Abstract
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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Hales, C.N. et al. Fetal and infant growth and impaired glucose tolerance at age 64. B.M.J. 303, 1019–1022 ( 1991).
Phipps, K. et al. Fetal growth and impaired glucose tolerance in men and women. Diabetologia 36, 225–228 (1993).
Yajnik, C.S. et al. Fetal growth and glucose and insulin metabolism in four-year-old Indian children . Diabet. Med. 12, 330– 336 (1995).
Law, C.M., Gordon, G.S., Shiell, A.W., Barker, D.J. & Hales, C.N. Thinness at birth and glucose tolerance in seven-year-old children. Diabet. Med. 12, 24– 29 (1995).
Lithell, H.O. et al. Relation of size at birth to non-insulin dependent diabetes and insulin concentrations in men aged 50-60 years. B.M.J. 312, 406 –410 (1996).
Clausen, J.O., Borch-Johnsen, K. et al. Relation between birth weight and the insulin sensitivity index in a population sample of 331 young, healthy Caucasians. Am. J. Epidemiol. 146, 23–31 (1997).
Hales, C.N. The pathogenesis of NIDDM. Diabetologia 37, S162– 168 (1994).
Barker, D.J. Intrauterine programming of adult disease. Mol. Med. Today 1, 418–423 (1995).
Byrne, M.M. et al. Insulin secretory abnormalities in subjects with hyperglycemia due to glucokinase mutations. J. Clin. Invest. 93, 1120– 1130 (1994).
Randle, P.J. Glucokinase and candidate genes for type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 36, 269–275 (1993).
Froguel, P. et al. Close linkage of glucokinase locus on chromosome 7p to early-onset non-insulin-dependent diabetes mellitus. Nature 356, 162– 164 (1992).
Hattersley, A.T. et al. Linkage of type 2 diabetes to the glucokinase gene. Lancet 339, 1307–1310 (1992).
Froguel, P. et al. Familial hyperglycemia due to mutations in glucokinase. Definition of a subtype of diabetes mellitus. N. Engl. J. Med. 328, 697–702 (1993).
Velho, G. et al. Primary pancreatic beta-cell secretory defect caused by mutations in glucokinase gene in kindreds of maturity onset diabetes of the young. Lancet 340, 444–448 ( 1992).
Velho, G. et al. Impaired hepatic glycogen-synthesis in glucokinase-deficient (MODY2) subjects . J. Clin. Invest. 98, 1755– 1761 (1996).
Tanner, J.M. & Thomson, A.M. Standards for birth weights at gestation periods from 32 to 42 weeks, allowing for maternal height and weight . Arch. Dis. Child. 45, 566– 569 (1970).
Wright, N.M., Metzger, D.L., Borowitz, S.M. & Clarke, W.L. Permanent neonatal diabetes mellitus and pancreatic exocrine insufficiency resulting from congenital pancreatic agenesis. Am. J. Dis. Child. 147, 607–609 (1993).
Stoffers, D.A., Zinkin, N.T., Stanojevic, V., Clarke, W.L. & Habener, J.F. Pancreatic agenesis attributable to a single nucleotidedeletion in the human IPF1 gene coding sequence. Nature Genet. 15, 106–110 (1997).
Donohue, W.L. & Uchida, I.A. Leprechaunism: a euphenism for a rare familial disorder. J. Pediat. 45, 505–519 (1954).
Elsas, L.J., Endo, F., Strumlauf, E., Elders, J. & Priest, J.H. Leprechaunism: an inherited defect in a high-affinity insulin receptor. Am. J. Hum. Genet. 37, 73–88 (1985).
Pederson, J. The Pregnant Diabetic and Her New Born: Problems and Management (Williams & Wilkins, Baltimore, 1977).
Barker, D.J.P., Bull, A.R., Osmond, C. & Simmonds, S.J. Fetal and placental size and risk of hypertension in adult life. B.M.J. 301, 259–262 (1990).
Barker, D.J.P., Godfrey, K.M., Osmond, C. & Bull, A. The relation of fetal length, ponderal index and head circumference to blood pressure and the risk of hypertension in adult life. Paediatr. Perinat. Epidemiol. 6, 35–44 ( 1992).
Beards, F.E., Ellard, S., Appleton, M., Harvey, R. & Hattersley, A.T. Selective genetic screening in gestational diabetes: glucokinase mutation detection in patients with gestational diabetes selected on phenotypic criteria. Diabetic Medicine ( 1998).
Stoffel, M. et al. Missense glucokinase mutation in maturity-onset diabetes of the young and mutation screening in late-onset diabetes. Nature Genet. 2, 153–156 (1992).
Stoffel, M. et al. Human glucokinase gene: isolation, characterization, and identification of two missense mutations linked to early-onset non-insulin-dependent. Proc. Natl Acad. Sci. USA 89, 7698– 7702 (1992).
Frayling, T. et al. Mutations in the Hepatocyte Nuclear Factor 1 Alpha gene are a common cause of maturity-onset diabetes of the young in the United Kingdom. Diabetes 46, 720–725 ( 1997).
Acknowledgements
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.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/953
This article is cited by
-
A comprehensive map of human glucokinase variant activity
Genome Biology (2023)
-
The influence of insulin-related genetic variants on fetal growth, fetal blood flow, and placental weight in a prospective pregnancy cohort
Scientific Reports (2023)
-
Low birthweight is associated with a higher incidence of type 2 diabetes over two decades independent of adult BMI and genetic predisposition
Diabetologia (2023)
-
Bringing precision medicine to the management of pregnancy in women with glucokinase-MODY: a study of diagnostic accuracy and feasibility of non-invasive prenatal testing
Diabetologia (2023)
-
Study of ten causal genes in Turkish patients with clinically suspected maturity-onset diabetes of the young (MODY) using a targeted next-generation sequencing panel
Molecular Biology Reports (2022)