Low birth weight and fetal thinness have been associated with non-insulin dependent diabetes mellitus (NIDDM) and insulin resistance in childhood and adulthood1,2,3,4,5,6. It has been proposed that this association results from fetal programming in response to the intrauterine environment7,8. An alternative explanation is that the same genetic influences alter both intrauterine growth and adult glucose tolerance. Fetal insulin secretion in response to maternal glycaemia plays a key role in fetal growth, and adult insulin secretion is a primary determinant of glucose tolerance. We hypothesized that a defect in the sensing of glucose by the pancreas, caused by a heterozygous mutation in the glucokinase gene9, could reduce fetal growth and birth weight in addition to causing hyperglycaemia after birth. In 58 offspring, where one parent has a glucokinase mutation, the inheritance of a glucokinase mutation by the fetus resulted in a mean reduction of birth weight of 533 g (P = 0.002). In 19 of 21 sibpairs discordant for the presence of a glucokinase mutation, the child with the mutation had a lower birth weight, with a mean difference of 521 g (P = 0.0002). Maternal hyperglycaemia due to a glucokinase mutation resulted in a mean increase in birth weight of 601 g (P = 0.001). The effects of maternal and fetal glucokinase mutations on birth weight were additive. We propose that these changes in birth weight reflect changes in fetal insulin secretion which are influenced directly by the fetal genotype and indirectly, through maternal hyperglycaemia, by the maternal genotype. This observation suggests that variation in fetal growth could be used in the assessment of the role of genes which modify either insulin secretion or insulin action.
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We thank all the families and physicians who took part, particularly A. Milward, T. Harvey, R. Mann, R. Turner, D. Matthews, M. Gillmer, D. Dunger, J. Perkin, R. Sturley and K. Macleod. We acknowledge the technical help and support of S. Ayres, L. Allen, M. Bulman, M. Boyce, S. Corbett, T. Frayling, D. Jarvis, M. Goddard, C. Sandercock and K. Walters. We thank J. Welsman and A. Shore for their guidance on statistical analysis. The study was funded by the British Diabetic Association, Medical Research Council, Northcott Devon Medical foundation, DIRECT, the Royal Devon and Exeter NHS Healthcare trust, University of Exeter and PPP Healthcare.
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Hattersley, A., Beards, F., Ballantyne, E. et al. Mutations in the glucokinase gene of the fetus result in reduced birth weight. Nat Genet 19, 268–270 (1998). https://doi.org/10.1038/953
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