Single-cell phenotypic characterization of human pituitary GHomas and non-functioning adenomas based on hormone content and calcium responses to hypothalamic releasing hormones

Producción CientíficaHuman pituitary tumors are generally benign adenomas causing considerable morbidity due to excess hormone secretion, hypopituitarism, and other tumor mass effects. Pituitary tumors are highly heterogeneous and difficult to type, often containing mixed cell phenotypes. We have used calcium imaging followed by multiple immunocytochemistry to type growth hormone secreting (GHomas) and non-functioning pituitary adenomas (NFPAs). Individual cells were typed for stored hormones and calcium responses to classic hypothalamic releasing hormones (HRHs). We found that GHomas contained growth hormone cells either lacking responses to HRHs or responding to all four HRHs. However, most GHoma cells were polyhormonal cells responsive to both thyrotropin-releasing hormone (TRH) and GH-releasing hormone. NFPAs were also highly heterogeneous. Some of them contained ACTH cells lacking responses to HRHs or polyhormonal gonadotropes responsive to LHRH and TRH. However, most NFPAs were made of cells storing no hormone and responded only to TRH. These results may provide new insights on the ontogeny of GHomas and NFPAs.Ministerio de Economía, Industria y Competitividad (Project BFU2012-37146)Instituto de Salud CarlosIII (FIS03/1231

3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial

Background: Liraglutide 3·0 mg was shown to reduce bodyweight and improve glucose metabolism after the 56-week period of this trial, one of four trials in the SCALE programme. In the 3-year assessment of the SCALE Obesity and Prediabetes trial we aimed to evaluate the proportion of individuals with prediabetes who were diagnosed with type 2 diabetes. Methods: In this randomised, double-blind, placebo-controlled trial, adults with prediabetes and a body-mass index of at least 30 kg/m2, or at least 27 kg/m2 with comorbidities, were randomised 2:1, using a telephone or web-based system, to once-daily subcutaneous liraglutide 3·0 mg or matched placebo, as an adjunct to a reduced-calorie diet and increased physical activity. Time to diabetes onset by 160 weeks was the primary outcome, evaluated in all randomised treated individuals with at least one post-baseline assessment. The trial was conducted at 191 clinical research sites in 27 countries and is registered with ClinicalTrials.gov, number NCT01272219. Findings: The study ran between June 1, 2011, and March 2, 2015. We randomly assigned 2254 patients to receive liraglutide (n=1505) or placebo (n=749). 1128 (50%) participants completed the study up to week 160, after withdrawal of 714 (47%) participants in the liraglutide group and 412 (55%) participants in the placebo group. By week 160, 26 (2%) of 1472 individuals in the liraglutide group versus 46 (6%) of 738 in the placebo group were diagnosed with diabetes while on treatment. The mean time from randomisation to diagnosis was 99 (SD 47) weeks for the 26 individuals in the liraglutide group versus 87 (47) weeks for the 46 individuals in the placebo group. Taking the different diagnosis frequencies between the treatment groups into account, the time to onset of diabetes over 160 weeks among all randomised individuals was 2·7 times longer with liraglutide than with placebo (95% CI 1·9 to 3·9, p<0·0001), corresponding with a hazard ratio of 0·21 (95% CI 0·13–0·34). Liraglutide induced greater weight loss than placebo at week 160 (–6·1 [SD 7·3] vs −1·9% [6·3]; estimated treatment difference −4·3%, 95% CI −4·9 to −3·7, p<0·0001). Serious adverse events were reported by 227 (15%) of 1501 randomised treated individuals in the liraglutide group versus 96 (13%) of 747 individuals in the placebo group. Interpretation: In this trial, we provide results for 3 years of treatment, with the limitation that withdrawn individuals were not followed up after discontinuation. Liraglutide 3·0 mg might provide health benefits in terms of reduced risk of diabetes in individuals with obesity and prediabetes. Funding: Novo Nordisk, Denmark

Descripción de factores de riesgo cardiovascular de una muestra de pacientes con isquemia crítica de miembros inferiores

Resumen. Objetivo. Describir los factores de riesgo cardiovascular de la poblacion intervenida por arterioesclerosis grave de miembros inferiores. Pacientes y metodos. Se ha realizado un estudio observacional durante un periodo de dos años, comprendido entre enero de 1999 y diciembre del 2000, con 330 pacientes intervenidos por enfermedad ateroesclerotica grave de miembros inferiores, con isquemia critica. Resultados. La edad media fue de 74,78 ¿} 10,35 anos; la edad de las mujeres fue mayor (78,88 ¿} 10,45 anos) que la de los hombres (73,7 ¿} 10,07) (p < 0,0001), con una distribucion por sexos de 261 hombres (79,1%) y 69 mujeres (20,9%). Si analizamos el porcentaje de pacientes obesos (indice de masa corporal . 30), observamos una prevalencia del 12,2% de obesidad. El 37,4% de la poblacion (n = 123) presentaba hipertension arterial y solo fue tratado el 63,4%. El 59,9% (n = 178) de la poblacion del estudio mostraba dislipemia. Los niveles medios de glucosa plasmatica fueron de 121,9 ¿} 55,8 mg/dL; el 42,4% (n = 140) de la poblacion padecia diabetes mellitus y todos eran diabeticos de tipo 2. El 35,2% de los pacientes de nuestro estudio manifestaba dolor en reposo (estadio clinico III) y el 64,8% mostraba lesiones troficas y/o gangrena, en correspondencia con el estadio IV de Fontaine. A los pacientes con isquemia cronica de miembros inferiores se les intervino quirurgicamente .en un intento de revascularizar los tejidos isquemicos. una media de 2,2 ¿} 1,7 veces. Conclusion. Los pacientes con isquemia critica de miembros inferiores presentan una alta prevalencia de factores de riesgo cardiovascular infratratados. El tipo de cirugia depende del estadio clinico

Multifunctional cells in human pituitary adenomas: Implications for paradoxical secretion and tumorigenesis

Producción CientíficaPituitary adenomas are very common in humans. They are of monoclonal origin, very heterogeneous, and produce frequently paradoxical secretion. The normal anterior pituitary (AP) contains some unorthodox multifunctional cells able to store more than one AP hormone (polyhormonal) and/or to express multiple hypothalamic-releasing hormone receptors (multiresponsive). Multifunctional AP cells seem to be involved in plasticity processes such as transdifferentiation or paradoxical secretion. Here, we have characterized the single-cell phenotypes of 15 human pituitary tumors, including prolactinomas, nonfunctioning adenomas, and adenomas from multiple endocrine neoplasia type I (MEN-I) and pituitary Cushing’s disease patients. Individual tumor cells were typed according to expression of AP hormones and hypothalamic-releasing hormone receptors by combination of calcium imaging and multiple sequential immunocytochemistry in the same cells. We found a large heterogeneity among the different tumors. In eight of the 15 tumors studied, more than 80% of the cells presented a multifunctional phenotype. This may explain the occurrence of paradoxical secretion. In addition, our results suggest that human pituitary adenomas might derive from multifunctional cells. This is consistent with the existence of a link between pituitary plasticity and tumorigenesis.Fondo de Investigaciones Sanitarias (grant FIS 01/0769)Ministerio de Ciencia, Innovación y Universidades (grant BFI2001-2073