Research project P6/40 (Research action P6)
Objective and rationale of the program
Diabetes is defined as a state of chronically elevated glucose concentrations in the blood. It is caused by failure of the pancreatic beta cells to produce the amounts of insulin that are needed to control blood glucose levels. This program will search for intervention targets through which survival and function of beta cells can be preserved or corrected. Our working hypothesis is that the phenotype of these cells determines their life span and their ability to respond to metabolic demands. We have shown in previous work that this phenotype can vary among cells and undergo alterations under influence of environmental conditions. It is therefore considered as a potential target for interventions. Further work is needed to define the various beta cell phenotypes and their (extra) cellular regulation, and to identify crucial sites in the pathways that lead to their apoptosis or their impaired insulin release. Since the loss of beta cells in type 1 diabetes is immune mediated, protocols aiming a shift of beta cells to a protective phenotype will have to be tested in combination with immune modulation. According to this rationale, our program will undertake five basic laboratory projects each addressing a major issue in the outlined long-term objective:
1. Identification and regulation of beta cell phenotypes in the postnatal pancreas
2. Molecular basis for food intake-dependent plasticity of functional beta cell mass
3. Dual regulation of fuel-induced insulin secretion in normal and dysfunctional beta cells
4. Mechanisms in beta cell apoptosis and targets for intervention
5. Modulation of immune cells in combination with beta cell protection
Network
The program is undertaken by a network of 5 Belgian teams working in a radius of 25 km at the Vrije Universiteit Brussel-VUB, Katholieke Universiteit Leuven-KUL, Université Catholique de Louvain-UCL and Université Libre de Bruxelles-ULB. Each team has an ongoing collaboration with at least one of the other teams that will be continued and extended in the present program. The director of each team will serve as a project leader for one of the five projects, and organize its intraproject collaborations. The five project leaders have established communication routes for exchange of materials, scientific and technical information and for on site collaborations and discussions. The network combines all expertise that is nationally operative in the field of beta cell biology and its usage in developing strategies for prevention and treatment of diabetes. Each partner is actively involved in international collaborations and networks within the project area of his commitment to IAP-VI.
Areas of expertise
The five partner laboratories have a long track record in the fields of diabetes and of beta cell biology and therapy. They all participate with young and less young investigators who have specialized in the proposed projects, and will continue to train novel recruits. They bring in their complementary areas of expertise which helps to address the complex objective of the network. These areas range from techniques in molecular and cellular biology to in vivo models of disease, in particular:
- Microarray analysis and bioinformatics
- Subcellular analysis of Ca metabolism, electrophysiology, mitochondrial functions, ER stress
- Functional cytomics with FACS sorting and confocal cell imaging
- Chemokine and cytokine signal analysis
- Rodent models of diabetes and treatment
Applications
The objective is clinically relevant and the proposed projects have endpoints with potential clinical implementation. This work will clarify how feeding maintains beta cell functions and how nutrient excess can impair their metabolic control and lead to diabetes. It will investigate the role of cytokines and chemokines in beta cell dysfunction and death, and in the development of insulitis. It will assess whether currently used diabetes drugs correct the molecular dysfunction and functional state of these cells, and examine novel drug targets for their ability to control beta cell survival and functions. Cell phenotypes with therapeutic potential will be identified and markers for their in vitro and in vivo recognition will be identified. Clinical implementation of findings by the proposed IAP network will be conducted in collaboration with the Belgian Diabetes Registry and the JDRF Center for Beta Cell Therapy in Diabetes, but this is not part of this program.
