Centro Andaluz de Biología Molecular y Medicina Regenerativa

Pancreatic Islet Development & Regeneration

Research Lines:

1. Pancreatic islet physiology and pathophysiology
2. Gene regulatory networks implicated in b-cell plasticity
3. Anti-diabetic drug development and testing

Summary of activities:

To date, over 366 million people worldwide have been diagnosed with Diabetes Mellitus (DM) and this number is predicted to reach 552 million by 2030 (www.idf.org). Global healthcare costs to treat or prevent diabetes are estimated to be 267 billion €. Both in Type 1 and Type 2 diabetes, progression of the disease ultimately results in b-cells death and insulin insufficiency.

b-cell regeneration

The ultimate goal of diabetes treatment is to prevent -β-cell death, maintain insulin production and sustain normal blood glucose levels. In this scope, new therapies focusing on the preservation and/or regeneration of pancreatic islet b-cells that produce insulin would benefit patients and alleviate the necessity of daily insulin injections. Our patient-oriented research focuses on harnessing the molecular pathways regulating b-cell replication and functional performance as well as increasing survival to physiological insults. More specifically, we are deciphering the functional role of key factors such as Pax4 and HMG20A in rodent as well as in human islet physiology. Mutations and polymorphisms in these genes have been associated to DM. We are also exploring the impact of novel factors such as LRH-1 and Pax8 on islet development and mature function. Using a combination of genomic and proteomic tools, we are gradually deciphering the molecular targets of these master regulators.

Anti-diabetic drug development and testing

A major goal in the treatment of diabetes and its related complications is to identify new ‘druggable’ factors that can be pharmacologically modulated to improve the functional -β-cell mass and insulin target tissues in diabetic patients. In this perspective, we have already characterized a promising small LRH-1 agonist, BL001, capable of protecting human islets against stress-induced cell death. Transgenic animals are also being developed as model system to comprehend the role of these factors on islet physiology and determine their impact on whole organism glucose metabolism. Novel technologies such as non-invasive in vivo imaging are being applied to assess alterations in β-cell mass in response to environmental insults in living transgenic animals.Additionally, new lines of research are investigating novel therapeutically promising agents inhibiting lipogenic pathways to increase insulin responsiveness in insulin-target tissues. The long-term objective is to translate quality basic research to new innovative therapies for the treatment of diabetes.

Financial support:

-Ministerio de Economía y Competitividad (Instituto de Salud Carlos III)
-Junta de Andalucía (Consejería de Salud)
-Junta de Andalucía (Consejería de Innovación, Ciencia y Empresa)
-European Union (FEDER)
-Fundación Publica Andaluza Progreso y Salud
-Fundación Vencer el Cáncer
-Asociación Lucha y Sonríe por la Vida – Pilas
-Juvenile Diabetes Research Foundation – New York

1. Lorenzo PI, Fuente-Martin E, Brun T, Cobo-Vuilleumier N, Jimenez-Moreno CM, de Gracia Herrera Gomez I, Lopez Noriega N, Mellado-Gil JM, Martin-Montalvo A, Soria B, and Gauthier BR. Pax4 Defines an Expandable ?-Cell Subpopulation in the Adult Pancreatic Islet. Scientific Reports-UK. 2015.

2. Soria B, Gauthier BR, Martín F, Tejedo JR, Bedoya FJ, Rojas A, Hmadcha A. Using stem cells to produce insulin. Expert Opin Biol Ther. 2015.

3. Jimenez-Moreno CM, de Gracia Herrera-Gomez I, Lopez-Noriega L, Lorenzo PI, Cobo-Vuilleumier N, Fuente-Martin E, Mellado-Gil JM, Parnaud G, Bosco D, Gauthier BR, Martin-Montalvo A. A Simple High Efficiency Intra-Islet Transduction Protocol Using Lentiviral Vectors. Curr Gene Ther. 2015

4. Acosta L, Hmadcha A, Escacena N, Pérez-Camacho I, de la Cuesta A, Ruiz-Salmeron R, Gauthier BR, Soria B. Adipose mesenchymal stromal cells isolated from type 2 diabetic patients display reduced fibrinolytic activity. Diabetes. 2013

5. Alvarez Mercado, A., Cobo-Vuilleumier, N., Suarez Martin, E. and Gauthier, B.R. Emerging Therapeutic Targets in Regenerative Medicine for the Treatment of Diabetes Mellitus: A Patent Literature Review. 2013. Rec. Pat. Regen. Med.

6. Soria, B. and Gauthier, B.R. The dual trade of Bcl-2 and Bcl-xL in islet physiology: Balancing life and death with metabolism secretion coupling. 2012. Diabetes.

7. Mellado-Gil, J.M., Cobo-Vuilleumier, N. and Gauthier, B.R. Islet b-cell Mass Preservation and Regeneration in Diabetes Mellitus: Four Factors with Potential Therapeutic Interest. 2012. J. Transpl. 2012: 230870

8. Cobo-Vuilleumier, N. and Gauthier, B.R. PARP-1 and cytokine-mediated beta cell damage: A nick the Okamoto model? 2012. Am. J. Physiol. Endocrinol. Metab. 303:E170-17.

9. Jimenez Moreno, C.M., Lorenzo, P.I., Delgado, I., Cobo-Vuilleumier, N., Gomez-Izquierdo, L., Garcia-Carbonero, R., Rojas, A and Gauthier, B.R. Pax8 in well differentiated pancreatic neuroendocrine tumors: How reliable is it? 2011. Am. J. Surg. Pathol. 35: 1906-1908.

10. Lorenzo, P.I., Jimenez Moreno, C.M., Delgado, I., Cobo-Vuilleumier, N., Meier, R., Gomez-Izquierdo, L., Berney, T., Garcia-Carbonero, R., Rojas, A and Gauthier, B.R. Immunohistochemical assessment of Pax8 expression during pancreatic islet development and in human neuroendocrine tumors. 2011. Hist. Cell. Biol. 136: 595-607.

11. Kirkpatrick C.L., Wiederkehr A., Baquie M., Akhmedov D., Wang H., Gauthier B.R., Akerman I., Ishihara H., Ferrer J., Wollheim C.B. Hepatic nuclear factor 1a (HNF-1a) dysfunction downregulates X-box binding protein 1 (Xbp-1) and sensitizes b-cells to endoplasmic reticulum stress. 2011. J. Biol. Chem. 286: 32300-12.

12. Baquié, M., St-Onge, L., Kerr-Conte, J., Cobo-Vuilleumier, N., Lorenzo, P.I., Jimenez Moreno, C.M., Cederroth, C.R., Nef, S., Borot, S., Bosco, D., Wang, H., Marchetti, P., Pattou, F., Wollheim, C.B. and Gauthier, B.R. The Liver receptor homolog-1 (LRH-1) is expressed in human islets and protects b-cells against stress-induced apoptosis. 2011. Hum. Mol. Genet. 20:2823-33.

13. Hu He, K.H., Lorenzo, P.I., Brun, T., Jimenez Moreno, C.M., Aeberhard, D., Cornu, M., Thorel, F., Gjinovci, A., Thorens, B., Herrera, P.L., Meda, P., Wollheim, C.B., and Gauthier, B.R. In vivo conditional Pax4 overexpression in mature islet b-cells prevents stress-induced hyperglycemia in mice. 2011. Diabetes 60:1705-1715.

Patents:

1. Use of PAX4 in pancreatic cell proliferation. 2006. WO/2006/015853
2. Novel methods for preventing or treating diabetes. 2011. WO/2011/144725.
3. Anti-inflammatory Agents. 2015 EP15382160.

Group leader:
  • Dr. Benoit Gauthier
Senior Researchers:
Postdoctorals:
  • Dr. José Manuel Mellado Gil
PhD students:
  • Maria Eugenia Martin Vazquez Garcia
Technicians:
  • Nadia Cobo