MUTATIONS IN THE GLUCOKINASE GENE OF THE FETUS RESULT IN REDUCED BIRTH-WEIGHT

Low birth weight and fetal thinness have been associated with non-insu lin dependent diabetes mellitus (NIDDM) and insulin resistance in chil dhood and adulthood(1-6). It has been proposed that this association r esults from fetal programming in response to the intrauterine environm ent(7,8). An alternative explanation is that the same genetic influenc es alter both intrauterine growth and adult glucose tolerance. Fetal i nsulin 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 gl ucose by the pancreas, caused by a heterozygous mutation in the glucok inase gene(9), could reduce fetal growth and birth weight in addition to causing hyperglycaemia after birth. In 58 offspring, where one pare nt has a glucokinase mutation, the inheritance of a glucokinase mutati on 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 gluco kinase mutation, the child with the mutation had a lower birth weight, with a mean difference of 521 g (P=0.0002). Maternal hyperglycaemia d ue to a glucokinase mutation resulted in a mean increase in birth weig ht of 601 g (P=0.001). The effects of maternal and fetal glucokinase m utations on birth weight were additive. We propose that these changes in birth weight reflect changes in fetal insulin secretion which are i nfluenced directly by the fetal genotype and indirectly, through mater nal hyperglycaemia, by the maternal genotype. This observation suggest s that variation in fetal growth could be used in the assessment of th e role of genes which modify either insulin secretion or insulin actio n.