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.

Phenotypic selection of subjects with gestational diabetes greatly increases the likelihood of detecting a mutation in the glucokinase gene as previous studies have suggested a prevalence of 2.5% (range 0-6%). Our study in gestational diabetes to successfully used clinical criteria to assist in the definition of a genetic subgroup.

Familial glucocorticoid deficiency is an autosomal recessive syndrome of adrenal unresponsiveness to ACTH characterized by glucocorticoid deficiency, high plasma ACTH levels, and a normal renin-aldosterone axis. Defects of the ACTH receptor have been suggested as a possible cause, and we have previously reported a number of novel mutations of the ACTH receptor gene in some, but not all, cases, suggesting that familial glucocorticoid deficiency may have a heterogeneous molecular etiology. Here we report the clinical features and ACTH receptor gene analysis in four patients from different families. We found that two patients were compound heterozygotes for the S74I and R128C mutations (patient A) and I44M and L192fs frame shift mutations (patient B). The other two patients (C and D) were of different ethnic ancestry, but were both homozygous for a R146H mutation. Segregation studies within families revealed heterozygosity in the parents and several other family members. Human CRH tests in the parents of patients A and B showed normal cortisol and ACTH responses in the S74I, R128C, and I44M heterozygotes and exaggerated cortisol and ACTH responses in the L192fs heterozygote, suggesting that the physiological ACTH increment induced in this test did not reveal evidence of subclinical ACTH resistance, and that this test may not be of value in ascertaining heterozygosity.

The most common cause of maturity-onset diabetes of the young (MODY) is a mutation in the hepatic nuclear factor 1α (HNF1α) gene (MODY3). We describe a family in which a missense mutation causing a Thr-Ile substitution at codon 620 has been found in all affected members. The mutation is not fully penetrant as two family members aged 87 and 46 have the mutation but do not have diabetes. The severity and age of diagnosis of diabetes varies widely within the family, and most presented over the age of 25. HNF1α mutation screening should be considered in any family with autosomal dominant inheritance of diabetes where one member has presented with diabetes before the age of 25. Predictive testing is now possible within the majority of MODY families, and is of clinical benefit, but the possibility of non-penetrance should be addressed during counselling and interpretation of results.