Maturity onset diabetes of the young and pregnancy

doi:10.1016/j.beem.2010.05.008

Best Practice & Research Clinical Endocrinology & Metabolism

Volume 24, Issue 4, August 2010, Pages 605-615

https://doi.org/10.1016/j.beem.2010.05.008 Get rights and content

Three and a half decades after the clinical description of “Maturity Onset Diabetes of the Young” (MODY), and despite its low prevalence, important knowledge has been gathered concerning its genetic basis, molecular pathways, clinical phenotypes and pharmacogenetic issues. This knowledge has proved to be important not only for the attention of subjects carrying a mutation but also for the insight provided in Type 2 diabetes mellitus.

In recent years, a shift from the term “MODY” to “monogenic diabetes” has taken place, the latter term being a better and more comprehensive descriptor. We stick to the “old” term because information on other types of monogenic diabetes and pregnancy is scarce. In this review we perform an overview of the entity, the prevalence rates reported in women with gestational diabetes mellitus and the specific impact of each type on pregnancy outcome.

Section snippets

Summary

In relation to pregnancy, findings in monogenic diabetes have meant several turns of the screw in our understanding. First, birth weight distribution in families with a glucokinase mutation have illustrated that fetal genetics is at least as important as maternal glucose control; and indirectly that near-normal glycemic control should be the gold standard for treatment of most but not all diabetic pregnant women. In the opposite direction, the birth of a macrosomic baby that suffers from

Monogenic DM due to mutations in the glucokinase gene

Mutations in the GCK gene usually present as mild fasting hyperglycaemia. Outside pregnancy, the following features have been identified as suggesting a GCK mutation and encouraging genetic testing for it: ¹⁶

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Fasting hyperglycaemia ≥5.5 mmol/l, persistent and stable
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HbA1c typically just above the upper limit of normal
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In an oral glucose tolerance test the increment [(2 h glucose) − (fasting glucose)] is small, usually <4.6 mmol/l
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Parents may have ‘type 2 DM’ with no complications or may not be

Prevalence (Table 2)

In addition with mild fasting hyperglycaemia, patients with DM due a mutated GCK gene typically do not have signs of insulin resistance.¹¹ If it has not been diagnosed before, the diagnosis will probably be made during gestation because the physiological resistance to insulin during the second half of pregnancy will uncover the defect in beta cell function.

Studies examining the prevalence of mutation GCK gene (Table 2)18, 19, 20, 21, 22, 23, 24, 25, 26 are characterized by being restricted to

Short term

In the DM and pregnancy field, Pedersen’s hypothesis has been crucial to understanding fetal growth: ²⁷The fetus of a woman with poorly regulated DM during pregnancy, is exposed to a higher than normal glucose load and responds with an increased insulin secretion which in turn leads to increased fetal growth. After the seminal contribution of Hattersley in 1998,²⁸ we now know that the presence of a normal GCK genotype is essential for this response to take place. As GCK acts as the beta cell

Treatment

During pregnancy it is very likely that women with DM due to a GCK mutation will present with raised blood glucose values usually prompting pharmacological treatment. However, we have already referred to the opposing effects of maternal hyperglycaemia and the presence of a fetal GCK mutation30, *32, 33, 34, 35, 36, so that maternal treatment should take into account the fetal genotype. Normal maternal blood glucose should be aimed at when the fetus does not have a GCK mutation but a less tight

Monogenic DM due to mutations in the transcription factor HNF-1α gene

Monogenic DM due to mutations in the gene transcription factor HNF-1α is the most common cause of MODY diabetes in most populations investigated and accounts for 1–2% of all diabetes.⁴⁹ Progressive deterioration of insulin secretion does occur, often requires pharmacological treatment and patients present late diabetic complications, especially microangiopathic ones.

Outside pregnancy, the following features have been identified as suggesting a HNF-1α mutation and encouraging genetic testing for

Prevalence

Only two studies have addressed the prevalence of HNF-1α mutations in women with GDM,25, 26 both of them applying selection criteria and the rates being 0 and 1%.

Short-term

Contrary to other forms of monogenic DM, a fetus carrying a mutation in HNF-1α does not display differences in BW. Pearson et al,⁵⁰ studied 134 subjects of 38 affected families and found no significant influence of fetal genotype. Estalella et al also described that while BW of patients with a GCK mutation was around the 10th centile of the population that of patients with a HNF-1α was similar to the mean of the population.³⁵

Long term

Two publications in 2002 established that the parent of origin of the

Treatment

The fact that maternal origin of the mutation has an important impact on the age at presentation of DM in HNF-1α heterozygotes seems to put special emphasis on achieving near-normal maternal glycemic control during pregnancy. However, there is no information relating glucose tolerance in the offspring to maternal glucose control during pregnancy.

Patients with a HNF-1α mutation show special sensitivity to sulfonylureas⁵³ because these drugs act on potassium channels of the beta cell, downstream

Monogenic DM due to mutations in the transcription factor HNF-4 α gene

The prevalence of mutations in HNF-4 α is much lower than that of HNF-1α. Outside pregnancy, the following features have been identified as suggesting a HNF-4 α mutation and encouraging genetic testing for it in children and young adults with DM and a strong family history of DM: ¹⁶

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Similar characteristics to HNF-1α (see above) but later onset and no renal glycosuria
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Similar characteristics to HNF-1α (see above) and negative genetic testing for HNF-1α
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Macrosomia and neonatal hypoglycemia

There is a

Monogenic DM due to mutations in the PDX1 gene

In the single study addressing the prevalence of PDX1 mutations in women with GDM and positive family history of DM, the prevalence was 1%.²⁵ As to its impact on pregnancy outcome, in an extended Italian family, female carriers of mutations in PDX1 reported pregnancies complicated with miscarriages and early postnatal death; newborns carrying the mutation also had reduced birth weight.⁵⁷

Monogenic DM due to mutations in the HNF-1-β gene

There are no data on the prevalence of HNF-1-β mutations in pregnancy. In relation to its potential impact, infertility can result from repeated miscarriages secondary to genital anomalies [unpublished observation]. In mutations leading to neonatal DM, Edghill has reported a decreased BW (52% newborns were small-for-gestational age), that was especially pronounced when the mother did not have the mutation.⁵⁸ The impact on fetal growth of mutations displaying a less severe phenotype is not known.

Monogenic diabetes due to mutations in the gene transcription factor Neuro D1

Only one study has investigated mutations of the NEUROD1 gene, in 51 women with GDM and no mutation was found.⁵⁹ The impact of this mutation on pregnancy outcome is not known.

Conflict of interest statement

The authors declare that they do not have any financial or personal conflicts of interest that could influence the content of this article.

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Cited by (51)

Maternal Diabetes
2023, Avery's Diseases of the Newborn
The incidence of diabetes in pregnancy is steadily rising in parallel with the rising incidence of obesity among pregnant patients. The current rate of diabetes in pregnancy is up to 9% with 80% to 90% of cases due to gestational diabetes. Pregnant patients with diabetes are at increased risk for fetal complications (such as congenital malformations, abnormal fetal growth, and stillbirth) and perinatal/neonatal complications (such as prematurity, respiratory distress, and metabolic abnormalities, including hypoglycemia and electrolyte derangements). Maternal complications include an increased risk for preeclampsia and need for cesarean delivery. Tight maternal glycemic control, achieved preconception and maintained throughout pregnancy, is key to optimizing short- and long-term maternal, fetal, and neonatal outcomes. Breastfeeding should be encouraged and supported as it may reduce some of the possible adverse effects of intrauterine programming in the context of maternal diabetes.
Monogenic diabetes caused by GCK gene mutation is misdiagnosed as gestational diabetes - A multicenter study in Portugal
2021, Diabetes and Metabolic Syndrome: Clinical Research and Reviews
Citation Excerpt :
Accordingly, these results corroborate the significant impact of the diagnosis or suspicion of GCK-MODY. A proper management during pregnancy, which is different as compared to other types of DM, allows to avoid overtreatment and insufficient fetal growth if the fetus has the mutation, or to prevent deficient treatment, macrosomia and the subsequent obstetric complications if the fetus has not inherited the mutation [10,20]. In addition to a safer approach for fetuses and neonates, the diagnosis of GCK-MODY improves patient care and implies a better management of economic and human resources, since it prevents unnecessary and lifelong glycemic monitoring and glucose-lowering treatment of the affected patients (mothers, children, family members).
Monogenic diabetes is an underdiagnosed type of diabetes mellitus, which can be harmful in pregnancy. We aim to estimate the prevalence of diabetes caused by the mutation of the glucokinase gene (GCK-MODY) in pregnant women diagnosed with gestational diabetes mellitus (GDM) and to characterize pregnant women with this suspicion.
A multicenter observational study with data prospectively collected from pregnancies with GDM was conducted. Two groups of pregnant women were considered: those with GCK-MODY criteria and those without those criteria.
Of 18421 women with GDM, 3.6% (n = 730) had the GCK-MODY clinical criteria. A prevalence of 1.5% of GCK-MODY is estimated in women with GDM in Portugal, which is higher than in Northern European countries. Suspected GCK-MODY women had statistically higher odds of having neonates below the 25th percentile (OR = 1.23, 95%CI = 1.04–1.46, p = 0.016) and having prediabetes and diabetes in postpartum reclassification (OR = 2.11, 95%CI = 1.55–2.82, p < 0.001 and OR = 5.96, 95%CI = 3.38–10.06, p < 0.001, respectively).
Higher odds of neonates below the 25th percentile was probably due to excessive insulin treatment in cases where both the mother and the fetus have the mutation. It is essential to consider the diagnosis of GCK-MODY in all women with GDM criteria for better management of diabetes in pregnancy.
Differentiating Among Type 1, Type 2 Diabetes, and MODY: Raising Awareness About the Clinical Implementation of Genetic Testing in Latin America
2021, AACE Clinical Case Reports
Citation Excerpt :
We can speculate that both pregnancies with low birthweight products were caused by the latter mechanism. Based on the aforementioned observations, it is recommended that pregnant mothers with hyperglycemia due to a GCK mutation be treated only when there is ultrasound evidence of accelerated fetal growth.15 Over 600 different GCK-MODY mutations have been described in a variety of populations, mainly from Europeans countries.11
To describe a case of maturity-onset diabetes of the young (MODY) to highlight the importance of a correct diabetes diagnosis.
We describe a Mexican family misdiagnosed with T1D and T2D.
A 36-year-old woman with diabetes and adverse outcomes during 2 pregnancies had been diagnosed with T2D 10 years ago. Genetic testing was performed due to clinical and family history, which showed a pathogenic heterozygous variant c.544G>T (p.Val182Leu) in the GCK gene. This mutation was also confirmed in most of the family members who had been diagnosed with diabetes.
This case highlights the need for a correct diabetes classification. Reassessment of diabetes etiology is justified, especially in individuals with unclear clinical presentation or when family history is suggestive.
Management and Outcomes of Maturity-Onset Diabetes of the Young in Pregnancy
2019, Canadian Journal of Diabetes
Citation Excerpt :
HNF1A-MODY is the most common type of MODY, accounting for up to 65% of cases. In pregnancy, the reported prevalence is 1% (10). It is caused by a defect in hepatocyte nuclear factor HNF1A, which regulates the expression of key enzymes in the glucose metabolism pathway.
Maturity-onset diabetes of the young (MODY) is a group of monogenic disorders that accounts for 1% to 5% of diabetes. The most common mutations are those in the hepatocyte nuclear factor-1-alpha (HNF-1-alpha) and in the glucokinase (GCK) genes. Although management of MODY is well established, no guidelines currently exist for management during pregnancy. Both maternal glycemic control and fetal mutation status are factors that may influence outcomes during pregnancy. The primary aim of this project was to describe cases of MODY during pregnancy to highlight the clinical implications of management of this disorder during pregnancy. The Ottawa Hospital is the primary referral centre for high-risk obstetrical patients, including those with diabetes in pregnancy, in Ottawa, Canada. Referrals between 2008 and 2018 were reviewed and a case series of three women and five pregnancies is described. Together with the illustrative cases, a literature review of MODY in pregnancy is used to highlight clinical considerations unique to MODY in pregnancy. We describe 5 pregnancies with MODY-2 (GCK mutation) and MODY 3 (HNF-1-alpha mutation). Important issues identified included monitoring of fetal growth and individualization of maternal glycemic control, particularly in cases where fetal mutation status is unknown. Management of MODY in pregnancy is challenging and there is little evidence to guide recommendations. Fetal growth can be used to guide management of maternal glycemic targets when fetal mutation status is unknown.
Le diabète de la maturité apparaissant chez le jeune (MODY) constitue un groupe d'anomalies monogéniques qui représente de 1 % à 5 % des types de diabète. Les mutations les plus fréquentes sont celles des gènes codant pour le hépatocyte nucléaire facteur 1-alpha (HNF-1-alpha) et pour la glucokinase (GCK). Bien que la prise en charge du MODY soit bien établie, il n'existe actuellement aucune ligne directrice sur sa prise en charge durant la grossesse. La régulation de la glycémie maternelle et le statut mutationnel du fœtus sont des facteurs qui peuvent influencer les issues de la grossesse. L'objectif principal de la présente étude était de décrire les cas de MODY durant la grossesse pour démontrer les conséquences cliniques de la prise en charge de cette anomalie durant la grossesse. L’Hôpital d’Ottawa est le principal centre, à Ottawa, au Canada, qui offre des services de consultation en obstétrique aux patientes exposées à un risque élevé, y compris aux patientes diabétiques durant leur grossesse. Nous avons passé en revue les consultations entre 2008 et 2018, et nous avons décrit des séries de cas de 3 femmes et de 5 grossesses. Conjointement aux cas cités en exemple, une revue de littérature du MODY durant la grossesse est utilisée pour faire valoir les considérations cliniques propres au MODY durant la grossesse. Nous décrivons 5 grossesses de femmes ayant le MODY-2 (mutation codant pour la GCK) et le MODY-3 (mutation codant pour le HNF-1-alpha). Les points importants sont la surveillance de la croissance fœtale et l'individualisation de la régulation de la glycémie maternelle, notamment dans les cas où l'on ignore le statut mutationnel du fœtus. La prise en charge du MODY durant la grossesse est difficile. Il existe peu de données probantes pour mener à des recommandations. La croissance fœtale peut être utilisée pour orienter la prise en charge des valeurs cibles de la glycémie maternelle lorsqu'on ignore l’état mutationnel du fœtus.
Maturity Onset Diabetes of the Young (MODY) in Tunisia: Low frequencies of GCK and HNF1A mutations
2018, Gene
Citation Excerpt :
In fact, GCK-MODY is characterized by mild and stable hyperglycemia (5.5–8.0 mmol/L) that shows little deterioration with age and an HbA1c level below 8% (10 mmol/L). Patients are generally asymptomatic and do not develop diabetes-related microvascular complications, hyperglycemia is commonly discovered during routine screening such as during pregnancy (Gardner and Tai, 2012; Colom and Corcoy, 2010). Subjects with no identified mutations accounted for most of the clinical MODY cases in this study.
Maturity Onset Diabetes of the Young (MODY) is a monogenic form of diabetes characterized by autosomal dominant inheritance, an early clinical onset and a primary defect in β-cell function. Mutations in the GCK and HNF1A genes are the most common cause of MODY among Caucasians. The etiology of MODY in Tunisia stills a challenge for researchers. The aim of this study was to screen for mutations in GCK, HNF1A, HNF4A and INS genes in North African Tunisians subjects, in whom the clinical profile was very suggestive of MODY. A total of 23 unrelated patients, with clinical presentation of MODY were tested for mutations in GCK, HNF1A, HNF4A and INS genes, using Denaturing High Performance Liquid Chromatography (DHPLC), Multiplex Ligation-depend Probe Amplification (MLPA) and sequencing analysis. We identified the previously reported mutation c-169C > T in one patient as well as a new mutation c-457C > T in two unrelated patients. No mutations were detected in the HNF1A and INS genes. Despite restrictive clinical criteria used for selecting patients in this study, the most common genes known for MODY do not explain the majority of cases in Tunisians. This suggests that there are others candidate or unidentified genes contributing to the etiology of MODY in Tunisians families.
Maternal Diabetes
2018, Avery's Diseases of the Newborn: Tenth Edition
- •
  The incidence of diabetes in pregnancy is steadily rising, likely in parallel with the rising incidence of obesity among women of reproductive age.
- •
  Women with diabetes are at increased risk for fetal complications (such as congenital malformations, fetal growth abnormalities, and stillbirth) and perinatal/neonatal complications (such as prematurity, respiratory distress, and metabolic abnormalities including hypoglycemia and electrolyte derangements).
- •
  Good maternal glycemic control achieved preconception and maintained throughout pregnancy is key to optimizing fetal and neonatal outcomes.
- •
  Breastfeeding should be strongly encouraged and supported as it may reduce some of the possible adverse effects of intrauterine programming in the context of maternal diabetes.

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7Maturity onset diabetes of the young and pregnancy

Section snippets

Summary

Monogenic DM due to mutations in the glucokinase gene

Prevalence (Table 2)

Short term

Treatment

Monogenic DM due to mutations in the transcription factor HNF-1α gene

Prevalence

Short-term

Long term

Treatment

Monogenic DM due to mutations in the transcription factor HNF-4 α gene

Monogenic DM due to mutations in the PDX1 gene

Monogenic DM due to mutations in the HNF-1-β gene

Monogenic diabetes due to mutations in the gene transcription factor Neuro D1

Conflict of interest statement

Lancet

Diabetes Research and Clinical Practice

Diabetes Research and Clinical Practice

American Journal of Human Genetics

Lancet

American Journal of Obstetrics and Gynecology

Molecular and Cellular Endocrinology

The Journal of Pediatrics

Lancet

Metabolism

Mild familial diabetes with dominant inheritance

The Quarterly Journal of Medicine

A difference between the inheritance of classical juvenile-onset and maturity-onset diabetes

Diabetes

A family with dominantly inherited mild juvenile diabetes

Acta Medica Scandinavica

Genetic diabetes not linked to the HLA locus

British Medical Journal

Sequencing of candidate genes selected by beta cell experts in monogenic diabetes of unknown aetiology

Journal of the Pancreas

Insulin secretion and insulin sensitivity in diabetic and non-diabetic subjects with hepatic nuclear factor-1alpha (maturity-onset diabetes of the young-3) mutations

European Journal of Endocrinology

Expanded clinical spectrum in hepatocyte nuclear factor 1b-maturity-onset diabetes of the young

The Journal of Clinical Endocrinology and Metabolism

A genetic diagnosis of HNF1A diabetes alters treatment and improves glycaemic control in the majority of insulin-treated patients

Diabetic Medicine

Monogenic diabetes in the young, pharmacogenetics and relevance to multifactorial forms of type 2 diabetes

Endocrine Reviews

Clinical implications of a molecular genetic classification of monogenic beta-cell diabetes

Nature Clinical Practice. Endocrinology & Metabolism

Insulin mutation screening in 1,044 patients with diabetes: mutations in the INS gene are a common cause of neonatal diabetes but a rare cause of diabetes diagnosed in childhood or adulthood

Diabetes

Evaluation of common variants in the six known maturity – onset diabetes of the young (MODY) genes for association with type 2 diabetes

Diabetes

Common variants in maturity-onset diabetes of the young genes and future risk of type 2 diabetes

Diabetes

Common variants in MODY genes increase the risk of gestational diabetes mellitus

Diabetologia

Best practice guidelines for the molecular genetic diagnosis of maturity-onset diabetes of the young

Diabetologia

Mutation in the mitochondrial tRNA(leu) at position 3243 and spontaneous abortions in Japanese women attending a clinic for diabetic pregnancies

Diabetologia

Linkage analysis and molecular scanning of glucokinase gene in NIDDM families

Diabetes

Identification of glucokinase mutations in subjects with gestational diabetes mellitus

Diabetes

Glucokinase gene in gestational diabetes mellitus: population association study and molecular scanning

Diabetologia

7
Maturity onset diabetes of the young and pregnancy