Raised blood glucose due to heterozygous glucokinase gene mutation (GCK-MODY) diagnosed for the first time in pregnancy: The dilemmas and successful management – Case report and review of literature

Abstract

Glucokinase mutation (GCK-MODY) is frequently misdiagnosed as either type I or type II diabetes mellitus, especially if presented for the first time during pregnancy. Generally GCK-MODY affects 1–2% of individuals with a diagnosis of diabetes. The defect in the glucose sensing mechanism in GCK-MODY results in a higher set point for maintenance of glucose homeostasis. Treatment is not recommended outside the pregnancy; however, in pregnancy, fetal abdominal circumference helps to decide about the likelihood of the fetus having inherited the condition and therefore whether insulin is required in pregnancy. We present a case in which GCK-MODY was diagnosed for the first time after pregnancy; the subsequent pregnancy was uneventful. Genetic testing is mandatory to establish the diagnosis. Here the implications of MODY and its subtypes, along with the pattern of inheritance and management aspects are discussed.

Introduction

Gestational diabetes is one of the most common medical disorders in pregnancy alongside anaemia and hypertensive disorders. It is defined as glucose intolerance that develops or is recognised for the first time during pregnancy. It is not uncommon for type 2 or even type 1 diabetes to be recognised for the first time in pregnancy. Maturity-onset diabetes of the young related to a glucokinase gene mutation (GCK-MODY) may rarely be detected for the first time in pregnancy.¹ When first detected during pregnancy, it may be misdiagnosed as gestational diabetes mellitus (GDM). However, these women may not respond to the usual treatment modalities for gestational diabetes. A case of a pregnant woman with a glucokinase mutation identified between her first and second pregnancies is described here. The contrasting management in her two pregnancies illustrates the difficulties of managing unrecognised GCK-MODY in pregnancy.

Case details

A 28-year-old woman in her second pregnancy presented to our department at 24 weeks of gestation. A diagnosis of GCK-MODY had been made following her first pregnancy. She had high fasting blood glucose values between 6.7 mmol/L and 7.1 mmol/L at the time of presentation. Her previous pregnancy had been managed at a different hospital. She had been diagnosed with GDM at 28 weeks in her first pregnancy based on a 75 gm oral glucose tolerance test (OGTT) (fasting – 7.1 mmol/L, 1 h – 10.5 mmol/L and 2 h – 8.2 mmol/L) and she had been treated with insulin as well as dietary modification. Despite the use of increasing insulin doses of up to 80 units (1.2 u/kg of insulin per day), it had been difficult to achieve normal blood glucose throughout the pregnancy. Fetal growth restriction (FGR) was identified (the fetus was on the third centile), and an elective caesarean section was performed at 36 weeks of gestation. A live female infant was delivered, with a birthweight of 2.38 kg and an APGAR score at 5 min of 8. There was no neonatal hypoglycaemia, respiratory distress or any problem which required admission to the neonatal intensive care unit. Her blood glucose level did not come down postnatally as expected in cases of GDM and hence she was evaluated for GCK-MODY. Genetic analysis revealed that there was genetic variation in C.761A>G localised to exon 9 (Asn254Ser), and she was found to be heterozygous for a mutation in the gene encoding the glucokinase enzyme. This was felt to be responsible for the marginal fasting hyperglycaemia and her medications were stopped.

Four years after the first pregnancy she conceived again. She had high fasting blood glucose values and mild post prandial hyperglycaemia. In discussion with her endocrinologist, it was decided to withhold insulin treatment unless fetal macrosomia developed, using the abdominal circumference of the growing fetus as a guide. With minimal physical activity and diet, her blood glucose levels were maintained between 7.8 and 8.9 mmol/L. She did not develop any other complications and ultrasound imaging showed normal fetal anatomy. Fetal biometry at appropriate intervals did not show any evidence of macrosomia. After thorough counselling regarding the risks and benefits, she opted for a trial of labour after caesarean section. Epidural analgesia was offered as labour analgesia in discussion with anaesthesiologist colleagues. She came to the emergency room with a history of pre-labour rupture of membranes at 37 weeks of gestation and labour was induced with oxytocin. A female infant was delivered vaginally but the delivery was complicated by shoulder dystocia. This was managed with McRobert’s manoeuvre and the APGAR was 8 at 5 min. The baby weighed 3.2 kg, and was noted to have a mild Erb’s palsy. This completely resolved in the first six weeks of life. The couple was advised to evaluate both children for a GCK mutation.

Discussion

Monogenic diabetes was first described by Tattersall and Fajans in 1974.² There is a paucity of specific data about monogenic diabetes in pregnancy. GCK-MODY is unique and it differs from other subgroups. Glucokinase is the key regulatory enzyme in insulin secretion from pancreatic cells.^3,4 Approximately 195 mutations have been identified.⁵ Heterozygous mutations in the gene encoding this enzyme usually present in later part of life even though it is a lifelong condition and can be detected at any age. As a result of a defect in the glucose-sensing mechanism, glucose homeostasis is maintained at a higher set point resulting in mild, asymptomatic fasting hyperglycaemia. GCK-MODY differs from other forms of diabetes in that patients usually do not develop microvascular complications. The prevalence of macrovascular disease is similar to the general population.⁶

GCK-MODY is thought to affect 1–3% of all women with a diagnosis of GDM. The prevalence of GCK-MODY may be even across different ethnic groups, unlike type 2 DM which is more prevalent in some ethnic groups such as the black and south Indian population.¹ Screening for GDM provides an opportunity to pick up the condition in pregnancy. Mild fasting hyperglycaemia in a non-obese individual with a positive family history are the clues for GCK-MODY. Persistent hyperglycaemia in the postnatal period also should raise the suspicion of a diagnosis other than GDM, including a GCK mutation. Establishing the diagnosis of GCK-MODY will potentially avoid unnecessary treatment with insulin in subsequent pregnancies. Lachance et al. reviewed 11 cases in a cohort study in which 4 were diagnosed in pregnancy and 7 were diagnosed after pregnancy.⁷ It was found that fasting blood glucose was 5.5 mmol/L or more in 98% of cases. Most of the time, however, the women were erroneously diagnosed with either GDM or type 2 DM which can lead to unnecessary interventions. Generally, treatment with an intent to normalise the blood glucose is not required outside pregnancy in women with GCK-MODY as there is a lack of evidence of long-term complications arising from the associated hyperglycaemia.^1,6

Table 1.

Diagnostic criteria for glucokinase gene mutation related hyperglycaemia in pregnancy.

Persistent fasting hyperglycaemia before, during and after pregnancy, in the range of 5.5–8.1 mmol/L

An increment of less than 4.6 mmol/L on at least 1 OGTT (either during or after pregnancy)

A parent may have mild type II DM but often it has not been detected. A negative family history does not exclude the condition

BMI < 25 kg/m2

Reproduced from Ellard et al.¹³

Fetal growth depends on whether the fetus inherits the GCK mutation from the mother. If there is increased abdominal growth on ultrasound, it suggests that the fetus is unaffected and insulin treatment is required.^8,9 If a fetus has inherited the GCK mutation and insulin treatment is initiated, it may result in fetal growth restriction as happened in her first pregnancy. In this scenario, high doses of insulin to optimise glucose homeostasis are likely to have contributed to the relatively low birth weight of the infant at 2.25 kg. Generally, treatment is not advocated before 32 weeks. As this is an autosomal dominant condition, there is a 50% chance that the offspring is affected.¹⁰ In the absence of fetal genotyping, measurement of abdominal circumference is used as an indicator of fetal hyperglycaemia and macrosomia (see Figure 1). If fetal hyperglycaemia is suspected from an increased abdominal circumference, most clinicians advocate treatment with insulin, and large doses may be required to achieve normoglycaemia.

Figure 1.

Flow chart of management of glucokinase mutation in pregnancy (Reproduced from Chakera et al.¹). AC: abdominal circumference; US: ultrasound.

Birth weight was more than the 90th percentile in 55% of babies who did not inherit a GCK mutation compared to only 9% who inherited the mutated gene.⁸ It was also found that there was a reduction in birth weight of around 400 g in those babies with the GCK mutation, occurring either de novo or paternally inherited.¹ There is no increased risk of congenital anomalies reported so far in women with GCK mutations. Despite the potential impact on fetal growth of a maternal GCK mutation, the evidence is lacking for the development of any long-term complications in the offspring.¹¹

There are data on metformin in the non-pregnant population which shows that this is ineffective in lowering blood glucose in women with GCK-MODY. There is no place for oral hypoglycaemic agents in women with a GCK mutation in pregnancy.

If fetal growth is unaffected, pregnancy can be continued until term; however, delivery should be considered from 38 weeks if there is any evidence of macrosomia. Women who have persistent hyperglycaemia postpartum especially in the fasting state should undergo evaluation in the post-partum period with genetic screening. There is no need for routine follow-up of women with a GCK mutation.¹² Dietary modification has little impact on blood glucose level in women with GCK mutations. If the woman is already on treatment and is subsequently diagnosed as having GCK-MODY, the treatment can be stopped. A longitudinal study of 799 GCK-MODY patients showed that the HbA1c levels of those who received treatment were not different from those who were not on treatment (6.5% vs. 6.4%).⁵

Conclusion

Heterozygous mutations of GCK result in mild fasting hyperglycaemia. It does not require treatment in non-pregnant individuals. They are not at risk of developing long-term complications, and they do not respond to oral hypoglycaemic agents. If the fetus does not inherit the mutation and ultrasound suggests features of macrosomia, then insulin treatment is indicated. Mild fasting hyperglycaemia despite high doses of insulin in a woman should always alert the clinician to evaluate the woman for a GCK enzyme mutation, particularly those with low body mass index and/or a positive family history.