Main lines of research

Our group investigates on the identification of the cellular and molecular mechanisms that link poor perinatal growth and increased risk of metabolic syndrome and type 2 diabetes in adult life through the use of animal models of nutritional manipulation: maternal undernutrition followed or not by overnutrition. To this end we have focused on: 

1.-The search of new growth factors and mechanisms regulating the development, growth and death of pancreatic islet cells.

2. - The study of the effect of nutrients on glucagon and insulin production and release from pancreatic alfa and beta cells.

3. - The potential role of incretins (GLP-1 and GIP) in the relationship between intrauterine growth restriction and the development of type 2 diabetes in adulthood.

4. - The impact of early undernutrition on the insulin and leptin hypothalamic responses and the hypothalamic expression of orexigenic and anorexigenic factors (NPY, POMC).

5. - The study of the gut microbiota as a new environmental factor involved in the increased risk of developing metabolic syndrome under perinatal growth restricted conditions: possible alterations of the entero-adipo-insular axis.

 

Members of the Group

-Carmen Álvarez Escolá, Profesor Titular de  la UCM. E-mail: calvarez@ucm.es 

-Fernando Escrivá Pons, Profesor Titular de  la UCM

-Elisa Fernández Millán, Investigador Contratado CIBERDEM

-*María Ángeles Martín ArribasTitulado Superior CSIC.

*Member of CIBERDEM Group

 

Postdoctoral student:

-Esther Lizárraga Mollinedo

 

Former members of the group:

-Juan de Toro Martín, Laval University. Quebeck. Canada

 

Publications (last years)

Lizárraga-Mollinedo E, Fernández-Millán E, García-San Frutos M, de Toro-Martín J, Fernández-Agulló T, Ros M, Álvarez C, Escrivá F. Early and long-term undernutrition in female rats exacerbates the metabolic risk associated with nutritional rehabilitation. J Biol Chem. 2015 Jun 23. pii: jbc.M114.549204. [Epub ahead of print] PMID: 26105051

 

De Toro-Martín J, Fernández-Millán E, Lizárraga-Mollinedo E, López-Oliva E, Serradas P, Escrivá F, Alvarez C. Predominant Role of GIP in the Development of a Metabolic Syndrome-like Phenotype in Female Wistar Rats Submitted to Forced Catch-up Growth. Endocrinology. 2014 Oct; 155(10):3769-80.

 

E. Fernández-Millán,  J. de Toro-Martín, E. Lizárraga-Mollinedo, F. Escrivá and C. Álvarez.

Role of endogenous interleukin-6 in the neonatal expansion and functionality of rat pancreatic

alpha cells. Diabetologia. 2013 56(5):1098-107

 

Lizárraga-Mollinedo E, Fernandez-Millan E, de Toro Martín J, Martínez-Honduvilla CJ, Escrivá F, Alvarez C. Early undernutrition induces glucagon resistance and insulin hypersensitivity in the liver of suckling rats. Am J Physiol Endocrinol Metab. 2012 302(9):E1070-7.

 

Laura de Miguel - Santos, Elisa Fernández-Millán, María Ángels Martín, Fernando Escrivá, Carmen Álvarez. Maternal undernutrition increases pancreatic IGF-2 and partially supresses the physiological wave of beta-cell apoptosis during the neonatal period. J Mol  Endocrinol. 2010 44(1):25-36.

 

E. Lizárraga-Mollinedo, E. Fernández-Millán, L.de Miguel-Santos, C.J. Martínez- Honduvilla, C. Álvarez and F. Escrivá. Early undernutrition increases glycogen content and reduces the activated forms of GSK3, AMPK, p38 MAPK and JNK in the cerebral cortex of suckling rats.  J Neurochem. 2010 112(1):123-33

 

Elisa Fernández-Millán, Marie Noëlle Gangnerau Laura de Miguel-Santos, Sophie Calderari, Patricia Serradas, Fernando Escrivá, Bernard Portha, Carmen Álvarez. Undernutrition of the GK rat during gestation improves pancreatic IGF2 and beta-cell mass in the fetuses. Growth Factors 2009 27(6):409-18

 

Fernández E, Martín MA, Fajardo S,  Escrivá F, Álvarez C. Increased IRS-2 content and activation of IGF-1 pathway contribute to enhance beta cell mass in fetuses from undernourished pregnant rats. Am J Physiol Endocrinol Metab. 2007 292(1):E187-95 

E. Fernández, M.A. Martín,  1 S. Fajardo,  2D. Bailbé, M.N. Gangnerau,  B. Portha, F. Escrivá, P. Serradas, C. Álvarez. Undernutrition stimulates both beta–cell neogenesis and replication in undernourished adult rats after partial pancreatectomy. Am J Physiol Endocrinol Metab. 2006 291(5):E913-21

 

Martín MA, SerradasP, Ramos R, Fernández E, Goya L, Gangnerau MN, Lacorne M, Pascual-Leone AM, Escrivá F, Portha B and Álvarez C. Protein-caloric food restriction affects Insulin-Like Growth Factor -1 in fetal rat pancreas. Endocrinology 2005 146: 1364-1371

 

Gavete ML, , Martín MA, Alvarez C, Escrivá F. “Maternal food restriction enhances insulin-induced GLUT-4 translocation and insulin pathway in skeletal muscle from suckling rats". Endocrinology, 2005 146(8): 3368-78

 

Scientific collaborations and Publications (last years):

 

Dr. LF Alguacil. Universidad San Pablo-CEU. Madrid

-E. Lizárraga-Mollinedo & C. Álvarez & E. Fernández-Millán & F. Escrivá & C. González-Martín & E. Salas & J. M. Pérez-Ortiz & L. F. Alguacil. Undernutrition upregulates fumarate hydratase in the rat nucleus accumbens. Metab Brain Dis. Metab Brain Dis. 2013 28(1):111-5.

 

Dr. L Goya. Ictan. CSIC. Madrid

-Isabel Cordero-Herrera, María Ángeles Martín Elisa Fernández-Millán b, Carmen Álvarez, Luis Goya, Sonia Ramos. Cocoa and cocoa flavanol epicatechin improve hepatic lipid metabolism in in vivo and in vitro models. Role of PKCζ. J Funct Foods 17 2015 761–773

 

-Fernández-Millán E, Cordero-Herrera I, Ramos S, Escrivá F, Alvarez C, Goya L, Martín MA.

Cocoa-rich diet attenuates beta cell mass loss and function in young Zucker diabetic fatty rats by preventing oxidative stress and beta cell apoptosis. Mol Nutr Food Res. 2015 59(4):820-4

 

-Cordero-Herrera I, Martín MÁ, Escrivá F, Álvarez C, Goya L, and Ramos, S. Cocoa-rich diet ameliorates hepatic insulin resistance by modulating insulin signaling and glucose homeostasis in Zucker diabetic fatty rats. J Nutr Biochem. 2015 26(7):704-12.

 

Fernández-Millán E, Ramos S, Alvarez C, Bravo L, Goya L, Martín MA.Microbial phenolic metabolites improve glucose-stimulated insulin secretion and protect pancreatic beta cells against tert-butyl hydroperoxide-induced toxicity via ERKs and PKC pathways. Food Chem Toxicol. 2014 66C:245-253.

 

Dra. A Martinez Valverde. Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC. Madrid.

-González-Rodríguez Á, Santamaría B, Mas-Gutierrez JA, Rada P, Fernández-Millán E, Pardo V, Álvarez C, Cuadrado A, Ros M, Serrano M, Valverde ÁM. Resveratrol treatment restores peripheral insulin sensitivity in diabetic mice in a sirt1-independent manner.Mol Nutr Food Res. 2015 Mar 25. doi: 10.1002/mnfr.201400933

 

-Mobasher MA, de Toro-Martín J, González-Rodríguez A, Ramos S, Letzig LG, James LP, Muntané J, Alvarez C, Valverde AM. Essential Role of Protein-Tyrosine Phosphatase 1B in the Modulation of Insulin Signaling by Acetaminophen in Hepatocytes. J Biol Chem. 2014 289(42):29406-19

 

-Fernando Escrivá, Águeda González-Rodriguez, Elisa Fernández-Millán, Cristina M. Rondinone Carmen Álvarez, and Ángela M. Valverde. PTP1B Deficiency Enhances Liver Growth During Suckling By Increasing The Expression of Insulin-Like Growth Factor-I. J Cell Physiol. 2010 225(1):214-22

 

-González-Rodríguez, A.; Nevado, C.; Escrivá, F.; Sesti, G.; Rondinone, C.M.; Beniro, M.; Valverde, A.M. PTP1B deficiency increases glucose uptake in neonatal hepatocytes: involvement of IRA/GLUT2 complexes. Am. J. Physiol. Gastrointest. Liver Physiol. 2008 295:G338-G347

 

Dr. B Portha. University Paris-Diderot, Sorbonne-Paris-Cité. France

-Movassat J, Calderari S, Fernández E, Martín MA Escrivá F, Plachot C Gangnerau MN, Serradas P, Álvarez C, Portha B.Type 2 Diabetes-A matter of failing beta-cell neogenesis? Clues from the GK rat model? Diabetes Obes Metab. 2007 9  Suppl 2:187-95

 

Dr. M Ros. Universidad Rey Juan Carlos-  Alcorcon  Madrid

-Escrivá F,  Gavete ML, Pérez C, Álvarez C, Andrés A , Ros M and  Carrascosa J.M. Effect of age and moderate food restriction on insulin sensitivity in Wistar rats: role of adiposity. J Endocrinol.2007 194(1):131-41

 

Dr. GA Rutter. Imperial College London, United Kingdom

-Leclerc I, Sun G, Morris C, Fernández-Millán E, Nyirenda M, Rutter GA. AMP-Activated Protein Kinase Regulates Glucagon Secretion from Pancreatic Alpha-Cells. Diabetologia, 2011 54:125–134.           

 

Dra. P Serradas. Université Pierre et Marie Curie-Paris 6. France.

-Calderari S, Gangnerau MN, Álvarez C, Portha B and Serradas P. Defective early b-cell Development in the GK rat model of type-2 diabetes: Roles of insulin-like growth factors and metabolic environment. Diabetologia. 2007 50: 1463-1471

 

 

Research Grants (last years)

 

National Projects:

 

Molecular and cellular mechanisms involved in T2DM and obesity pathogenesis in rats submitted to maternal undernutrition and refed a high fat diet after weaning. MINECO. Ref.BFU 2011-25420. Principal Investigator (PI): Carmen Álvarez Escolá. (2012-2015).

 

Molecular mechanisms regulating the growth and death of pancreatic beta-cells and insulin actions on CNS: study on undernourished and diabetic rats Ref.BFU 2008-02930.  PI: Carmen Álvarez Escolá. (2009-2011).

 

Alterations in development and function of beta- cells and insulin tissue sensitivity in a model of protein-caloric undernourished rat from the fetal stage: study of molecular mechanisms involved. DGICYT Ref. BFU 2005-02849.PI: Carmen Álvarez Escolá. (2006-2008)

 

Molecular mechanisms of the alterations of development  and function of the pancreatic beta cell and of the periferic response to insulin induced by undernutrition DGICYT. BFI2002-00253. PI: Carmen Alvarez Escolá (2003-2005).

Autonomous  Community Projects

 

Study of the mechanisms of insulin resistance implication in obesity, diabetes and metabolic syndrome. (MOIR), CAM. Ref.P2010/BMD-2423 Programs I+D Biomedicina/2010. Coordinator Manuel Ros Pérez. URJC. Group Enmeper at UCM, PI: Fernando Escrivá Pons. (2012-2015)

 

Endocrinologia y Metabolismo perinatal. UCM Groups -UCM-BSCH  950610 (2007-2015) Directors: Fernando Escrivá Pons/ Carmen Álvarez Escolá

 

International Project

 

Programming of beta cell mass Homeostasis in Diabetes. Relationship with pancreatic IGFs.  Action Spain- France (UCM-PARIS-DIDEROT) Ref. HF2007-0076

PIs: Carmen Álvarez Escolá/Bernard Portha. (2008-2010) €

 

Research Networks

 

 

CIBERDEM: Spanish Biomedical research Centre in Diabetes and Associated Metabolic Disorders. ISCIII. Spain. Director: Eduard Montanya. PI Group Endocrinology and Metabolism: Carmen Álvarez Escolá. (2008-nowdays)

 

MOIR: Mechanisms of insulin resistance implication in obesity, diabetes and metabolic syndrome. Research Network in Madrid (P2010/BMD-2423). 2012-2015