Monogenic Causes of Diabetes : Glucokinase MODY and pregnancy
المؤلف:
Holt, Richard IG, and Allan Flyvbjerg
المصدر:
Textbook of diabetes (2024)
الجزء والصفحة:
6th ed , page 280-281
2025-12-14
38
Clinical features
Women with GCK variants are frequently found to have hyperglycaemia during screening in pregnancy and represent 2% of white European women with gestational diabetes. Their identification is important because they have a different clinical course than others with gestational diabetes. The birth weight of the new born infant will depend on the variant status of both the mother and the fetus (Figure 1). Where only the mother carries the variant, maternal hyperglycaemia may result in increased fetal insulin secretion and growth, causing the fetus to be large for gestational age. Infants that do not inherit the maternal GCK gene variation are at increased risk of macrosomia and its associated obstetric complications. If the fetus inherits the variant from the father, however, birth weight is reduced by approximately 500 g as a result of reduced fetal insulin secretion and insulin- mediated fetal growth. If both mother and fetus have the GCK variant, the two opposing effects are cancelled out and the newborn infant is of normal weight, provided that maternal blood glucose has been left untreated.
Fig1. The centile birth weight of children in families with glucokinase variants. The weight is increased by the presence of a maternal variant and decreased by the presence of a fetal variant. Source: Data from Hattersley et al..
Genetic testing for GCK variants in pregnancy
We recommend testing for GCK variants when a pregnant woman is found to have persistently raised fasting plasma glucose, 5.4 8.3 mmol/l (97–149 mg/dl), both during or outside pregnancy. An absence of family history should not exclude the diagnosis, as asymptomatic hyperglycaemia in a parent may not have been detected. Genetic testing of women with a body mass index (BMI) 5.5 mmol/l (>100 mg/dl) has a sensitivity of 68% and on average 2.7 women will need to be tested to identify one case of GCK MODY.
Management
Women with hyperglycaemia resulting from glucokinase variants are often treated with insulin during pregnancy in an attempt to correct the fasting hyperglycaemia. Fetal genotype, however, is a far greater determinant of fetal birth weight than maternal treatment and insulin appears to have little effect on fetal growth. This probably reflects the difficulty in lowering the blood glucose in women with GCK MODY because of increased counter- regulation. Women stop producing their own insulin and produce counter- regulatory hormones if blood glucose is reduced to normal levels, making successful control of blood glucose with insulin difficult. This results in frequent hypoglycaemic symptoms at non- hypoglycaemic blood glucose concentration and means that large doses of insulin may be required to reduce fasting hyperglycaemia to normal levels. In some cases where the fetus has inherited the variant, intensive insulin treatment has resulted in a low–birth weight child. This is to be expected, as a small baby is seen when the fetus inherits a variant from the father and is born to a normoglycaemic mother.
At present treatment decisions in glucokinase gestational diabetes are related to fetal growth as shown by ultrasound scans, rather than being made solely on maternal glycaemia. If the abdominal circumference is greater than the 75th centile, insulin may be used, but early delivery is the most successful strategy. Testing fetal genotype in utero is not without risk and is not recommended unless amniocentesis or chorionic villus sampling is being under taken for an alternative reason. However, assays to detect cell- free fetal DNA (cffDNA) in maternal serum have recently been developed to allow non- invasive fetal genotyping, which can be used to determine appropriate treatment for maternal hyperglycaemia and identify pregnancies at risk of macrosomia. The test is highly sensitive and specific (86.8% and 100%, respectively), with no reported false positives or false negatives. Further guide lines for the management of pregnancy in individuals with GCK variants are available at www.diabetesgenes.org.
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