Pancreatic Islet Development & Regeneration

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Blood glucose homeostasis is achieved by the regulation of insulin and glucagon secretion from the pancreatic islet β- and α-cells. Diabetes mellitus, which comprises a heterogeneous group of hyperglycemic disorders, results mainly from inadequate mass and function of islet β-cells. Autoimmune destruction of β-cells causes Type 1 diabetes while Type 2 is characterized by impaired insulin secretion and is often associated with diminished insulin action on its target tissues. Similar to Type 1 diabetes a gradual loss of β-cell mass is also observed in Type 2 diabetes often requiring insulin therapy. Understanding the molecular mechanism that governs &β-cell survival and regeneration as well as function may provide means to develop new strategies for the treatment of diabetes.

Research Line:

Our research focuses on the implication of key pancreatic transcription factors that play an important role not only in development but also in sustaining mature islet β-cell function. Mutations in these factors have been linked to both Type 1 and Type 2 diabetes. Using a combination of genomic and proteomic tools, we are gradually deciphering the molecular targets of these master regulators in both rodent and human primary pancreatic islets (Figure 1). 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 (Figure 2).





Ongoing research projects:

•    The functional impact of Pax4 on pancreatic islet β-cell mass
•    β-cell expansion by epigenetic regulation
•    The role of Pdx1 in β-cell function and survival
•    The implication of Pax8 in islet expansion during pregnancy
•    LRH-1 and islet physiology


Funded by:

Swiss National Research Foundation
Fundación Progreso y Salud
Spanish Ministry of Health (Instituto de Salud Carlos III)


Selected publications:

Cobo-Vuilleumier, N. and Gauthier, B.R. To b(e) or not to b(e) replicating after 30: Retrospective dating of human pancreatic islets, J. Clin. Endocrinol and Metab. In press

Wang, H., Hagenfeldt-Johansson, K., Otten, L.A., Gauthier, B.R., Herrera, P.L. and Wollheim, C.B. Experimental Models of Transcription Factor-Associated Maturity Onset Diabetes of the Young. Diabetes. 51: S333-S342, 2002.

Gauthier, B.R., Brun, T., Sarret, E.-J., Ishihara, H., Schaad, O., Descombes, P. & Wollheim, C.B. Oligonucleotide microarray analysis reveals PDX1 as an essential regulator of mitochondrial metabolism in rat islets. J Biol Chem. 279:31121-30, 2004.

Brun, T., Franklin, I., St-Onge, L., Biason-Lauber, A., Schoenle, J.E., Wollheim, C.B. & Gauthier, B.R. The diabetes-linked transcription factor PAX4 promotes ß-cell proliferation and survival in rat and human islets. J. Cell Biol., 167:1123-35, 2004.

Biason-Lauber, A., Boehm, B., Lang-Muritano, M., Gauthier, B.R., Brun, T., Wollheim, C.B. & Schoenle E.J. Deficient ß-cell repair due to a genomic variant of Pax4 is associated with type 1 diabetes in children. Diabetologia 48:900-9005, 2005.

Gauthier, B.R. and Wollheim, C.B. MicroRNAs: Ribo-regulators of glucose Homeostasis. Nature Medicine 12:36-38, 2006.

Brun T, Duhamel D, Hu He KH, Wollheim CB, Gauthier B.R. The transcription factor PAX4 acts as a survival gene in INS-1E insulinoma cells. Oncogene, 26:4261-71, 2007.

Schumann, D.M, Maedler, K., Franklin, I., Konrad, D., Størling, J., Böni-Schnetzler, M., Gjinovci, A., Kurrer, M.O., Gauthier, B.R., Bosco, D., Andres, A., Berney, T., Greter, M., Becher, B., Chervonsky, A.V., Halban, P.A., Mandrup-Poulsen, T., Wollheim, C.B., and Donath, M-Y. The Fas pathway is involved in β-cell secretory function. PNAS, 104:2861-6, 2007.

Brun,T. and Gauthier, B.R. A focus on the role of Pax4 in mature pancreatic islet beta-cell plasticity in health and disease. J. Mol. Endo. 40:37-45, 2008.

Brun, T., Hu He, K.H., Lupi, R., Boehm, B., Wojtusciszyn, A., Sauter, N., Donath, M., Marchetti, P., Maedler, K. and Gauthier, B.R. The diabetes-linked transcription factor Pax4 is expressed in human pancreatic islets and is activated by mitogens and GLP-1. Hum. Mol. Gen. 17:478-89, 2008.

Gauthier, B.R., Wiederkehr, A., Baquié, M., Dai, C., Powers, A.C., Kerr-Conte, J., Pattou, F., MacDonald, R.J., Ferrer, J. and Wollheim, C.B. Pdx1 deficiency causes mitochondrial dysfunction and defective insulin secretion through TFAM suppression. Cell Met, 10:110-18, 2009.

Patent:

Inventors: B.R., Gauthier, T., Brun, C.B., Wollheim and R Wehr. Title: Use of PAX4 in pancreatic cell proliferation. Registration number: PCT/EP2005/008653. Registration date: 09.08.2005. Countries: Europe, Canada.