Mutations in the glucokinase gene of the fetus result in reduced birth weight

Abstract

Low birth weight and fetal thinness have been associated with non-insulin dependent diabetes mellitus (NIDDM) and insulin resistance in childhood and adulthood. It has been proposed that this association results from fetal programming in response to the intrauterine environment. 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 gene, 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.

Adult BMI and fat distribution but not height amplify the effect of low birthweight on insulin resistance and increased blood pressure in 20-year-old South Africans

“…It has been postulated that genetic factors may play a role in the relationship between birthweight and the adult onset chronic diseases [34][35][36][37][38][39][40][41]. What is unclear, however, is the extent to which genetic factors may impact both on birthweight and subsequent fat accrual in childhood, and the adult outcomes.…”

Insights Into the Biochemical and Genetic Basis of Glucokinase Activation From Naturally Occurring Hypoglycemia Mutations

“…The differences in phenotype begin in utero, SUR1/ Kir6.2-HI babies are born large for gestational age, but the GCK-HI children do not show increased birth weight. In some cases, e.g., family 1, this is because the mother was hypoglycemic during pregnancy [similar to the normal weight seen when the mother and fetus inherit an inactivating mutation, and the baby is normal birth weight (22)]. The treatment of these two forms of HI differs.…”

Low birthweight is associated with specific changes in muscle insulin-signalling protein expression

“…Mutations in the glucokinase gene have been identified, which are associated with a reduced birthweight and the development of maturity-onset diabetes of the young [2]. However, these are rare, and extensive genome-wide scans have thus far failed to identify universal diabetes susceptibility genes/polymorphisms.…”