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1.
Endocrinol. diabetes nutr. (Ed. impr.) ; 66(10): 654-662, dic. 2019.
Artigo em Espanhol | IBECS | ID: ibc-184793

RESUMO

Las enfermedades endocrinas están experimentando un importante incremento de su prevalencia, debido a causas de diversa índole, entre ellas la epidemia de obesidad y de desnutrición, el envejecimiento de la población, pero también el efecto de los disruptores endocrinos, entre otros. Por otra parte, las nuevas tecnologías, tanto a nivel de analítica molecular y genética, de imagen y de nuevos dispositivos terapéuticos, obligan a que la comunidad profesional endocrina en España tenga que estar en constante formación. La conexión con los pacientes a través de sus asociaciones, cada vez más activas, y con la sociedad civil en general, el compromiso profesional y la demanda de diversos colectivos sociales de una atención moderna y equitativa, y a llevar a cabo investigación que facilite la consecución de avances para los pacientes, obligan al especialista en Endocrinología y Nutrición, y a la Sociedad Española de Endocrinología y Nutrición (SEEN), a posicionarse y dar respuesta a todos estos retos. En el presente documento, la SEEN expone sus propuestas y su estrategia hasta el 2022


Endocrine diseases are experiencing an important increase in their prevalence, due to causes of various kinds, including the epidemic of obesity and malnutrition, the aging of the population, but also the effect of endocrine disruptors, among others. On the other hand, new technologies, both in terms of molecular and genetic analysis, image and new therapeutic devices, require that the endocrine professional community in Spain must be in constant training. The connection with patients through their associations, increasingly active, and with the civil society in general, the professional commitment and demand of various social groups for a modern and equitable care, and to carry out research that facilitates the achievement of advances for patients, forces the specialist in endocrinology and nutrition and the Spanish Society of Endocrinology and Nutrition (SEEN) to position themselves and respond to all these challenges. In this document, the SEEN presents its proposals and its strategy until 2022


Assuntos
Endocrinologia/organização & administração , Sociedades Médicas/organização & administração , Sociedades Médicas/tendências , Estratégias , Endocrinologia/tendências , Sistemas Nacionais de Saúde , Medicina/organização & administração , Promoção da Saúde , Espanha
2.
Endocrinol Diabetes Nutr ; 66(10): 654-662, 2019 Dec.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-31272927

RESUMO

Endocrine diseases are experiencing an important increase in their prevalence, due to causes of various kinds, including the epidemic of obesity and malnutrition, the aging of the population, but also the effect of endocrine disruptors, among others. On the other hand, new technologies, both in terms of molecular and genetic analysis, image and new therapeutic devices, require that the endocrine professional community in Spain must be in constant training. The connection with patients through their associations, increasingly active, and with the civil society in general, the professional commitment and demand of various social groups for a modern and equitable care, and to carry out research that facilitates the achievement of advances for patients, forces the specialist in endocrinology and nutrition and the Spanish Society of Endocrinology and Nutrition (SEEN) to position themselves and respond to all these challenges. In this document, the SEEN presents its proposals and its strategy until 2022.

3.
Med. clín (Ed. impr.) ; 153(2): 82.e1-82.e17, jul. 2019. tab
Artigo em Espanhol | IBECS | ID: ibc-183369

RESUMO

Antecedentes y objetivos: La enfermedad de Steinert o distrofia miotónica tipo 1 (DM1), (OMIM 160900) es la miopatía más prevalente en el adulto. Es una enfermedad multisistémica con alteración de prácticamente todos los órganos y tejidos y una variabilidad fenotípica muy amplia, lo que implica que deba ser atendida por diferentes especialistas que dominen las alteraciones más importantes. En los últimos años se ha avanzado de manera exponencial en el conocimiento de la enfermedad y en su manejo. El objetivo de la guía es establecer recomendaciones para el diagnóstico, el pronóstico, el seguimiento y el tratamiento de las diferentes alteraciones de la DM1. Material y métodos: Esta guía de consenso se ha realizado de manera multidisciplinar. Se ha contado con neurólogos, neumólogos, cardiólogos, endocrinólogos, neuropediatras y genetistas que han realizado una revisión sistemática de la literatura. Recomendaciones: Se recomienda realizar un diagnóstico genético con cuantificación precisa de tripletes CTG. Los pacientes con DM1 deben seguir control cardiológico y neumológico de por vida. Antes de cualquier cirugía con anestesia general debe realizarse una evaluación respiratoria. Debe monitorizarse la presencia de síntomas de disfagia periódicamente. Debe ofrecerse consejo genético a los pacientes con DM1 y a sus familiares. Conclusión: La DM1 es una enfermedad multisistémica que requiere un seguimiento en unidades especializadas multidisciplinares


Background and objectives: Steinert's disease or myotonic dystrophy type 1 (MD1), (OMIM 160900), is the most prevalent myopathy in adults. It is a multisystemic disorder with dysfunction of virtually all organs and tissues and a great phenotypical variability, which implies that it has to be addressed by different specialities with experience in the disease. The knowledge of the disease and its management has changed dramatically in recent years. This guide tries to establish recommendations for the diagnosis, prognosis, follow-up and treatment of the complications of MD1. Material and methods: Consensus guide developed through a multidisciplinary approach with a systematic literature review. Neurologists, pulmonologists, cardiologists, endocrinologists, neuropaediatricians and geneticists have participated in the guide. Recommendations: The genetic diagnosis should quantify the number of CTG repetitions. MD1 patients need cardiac and respiratory lifetime follow-up. Before any surgery under general anaesthesia, a respiratory evaluation must be done. Dysphagia must be screened periodically. Genetic counselling must be offered to patients and relatives. Conclusion: MD1 is a multisystemic disease that requires specialised multidisciplinary follow-up


Assuntos
Humanos , Distrofia Miotônica/diagnóstico , Distrofia Miotônica/fisiopatologia , Prognóstico , Seguimentos , Distrofia Miotônica/genética , Neurofisiologia , Planejamento Familiar , Diagnóstico Pré-Natal , Miotonia , Neuroimagem
4.
Med Clin (Barc) ; 153(2): 82.e1-82.e17, 2019 07 19.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-30685181

RESUMO

BACKGROUND AND OBJECTIVES: Steinert's disease or myotonic dystrophy type 1 (MD1), (OMIM 160900), is the most prevalent myopathy in adults. It is a multisystemic disorder with dysfunction of virtually all organs and tissues and a great phenotypical variability, which implies that it has to be addressed by different specialities with experience in the disease. The knowledge of the disease and its management has changed dramatically in recent years. This guide tries to establish recommendations for the diagnosis, prognosis, follow-up and treatment of the complications of MD1. MATERIAL AND METHODS: Consensus guide developed through a multidisciplinary approach with a systematic literature review. Neurologists, pulmonologists, cardiologists, endocrinologists, neuropaediatricians and geneticists have participated in the guide. RECOMMENDATIONS: The genetic diagnosis should quantify the number of CTG repetitions. MD1 patients need cardiac and respiratory lifetime follow-up. Before any surgery under general anaesthesia, a respiratory evaluation must be done. Dysphagia must be screened periodically. Genetic counselling must be offered to patients and relatives. CONCLUSION: MD1 is a multisystemic disease that requires specialised multidisciplinary follow-up.

5.
Artigo em Inglês | MEDLINE | ID: mdl-30530875

RESUMO

Familial hypocalciuric hypercalcemia type I is an autosomal dominant disorder caused by heterozygous loss-of-function mutations in the CASR gene and is characterized by moderately elevated serum calcium concentrations, low urinary calcium excretion and inappropriately normal or mildly elevated parathyroid hormone (PTH) concentrations. We performed a clinical and genetic characterization of one patient suspected of familial hypocalciuric hypercalcemia type I. Patient presented persistent hypercalcemia with normal PTH and 25-hydroxyvitamin D levels. The CASR was screened for mutations by PCR followed by direct Sanger sequencing and, in order to detect large deletions or duplications, multiplex ligation-dependent probe amplification (MLPA) was used. One large deletion of 973 nucleotides in heterozygous state (c.1733-255_2450del) was detected. This is the first large deletion detected by the MLPA technique in the CASR gene. Learning points: Molecular studies are important to confirm the differential diagnosis of FHH from primary hyperparathyroidism. Large deletions or duplications in the CASR gene can be detected by the MLPA technique. Understanding the functional impact of the mutations is critical for leading pharmacological research and could facilitate the therapy of patients.

6.
J Natl Cancer Inst ; 107(5)2015 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-25766404

RESUMO

Disruption of the Krebs cycle is a hallmark of cancer. IDH1 and IDH2 mutations are found in many neoplasms, and germline alterations in SDH genes and FH predispose to pheochromocytoma/paraganglioma and other cancers. We describe a paraganglioma family carrying a germline mutation in MDH2, which encodes a Krebs cycle enzyme. Whole-exome sequencing was applied to tumor DNA obtained from a man age 55 years diagnosed with multiple malignant paragangliomas. Data were analyzed with the two-sided Student's t and Mann-Whitney U tests with Bonferroni correction for multiple comparisons. Between six- and 14-fold lower levels of MDH2 expression were observed in MDH2-mutated tumors compared with control patients. Knockdown (KD) of MDH2 in HeLa cells by shRNA triggered the accumulation of both malate (mean ± SD: wild-type [WT] = 1±0.18; KD = 2.24±0.17, P = .043) and fumarate (WT = 1±0.06; KD = 2.6±0.25, P = .033), which was reversed by transient introduction of WT MDH2 cDNA. Segregation of the mutation with disease and absence of MDH2 in mutated tumors revealed MDH2 as a novel pheochromocytoma/paraganglioma susceptibility gene.


Assuntos
DNA de Neoplasias/análise , Exoma , Mutação em Linhagem Germinativa , Malato Desidrogenase/genética , Paraganglioma/genética , Paraganglioma/metabolismo , Ciclo do Ácido Cítrico , Regulação para Baixo , Fumaratos/metabolismo , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Células HeLa , Humanos , Malato Desidrogenase/metabolismo , Malatos/metabolismo , Masculino , Pessoa de Meia-Idade , Feocromocitoma/genética , Feocromocitoma/metabolismo , Análise de Sequência de DNA
7.
Int J Clin Pharmacol Ther ; 53(3): 230-40, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25066229

RESUMO

Despite the variety of therapeutic options for the management of type 2 diabetes mellitus, many patients fail to meet glycated hemoglobin (HbA1c) targets. The relative contribution of postprandial plasma glucose (PPG) to overall HbA1c is estimated at 40-60%, with the effect of PPG on HbA1c being prominent in patients on basal insulin. The development of glucagon-like peptide-1 receptor agonists (GLP-1RAs) has been an important achievement in diabetes management and has become an established treatment. Of available GLP-1RAs, lixisenatide is a once-daily prandial GLP-1RA that has been shown to produce a reduction in HbA1c with a pronounced postprandial effect, suggesting a complementary effect between lixisenatide and basal insulin on PPG and fasting plasma glucose, resulting in a beneficial effect on body weight in all populations. Therefore, lixisenatide will make an important addition to current options for treating diabetes, especially for patients not achieving glycemic targets with basal insulin therapy.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Peptídeos/uso terapêutico , Receptores de Glucagon/agonistas , Animais , Biomarcadores/sangue , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Quimioterapia Combinada , Receptor do Peptídeo Semelhante ao Glucagon 1 , Hemoglobina A Glicada/metabolismo , Humanos , Hipoglicemiantes/efeitos adversos , Insulina/efeitos adversos , Peptídeos/efeitos adversos , Receptores de Glucagon/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Resultado do Tratamento
8.
Endocrinol. nutr. (Ed. impr.) ; 61(10): 541-547, dic. 2014. ilus
Artigo em Espanhol | IBECS | ID: ibc-130975

RESUMO

Objetivo Evaluar el control glucémico en pacientes con diabetes tipo 2 que son remitidos a Endocrinología desde Atención Primaria (AP) por no estar controlados con antidiabéticos orales sin insulinoterapia; y el grado de implementación del consenso nacional de la Sociedad Española de Diabetes, valorando los sucesivos escalones, primero (Pe), segundo (Se) y tercero (Te), del abordaje terapéutico. Material y métodos Estudio observacional retrospectivo en el que 81 endocrinólogos evaluaron los pacientes mayores de 40 años remitidos por AP entre julio de 2012 y julio de 2013, tratados con 1-2 antidiabéticos orales, no insulinizados, con una hemoglobina glucosilada (HbA1c) ≥ 6,5%, y en los que se disponía en los 3 meses previos de Hb1Ac, glucosa capilar en ayunas y glucosa capilar posprandial. Resultados Fueron evaluables 285 pacientes (57,6% varones), con una edad media (DE) de 63,1 (9,7) años, HbA1c media de 8,5 (1,2) %, glucosa capilar en ayunas 171,7 (43) mg/dl y glucosa capilar posprandial 206,8 (50) mg/dl. En AP el 26,0% de los pacientes se situaban en Pe terapéutico y el 74,0% en el Se. En atención especializada solo el 9,8% de la cohorte está en el Pe, el 42,8% en el Se y el 47,4% en el Te. Los fármacos más prescritos en AP fueron metformina (90,2%), inhibidores DPP-4 (34,4%) y sulfonilureas (30,5%), mientras que en Endocrinología fueron metformina (86%), insulina (56,8%) e inhibidores DPP-4 (49,8%). Las guías clínicas más seguidas fueron las de la American Diabetes Association y el consenso de la Sociedad Española de Diabetes, en un 77 y 45% respectivamente. Conclusiones Aproximadamente la mitad de los pacientes con diabetes mellitus 2 no insulinizados y tratados con antidiabéticos orales en AP, son tratados con insulina en Endocrinología. La guía clínica más seguida por el especialista es la de la American Diabetes Association (AU)


Objective To assess blood glucose in patients with uncontrolled type 2 diabetes mellitus treated with oral antidiabetic drugs in primary care at the time of referral to specialized endocrinologists, and the degree of implementation of the national consensus guidelines of the Spanish Society of Diabetes by evaluating steps one (S1), two (S2), and three (S3) of the escalating therapy. Material and methods Retrospective, observational study where 81 endocrinologists evaluated patients ≥40 years of age referred from primary care between July 2012 and July 2013, treated with 1 to 2 oral antidiabetic drugs but no insulin therapy, and with glycosylated hemoglobin (HbA1c) levels ≥6.5%. Patients also had to have HbA1c levels and both fasting and postprandial plasma glucose measurements from the previous three months. Results A total of 285 patients (57.6% males) were assessed. Mean (SD) age was 63.1 (9.7) years, mean HbA1c was 8.5 (1.2) %, mean FPG was 171.7 (43) mg/dL, and mean postprandial plasma glucose was 206.8 (50) mg/dL. In primary care, 26.0% of patients were at S1 and 74.0% were at S2. After referral to the endocrinologist, 9.8% of patients moved onto S1, 42.8% onto S2, and 47.4% onto S3. Oral antidiabetic drugs most commonly prescribed in primary care were metformin (90.2%), DPP-4 inhibitors (34.4%), and sulfonylureas (30.5%), while drugs most commonly used in the specialized endocrinology setting were metformin (86%), insulin (56.8%), and DPP-4 inhibitors (49.8%). The most commonly followed guidelines were those of the American Diabetes Association and the consensus guidelines of the Spanish Society of Diabetes, in 77% and 45% of cases respectively. Conclusions Approximately half the patients treated with oral antidiabetic drugs in primary care are prescribed insulin after referral to an endocrinology specialist. The most commonly followed guidelines in specialized care are the American Diabetes Association guidelines (AU)


Assuntos
Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hiperglicemia/prevenção & controle , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Índice Glicêmico
9.
Endocrinol Nutr ; 61(10): 541-7, 2014 Dec.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-25260336

RESUMO

OBJECTIVE: To assess blood glucose in patients with uncontrolled type 2 diabetes mellitus treated with oral antidiabetic drugs in primary care at the time of referral to specialized endocrinologists, and the degree of implementation of the national consensus guidelines of the Spanish Society of Diabetes by evaluating steps one (S1), two (S2), and three (S3) of the escalating therapy. MATERIAL AND METHODS: Retrospective, observational study where 81 endocrinologists evaluated patients ≥40 years of age referred from primary care between July 2012 and July 2013, treated with 1 to 2 oral antidiabetic drugs but no insulin therapy, and with glycosylated hemoglobin (HbA(1c)) levels ≥6.5%. Patients also had to have HbA(1c) levels and both fasting and postprandial plasma glucose measurements from the previous three months. RESULTS: A total of 285 patients (57.6% males) were assessed. Mean (SD) age was 63.1 (9.7) years, mean HbA1c was 8.5 (1.2) %, mean FPG was 171.7 (43) mg/dL, and mean postprandial plasma glucose was 206.8 (50) mg/dL. In primary care, 26.0% of patients were at S1 and 74.0% were at S2. After referral to the endocrinologist, 9.8% of patients moved onto S1, 42.8% onto S2, and 47.4% onto S3. Oral antidiabetic drugs most commonly prescribed in primary care were metformin (90.2%), DPP-4 inhibitors (34.4%), and sulfonylureas (30.5%), while drugs most commonly used in the specialized endocrinology setting were metformin (86%), insulin (56.8%), and DPP-4 inhibitors (49.8%). The most commonly followed guidelines were those of the American Diabetes Association and the consensus guidelines of the Spanish Society of Diabetes, in 77% and 45% of cases respectively. CONCLUSIONS: Approximately half the patients treated with oral antidiabetic drugs in primary care are prescribed insulin after referral to an endocrinology specialist. The most commonly followed guidelines in specialized care are the American Diabetes Association guidelines.


Assuntos
Diabetes Mellitus Tipo 2/sangue , Idoso , Glicemia/análise , Diabetes Mellitus Tipo 2/tratamento farmacológico , Endocrinologia , Jejum/sangue , Hemoglobina A Glicada/análise , Fidelidade a Diretrizes , Humanos , Hiperglicemia/sangue , Hiperglicemia/prevenção & controle , Hipoglicemiantes/uso terapêutico , Pessoa de Meia-Idade , Período Pós-Prandial , Guias de Prática Clínica como Assunto , Encaminhamento e Consulta , Estudos Retrospectivos , Espanha
10.
J Pediatr Endocrinol Metab ; 27(11-12): 1089-94, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24945424

RESUMO

OBJECTIVES: Given that tricho-rhino-phalangeal syndrome (TRPS) and pseudohypoparathyroidism/pseudopseudohypoparathyroidism (PHP/PPHP) are very rare monogenic disorders that share some features (distinctive facies, short stature, brachydactyly and, in some patients, intellectual disability) that lead to their misdiagnosis in some cases, our objective was to identify clinical, biochemical or radiological signs that could help to distinguish these two syndromes. METHODS AND RESULTS: We report on two cases, which were referred to the Endocrinology and Pediatric Endocrinology Services for obesity. Clinical evaluation initially suggested the diagnosis of PHP-Ia [phenotype suggestive of Albright hereditary osteodystrophy (AHO) with parathyroid hormone (PTH) resistance] and PPHP (phenotype resembling AHO, without PTH resistance), but (epi)genetic analysis of the GNAS locus ruled out the suspected diagnosis. Further clinical re-evaluation prompted us to suspect TRPS, and this was confirmed genetically. CONCLUSION: TRPS was mistakenly identified as PHP/PPHP because of the coexistence of obesity and brachydactyly, with PTH resistance in one of the cases. Specific traits such as sparse scalp hair and a pear-shaped nose, present in both cases, can be considered pathognomonic signs of TRPS, which could help us to reach a correct diagnosis.


Assuntos
Anormalidades Múltiplas/classificação , Anormalidades Múltiplas/diagnóstico , Pseudopseudo-Hipoparatireoidismo/classificação , Pseudopseudo-Hipoparatireoidismo/diagnóstico , Anormalidades Múltiplas/genética , Adulto , Sequência de Bases , Braquidactilia/patologia , Criança , Análise Mutacional de DNA , Proteínas de Ligação a DNA/genética , Diagnóstico Diferencial , Feminino , Dedos/anormalidades , Dedos/patologia , Cabelo/anormalidades , Cabelo/patologia , Mãos/patologia , Humanos , Dados de Sequência Molecular , Mutação/genética , Nariz/anormalidades , Nariz/patologia , Obesidade , Fenótipo , Pseudopseudo-Hipoparatireoidismo/genética , Síndrome , Fatores de Transcrição/genética
11.
Hum Mol Genet ; 23(9): 2440-6, 2014 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-24334767

RESUMO

Malignant pheochromocytoma (PCC) and paraganglioma (PGL) are mostly caused by germline mutations of SDHB, encoding a subunit of succinate dehydrogenase. Using whole-exome sequencing, we recently identified a mutation in the FH gene encoding fumarate hydratase, in a PCC with an 'SDH-like' molecular phenotype. Here, we investigated the role of FH in PCC/PGL predisposition, by screening for germline FH mutations in a large international cohort of patients. We screened 598 patients with PCC/PGL without mutations in known PCC/PGL susceptibility genes. We searched for FH germline mutations and large deletions, by direct sequencing and multiplex ligation-dependent probe amplification methods. Global alterations in DNA methylation and protein succination were assessed by immunohistochemical staining for 5-hydroxymethylcytosine (5-hmC) and S-(2-succinyl) cysteine (2SC), respectively. We identified five pathogenic germline FH mutations (four missense and one splice mutation) in five patients. Somatic inactivation of the second allele, resulting in a loss of fumarate hydratase activity, was demonstrated in tumors with FH mutations. Low tumor levels of 5-hmC, resembling those in SDHB-deficient tumors, and positive 2SC staining were detected in tumors with FH mutations. Clinically, metastatic phenotype (P = 0.007) and multiple tumors (P = 0.02) were significantly more frequent in patients with FH mutations than those without such mutations. This study reveals a new role for FH in susceptibility to malignant and/or multiple PCC/PGL. Remarkably, FH-deficient PCC/PGLs display the same pattern of epigenetic deregulation as SDHB-mutated malignant PCC/PGL. Therefore, we propose that mutation screening for FH should be included in PCC/PGL genetic testing, at least for tumors with malignant behavior.


Assuntos
Fumarato Hidratase/genética , Mutação em Linhagem Germinativa/genética , Paraganglioma/genética , Feocromocitoma/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Éxons/genética , Feminino , Predisposição Genética para Doença/genética , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
12.
PLoS One ; 7(1): e30518, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22291974

RESUMO

Glucokinase (GK) acts as a glucose sensor in the pancreatic beta-cell and regulates insulin secretion. Heterozygous mutations in the human GK-encoding GCK gene that reduce the activity index increase the glucose-stimulated insulin secretion threshold and cause familial, mild fasting hyperglycaemia, also known as Maturity Onset Diabetes of the Young type 2 (MODY2). Here we describe the biochemical characterization of five missense GK mutations: p.Ile130Thr, p.Asp205His, p.Gly223Ser, p.His416Arg and p.Ala449Thr. The enzymatic analysis of the corresponding bacterially expressed GST-GK mutant proteins show that all of them impair the kinetic characteristics of the enzyme. In keeping with their position within the protein, mutations p.Ile130Thr, p.Asp205His, p.Gly223Ser, and p.His416Arg strongly decrease the activity index of GK, affecting to one or more kinetic parameters. In contrast, the p.Ala449Thr mutation, which is located in the allosteric activator site, does not affect significantly the activity index of GK, but dramatically modifies the main kinetic parameters responsible for the function of this enzyme as a glucose sensor. The reduced Kcat of the mutant (3.21±0.28 s(-1) vs 47.86±2.78 s(-1)) is balanced by an increased glucose affinity (S(0.5) = 1.33±0.08 mM vs 7.86±0.09 mM) and loss of cooperativity for this substrate. We further studied the mechanism by which this mutation impaired GK kinetics by measuring the differential effects of several competitive inhibitors and one allosteric activator on the mutant protein. Our results suggest that this mutation alters the equilibrium between the conformational states of glucokinase and highlights the importance of the fine-tuning of GK and its role in glucose sensing.


Assuntos
Diabetes Mellitus Tipo 2/genética , Glucoquinase/genética , Glucoquinase/metabolismo , Glucose/metabolismo , Mutação de Sentido Incorreto/fisiologia , Adolescente , Adulto , Alanina/genética , Substituição de Aminoácidos/genética , Substituição de Aminoácidos/fisiologia , Criança , Pré-Escolar , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Glucoquinase/fisiologia , Humanos , Lactente , Masculino , Treonina/genética , Adulto Jovem
13.
Mol Med ; 17(3-4): 256-65, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21170474

RESUMO

Hepatocyte nuclear factor 1-α (HNF-1α) is a homeodomain transcription factor expressed in a variety of tissues (including liver and pancreas) that regulates a wide range of genes. Heterozygous mutations in the gene encoding HNF-1α (HNF1A) cause familial young-onset diabetes, also known as maturity-onset diabetes of the young, type 3 (MODY3). The variability of the MODY3 clinical phenotype can be due to environmental and genetic factors as well as to the type and position of mutations. Thus, functional characterization of HNF1A mutations might provide insight into the molecular defects explaining the variability of the MODY3 phenotype. We have functionally characterized six HNF1A mutations identified in diabetic patients: two novel ones, p.Glu235Gly and c-57-64delCACGCGGT;c-55G>C; and four previously described, p.Val133Met, p.Thr196Ala, p.Arg271Trp and p.Pro379Arg. The effects of mutations on transcriptional activity have been measured by reporter assays on a subset of HNF-1α target promoters in Cos7 and Min6 cells. Target DNA binding affinities have been quantified by electrophoretic mobility shift assay using bacterially expressed glutathione-S-transferase (GST)-HNF-1α fusion proteins and nuclear extracts of transfected Cos7 cells. Our functional studies revealed that mutation c-57-64delCACGCGGT;c-55G>C reduces HNF1A promoter activity in Min6 cells and that missense mutations have variable effects. Mutation p.Arg271Trp impairs HNF-1α activity in all conditions tested, whereas mutations p.Val133Met, p.Glu235Gly and p.Pro379Arg exert differential effects depending on the target promoter. In contrast, substitution p.Thr196Ala does not appear to alter HNF-1α function. Our results suggest that HNF1A mutations may have differential effects on the regulation of specific target genes, which could contribute to the variability of the MODY3 clinical phenotype.


Assuntos
Diabetes Mellitus/genética , Regulação da Expressão Gênica , Fator 1-alfa Nuclear de Hepatócito/genética , Mutação , Adolescente , Adulto , Idade de Início , Animais , Sequência de Bases , Western Blotting , Células COS , Linhagem Celular Tumoral , Análise Mutacional de DNA , Diabetes Mellitus/classificação , Diabetes Mellitus/epidemiologia , Saúde da Família , Feminino , Testes Genéticos , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Humanos , Luciferases/genética , Luciferases/metabolismo , Masculino , Mutação de Sentido Incorreto , Regiões Promotoras Genéticas/genética , Espanha/epidemiologia , Adulto Jovem
14.
Endocrinol. nutr. (Ed. impr.) ; 55(9): 433-435, nov. 2008.
Artigo em Espanhol | IBECS | ID: ibc-70732

RESUMO

El caso que se presenta es el de una mujer joven, cuyo diagnóstico de diabetes monogénica por mutación del gen de la glucocinasa, en el tercer embarazo, planteó un cambio en la actitud terapéutica respecto a susgestaciones previas. Se hace, asimismo, un breve repaso de la literatura sobre las implicaciones obstétricas de las pacientes gestantes condiabetes mellitus MODY 2 (AU)


We report the case of a young woman who was diagnosed with monogenic diabetes caused by a glucokinase gene mutation during the third trimester of pregnancy,r equiring a change in treatment plan in comparison with her previous pregnancies. We also discuss the implications for obstetric management in patients with maturity onset diabetes of the young, type2 (MODY-2) (AU)


Assuntos
Humanos , Feminino , Gravidez , Adulto , Diabetes Gestacional/metabolismo , Diabetes Mellitus Tipo 2/genética , Reação em Cadeia da Polimerase , Mutação
15.
Endocrinol Nutr ; 55(9): 433-5, 2008 Oct.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-22974456

RESUMO

We report the case of a young woman who was diagnosed with monogenic diabetes caused by a glucokinase gene mutation during the third trimester of pregnancy, requiring a change in treatment plan in comparison with her previous pregnancies. We also discuss the implications for obstetric management in patients with maturity onset diabetes of the young, type 2 (MODY-2).

16.
Endocrinol. nutr. (Ed. impr.) ; 54(3): 186-188, mar. 2007.
Artigo em Espanhol | IBECS | ID: ibc-052520

RESUMO

El acetato de megestrol es un progestágeno sintético con acciones e indicaciones similares a las de la progesterona y más recientemente ha sido utilizado para estimular el apetito en pacientes con caquexia asociada al cáncer y al síndrome de inmunodeficiencia humana adquirida (sida). Entre los efectos adversos descritos en relación con este fármaco están las anomalías del metabolismo hidrocarbonado. Presentamos el caso de un paciente que desarrolló un síndrome de descompensación hiperglucémica hiperosmolar no cetósica tras la introducción de acetato de megestrol como estimulante del apetito (AU)


Megestrol acetate is a synthetic, orally active progestational agent with actions and indications similar to those of progesterone. This agent has been used as an appetite stimulant in patients with cachexia associated with cancer and acquired immunodeficiency syndrome (AIDS). One of the adverse effects that has been described in relation with this drug is abnormal glucose metabolism. We present a case of hyperglycemic hyperosmolar nonketotic syndrome in a patient who received this agent as an appetite stimulant (AU)


Assuntos
Masculino , Pessoa de Meia-Idade , Humanos , Coma Hiperglicêmico Hiperosmolar não Cetótico/induzido quimicamente , Acetato de Megestrol/efeitos adversos , Anorexia/tratamento farmacológico , Perda de Peso , Estimulantes do Apetite/efeitos adversos , Acetato de Megestrol/uso terapêutico
17.
Endocrinol. nutr. (Ed. impr.) ; 54(1): 10-12, ene. 2007.
Artigo em Espanhol | IBECS | ID: ibc-052495

RESUMO

El hipotiroidismo primario es una alteración endocrinológica muy frecuente. Puede aparecer asociado a varios síndromes genéticos de escasa prevalencia. El síndrome 18q se produce por una deleción de la región terminal del brazo largo del cromosoma 18. Asocia rasgos dismórficos, anomalías endocrinológicas, oftalmológicas, neuromusculares e inmunológicas. El diagnóstico se suele establecer en los primeros años de vida. Presentamos el caso de una mujer de 42 años con rasgos dismórficos que consultaba por astenia y dificultad para perder peso, detectándose en el estudio hormonal un hipotiroidismo subclínico y un hipogonadismo hipergonadotropo y en el estudio genético un síndrome 18q (AU)


Primary hypothyroidism is a highly common endocrinological disease, which can be associated with several genetic syndromes with a very low prevalence. Chromosome 18q- syndrome is caused by a deletion of the long arm of chromosome 18. An association of dysmorphic features with endocrinologic, ophthalmologic, neuromuscular and immune anomalies can be found. Diagnosis is usually made in the first few years of life. We present a 42-year-old dysmorphic woman who complained of asthenia and difficulty in losing weight. Subclinical hypothyroidism and a hypergonadotropic hypogonadism were found in hormone analysis and chromosome 18q- syndrome was found in genetic analysis (AU)


Assuntos
Feminino , Adulto , Humanos , Cromossomos Humanos Par 18/genética , Deleção Cromossômica , Hipotireoidismo/genética , Hipogonadismo/genética , Astenia/genética , Síndrome
18.
J Perinat Med ; 34(4): 323-31, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16856824

RESUMO

OBJECTIVE: To investigate the effects of pregestational diabetes on pregnancy outcome. METHODS: Data of 126 women with pregestational diabetes prospectively collected and controlled in a single tertiary center. HbA(1C) levels at early pregnancy were registered. Adverse pregnancy outcome was defined as spontaneous abortion, congenital defect, stillbirth, or neonatal death. RESULTS: There were 10 spontaneous abortions (7.9%) and 17 fetuses with congenital anomalies (13.4%), including 8 major malformations (6.3%). Compared with pregnancies with a favorable outcome, a higher HbA(1C) concentration in early pregnancy was observed in pregnancies with adverse perinatal outcome [mean (SD): 6.3 (1.6) vs. 7.2 (1.7), P=0.001]. A positive correlation between increased maternal HbA(1C) levels and the rate of fetal malformations was observed, and the group of women with poor metabolic control (early maternal HbA(1c) concentration >7%) showed a 3 to 5-fold increase in the major malformation rate. Cardiovascular and genitourinary defects accounted for 58.8% of the anomalies, and the ultrasound examinations detected seven of them (41.2%). For major malformations, the detection rate was 50% (4/8). Perinatal mortality rate was 26 per thousand (3/116). There was almost 5-fold increase in the total pregnancy loss rate in the poor control group compared with the group with fair control [22.2% vs. 5.3%, OR (95% CI): 5.1 (1.4-17.1)]. Only 11.9% of mothers used a preconception care program. CONCLUSIONS: Pregestational diabetes mellitus is a significant risk factor for the developing fetus. Spontaneous abortions and congenital defects are more common when a poor metabolic control is present in early pregnancy. It is most important to improve access to preconception care programs for achieving a good metabolic control in early pregnancy. Ultrasound examinations have a low performance for detecting congenital defects in diabetic pregnancies.


Assuntos
Gravidez em Diabéticas , Aborto Espontâneo/epidemiologia , Aborto Espontâneo/etiologia , Adulto , Anormalidades Congênitas/epidemiologia , Anormalidades Congênitas/etiologia , Feminino , Morte Fetal/epidemiologia , Morte Fetal/etiologia , Hemoglobina A Glicada/metabolismo , Humanos , Recém-Nascido , Cuidado Pré-Concepcional/estatística & dados numéricos , Gravidez , Resultado da Gravidez , Gravidez em Diabéticas/sangue , Estudos Prospectivos , Espanha/epidemiologia , Natimorto/epidemiologia
19.
Biochem J ; 393(Pt 1): 389-96, 2006 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-16173921

RESUMO

Glucokinase acts as the pancreatic glucose sensor and plays a critical role in the regulation of insulin secretion by the beta-cell. Heterozygous mutations in the glucokinase-encoding GCK gene, which result in a reduction of the enzymatic activity, cause the monogenic form of diabetes, MODY2 (maturity-onset diabetes of the young 2). We have identified and functionally characterized missense mutations in the GCK gene in diabetic families that result in protein mutations Leu165-->Phe, Glu265-->Lys and Thr206-->Met. The first two are novel GCK mutations that co-segregate with the diabetes phenotype in their respective families and are not found in more than 50 healthy control individuals. In order to measure the biochemical effects of these missense mutations on glucokinase activity, we bacterially expressed and affinity-purified islet human glucokinase proteins carrying the respective mutations and fused to GST (glutathione S-transferase). Enzymatic assays on the recombinant proteins revealed that mutations Thr206-->Met and Leu165-->Phe strongly affect the kinetic parameters of glucokinase, in agreement with the localization of both residues close to the active site of the enzyme. In contrast, mutation Glu265-->Lys, which has a weaker effect on the kinetics of glucokinase, strongly affects the protein stability, suggesting a possible structural defect of this mutant protein. Finally, none of the mutations tested appears to affect the interaction of gluco-kinase with the glucokinase regulatory protein in the yeast two-hybrid system.


Assuntos
Diabetes Mellitus Tipo 2/enzimologia , Diabetes Mellitus Tipo 2/genética , Glucoquinase/genética , Glucoquinase/metabolismo , Mutação/genética , Adulto , Sequência de Aminoácidos , Estabilidade Enzimática/genética , Feminino , Predisposição Genética para Doença , Glucoquinase/química , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Linhagem , Fenótipo , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos
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