RESUMEN
AIMS/HYPOTHESIS: In pregnancies where the mother has glucokinase-MODY (GCK-MODY), fetal growth is determined by fetal genotype. When the fetus inherits a maternal pathogenic GCK variant, normal fetal growth is anticipated, and insulin treatment of maternal hyperglycaemia is not recommended. At present, fetal genotype is estimated from measurement of fetal abdominal circumference on ultrasound. Non-invasive prenatal testing of fetal GCK genotype (NIPT-GCK) using cell-free DNA in maternal blood has recently been developed. We aimed to compare the diagnostic accuracy of NIPT-GCK with that of ultrasound, and determine the feasibility of using NIPT-GCK to guide pregnancy management. METHODS: We studied an international cohort of pregnant women with hyperglycaemia due to GCK-MODY. We compared the diagnostic accuracy of NIPT-GCK with that of measurement of fetal abdominal circumference at 28 weeks' gestation (n=38) using a directly genotyped offspring sample as the reference standard. In a feasibility study, we assessed the time to result given to clinicians in 43 consecutive pregnancies affected by GCK-MODY between July 2019 and September 2021. RESULTS: In terms of diagnostic accuracy, NIPT-GCK was more sensitive and specific than ultrasound in predicting fetal genotype (sensitivity 100% and specificity 96% for NIPT-GCK vs sensitivity 53% and specificity 61% for fetal abdominal circumference 75th percentile). In terms of feasibility, a valid NIPT-GCK fetal genotype (≥95% probability) was reported in all 38 pregnancies with an amenable variant and repeated samples when needed. The median time to report was 5 weeks (IQR 3-8 weeks). For the 25 samples received before 20 weeks' gestation, results were reported at a median gestational age of 20 weeks (IQR 18-24), with 23/25 (92%) reported before 28 weeks. CONCLUSIONS/INTERPRETATION: Non-invasive prenatal testing of fetal genotype in GCK-MODY pregnancies is highly accurate and is capable of providing a result before the last trimester for most patients. This means that non-invasive prenatal testing of fetal genotype is the optimal approach to management of GCK-MODY pregnancies.
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Diabetes Mellitus Tipo 2 , Hiperglucemia , Embarazo , Humanos , Femenino , Lactante , Glucoquinasa/genética , Estudios de Factibilidad , Medicina de Precisión , Diabetes Mellitus Tipo 2/genética , Hiperglucemia/genética , MutaciónRESUMEN
OBJECTIVE: Appropriate glucose levels are essential for survival; thus, the detection and correction of low blood glucose is of paramount importance. Hypoglycemia prompts an integrated response involving reduction in insulin release and secretion of key counter-regulatory hormones glucagon and epinephrine that together promote endogenous glucose production to restore normoglycemia. However, specifically how this response is orchestrated remains to be fully clarified. The low affinity hexokinase glucokinase is found in glucose-sensing cells involved in glucose homeostasis including pancreatic ß-cells and in certain brain areas. Here, we aimed to examine the role of glucokinase in triggering counter-regulatory hormonal responses to hypoglycemia, hypothesizing that reduced glucokinase activity would lead to increased and/or earlier triggering of responses. METHODS: Hyperinsulinemic glucose clamps were performed to examine counter-regulatory responses to controlled hypoglycemic challenges created in humans with monogenic diabetes resulting from heterozygous glucokinase mutations (GCK-MODY). To examine the relative importance of glucokinase in different sensing areas, we then examined responses to clamped hypoglycemia in mice with molecularly defined disruption of whole body and/or brain glucokinase. RESULTS: GCK-MODY patients displayed increased and earlier glucagon responses during hypoglycemia compared with a group of glycemia-matched patients with type 2 diabetes. Consistent with this, glucagon responses to hypoglycemia were also increased in I366F mice with mutated glucokinase and in streptozotocin-treated ß-cell ablated diabetic I366F mice. Glucagon responses were normal in conditional brain glucokinase-knockout mice, suggesting that glucagon release during hypoglycemia is controlled by glucokinase-mediated glucose sensing outside the brain but not in ß-cells. For epinephrine, we found increased responses in GCK-MODY patients, in ß-cell ablated diabetic I366F mice and in conditional (nestin lineage) brain glucokinase-knockout mice, supporting a role for brain glucokinase in triggering epinephrine release. CONCLUSIONS: Our data suggest that glucokinase in brain and other non ß-cell peripheral hypoglycemia sensors is important in glucose homeostasis, allowing the body to detect and respond to a falling blood glucose.
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Diabetes Mellitus/metabolismo , Glucoquinasa/fisiología , Hipoglucemia/metabolismo , Adulto , Animales , Glucemia/análisis , Diabetes Mellitus/genética , Modelos Animales de Enfermedad , Epinefrina , Femenino , Glucagón/sangre , Glucoquinasa/metabolismo , Glucosa/metabolismo , Técnica de Clampeo de la Glucosa , Humanos , Hiperinsulinismo , Hipoglucemia/fisiopatología , Hipoglucemiantes , Insulina/sangre , Células Secretoras de Insulina/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Persona de Mediana EdadRESUMEN
The multiple endocrine neoplasia (MEN) type 2B is an autosomal dominant condition characterized by aggressive medullary C-cell tumors, pheochromocytoma, and a discrete physical appearance (marfanoid habitus, prominent corneal nerve fibers, thick lips, and mucosal and intestinal neuromas). A specific point mutation in the RET proto-oncogene is present in 95% cases. Occasionally cases present with the characteristic physical appearance of MEN 2B but no identifiable germline mutation or endocrinopathy, and it has been suggested that these patients may represent a discrete subgroup termed pure mucosal neuroma syndrome (MNS). We present a patient with MNS, who had a thyroidectomy at age 14.5 years with normal thyroid histology. Direct sequencing of all 20 exons of the RET gene showed no mutation. This case supports the suggestion that pure MNS can exist in the absence of an identifiable RET gene mutation. We suggest that prophylactic thyroidectomy is unnecessary in these patients although they should still be screened for endocrinopathy on a regular basis.
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Enfermedades del Sistema Endocrino/patología , Neoplasia Endocrina Múltiple Tipo 2b/genética , Neoplasia Endocrina Múltiple Tipo 2b/terapia , Mutación , Proteínas Proto-Oncogénicas c-ret/genética , Adolescente , Exones , Femenino , Humanos , Neoplasia Endocrina Múltiple Tipo 2b/diagnóstico , Fenotipo , Proto-Oncogenes Mas , Tiroidectomía , Resultado del TratamientoRESUMEN
OBJECTIVE: Identifying glucokinase monogenic diabetes (GCK-MODY) in pregnancy is important, as management is different from management for other forms of gestational diabetes mellitus (GDM) and there is no increased maternal risk of type 2 diabetes. We calculated the population prevalence of GCK-MODY in pregnancy and determined the clinical characteristics that differentiate pregnant women with GCK-MODY from those with GDM. RESEARCH DESIGN AND METHODS: We calculated the population prevalence of GCK-MODY in pregnancy by testing a subset of patients from the population-based Atlantic Diabetes in Pregnancy (Atlantic DIP) study (n = 5,500). We sequenced for GCK mutations in 247 women with a fasting glucose ≥5.1 mmol/L and 109 randomly selected control subjects with normal fasting glucose. Using data from the cases found and 40 previously identified GCK-MODY pregnancies, we analyzed whether clinical criteria could be used to differentiate GCK-MODY from GDM. RESULTS: Four women with fasting glucose ≥5.1 mmol/L were diagnosed with GCK-MODY. No cases were identified with normal fasting glucose. The population prevalence of GCK-MODY is 1.1 in 1,000 (95% CI 0.3-2.9 in 1,000) and prevalence in GDM is 0.9% (95% CI 0.3-2.3). Fasting glucose and BMI significantly differentiate GCK-MODY from GDM (P < 0.0001). Combined criteria of BMI <25 kg/m(2) and fasting glucose ≥5.5 mmol/L has a sensitivity 68%, specificity 96%, and number needed to test of 2.7 women with GDM to find one case of GCK-MODY. CONCLUSIONS: Our large population cohort of pregnant women tested estimates the population prevalence of GCK-MODY of 1.1 in 1,000. We have shown routine clinical criteria that can identify which women should be tested for GCK-MODY in pregnancy.
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Glucemia/metabolismo , Diabetes Gestacional/diagnóstico , Glucoquinasa/genética , Mutación/genética , Complicaciones del Embarazo/diagnóstico , Embarazo en Diabéticas/diagnóstico , Embarazo en Diabéticas/genética , Adolescente , Adulto , Índice de Masa Corporal , Estudios de Casos y Controles , Estudios de Cohortes , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Gestacional/sangre , Diagnóstico Diferencial , Ayuno , Femenino , Humanos , Persona de Mediana Edad , Embarazo , Complicaciones del Embarazo/sangre , Embarazo en Diabéticas/sangre , Prevalencia , Factores de Riesgo , Sensibilidad y Especificidad , Adulto JovenRESUMEN
OBJECTIVE: In human pregnancy, placental weight is strongly associated with birth weight. It is uncertain whether there is regulation of the placenta by the fetus or vice versa. We aimed to test the hypothesis that placental growth is mediated, either directly or indirectly, by fetal insulin. RESEARCH DESIGN AND METHODS: Birth weight and placental weight were measured in 43 offspring of 21 parents with mutations in the glucokinase (GCK) gene (25 had inherited the mutation and 18 had not), which results in reduced fetal insulin secretion. Birth weight, placental weight, umbilical cord insulin, and maternal glucose and insulin concentrations were measured in 573 nondiabetic, healthy, term pregnancies. RESULTS: GCK mutation carriers were lighter and also had smaller placentas (610 vs. 720 g, P = 0.042). This difference was also seen in 17 discordant sibling pairs (600 vs. 720 g, P = 0.003). GCK mRNA was not detected in the placenta by RT-PCR. In the normal pregnancies, placental weight was strongly correlated with birth weight (r = 0.61, P < 0.001). Cord insulin concentrations were directly related to placental weight (r = 0.28) and birth weight (r = 0.36) (P < 0.001 for both). CONCLUSIONS: These results suggest that insulin, directly or indirectly, plays a role in placental growth, especially as a mutation in the GCK gene, which is known to only alter fetal insulin secretion, results in altered placental weight. This finding is consistent with the preferential localization of the insulin receptors in the fetal endothelium of the placenta in the last trimester of pregnancy.
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Feto/fisiología , Glucoquinasa/genética , Insulina/metabolismo , Mutación , Placenta/anatomía & histología , Peso al Nacer , Femenino , Edad Gestacional , Humanos , Recién Nacido , Secreción de Insulina , Masculino , Embarazo , Cordón Umbilical/metabolismoRESUMEN
OBJECTIVE: Nonautoimmune hyperthyroidism (NAH), a rare autosomal dominantly inherited condition characterized by nonremitting thyrotoxicosis and the absence of features of autoimmune thyrotoxicosis, can result from activating germline mutations in the thyrotropin receptor (TSHR) gene. We report clinical and genetic features of a new family with NAH, and highlight that premature delivery and low birth weight are important characteristics of this condition. PATIENTS AND METHODS: Thyrotoxicosis was diagnosed in two children at the ages 20 months and 4 years and in their father at the age of 9 years. Both children were born prematurely by Caesarian section at 33 and 30 weeks following early rupture of the membranes. Their birth weights were 1750 g (27th centile) and 790 g (< 3rd centile), respectively. Mutation analysis of the TSHR gene was performed in both children and their parents by direct DNA sequencing. RESULTS: A heterozygous germline mutation of the TSHR gene resulting in the substitution of serine (AGC) by asparagine (AAC) at codon 505 (S505N) was found, which co-segregated with thyrotoxicosis in the family. A review of all previously reported cases of NAH due to an activating TSHR germline mutation showed that the mean duration of gestation in these patients was significantly lower than in patients with inactivating TSHR mutations causing congenital hypothyroidism (35.8 weeks vs. 39.4 weeks, P = 0.003). In addition, the mean birth weight in patients with activating TSHR mutations was lower than in patients with inactivating TSHR mutations (2338 g vs. 3470 g, P = 0.004). CONCLUSIONS: Premature delivery and low birth weight are consistent features of NAH due to activating TSHR germline mutations. This suggests a possible role for the fetal thyroid axis in the regulation of the timing of delivery and possibly fetal growth.