Abstract
Heterozygous loss-of-function variants of the glucokinase (GCK) gene are responsible for a subtype of maturity-onset diabetes of the young (MODY). GCK-MODY is characterized by a mild hyperglycemia, mainly due to a higher blood glucose threshold for insulin secretion, and an up-regulated glucose counterregulation. GCK-MODY patients are asymptomatic, are not exposed to diabetes long-term complications, and do not require treatment. The diagnosis of GCK-MODY is made on the discovery of hyperglycemia by systematic screening, or by family screening. The situation is peculiar in GCK-MODY women during pregnancy for three reasons: 1. the degree of maternal hyperglycemia is sufficient to induce pregnancy adverse outcomes, as in pregestational or gestational diabetes; 2. the probability that a fetus inherits the maternal mutation is 50% and; 3. fetal insulin secretion is a major stimulus of fetal growth. Consequently, when the fetus has not inherited the maternal mutation, maternal hyperglycemia will trigger increased fetal insulin secretion and growth, with a high risk of macrosomia. By contrast, when the fetus has inherited the maternal mutation, its insulin secretion is set at the same threshold as the mother’s, and no fetal growth excess will occur. Thus, treatment of maternal hyperglycemia is necessary only in the former situation, and will lead to a risk of fetal growth restriction in the latter. It has been recommended that the management of diabetes in GCK-MODY pregnant women should be guided by assessment of fetal growth by serial ultrasounds, and institution of insulin therapy when the abdominal circumference is ≥ 75th percentile, considered as a surrogate for the fetal genotype. This strategy has not been validated in women with in GCK-MODY. Recently, the feasibility of non-invasive fetal genotyping has been demonstrated, that will improve the care of these women. Several challenges persist, including the identification of women with GCK-MODY before or early in pregnancy, and the modalities of insulin therapy. Yet, retrospective observational studies have shown that fetal genotype, not maternal treatment with insulin, is the main determinant of fetal growth and of the risk of macrosomia. Thus, further studies are needed to specify the management of GCK-MODY pregnant women during pregnancy.
Highlights
Heterozygous pathogenic variants of the glucokinase (GCK) gene are associated with an autosomal dominant monogenic diabetes called GCK-maturity-onset-diabetes of the young (GCKMODY)
A longitudinal study suggested that the deterioration of glucose tolerance observed in some GCK-MODY patients was due to a decrease in insulin sensitivity, which could be related to aging, weight gain, and/or polygenic susceptibility [32]
GCK-MODY is a quasi-experimental human model that allowed to define the respective roles of maternal hyperglycemia and fetal genotype on fetal growth, and to confirm the central role of fetal insulin secretion in fetal growth
Summary
Heterozygous pathogenic variants of the glucokinase (GCK) gene are associated with an autosomal dominant monogenic diabetes called GCK-maturity-onset-diabetes of the young (GCKMODY). The GCK-MODY phenotype is restricted to a mild hyperglycemia that usually does not require any treatment. During pregnancy, the glucose levels of GCK-MODY mothers are high enough to potentially generate adverse outcomes similar to those observed in other forms of pregestational or gestational diabetes. The goal of the present review is to summarize current knowledge and challenges about this condition, its diagnosis, and its treatment during pregnancy. The literature was searched using the terms “glucokinase” or “GCK-MODY” or “MODY2” and “pregnancy”, and all clinical publications were reviewed. Single case reports were not retained, unless they provided important information (e.g. the occurrence of congenital malformations)
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