Real-world safety and effectiveness of dapagliflozin in people living with type 1 diabetes in Spain: The Dapa-ON multicenter retrospective study.

OBJECTIVE: To assess real-world safety and effectiveness of dapagliflozin in people living with type 1 diabetes mellitus (T1DM). METHODS: We conducted a multicenter retrospective study in Spain including data from 250 people living with T1DM receiving dapagliflozin as add-on therapy to insulin (80.8 % on-label use). The number of diabetic ketoacidosis (DKA) events was calculated over a 12-month follow-up (primary outcome). Changes in body weight, HbA1c, total daily insulin dose, and continuous glucose monitoring (CGM) metrics from baseline (at dapagliflozin prescription) to 12 months were also evaluated. RESULTS: A total of five DKA events (2.4 % [95 % CI 0.3;4.5] were reported in patients with a 12-month follow-up, n = 207): two events related to insulin pump malfunction, two events related to concomitant illnesses, and one event related to insulin dose omission. DKA events were more frequent among insulin pump users than among participants on multiple daily injections (7.7 % versus 1.2 %). Four of the reported DKA events occurred within the first six months after initiation of dapagliflozin. No deaths or persistent sequelae due to DKA were reported. No severe hypoglycemia episodes were reported. Significant reductions in mean body weight (-3.3 kg), HbA1c (-0.6 %), and total daily insulin dose (-8.6 %), P < 0.001, were observed 12 months after dapagliflozin prescription. Significant improvements in TIR (+9.3 %), TAR (-7.2 %), TBR (-2.5 %), and coefficient of variation (-5.1 %), P < 0.001, were also observed in the subgroup of patients with available CGM data. Finally, an improvement in urinary albumin-to-creatinine ratio (UACR) was found among participants with UACR ≥ 30 mg/g at baseline (median decrease of 99 mg/g in UACR, P = 0.001). CONCLUSION: The use of dapagliflozin in people living with T1DM has an appropriate safety profile after careful selection of participants and implementation of strategies to reduce the risk of DKA (i.e., prescribed according to the recommendations of the European Medicines Agency), and also leads to clinical improvements in this population.

Ultrarapid Insulin Use Can Reduce Postprandial Hyperglycemia and Late Hypoglycemia, Even in Delayed Insulin Injections: A Connected Insulin Cap-Based Real-World Study.

Objectives: Reaching optimal postprandial glucose dynamics is a daily challenge for people with type 1 diabetes (T1D). This study aimed to analyze the postprandial hyperglycemic excursion (PHEs) and late postprandial hypoglycemia (LPH) risk according to prandial insulin time and type. Research Design and Methods: Real-world, retrospective study in T1D using multiple daily injections (MDI) analyzing 5 h of paired continuous glucose monitoring and insulin injections data collected from the connected cap Insulclock®. Meal events were identified using the rate of change detection methodology. Postprandial glucometrics and LPH (glucose <70 mg/dL 2-5 h after a meal) were evaluated according to insulin injection time and rapid (RI) or ultrarapid analog, Fiasp® (URI), use. Results: Meal glycemic excursions (n = 2488), RI: 1211, 48.7%; UR: 1277, 51.3%, in 82 people were analyzed according to injection time around the PHE: -45 to -15 min; -15 to 0 min; and 0 to +45 min. In 63% of the meals, insulin was injected after the PHE started. Lower PHE was observed with URI versus RI (glucose peak-baseline; mg/dL; mean ± standard deviation): 106.7 ± 35.2 versus 111.2 ± 40.3 (P = 0.003), particularly in 0/+45 injections: 111.6 ± 40.2 versus 118.1 ± 43.3; (P = 0.002). One third (29.1%) of participants added a second (correction) injection. The use of URI and avoiding a second injection were independently associated with less LPH risk, even in delayed injections (0/+45), (-36%, odds ratio [OR] 0.641; confidence interval [CI]: 0.462-0.909; P = 0.012) and -56% (OR 0.641; CI: 0.462-0.909 P = 0.038), respectively. Conclusions: URI analog use as prandial insulin reduces postprandial hyper- and hypoglycemia, even in delayed injections.

Magnetic resonance imaging as a predictor of therapeutic response to pasireotide in acromegaly.

OBJECTIVE: Hyperintensity signal in T2-weighted magnetic resonance imaging (MRI) has been related to better therapeutic response during pasireotide treatment in acromegaly. The aim of the study was to evaluate T2 MRI signal intensity and its relation with pasireotide therapeutic effectiveness in real-life clinical practice. DESIGN, PATIENTS AND MEASUREMENTS: Retrospective multicentre study including acromegaly patients treated with pasireotide. Adenoma T2-weighted MRI signal at diagnosis was qualitatively classified as iso-hyperintense or hypointense. Insulin-like growth factor (IGF-I), growth hormone (GH) and tumour volume reduction were assessed after 6 and 12 months of treatment and its effectiveness evaluated according to baseline MRI signal. Hormonal response was considered 'complete' when normalization of IGF-I levels was achieved. Significant tumour shrinkage was defined as a volume reduction of ≥25% from baseline. RESULTS: Eighty-one patients were included (48% women, 50 ± 1.5 years); 93% had previously received somatostatin receptor ligands (SRLs) treatment. MRI signal was hypointense in 25 (31%) and hyperintense in 56 (69%) cases. At 12 months of follow-up, 42/73 cases (58%) showed normalization of IGF-I and 37% both GH and IGF-I. MRI signal intensity was not associated with hormonal control. 19/51 cases (37%) presented a significant tumour volume shrinkage, 16 (41%) from the hyperintense group and 3 (25%) from the hypointense. CONCLUSIONS: T2-signal hyperintensity was more frequently observed in pasireotide treated patients. Almost 60% of SRLs resistant patients showed a complete normalization of IGF-I after 1 year of pasireotide treatment, regardless of the MRI signal. There was also no difference in the percentage tumour shrinkage over basal residual volume between the two groups.

CD133 Expression in Medullary Thyroid Cancer Cells Identifies Patients with Poor Prognosis.

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 < 0.003). Univariate analysis for progression-free survival revealed CD133 expression and presence of tumor emboli in peritumoral blood vessels as the most significant prognostic covariates among others such as age, gender, and prognostic stage. Multivariate analysis identified both variables as independent factors of poor prognosis (hazard ratio = 16.6 and 2; P = 0.001 and 0.010, respectively). Finally, we defined hsa-miR-30a-5p, a miRNA downregulated in aggressive MTCs, as a CD133 expression regulator. Ectopic expression of hsa-miR-30a-5p in MZ-CRC-1 (RETM918T) cells significantly reduced CD133 mRNA expression. 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.

Reflexión estratégica de la Sociedad Española de Endocrinología y Nutrición sobre el futuro de la especialidad en el periodo 2018-2022 / Strategic reflections of the Spanish Society of Endocrinology and Nutrition on the future of the speciality in the period 2018-2022

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

Strategic reflections of the Spanish Society of Endocrinology and Nutrition on the future of the speciality in the period 2018-2022. / Reflexión estratégica de la Sociedad Española de Endocrinología y Nutrición sobre el futuro de la especialidad en el periodo 2018-2022.

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.

Guía clínica para el diagnóstico y seguimiento de la distrofia miotónica tipo 1, DM1 o enfermedad de Steinert / Clinical guide for the diagnosis and follow-up of myotonic dystrophy type 1, MD1 or Steinert's disease

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

Clinical guide for the diagnosis and follow-up of myotonic dystrophy type 1, MD1 or Steinert's disease. / Guía clínica para el diagnóstico y seguimiento de la distrofia miotónica tipo 1, DM1 o enfermedad de Steinert.

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.

Identification of a novel large CASR deletion in a patient with familial hypocalciuric hypercalcemia.

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.

Whole-exome sequencing identifies MDH2 as a new familial paraganglioma gene.

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.

Glucagon-like peptide-1 receptor agonists as insulin add-on therapy in patients with inadequate glycemic control in type 2 diabetes mellitus: lixisenatide as a new therapeutic option.

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.

Parámetros de control glucémico en pacientes con diabetes tipo 2 no insulinizados derivados a consulta de Endocrinología, y grado de implementación del consenso nacional sobre el tratamiento de la hiperglucemia / Glycemic control parameters in insulin-naïve patients with uncontrolled type 2 diabetes referred to endocrinologists, and degree of implementation of the national Spanish consensus for the management of hyperglycemia

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

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

Glycemic control parameters in insulin-naïve patients with uncontrolled type 2 diabetes referred to endocrinologists, and degree of implementation of the national Spanish consensus for the management of hyperglycemia.

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.

Pseudohypoparathyroidism vs. tricho-rhino-phalangeal syndrome: patient reclassification.

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.

Germline mutations in FH confer predisposition to malignant pheochromocytomas and paragangliomas.

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.

Functional characterization of MODY2 mutations highlights the importance of the fine-tuning of glucokinase and its role in glucose sensing.

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.

Differential effects of HNF-1α mutations associated with familial young-onset diabetes on target gene regulation.

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.

Un caso especial de diabetes mellitus gestacional / A special case of gestacional diabetes mellitus

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)

A special case of gestational diabetes mellitus.

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).

Descompensación hiperglucémica hiperosmolar en paciente trasplantado hepático en tratamiento con acetato de megestrol / Hyperosmolar hyperglycemic nonketotic syndrome in a liver transplant recipient treated with megestrol acetate

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)