Hepir: MECANISMOS MOLECULARES DE RESISTENCIA A LA INSULINA
Insulin resistance is an early event in the development of type 2 diabetes mellitus (T2DM). The close relationship between metabolism and the immune system (immunometabolism) plays an essential role in the development of insulin resistance and T2DM associated with obesity. The changes in the intestinal microbiota detected in obese individuals are the first trigger of the chronic low-grade inflammation that alters functionality of the relevant tissues responsible for controlling whole body glucose homeostasis. Among them, the liver is a target organ for pro-inflammatory mediators released by the gut (endotoxins) and adipose tissue (cytokines, adipokines, free fatty acids and reactive lipid species) and, in addition, this organ is capable of recruiting circulating monocytes that, along with the resident macrophages (Kuppfer cells), exacerbate the intrahepatic inflammatory responses. These conditions determine the progression of nonalcoholic fatty liver disease (NAFLD), a high incidence chronic liver disease within the insulin resistant obese population that begins with the accumulation of fat in the liver (steatosis) and progresses to steatohepatitis (NASH), fibrosis, cirrhosis and, finally, hepatocellular carcinoma (HCC). Our laboratory investigates on the molecular mechanisms responsible of NAFLD progression and regression from insulin resistance to NASH and fibrosis. For this goal we have developed cellular models (hepatocytes, Kuppfer cells, oval progenitor cells and hepatic stellar cells), as well as preclinical mouse models that recapitulate the different stages of NAFLD, with a particular interest in NASH and fibrosis phases. In this context, we approach therapeutic strategies with single or dual agonists of the GLP-1 and glucagon receptors to reverse or improve these pathologies. In addition, the group is interested in understanding the impact of chronic inflammation that occurs in the states of obesity and insulin resistance in the regulation of thermogenic genes of brown adipose tissue (BAT) and genes related to glucose and lipid metabolism On the other hand, inflammation induced by hyperglycemia is a central factor in the pathogenesis of diabetes complications such as diabetic retinopathy. Microglia is one of the cellular sources of inflammatory mediators and in the retina it interacts with neurons, photoreceptors and the vasculature. However, the polarization of microglia during the development of diabetic retinopathy in T2DM and also the role of the regulatory molecules of insulin signaling in microglia have not been studied in depth. Our laboratory has animal and cellular tools to address these issues.
Research Projects in the last 5 years:
Title: TREATMENT (Training European Network: Metabolic Dysfunctions associated with Pharmacological Treatment of Schizophrenia). Referencia: Grant Agreement number 721236. MARIE Skodowska-CURIE ACTIONS: call H2020-MSCA-ITN-2016 (2017-2020). Funding Body: European Union. Coordinators: María Monsalve and Ángela Martínez Valverde
Title: New messengers in the intreactome between hepatic and extra-hepatic cells in non-alcoholic fatty liver disease with diagnostic value. Funding Body: Fundación Ramón Areces. Convocatoria Proyectos Vida y Materia 2018 (2019-2021) (Spain). Principal Investigator: Ángela Martínez Valverde
Title: Inflammation associated with chronic metabolic damage in Type 2 diabetes and its complications. Reference: SAF2015-65.267 RETOS (2016-2018). Funding Body: Ministerio de Economía y Competitividad (Spain). Principal Investigator: ángela Martínez Valverde
Title: Extending the knowledge on cellular and molecular players in the progression and treatment of non-alcoholic fatty liver disease associated to obesity (FaTLiV). Reference: RTI2018-094052-B-I00 (2019-2021). Funding Body: Ministerio de Ciencia, Innovación y Universidades. Principal Investigator: ángela Martínez Valverde.
Title: Identification of novel modulators of chronic inflammation in prevalent diseases: unveiling divergent mechanisms of disease (INFLAMES). Reference PIE14/00045. Proyecto Integrado de Excelencia, Convocatoria 2014 de la Acción Estratégica en Salud 2013-16, ISCIII (Proyecto InterCiber) (2015-2018). Coordinator: Antonio Zorzano Olarte. Principal Investigator of WP3: Ángela Martínez Valverde.
Title: Network in research on NRF2 as node of the "patogenosome". Reference: SAF2015-71304-REDT (2016-2017). Funding Body: Ministerio de Economía y Competitividad (Spain) Coordinator: Antonio Cuadrado Pastor. Principal Investigator: Ángela Martínez Valverde.
Title: Neurodegeneration as an early event in the Pathogenesis of Diabetic Retinopathy: A multicentric, prospective, phase II-III, double blind randomized controlled trial to assess the efficacy of neuroprotective drugs administered topically to prevent or arrest Diabetic Retinopathy (EUROCONDOR). Grant Agreement 278040. FP7-HEALTH-2011-two-stage HEALTH.2011.2.4.3.1. Funding Bogy: European Union (2012-2016). Coordinator: Rafael Simó Canonge. Principal Investigator and Leader of WP5: Ángela Martínez Valverde.
Contracts with pharmaceutical companies:
Title: Unraveling the olecular mechanism of metformin glycinate in hepatocytes. Reference contract with CSIC: 20159770. Company: LABORATORIOS SILANES (Mexico DF, Mexico) (2015-2017). PI: Ángela Martínez Valverde.
Title: Effect of GLP-1/glucagon analogs in hepatic regeneration. Reference contract with CSIC: 20124527. Conpamy: MEDIMMUNE (Astra Zeneca) (2012-2016). Principal Investigator: Ángela Martínez Valverde.
Title: Experimental designs for studies on the role of G49 in diet-induced obesity in mice and human cells: impact on inflammation and mitochondria. Reference contact with CSIC: 20182844. Company: MEDIMMUNE (Astra Zeneca) (2018-2019). Principal Investigator: Ángela Martínez Valverde.