Endocrine, Thyroid and Obesity

Manuel Puig-Domingo

The Endocrine and Obesity Research group is coordinated by Prof Manuel Puig-Domingo, who is currently Head of the of Endocrinology and Nutrition Service at Germans Trias Hospital, Professor of Endocrinology at the Germans Trias Unit of the Faculty of Medicine of Autonomous University of Barcelona, and Scientific Director of Germans Trias Research Institute. He is also serving as President of the Spanish Society of Endocrinology and Nutrition (2015-2017).

Research lines

Molecular phenotyping of pituitary tumors and its application to personalized medicine

The group has been working in recent years to achieve results regarding the potential usefulness of different molecular and genetic markers that could be used to explain the biological and clinical behaviour of pituitary adenomas, while at the same time identifying biomarkers and bioimaging markers that could predict therapeutic responses. The ultimate goal is to translate these findings to clinical practice by including them in the therapeutic algorithms. The group is part of the CIBER de Enfermedades Raras (CIBERER) as an associated group since 2013 and it has obtained recent research grants from the Instituto Carlos III to develop related topics.

Dr Isabel Salinas participates in such studies as a clinical associate researcher and Dr Mireia Jordà is managing and coordinating the laboratory duties. Our investigators are closely involved with the Spanish Society of Endocrinology registry REMAH (Registro Español Molecular de Adenomas Hipofisarios), established in 2010, for which the Germans Trias Hospital is the Catalan node, one of the 5 different nodes of the Spanish state. In the REMAH initiative, more than 700 pituitary tumours have been obtained and included in a specific database, in which in more than 400 of the cases have clinical and molecular data associated with the sample.

Thyroid pathology

The group has also been working for many years on the evaluation of thyroid function in relation to iodine nutrition and its consequences during pregnancy. Several population studies have been performed over the last decade, either in children or in pregnant women. Position statements have been published in relation to this question and a specific project is currently ongoing, studying a cohort of pregnant women to define a TSH dependent risk score that could be predictive of obstetricl complications and foetal outcomes.

The group is participating in a European project, the EUthyroid project, as the Spanish partner. In the EUtyroid project, Dr Lluis Vila, who has participated in the last decade in different joint projects, and is currently the President of the Catalan Society of Endocrinology, is also co- local IP. In studies related to the thyroid gland, our investigators have made significant contributions over the last 20 years in autoimmune thyroid diseases, mostly through research carried out by Dr Anna Lucas, Dr Berta Soldevila and Prof Ricardo Pujol-Borrell (at present Chief and Professor of Immunology at Vall d'Hebron Research Institute and Hospital in Barcelona) and also Dr Eva Martínez-Cáceres, current Chief of the Immunology Department at Germans Trias Hospital.

Additionally, the group also carries out thyroid cancer research, as part and founder of a Catalan consortium for the study of thyroid cancer, in which 20 different hospitals have incorporated their clinical expertise. Currently, a database has been generated, including more than 4000 patients and a biobank tissue collection has been generated to study different issues. In particular our group is interested in defining biomarkers that could identify biological and clinical behaviour of poorly differentiated thyroid cancer, by applying genetic and epigenetic profiling. A shared initiative with Dr Mercedes Robledo at Centro Nacional de Investigaciones Oncológicas (CNIO, Madrid) is on-going since 2011 in which our local PIs are Dr Mireia Jordà from the basic science side and Dr Jordi Reverter as the clinical investigator.

Obesity

Since 2010, different research activities have been initiated to study the complications of Obesity and its potential reversal after therapeutic bariatric surgery. We have explored the implications of bariatric surgery weight loss in different hormonal systems such as the gonadotropic axis and the somatotropic axis, as well as the participation of the ghrelin system in surgical weight loss outcomes, with Dr Silvia Pellitero carrying out these studies as PI. In the last 2 years a project dealing with the epigenetic changes that take place after bariatric surgery has been underway coordinated by Dr José Balibrea (currently at the Surgery Dpt of Vall d'Hebrón Hospital); in the study human as well as a murine models have been explored. We have recently initiated a collaboration with Prof Joan Vendrell, Chief of the service of Endocrinology at Joan XXIII Hospital in Tarragona, and Dr Núria Villarrassa at Bellvitge University Hospital in Hospitalet de LLobregat. Adipose tissue of different topographies is being collected and studied for epigenetic changes. Other collaborators for these projects, from the Germans Trias Hospital are Drs Pau Moreno and Jordi Tarascó from the Dpt of Surgery. Finally, a basic researcher, Dr David Sánchez-Infantes has recently joined the Obesity research team. Dr Sánchez-Infantes is a Miguel Servet program researcher, mostly focussed on the study of brown adipose tissu, and different initiatives are on the way including  the human model, in which different approaches including thermographic and biological measurements are performed in order to elucidate the participation of different molecules and the consequences of different treatments in obesity patients and experimental models.

Research projects

ONGOING PROJECTS

Formulation of a personalized score for prediction of foetal and obstetric risk for maternal thyroid function
Code: PI15/02192
Principal Investigator Manel Puig
Start Date: 01/01/2016
End Date: 31/12/2019

Acromegaly is a chronic disorder usually diagnosed late in the disease evolution, leading to substantial morbidity and mortality related to this long period of undiagnosed state as well as the inability in achieving treatment goals of normalizing biochemical disease markers and controlling tumour mass, without harming normal pituitary function. Somatostatin analogs (SSA) are accepted as first-line medical therapy or as second-line therapy in patients undergoing unsuccessful surgery and are considered a cornerstone in the treatment of acromegaly. However, because nearly 50% of patients experience SSA treatment failure, the identification of biomarkers associated with a successful or non-successful response to SSA as well as to all classes of medical therapy would help to optimize the therapeutic decision-making process and potentially allow for a quicker normalization of the hormonal hypersecretory state. The current treatment algorithms for acromegaly are based upon a "trial and error" approach with additional treatment options subsequently provided when disease is not controlled. In many other diseases, their therapeutic algorithms have been evolving towards personalizing treatment by means of biomarkers that predict the therapeutic response, thus facilitating the choice of the  medication that best matches individual disease characteristics, and finally allowing the personalization of the therapy. This project has as main goal the application of a treatment algorithm for acromegaly addressing the biochemical control of the disease under a personalized approach based upon markers of prognostic and predictive significance, such as tumour size, MRI adenoma signal, GH value after acute octreotide test, granular adenoma pattern, Ki-67, somatostatin receptor phenotype, AIP expression, gsp mutations, RAF kinase activity, E-cadherin and beta arrestin-1.
The specific objectives will include: a) to evaluate if an acute octreotide test identifies accurately SSA response and its variability among centres; b) to assess if MRI T2 signal identifies responsive patients to SSA treatment; c) to confirm that a multimolecular expression array is able to identify therapeutic response; d) to study if a better time-response is obtained with the aforementioned algorithm; e) to evaluate if the personalized treatment protocol obtains a quicker improvement in neurocognitive dysfunction and QoL; and f) to perform a cost-effectiveness analysis of the proposed algorithm.

Improved and efficient therapy of acromegaly by implementation of a personalized and predictive algorithm including functional analysis, imaging and genomic information
Code: PMP15/00027
Principal Investigator Manel Puig
Start Date: 01/01/2016
End Date: 31/12/2019

Variabilidad funcional de las celulas madre mesenquimales del tejido adiposo (ASCs) tras la perdida de peso. Relación con metafactores vinculados a la microbiota intestinal

Codigo: PI17/00915
Investigador principal: Anna Silvia Pellitero
Fecha inicio: 01/01/2018
Fecha final: 31/12/2020

Estudio de efectos de las incretinas sobre la microbiota, la metainflamación y la plasticidad del tejido adiposo en pacientes con obesidad sin diabetes

Codigo: PI14/00633
Investigador principal: Anna Silvia Pellitero
Fecha inicio: 01/01/2015
Fecha final: 30/06/2018

La cirugía bariátrica (CB) es el único tratamiento eficaz de la obesidad mórbida (OM) en cuanto a la reducción ponderal mantenida, como a la mejoría del estado proinflamatorio y de resistencia a la insulina (RI). Se han propuesto cambios en la secreción incretínica y en la flora intestinal para intentar explicar estos cambios. En este subproyecto nº3 nos planteamos la hipótesis de que los cambios en la microbiota intestinal y en la secreción de las incretinas (sobre todo GLP2) pueden influir en la permeabilidad intestinal modulando el estado metainflamatorio y de RI del paciente obeso. Objetivos: Principal: Estudiar el papel de las incretinas como factores reguladores de la endotoxemia metabólica, la inflamación y la RI en un grupo de pacientes con OM no diabéticos. Objetivos intermedios: 1.- Evaluar los efectos de la CB en sujetos con OM sobre los cambios en la microbiota intestinal, el patrón secretor de incretinas y el estado metainflamatorio a corto y medio plazo (basal, 1 y 6 meses tras CB) 2.- Analizar la relación entre la secreción plasmática de GLPs y GIP y la expresión de sus receptores en tejido adiposo en sujetos obesos mórbidos. 3.- Evaluar el papel de las incretinas sobre la respuesta inflamatoria sistémica (estudiada en monocitos circulantes) tras sobrecarga lipídica de forma prospectiva.
Metodología: Estudio prospectivo de 20 pacientes con obesidad y sin diabetes (10 con elevada RI y 10 con RI disminuida) sometidos a gastrectomía tubular (GT). El estudio dinámico consistirá en un test de dieta estándar con determinación de hormonas (GLP-2, GLP-1, GIP), marcadores de inflamación (PCR, IL-6, adiponectina y LPS) y un test de sobrecarga lipídica (GLP-2, lípidos y marcadores de inflamación en monocitos) antes, 1 y 6 meses después de la GT. Se realizará un estudio de microbiota intestinal antes y 6 meses post-GT.

Dinámica de los patrones de metilación del DNA en la progresión del cáncer de tiroides: una nueva fuente de marcadores de pronóstico

Codigo: PI14/00308
Investigador principal: Mireia Jordà Ramos
Fecha inicio: 01/01/2015
Fecha final: 31/12/2017

Este proyecto nace de la necesidad clínica de biomarcadores que mejoren el pronóstico y el tratamiento del cáncer de tiroides, y para ello se proponen los siguientes objetivos: 1) caracterizar los perfiles de metilación del DNA en la progresión tumoral del cáncer de tiroides, 2) identificar marcadores pronósticos epigenéticos e inmunohistoquímicos, especialmente asociados a metástasis, 3) estudiar las implicaciones funcionales de genes alterados epigenéticamente, 4) analizar la hipometilación global del DNA mediante la cuantificación de secuencias repetitivas ALU desmetiladas y determinar su aplicabilidad clínica.

Muestras: tejido normal, tumores metastásicos y no metastásicos diferenciados, pobremente diferenciados y anaplásicos, y metástasis apareadas. Dada la baja prevalencia de los tumores de interés, para asegurar un número adecuado de muestras participan diferentes hospitales de Madrid y Barcelona.

Métodos: análisis de metilomas mediante Infinium HumanMethylation450 BeadChips; análisis bioinformático, incluyendo la integración de datos generados en los diferentes subproyectos y datos públicos; estudios específicos basados en metodologías de biología molecular y celular para validar candidatos e investigar sus implicaciones funcionales; análisis inmunohistoquímico mediante TMA; Quantification of Unmethylated ALU elements (qUALU); estudio de correlaciones clínicas.

 

More information

Contact

Marta Carrió, Administrative Assistant Endocrine, Thyroid and Obesity Research Group

(+34) 93 497 8694

mcarrio(ELIMINAR)@igtp.cat