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Background and Aims: Members of the diabetes community have started developing their own Do-It-Yourself Artificial Pancreas Systems (DIY APS) , also known as Open-Source Automated Insulin Delivery (AID) Systems and use the online hashtag “#WeAreNotWaiting” to promote the development of it. DIY APS systems inclued OpenAPS, Loop and AndroidAPS. The aim of the study was to evaluate retrospectively glycemic outcomes with the use of DIY APS in adults with T1D. Methods: Subjects with T1D started using open-source AID systems (AndroidAPS with Insight insulin pump and Dexcom G6 or FreeStyle Libre 2 CGM and Loop with Minimed Paradigm and Dexcom G6) . Glycemic outcomes at baseline on open-loop and after 12 months on DIY APS were compared including time in different glucose ranges, management indicator (GMI) , mean glucosa levels, glycemic variability and Patient Glycaemic Status (PGS) . Results: Patients with T1D users open-source AID systems (22 AndroidAPS and 1 Loop) were included (age 38.4±years, 56.5% females, diabetes duration 20.8±10.6 years and capillary HbA1c 6.6±0.5%) . 18 patients previous insulin pump users with a use 3.5±4 years, 5 patients previously treated with multidose and CGM use 2.6±2.1 years. GMI decreased from 6,6±0.6% to 6±0.5% (p180 and >250 mg/dL were reduced from 23.5±11,5% to 9.6±7.5% and from 5.1% (2-9) to 0.6% (0-3) , respectively (p Conclusions: Open-source AID systems is safe and improved outcomes glycemic after 12 months of use in a real-world clinical setting in adults with T1D. Disclosure S.Amuedo: None. M.Antequera: None. S.Azriel: None.

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.

Summary 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.

Context The identification of markers able to determine medullary thyroid cancer (MTC) patients at high-risk of disease progression is critical to improve their clinical management and outcome. Previous studies have suggested that expression of the stem cell marker CD133 is associated with MTC aggressiveness. Objective To evaluate CD133 impact on disease progression in MTC and explore the regulatory mechanisms leading to the upregulation of this protein in aggressive tumors. Patients We compiled a series of 74 MTCs with associated clinical data and characterized them for mutations in RET and RAS proto-oncogenes, presumed to be related with disease clinical behavior. Results We found that CD133 immunohistochemical expression was associated with adverse clinicopathological features and predicted a reduction in time to disease progression even when only RET-mutated cases were considered in the analysis (log-rank test P Conclusions Our results suggest that CD133 expression may be a useful tool to identify MTC patients with poor prognosis, who may benefit from a more extensive primary surgical management and follow-up.

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. (C) 2019 SEEN y SED. Published by Elsevier Espana, S.L.U. All rights reserved.

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. Resumen: 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.

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.

Resumen Objetivo Evaluar el control glucemico en pacientes con diabetes tipo 2 que son remitidos a Endocrinologia desde Atencion Primaria (AP) por no estar controlados con antidiabeticos orales sin insulinoterapia; y el grado de implementacion del consenso nacional de la Sociedad Espanola de Diabetes, valorando los sucesivos escalones, primero (Pe), segundo (Se) y tercero (Te), del abordaje terapeutico. Material y metodos Estudio observacional retrospectivo en el que 81 endocrinologos evaluaron los pacientes mayores de 40 anos remitidos por AP entre julio de 2012 y julio de 2013, tratados con 1-2 antidiabeticos orales, no insulinizados, con una hemoglobina glucosilada (HbA 1c ) ≥ 6,5%, y en los que se disponia 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) anos, HbA 1c 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 terapeutico y el 74,0% en el Se. En atencion especializada solo el 9,8% de la cohorte esta en el Pe, el 42,8% en el Se y el 47,4% en el Te. Los farmacos mas prescritos en AP fueron metformina (90,2%), inhibidores DPP-4 (34,4%) y sulfonilureas (30,5%), mientras que en Endocrinologia fueron metformina (86%), insulina (56,8%) e inhibidores DPP-4 (49,8%). Las guias clinicas mas seguidas fueron las de la American Diabetes Association y el consenso de la Sociedad Espanola de Diabetes, en un 77 y 45% respectivamente. Conclusiones Aproximadamente la mitad de los pacientes con diabetes mellitus 2 no insulinizados y tratados con antidiabeticos orales en AP, son tratados con insulina en Endocrinologia. La guia clinica mas seguida por el especialista es la de la American Diabetes Association .

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 1–2 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. Conclusion 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.

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.

To analyze the trends on diabetes mellitus (DM) healthcare management in Spain.Retrospective observational study between January 1st 2007 and 31th December 2015 with DM as the principal diagnosis. The main clinical outcome measures were all-cause, in-hospital mortality and 30-day readmissions. We also analyze three Prevention Quality Indicators (PQI) for DM.The number of hospitalization episodes decreased significantly as well as the frequentation rate and average length of stay (Incidence Rate Ratio [IRR] = 0.963, p 0.001; 0.91, p 0.001 and 0.986, p 0.001, respectively). Crude in-hospital mortality and readmissions rates and risk-standardized in-hospital mortality rates (RSMR), however, remained stable (IRR = 0.988, p = 0.073; IRR = 1.003, p = 0.334 and IRR = 0.997, p = 0.116, respectively). A relevant variability in RSMR, both at hospital (Median Odds Ratio 1.49) and regional level, was found. High volume hospitals (≥105 DM discharges at year) showed better outcomes. High variability was also found in PQI indicators al regional level.The present analysis shows an improvement in hospitalizations related to DM in Spain in the period 2007-2015. There was also a decrease in the frequentation rate and in the average length of stay. These findings are probably explained by quality improvements in the healthcare management of the DM at the ambulatory level. However, there were important differences in the management of diabetic inpatients both at the hospital and the regional level.

Resumen Objetivo Estimar el impacto sanitario y economico en Espana de las hipoglucemias nocturnas ligadas al tratamiento de la diabetes tipo 2 (DM2) de insulina glargina (IG) o insulina NPH, administradas al acostarse. Metodos Se calcularon el coste actual de las hipoglucemias nocturnas graves y sintomaticas y los ahorros que se producirian para el Sistema Nacional de Salud (SNS) por la reduccion de estas en el caso de que el tratamiento con NPH fuese parcialmente sustituido por IG. El uso de recursos sanitarios en la practica clinica y el coste anual de las hipoglucemias se estimo mediante un panel de expertos clinicos de atencion primaria y hospitalaria. La reduccion en la tasa de hipoglucemias con IG frente a NPH se obtuvo de un metaanalisis publicado. Resultados Coste anual de las hipoglucemias: 1.121,98 € (518,90-1.990,19 €) en el caso de las graves, 473,85 € (243,22-733,82 €) las sintomaticas con niveles de glucosa Conclusiones El tratamiento al acostarse de la DM2 con IG (en comparacion con NPH) podria reducir la tasa de hipoglucemias nocturnas y sus costes asociados para el SNS.

Entre un 5 y un 10% de los adultos diagnosticados inicialmente de diabetes mellitus tipo 2 (DM2) en realidad tienen diabetes autoinmunitaria de inicio en la edad adulta. Dado el elevado numero de pacientes con diagnostico de DM2, la entidad que ha sido denominada por algunos autores como LADA (latent autoimmune diabetes in adults) podria suponer la mitad de todos los diabeticos con DM1A. Presentamos el caso de una mujer de 75 anos de edad, con antecedentes de diabetes mellitus con labilidad en el control glucemico y sindrome de colon irritable, que finalmente fue diagnosticada de diabetes autoinmunitaria con enfermedad celiaca concomitante.

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.

Background Nowadays, 65-80% of pheochromocytoma and paraganglioma (PPGL) cases are explained by germline or somatic mutations in one of 22 genes. Several genetic testing algorithms have been proposed, but they usually exclude sporadic-PPGLs (S-PPGLs) and none include somatic testing. We aimed to genetically characterise S-PPGL cases and propose an evidence-based algorithm for genetic testing, prioritising DNA source. Methods The study included 329 probands fitting three criteria: single PPGL, no syndromic and no PPGL family history. Germline DNA was tested for point mutations in RET and for both point mutation and gross deletions in VHL, the SDH genes, TMEM127, MAX and FH. 99 tumours from patients negative for germline screening were available and tested for RET, VHL, HRAS, EPAS1, MAX and SDHB. Results Germline mutations were found in 46 (14.0%) patients, being more prevalent in paragangliomas (PGLs) (28.7%) than in pheochromocytomas (PCCs) (4.5%) (p= 6.62x10(-10)). Somatic mutations were found in 43% of those tested, being more prevalent in PCCs (48.5%) than in PGLs (32.3%) (p= 0.13). A quarter of S-PPGLs had a somatic mutation, regardless of age at presentation. Head and neck PGLs (HN-PGLs) and thoracic-PGLs (T-PGLs) more commonly had germline mutations (p= 2.0x10(-4) and p= 0.027, respectively). Five of the 29 metastatic cases harboured a somatic mutation, one in HRAS. Conclusions We recommend prioritising testing for germline mutations in patients with HN-PGLs and TPGLs, and for somatic mutations in those with PCC. Biochemical secretion and SDHB-immunohistochemistry should guide genetic screening in abdominal-PGLs. Paediatric and metastatic cases should not be excluded from somatic screening.

El carcinoma anaplasico de tiroides es un tumor muy agresivo con una supervivencia media de 3 a 7 meses. El 50% se desarrolla a partir de bocios multinodulares de larga evolucion y el 20-30% coexiste con carcinomas diferenciados. Presentamos los casos de 2 pacientes ancianas con bocio multinodular en seguimiento durante anos que sufrieron, de forma brusca, una transformacion anaplasica. Ante esta posibilidad, y dado el pronostico infausto de este tipo de carcinoma, se aconseja realizar un seguimiento de por vida en estos pacientes.

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.

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).

El acetato de megestrol es un progestageno sintetico con acciones e indicaciones similares a las de la progesterona y mas recientemente ha sido utilizado para estimular el apetito en pacientes con caquexia asociada al cancer y al sindrome de inmunodeficiencia humana adquirida (sida). Entre los efectos adversos descritos en relacion con este farmaco estan las anomalias del metabolismo hidrocarbonado. Presentamos el caso de un paciente que desarrollo un sindrome de descompensacion hiperglucemica hiperosmolar no cetosica tras la introduccion de acetato de megestrol como estimulante del apetito.

El hipotiroidismo primario es una alteracion endocrinologica muy frecuente. Puede aparecer asociado a varios sindromes geneticos de escasa prevalencia. El sindrome 18q se produce por una delecion de la region terminal del brazo largo del cromosoma 18. Asocia rasgos dismorficos, anomalias endocrinologicas, oftalmologicas, neuromusculares e inmunologicas. El diagnostico se suele establecer en los primeros anos de vida. Presentamos el caso de una mujer de 42 anos con rasgos dismorficos que consultaba por astenia y dificultad para perder peso, detectandose en el estudio hormonal un hipotiroidismo subclinico y un hipogonadismo hipergonadotropo y en el estudio genetico un sindrome 18q.

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.

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).

Between 5 and 10% of adults initially diagnosed with type 2 diabetes mellitus.(DM) actually have adult-onset autoimmune diabetes. Given the large number of patients diagnosed with DM type 2, the entity called latent autoimmune diabetes in adults (LADA) by some authors could represent half of all diabetics with type 1A diabetes. We report the case of a 75-year-old woman, with a history of brittle diabetes and irritable bowel syndrome, who was finally diagnosed with autoimmune diabetes and celiac disease.

To investigate the effects of pregestational diabetes on pregnancy outcome.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.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) concentration7%) 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.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.

8 pages, 4 figures, 3 tables., Glucokinase acts as the pancreatic glucose sensor and plays a critical role in the regulation of insulin secretion by the b-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 Leu165Phe, Glu265Lys and Thr206Met. 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 Thr206Met and Leu165Phe 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 Glu265Lys, 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., This work was supported by the Instituto de Salud Carlos III: grant PI030203 to M.-A. N. and network grant RGDM (G03/212) to E. B., I. R. and M.-A. N. M. G. was supported by a predoctoral FPU fellowship from the Comunidad Aut´onoma de Madrid. M.-A. N. and O. V. were supported by the Ram´on y Cajal Program of the Spanish Ministry of Education and Science.