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BACKGROUND: Maturity-onset diabetes of the young type 2 (MODY2) is a rare genetic disorder characterized as mild fasting hyperglycemia with low risk of vascular complications caused by glucokinase gene mutation. This study aims to investigate metabolites alteration associated with MODY2, exploring possible mechanism underlying characteristic clinical manifestations and low cardiovascular risks of MODY2 and providing serum metabolite biomarkers to facilitating MODY2 diagnosis. METHODS: Fasting serum samples from MODY2, type 1 diabetes (T1DM) and healthy individuals were collected. By using targeted metabolomics via liquid chromatography-tandem mass spectrometry platform, we quantified the metabolites involved in tricarboxylic acid (TCA) cycle and one-carbon metabolism. RESULTS: Metabolomic profiling revealed significant difference of intermediates from central metabolism cycle, methionine cycle and several amino acids between MODY2 and T1DM groups. Among these, serum citrate, α-ketoglutaric acid, serine, glycine, glutamine and homocysteine were significantly elevated in MODY2 patients compared with T1DM patients; and compared with healthy subjects, malate and methionine levels were significantly increased in the two groups of diabetic patients. The correlation analysis with clinical indexes showed that α- ketoglutarate, serine, glycine, and glutamine were negatively correlated with blood glucose indicators including fasting blood glucose, HbA1c, and GA, while citrate was positively correlated with C-peptide. And homocysteine displayed positive correlation with HDL and negative with C-reactive protein, which shed light on the mechanism of mild symptoms and low risk of cardiovascular complications in MODY2 patients. A panel of 4 metabolites differentiated MODY2 from T1DM with AUC of 0.924, and a combination of clinical indices and metabolite also gained good diagnostic value with AUC 0.948. CONCLUSION: In this research, we characterized the metabolite profiles of TCA cycle and one-carbon metabolism in MODY2 and T1DM and identified promising diagnostic biomarkers for MODY2. This study may provide novel insights into the pathogenesis and clinical manifestations of MODY2.
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BACKGROUND: To evaluate corneal deformation in Maturity Onset Diabetes of the Young type 2 (MODY2), paediatric subjects were analysed using a Scheimpflug-based device. The purpose of this analysis was to find new biomarkers for MODY2 disease and to gain a better understanding of the pathogenesis of the disease. METHODS: A total of 15 patients with genetic and metabolic diagnoses of MODY2 (mean age 12.8 ± 5.66 years) and 15 age-matched healthy subjects were included. The biochemical and anthropometric data of MODY2 patients were collected from clinical records, and a complete ophthalmic check with a Pentacam HR EM-3000 Specular Microscope and Corvis ST devices was performed in both groups. RESULTS: Highest concavity (HC) deflection length, Applanation 1 (A1) deflection amplitude, and A1 deflection area showed significantly lower values in MODY2 patients compared to healthy subjects. A significant positive correlation was observed between Body Mass Index (BMI) and HC deflection area and between waist circumference (WC) and the following parameters: maximum deformation amplitude, HC deformation amplitude, and HC deflection area. The glycosylated hemoglobin level (HbA1c) showed a significant positive correlation with Applanation 2 time and HC time. CONCLUSIONS: The obtained results show, for the first time, differences regarding corneal distortion features in the MODY2 population compared with healthy eyes.
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Glucokinase is a glycolytic enzyme that catalyzes the phosphorylation of glucose to glucose-6-phospate in the first step of the glycolytic pathway. It also regulates the threshold for insulin secretion from pancreatic beta cells by catalyzing the phosphorylation of glucose and plays an important role as a glucose sensor. Pathogenic variants in the glucokinase gene (GCK) cause non-progressive but persistent mild fasting hyperglycemia, also recognized as maturity-onset diabetes of the young 2 (MODY2). This report presents the case of two Japanese siblings with MODY2, who were initially diagnosed with impaired glucose intolerance at 20 and 17 years of age, and later developed diabetes mellitus. They had no history of obesity, were negative for islet-related autoantibodies and their serum C-peptide level were within the normal range. Diabetic complications were not observed. Next-generation sequencing revealed a novel heterozygous variant in GCK (NM_000162.5: c.1088A>G, p.Asp363Gly) in both siblings. This variant has not been reported previously. In silico functional analyses, using SIFT and MutationTaster, suggested that the variant was damaging. To confirm the functional impact of the mutated GCK, the HiBiT-tagged p.Asp363Gly variant and the wild-type GCK were transiently expressed in HEK293T cells. The cells expressing the variant GCK exhibited 79% less bioluminescence, compared to those expressing the wild-type GCK, suggesting that the pathophysiology of the variant was a result of haploinsufficiency.
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Diabetes Mellitus Tipo 2 , Glucoquinasa , Humanos , Glucoquinasa/genética , Glucoquinasa/metabolismo , Mutación , Pueblos del Este de Asia , Células HEK293 , Hermanos , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/diagnóstico , GlucosaRESUMEN
Glucokinase (GCK) is the pancreatic ß-cell glucose sensor, and its kinetics are key to that purpose. A slow transition step, displayed as non-hyperbolic kinetics, and a low affinity for glucose characterize GCK. Mutations in GCK associated with maturity-onset diabetes of the young type 2 (MODY2) previously described reduce the functionality of the human pancreatic ß-cell, leading to diabetic clinical phenotypes. We present a kinetic characterization of the G448D mutation identified in a MODY2 patient, which is one of the first mutations to exhibit increased functionality. This mutant displays increased activity, high affinity for both Mg2+ -ATP and glucose, hyperbolic kinetics and increased phosphorylation potential. Hyperbolic kinetics and assays in the presence of glycerol indicate that G448D lacks the slow transition step crucial for the pancreatic ß-cell glucose sensor function.
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Diabetes Mellitus Tipo 2 , Glucoquinasa , Humanos , Glucoquinasa/genética , Mutación , Diabetes Mellitus Tipo 2/genética , GlucosaRESUMEN
Maturity-onset diabetes of the young (MODY) is a rare form of non-autoimmune diabetes with an autosomal dominant inheritance. To date, 14 genes have been reported as genetic basis of MODY. GCK gene, encoding the glucokinase enzyme, was the first MODY gene to be identified. GCK heterozygous inactivating variants cause the GCK-MODY or MODY2 subtype. However, partial or whole gene deletions have been rarely identified, showing it to be a rare cause of GCK-MODY. We reported the molecular evaluation of a Ukrainian patient with clinical diagnosis of MODY2. We performed the Next generation sequencing of the clinical exome using the Clinical Exome Solution® kit (SOPHiA Genetics), followed by the design of a 14 genes virtual panel related to the suggestive diagnosis of MODY. Bioinformatics analysis was performed using the SOPHiA DDM platform (SOPHiA Genetics). The SALSA MLPA kit for MODY (MRC-Holland) was used for relative quantification of GCK exons. From the molecular evaluation, no pathogenic sequence variants were detected in the investigated genes. Copy Number Variation analysis was able to identify a large deletion involving the last three exons of the GCK gene. This result was confirmed by MLPA. To the best of our knowledge, the identified rearrangement has never been reported in the literature.
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Variaciones en el Número de Copia de ADN , Exoma , Humanos , GenómicaRESUMEN
Background: The optimal treatment strategy for the follow-up and management of women with glucokinase maturity-onset diabetes of the young (GCK−MODY)during pregnancy remains unknown. Data regarding maternal and fetal outcomes are lacking. Aim: This paper summarizes the existing literature regarding the maternal and fetal outcomes of women with glucokinase MODY to guide future treatment strategy. Methods: A literature search was conducted in Pubmed, Embace, and Cochrane library with citation follow-up using the terms: glucokinase, MODY, diabetes, pregnancy, gestation, and outcomes. We searched for articles with known fetal mutational status. Relevant outcomes included: birthweight, large for gestational age (LGA), small for gestational age (SGA), macrosomia, cesarean delivery (CD), shoulder dystocia, congenital anomalies, miscarriages, preterm births, and long-term outcomes. Results: Fourteen relevant manuscripts were identified describing maternal and fetal outcomes. The percentage of LGA and macrosomia in 102 glucokinase -unaffected offspring (GCK−) was significantly higher than in the glucokinase -affected offspring (GCK+) (44% vs. 10%, p < 0.001 and 22% vs. 2%, p < 0.001, respectively). Among the 173 GCK(+) offspring, only 5% were SGA, which can be expected according to the normal distribution. We observed higher rates of CD and shoulder dystocia in the GCK(−) offspring. Conclusions: GCK(−) offspring have significantly higher birthweights and more birth complications. The optimal treatment strategy to guide management should take into consideration multiple variables other than fetal mutational status.
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Embarazo en Diabéticas , Distocia de Hombros , Peso al Nacer , Diabetes Mellitus Tipo 2 , Femenino , Macrosomía Fetal , Glucoquinasa/genética , Humanos , Recién Nacido , EmbarazoRESUMEN
Glucokinase has an important role in regulating glycolysis as a glucose sensor in liver and pancreatic ß cells. Glucokinase-maturity onset diabetes in young (GCK-MODY also known as MODY2) is caused by autosomal dominant gene mutation of the GCK gene; it is characterized by mild fasting hyperglycemia and small 2-h glucose increment during 75 g-oral glucose tolerance test (OGTT) as well as near-normal postprandial glucose variabilities. A 10-year-old girl with family history of diabetes visited her physician after being found positive for urinary glucose by school medical checkup. She received a diagnosis of diabetes based on the laboratory data: 75 g-OGTT (mild fasting hyperglycemia and small 2-h glucose increment) and factory-calibrated glucose monitoring (mild elevation of average glucose level and near-normal glycemic variability), which raised suspicion of GCK-MODY. She was then referred to our institution for genetic examination, which revealed a GCK heterozygous mutation (NM_000162: exon10: c.1324G>T: p.E442X) in the proband as well as in her mother and maternal grandmother, who had been receiving anti-diabetes medications without knowing that they had GCK-MODY specifically. GCK-MODY cases show incidence of microvascular and macrovascular diseases similar to that of normal subjects, and their glucose levels are adequately controlled without anti-diabetes drug use. Thus, early and definitive diagnosis of MODY2 by genetic testing is important to avoid unnecessary medication.
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Diabetes Mellitus Tipo 2 , Hiperglucemia , Glucemia , Automonitorización de la Glucosa Sanguínea , Niño , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/genética , Femenino , Glucoquinasa/genética , Glucosa , Humanos , Hiperglucemia/genética , MutaciónRESUMEN
Maturity-onset diabetes of the young (MODY) is the most common monogenic form of diabetes, accounting for 1-2% of all diabetes cases. At least 14 different MODY subtypes have been identified the most common of which is MODY 2 caused by mutations in the glucokinase (GSK) gene. The mild hyperglycemia of MODY 2 is often first detected during pregnancy. Patients with MODY are usually misdiagnosed as either idiopathic type 1 or type 2 diabetes. The recognition of MODY 2 during pregnancy has important clinical implications as the management of hyperglycemia may differ from the established algorithm in gestational diabetes. Fetus development could be seriously affected in case it has inherited the GSK mutation and maternal hyperglycemia is insulin treated to the pregnancy adopted glycemic targets. The case report describes the stepwise diagnostic approach to a 43-year-old woman with a history of gestational diabetes and persistent prediabetes who was found to be a carrier of a heterozygous pathogenic variant in GSK (c.184G>A) and discusses the possible genotype of her two children according to their birth weight.
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Objective: To determine the pathogenic gene and explore the clinical characteristics of maturity-onset diabetes of the young type 2 (MODY2) pedigree caused by a mutation in the glucokinase (GCK) gene. Methods: Using whole-exome sequencing (WES), the pathogenic gene was detected in the proband-a 20-year-old young man who was accidentally found with hyperglycemia, no ketosis tendency, and a family history of diabetes. The family members of the proband were examined. In addition, relevant clinical data were obtained and genomic DNA from peripheral blood was obtained. Pathologic variants of the candidate were verified by Sanger sequencing technology, and cosegregation tests were conducted among other family members and non-related healthy controls. After adjusting the treatment plan based on the results of genetic testing, changes in biochemical parameters, such as blood glucose levels and HAblc levels were determined. Results: In the GCK gene (NM_000162) in exon 9, a heterozygous missense mutation c.1160C > T (p.Ala387Val) was found in the proband, his father, uncle, and grandmother. Thus mutation, which was found to co-segregate with diabetes, was the first discovery of such a mutation in the Asian population. After stopping hypoglycemic drug treatment, good glycemic control was achieved with diet and exercise therapy. Conclusion: GCK gene mutation c.1160C > T (p.Ala387Val) is the pathogenic gene in the GCK-MODY pedigree. Formulating an optimized and personalized treatment strategy can reduce unnecessary excessive medical treatment and adverse drug reactions, and maintain a good HbA1c compliance rate.
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Pueblo Asiatico/genética , Biomarcadores/análisis , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Pruebas Genéticas/métodos , Hipoglucemiantes/administración & dosificación , Mutación , Medicina de Precisión , Adulto , Anciano de 80 o más Años , Secuencia de Aminoácidos , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patología , Exones , Femenino , Humanos , Masculino , Persona de Mediana Edad , Linaje , Pronóstico , Homología de Secuencia de Aminoácido , Adulto JovenRESUMEN
MODY2 is caused by heterozygous inactivating mutations in the glucokinase (GCK) gene that result in persistent, stable and mild fasting hyperglycaemia (5.6-8.0 mmol/L, glycosylated haemoglobin range of 5.6-7.3%). Patients with GCK mutations usually do not require any drug treatment, except during pregnancy. The GCK gene is considered to be responsible for about 20% of all MODY cases, transcription factors for 67% and other genes for 13% of the cases. Based on our findings, GCK and HNF1A mutations together are responsible for about 90% of the cases in Hungary, this ratio being higher than the 70% reported in the literature. More than 70% of these patients have a mutation in the GCK gene, this means that GCK-MODY is the most prevalent form of MODY in Hungary. In the 91 index patients and their 72 family members examined, we have identified a total of 65 different pathogenic (18) and likely pathogenic (47) GCK mutations of which 28 were novel. In two families, de novo GCK mutations were detected. About 30% of the GCK-MODY patients examined were receiving unnecessary OAD or insulin therapy at the time of requesting their genetic testing, therefore the importance of having a molecular genetic diagnosis can lead to a major improvement in their quality of life.
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AIMS: To assess long-term outcome of patients with maturity onset diabetes of the young, type 2 (MODY2) in a unique large cohort of patients with the same genetic and environmental background. METHODS: We prospectively evaluated 162 patients aged 5 to 82 years, belonging to the same extended family living in the same village. All patients underwent molecular testing for the glucokinase (GCK) gene mutation identified in the proband, and were categorized into three groups (MODY2, type 2 diabetes and controls). RESULTS: The 5.5-year-old proband had the c.1278_1286del mutation in the GCK and was diagnosed with MODY2. Forty-two out of 162 participants were positive for the mutation and 39 had type 2 diabetes. Patients were followed for a mean 10.2 ± 3.7 years (range 0-14). Mean fasting blood glucose and HbA1c increased significantly over the years in MODY2 patients (133 vs. 146 mg/dL; 6.9% vs. 8.2%, respectively). Increase in HbA1c occurred only in the obese/overweight subgroups. Twenty-five percent of MODY2 patients developed diabetes complications, all were above 40 years of age. CONCLUSIONS: Although MODY2 commonly has a benign disease course, weight gain is a risk factor for diabetes complications, requiring life-long follow-up and in some patients, medical intervention.
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Familia/psicología , Glucoquinasa/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Diabetes Mellitus Tipo 2 , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Factores de Riesgo , Adulto JovenRESUMEN
Maturity-onset diabetes of the young (MODY) type 2 is caused by heterozygous inactivating mutations in the gene encoding glucokinase (GCK), a pivotal enzyme for glucose homeostasis. In the pancreas GCK regulates insulin secretion, while in the liver it promotes glucose utilization and storage. We showed that silencing the Drosophila GCK orthologs Hex-A and Hex-C results in a MODY-2-like hyperglycemia. Targeted knock-down revealed that Hex-A is expressed in insulin producing cells (IPCs) whereas Hex-C is specifically expressed in the fat body. We showed that Hex-A is essential for insulin secretion and it is required for Hex-C expression. Reduced levels of either Hex-A or Hex-C resulted in chromosome aberrations (CABs), together with an increased production of advanced glycation end-products (AGEs) and reactive oxygen species (ROS). This result suggests that CABs, in GCK depleted cells, are likely due to hyperglycemia, which produces oxidative stress through AGE metabolism. In agreement with this hypothesis, treating GCK-depleted larvae with the antioxidant vitamin B6 rescued CABs, whereas the treatment with a B6 inhibitor enhanced genomic instability. Although MODY-2 rarely produces complications, our data revealed the possibility that MODY-2 impacts genome integrity.
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Diabetes Mellitus Tipo 2/genética , Inestabilidad Genómica/genética , Glucoquinasa/genética , Estrés Oxidativo/genética , Animales , Glucemia/genética , Diabetes Mellitus Tipo 2/patología , Modelos Animales de Enfermedad , Drosophila/genética , Drosophila/crecimiento & desarrollo , Regulación del Desarrollo de la Expresión Génica/genética , Glucoquinasa/antagonistas & inhibidores , Productos Finales de Glicación Avanzada/genética , Heterocigoto , Humanos , Hiperglucemia/genética , Hiperglucemia/patología , Larva/genética , Larva/crecimiento & desarrollo , Mutación/genética , Vitamina B 6/metabolismoRESUMEN
AIMS: Heterozygous inactivating mutations in the GCK gene cause the familial, mild fasting hyperglycaemia named MODY2. Many patients with MODY2 in Asia have delayed timely treatment because they did not receive the correct diagnosis. This study aims to analyze the clinical characteristics and GCK mutations in Asian MODY2. METHODS: We have collected 110 Asian patients with MODY2 from the PubMed, Embase, Medline, Web of Science, CNKI, and Wanfang with the following search terms: 'maturity-onset diabetes of the young' OR 'MODY' OR 'maturity-onset diabetes of the young type 2' OR 'MODY2' OR 'GCK-DM' OR 'GCK-MODY'. Both mutations of GCK and clinical characteristics of MODY2 were analyzed. RESULTS: There were 96 different mutations that occurred in coding regions and non-coding regions. Exon 5 and 7 were the most common location in coding regions and missense was the primary mutation type. The proportion of probands younger than 25 was 81.8%, and 81.4% of the probands had family history of hyperglycaemia. Ninety percent and 93% of Asian MODY2 probands exhibited mild elevation in FPG (5.4-8.3 mmol/L) and HbA1c (5.6-7.6%), respectively. CONCLUSIONS: In most Asian patients, MODY2 occurred due to GCK mutation in coding regions, and exon 5 and 7 were the most common locations. FPG, HbA1c, and familial diabetes were important reference indicators for diagnosing MODY2. Altogether, the study indicates that for the young onset of diabetes with mild elevated blood glucose and HbA1c and family history of hyperglycaemia, molecular genetic testing is suggested in order to differentiate MODY2 from other types of diabetes earlier.
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Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 2/diagnóstico , Líquido Extracelular/metabolismo , Glucosa/metabolismo , Monitoreo Ambulatorio , Adulto , Biomarcadores/metabolismo , Análisis Mutacional de ADN , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Diagnóstico Diferencial , Predisposición Genética a la Enfermedad , Glucoquinasa/genética , Humanos , Monitoreo Ambulatorio/instrumentación , Mutación , Fenotipo , Valor Predictivo de las PruebasRESUMEN
The article presents a variant of maturity onset diabetes of the young type 2, caused by a rare mutation in the GCK gene. Maturity onset diabetes of the young (MODY) is a hereditary form of diabetes with an autosomal dominant type of inheritance, an onset at a young age, and a primary defect in pancreatic ß-cell function. This type of diabetes is different from classical types of diabetes mellitus (DM1 and DM2) in its clinical course, treatment strategies, and prognosis. Clinical manifestations of MODY are heterogeneous and may vary even among members of the same family, i. e., carriers of identical mutations. This phenotypic variation is due to the interaction of mutations with different genetic backgrounds and the influence of environmental factors (e. g., lifestyle). Using next-generation sequencing technology, the c.580-1G>A substitution (IVS5 -1G>A, rs1554335421) located in an acceptor splice site of intron 5 of the GCK gene was found in a proband. The identified variant cosegregated with a pathological phenotype in the examined family members. The GCK gene encodes glucokinase (hexokinase 4), which catalyzes the first step in a large number of glucose metabolic pathways such as glycolysis. Mutations in this gene are the cause of MODY2. The illness is characterized by an insignificant increase in the fasting glucose level, is a well-controlled disease without medication, and has a low prevalence of micro- and macrovascular complications of diabetes. The presented case of MODY2 reveals the clinical significance of a mutation in the splice site of the GCK gene. When nonclassical diabetes mellitus is being diagnosed in young people and pregnant women, genetic testing is needed to verify the diagnosis and to select the optimal treatment method. Key words: human; maturity onset diabetes of the young; MODY2; glucokinase gene; next-generation sequencing; genetic analysis; bioinformatics.
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Glucokinase (GCK) is a key enzyme in glucose sensing and glycemic regulation. In humans, mutations in the GCK gene cause maturity-onset diabetes of the young 2 (MODY-2), a disease that is characterized by an early-onset and persistent hyperglycemia. It is known that Gck knockout (KO) is lethal in mice with Gck KO mice dying within 2 weeks after birth. Therefore, Gck KO mice are not suitable for preclinical study and have limited suitability to study the pathophysiological role of glucokinase in vivo. Here, we report the generation of a novel rabbit with a non-frameshift mutation of GCK gene (GCK-NFS) by cytoplasm microinjection of Cas9 mRNA and gRNA. These GCK-NFS rabbits showed typical features of MODY-2 including hyperglycemia and glucose intolerance with similar survival rate and weight compared to wild-type (WT) rabbits. The diabetic phenotype including pancreatic and renal dysfunction was also found in the F1-generation rabbits, indicating that the genetic modification is germline transmissible. Treatment of GCK-NFS rabbit with glimepiride successfully reduced the fasting blood glucose drastically and improved its islet function. In conclusion, this novel GCK mutant rabbit generated with the CRISPR/Cas9 system mimics most, if not all, histopathological and functional defects seen in MODY-2 patients such as hyperglycemia and will be a valuable rabbit model for preclinical studies and drug screening for diabetes as well as for studying the pathophysiological role of glucokinase.
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Sistemas CRISPR-Cas/genética , Diabetes Mellitus Tipo 2/genética , Glucoquinasa/genética , Hiperglucemia/genética , Animales , Glucemia/genética , Eliminación de Gen , Humanos , Ratones , Ratones Noqueados , Mutación/genética , Fenotipo , ConejosRESUMEN
PURPOSE: Glucokinase-maturity onset diabetes of the young (GCK-MODY), also known as MODY2, is caused by heterozygous inactivating mutations in the GCK gene. The aim of this study is to investigate the relationship of birthweight and cardiometabolic characteristics in MODY2 patients. METHODS: Genetic screening for GCK mutations from 192 classical MODY families was performed, and birthweight and clinical profiles of 76 patients from 25 families with identified GCK mutations were collected. RESULTS: Mutations in GCK were identified in 25 (13%) of the 192 families. Four novel (c.1334 G > C, c.1289_1294delTGACGC, c.584 T > C, and c.30delC) and twenty-one previously reported mutations were identified and cosegregated with the clinical phenotypes of MODY2 within the pedigrees. MODY2 patients presented a mean birthweight of 3.11 ± 0.44 kg. Additionally, birthweight was negatively correlated with 2 h-postprandial glucose (r = -0.426, P = 0.006), glycated albumin (r = -0.462, P = 0.035), glycated hemoglobin (r = -0.529, P = 0.001), total cholesterol (r = -0.430, P = 0.016), and low-density lipoprotein cholesterol (LDL-C) (r = -0.383, P = 0.033) levels after adjustment for age, gender and BMI. Importantly, among the patients who inherited mutations from their mothers, 7 patients whose mothers were treated with insulin during pregnancy had particularly lower birthweight (2.83 ± 0.39 vs. 3.37 ± 0.39 kg; P = 0.003), higher total cholesterol (6.15 ± 0.43 vs. 4.06 ± 0.16 mmol/L; P = 0.002) and LDL-C (4.05 ± 0.35 vs. 2.21 ± 0.13 mmol/L; P = 0.001) levels compared to the other 21 patients whose mothers received no treatment. CONCLUSIONS: The correlations between birthweight and cardiometabolic indexes indicated that MODY2 patients with lower birthweight (<3.1 kg) should be monitored and treated more actively to prevent metabolic abnormalities, particularly dyslipidemia. Importantly, prenatal genic diagnosis is highly recommended to avoid inappropriate treatment in pregnancy leading to lower birthweight of offspring.
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Peso al Nacer/fisiología , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/metabolismo , Enfermedades Metabólicas/etiología , Adolescente , Adulto , Pueblo Asiatico/estadística & datos numéricos , Niño , China/epidemiología , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/genética , Femenino , Pruebas Genéticas , Quinasas del Centro Germinal/genética , Humanos , Recién Nacido , Masculino , Enfermedades Metabólicas/epidemiología , Persona de Mediana Edad , Mutación , Factores de Riesgo , Adulto JovenRESUMEN
OBJECTIVE: Heterozygous inactivating mutations in GCK are associated with defects in pancreatic insulin secretion and/or hepatic glycogen synthesis leading to mild chronic hyperglycaemia of maturity onset diabetes of young type 2 (MODY2). However, the effect of naturally occurring GCK mutations on the pathogenesis for MODY2 hyperglycaemia remains largely unclear, especially in the Asian population. The aim of this study is to explore the potential pathogenicity of novel GCK mutations related to MODY2. METHODS: Genetic screening for GCK mutations from 96 classical MODY families was performed, and structure-function characterization and clinical profile of identified GCK mutations were conducted. RESULTS: Five novel (F195S, I211T, V222D, E236G and K458R) and five known (T49N, I159V, R186X, A188T and M381T) mutations were identified and co-segregated with hyperglycaemia in their pedigrees. R186X generates non-functional truncated form and V222D and E236G fully inactivate glucokinase due to severe structure disruptions. The other seven GCK mutations exhibited marked reductions in catalytic efficiency and thermo-stability; notably, the interaction with GKRP was significantly enhanced in I211T, I159V, T49N and K458R, reduced in F195S and M381T, and completely lost with A188T. 31% (17/55) of MODY2 patients showed signs of insulin resistance. Conventional hypoglycaemia treatment did not improve the HbA1C in MODY2 patients when insulin resistance is not present. CONCLUSIONS: Five novel GCK mutations have been identified in Chinese MODY. The defects in enzymatic activity and protein stability, together with alteration of GKRP binding on GCK mutants may synergistically contribute to the development of MODY2 hyperglycaemia. No treatment should be prescribed to MODY2 patients when insulin resistance is not present.
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Diabetes Mellitus Tipo 2/genética , Glucoquinasa/genética , Adulto , Edad de Inicio , Pueblo Asiatico , China , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Femenino , Pruebas Genéticas , Glucoquinasa/metabolismo , Hemoglobina Glucada/análisis , Humanos , Hiperglucemia/genética , Hipoglucemiantes/uso terapéutico , Resistencia a la Insulina/genética , Masculino , Tamizaje Masivo , Modelos Moleculares , Mutación/genética , Linaje , Resultado del TratamientoRESUMEN
We report the case of a 12-year-old boy with a glucokinase (GCK) mutation, and diabetes with hyperinsulinemia and insulin resistance. For 4 years, the patient intermittently received insulin medications Actrapid HM and Protaphane HM (total dose 5 U/day), with glycated hemoglobin (HbA1c) levels of 6.6%-7.0%. After extensive screening the patient was found to carry a heterozygous mutation (p.E256K) in GCK (MIM #138079, reference sequence NM_000162.3). Insulin therapy was replaced by metformin at 1,700 mg/day. One year later, his HbA1c level was 6.9%, postprandial glycemia at 120 min of oral glucose tolerance test was 15.4 mmol/L, hyperinsulinemia had increased to 508.9 mU/L, homeostasis model assessment index was 114.2 and the Matsuda index was 0.15. Insulin resistance was confirmed by a hyperinsulinemic euglycemic clamp test - M-index was 2.85 mg/kg/min. This observation is a rare case of one of the clinical variants of diabetes, which should be taken into account by a vigilant endocrinologist due to the need for nonstandard diagnostic and therapeutic approaches.
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BACKGROUND: Maturity-onset diabetes of the young 2 (MODY2) is a form of diabetes that is clinically characterized by early age at onset and mild hyperglycemia, and has a low risk of late complications. It is often underdiagnosed due to its mild symptoms. To date, over 600 different GCK/MODY2 mutations have been reported. Despite only a few de novo mutations having been described, recent studies have reported the detection of a higher frequency of this kind of mutation. Therefore, de novo mutations could be more frequent than previously described. Even though common recommendations regarding the diagnosis of monogenic diabetes include the existence of a strong family history of diabetes, here we describe the study of mutations in two families with a symptomatic individual with clear clinical features of MODY2 but without any family history of diabetes. METHODS: Genetic diagnosis in a group of participants with MODY2 characteristics was carried out by direct sequencing of coding regions of the GCK gene and analysis of mutations found using bioinformatics tools. RESULTS: We found two de novo mutations, one of them novel, constituting 14.29% of all the participants who were phenotyped as MODY2. CONCLUSIONS: The number of mutations in GCK/MODY2 or even other MODY-related genes is undoubtedly underestimated, as accepted criteria for performing genetic tests include family history of the pathology. These cases illustrate the value of analyzing the GCK gene in patients with clinical features of MODY2, even in the absence of family history of the condition as it is essential for establishing the correct treatment.