maternal insulin resistance. If an inverse association between birth weight of offspring and parental insulin resistance exists, particularly in mothers, it would support the fetal insulin hypothesis. We investigated the associations between offspring birth weight and maternal insulin resistance in late adulthood.

Participants and methods

The British women's heart and health study is a sample of 60-79 year old women, randomly selected from general practitioners' lists in 23 towns in Great Britain. We selected towns, general practitioners, and participants in the same way as for the British regional heart study of men.12 Of the 7143 women invited, 4286 (60%) participated. We collected baseline data (via questionnaires, interviewing by a research nurse, and examinations) between April 1999 and March 2001. Ethics committee approval was obtained for the British women's heart andhealth study.

Details of all measurements are published elsewhere.13 Participants were asked how many pregnancies and live births they had experienced. We asked women with at least one live birth to provide the sex and birth weight of their first born child. We took fasting blood samples and estimated insulin resistance with the homoeostasis model assessment (the product of fasting glucose and insulin concentrations (in mmol/l) divided by 22.5).14 We considered women with a clinical diagnosis of diabetes and women with a fasting glucose concentration of 8 mmol/l to have diabetes, for the purpose of this study. Homoeostasis model assessment scores are not valid for these women, and were not calculated.14

Results

Of the 4286 women who participated, 3849 (90%) provided obstetric details. Of the 3456 (90%) women who had had at least one live birth, 3289 (94%) provided their firstborn's birth weight. For 24 women, birth weight of offspring was less than 1.5 kg; they were excluded. Of the 3265 women with offspring birth weight included in the analysis 1635 (50.1%) of the children were male with a mean birth weight of 3.38 (SD 0.53) kg and 1630 (49.9%) were female with a mean birth weight of 3.24(0.51) kg. A total of 169 (5.2%) women had been diagnosed with diabetes by a doctor and 41 (1.3%) had a glucose concentration after fasting of 8 mmol/l.

The table gives the relations between birth weight of offspring and age adjusted insulin resistance scores and other risk factors for cardiovascular disease, together with regression coefficient or odds ratios for each variable per kilogram difference in offspring birth weight. Women who had heavier babies were less resistant to insulin, had lower systolic blood pressure, had a higher body mass index, were less likely to smoke, and were more likely to belong to non-manual social classes both in childhood and adulthood.

Offspring birth weight was not linearly associated with maternal diabetes prevalence; women who had had babies with birth weights in the lowest and highest quarters were most likely to be diabetic in older age. When a quadratic term for birth weight of offspring was fitted, this model suggested a non-linear association (P=0.08). The relation between diabetes prevalence and birth weight of offspring was unaffected by control for current body mass index. The inverse relation between offspring birth weight and maternal insulin resistance contradicted the positive relation between birth weight of offspring and maternal body mass index. For each increase of 1 kg to offspring birth weight, the logarithm of the insulin resistance scores fell by 0.04, whereas body mass index (weight (kg)/(height (m)²) increased by 0.74.

The odds of maternal insulin resistance (top quarter of birth weights compared with all other participants, adjusted by age) decreased with increasing birth weight of offspring (odds ratio 0.85; 95% confidence interval 0.71 to 1.00). For each 1 kg increase in birth weight, after adjustment for body mass index alone, the odds of high maternal insulin resistance fell by 27% (odds ratio 0.73;0.60 to 0.87), and there was no further change after full adjustment for a wide range of other potential confounders (systolic blood pressure, diastolic blood pressure, high density lipoproteincholesterol, low density lipoprotein cholesterol, triglycerides, smoking status, adult social class, childhood social class). Because body mass index is positively related to insulin resistance (Pearson's correlation coefficient 0.43; 0.40 to 0.46) and also to birth weight of offspring, it acts as an important negative confounder between birth weight of offspring and maternal insulin resistance. The fully adjusted regression coefficient for the insulin resistance log scores and the birth weight of offspring was −0.08 (−12 to −0.04) per kilogram of offspring birth weight, compared with −0.04 (−0.08 to −0.01) per kilogram of offspring birth weight, for the coefficient adjusted for age. Adjustment for age and body mass index alone essentially produced the same findings as full adjustment (−0.08; −0.13 to −0.04) per kilogram of offspring birth weight.

Discussion

Birth weight of offspring is inversely related to maternal insulin resistance in later life. This supports the fetal insulin hypothesis, which says that genetic factors related to both insulin resistance and birth weight explain at least part of the relation between birth weight and risk ofadult cardiovascular disease and diabetes.2

We expected birth weight of offspring to be positively associated with maternal insulin resistance in later life, since maternal gestational diabetes is associated with increased birth weight of offspring and also with maternal diabetes in later life. 11 15Although the proportion of women with gestational diabetes may be insufficient to account for a population effect on the distribution of birth weight, there is evidence that gestational glycaemia across the population distribution (rather than a simple diabetic threshold effect) is positively associated with offspring birth weight and insulin resistance and frank diabetes in the mother in later life. 10 11 16 Our results are contrary to this expectation and provide important support for the fetal insulin hypothesis. Definitive support of this hypothesis requires the identification of genes that are associated with both low birth weight and insulin resistance. Although there is some evidence for potential genes,further research is required in this area. 2 17 18