Community Research and Development Information Service - CORDIS

FP6

SAVEBETA Report Summary

Project ID: 36903
Funded under: FP6-LIFESCIHEALTH
Country: Belgium

Final Report Summary - SAVEBETA (Molecular pathways underlying decreased beta cell mass in diabetes mellitus)

The two main forms of diabetes mellitus are T1D and T2D. They are a major cause of morbidity and mortality, decreasing both life quality and life expectancy of nearly 30 million affected individuals in Europe. T1D is characterised by a near complete lack of insulin production due to specific destruction of the pancreatic beta cells that typically develops over several years. Although some immune-related biomarkers can identify individuals at risk to develop T1D, the process by which the beta cells are destroyed is not well understood. As a consequence, there are no adequate strategies for preservation of beta cell mass and prevention of the disease. Accumulating evidence suggests that beta cell loss in T1D is the result of an autoimmune mediated process, where a chronic inflammation called insulitis causes beta cell destruction. This is mediated by cytokines and other mediators released by the activated immune cells invading the islets, which activate secondary pathways of cell death in the target beta cells. T2D results from a reduced ability of the pancreatic beta cells to secrete enough insulin to stimulate glucose utilisation by peripheral tissues. Initially, this causes impaired glucose tolerance, i.e. a reduced capacity to clear glucose from the blood following a glucose load. As beta cell mass decreases and beta cell secretory capacity further deteriorates, there is a progressive increase in the fasting glucose concentration, eventually culminating in overt hyperglycaemia. Defects in both insulin secretion and action contribute to the pathogenesis of T2D, but it is now acknowledged that T2D is an insulin deficiency syndrome associated with a progressive reduction in beta cell mass. The loss of beta cell mass in T2D is probably secondary to chronic exposure to high glucose and Free fatty acid (FFA) levels (glucolipotoxicity). In conclusion, a reduction in beta cell mass is a key component of diabetes mellitus and the molecular mechanisms underlying beta cell loss remain to be clarified.

This Specific Targeted Research Project (STREP) aims to utilise functional genomics to identify pathways responsible for the reduction of beta cell mass in diabetes, and use this knowledge to define targets for intervention to preserve beta cell mass. This will be reached through the following steps:
- identification of the regulatory molecular pathways that control physiological beta cell mass through regeneration, differentiation and apoptosis;
- use of functional genomics to identify key pathophysiological events in the above pathways that are responsible for reduction of beta cell mass in diabetes, with focus on the mechanisms regulating cytokine- and glucolipotoxicity-induced beta cell apoptosis;
- intervention in the defective signal transduction pathways identified above using genetically modified mice, long-acting viral vectors and small interfering RNAs. This step should identify and validate targets to preserve beta cell mass in diabetes.

To achieve this ambitious goal, we have established a consortium of leading European experts from seven European countries in the fields of pancreatic beta cell diabetes research, functional genomics and bioinformatics. The results to be obtained will foster the development of cutting-edge functional genomics technology and will contribute to the development of novel therapies to prevent diabetes.

Several important and novel findings were obtained by partners of SAVEBETA during the course of the project. These findings validate the proposed systems biology approach to understand the molecular pathways underlying decreased beta cell mass in diabetes mellitus and have provided important information for the development of novel alternatives to preserve beta cell mass in early diabetes. Highlights of the findings are:

- The role of EGFR signalling in beta cell expansion has been characterised using a Pdx-1-EGFR-dominant negative mouse, developed by members of the consortium. It was shown that these mice fail to increase their beta cell mass in response to a high fat diet and develop diabetes. This indicates that EGFR signalling is essential for compensatory beta cell growth in response to a form of metabolic demand highly prevalent in Western societies, namely high fat- (HF) and calorie-rich diets.
- Additional and novel information was obtained regarding the human diabetes syndrome 6q24 transient neonatal diabetes mellitus (6q24 TNDM), a rare form of diabetes caused by over-expression on imprinted chromosome 6q24.
- Major advances were made in the characterisation of neogenesis in human pancreatic tissue, with the identification of a double-layered basement membrane organisation of human pancreatic islets and its role in human beta cell differentiation and proliferation.
- Viral infections may contribute to the pathogenesis of T1D, but the mechanisms by which viruses or viral products such as double stranded RNA (dsRNA) affect beta cell survival and trigger autoimmunity remain unknown.
- In vitro (using siRNAs and adenoviral vectors), in vivo (using transgenic and KO mice) and in silico studies were used to characterise the role of the transcription factors NF-?B and STAT-1 in the process of beta cell apoptosis (these transcription factors were detected as key pro-apoptotic signals by previous array analysis made by SAVEBETA members).
- In vitro (using siRNAs and adenoviral vectors), in vivo (using transgenic and KO mice) and in silico studies were used to characterise the role of the transcription factors NF-?B and STAT-1 in the process of beta cell apoptosis (these transcription factors were detected as key pro-apoptotic signals by previous array analysis made by SAVEBETA members).
- Endoplasmic reticulum (ER) stress was identified via collaborative work from members of SAVEBETA as a common final pathway by which cytokines (involved in beta cell apoptosis in T1D) and free fatty acids (FFA; involved in beta cell apoptosis in T2D) trigger beta cell apoptosis.
- The antioxidant enzyme catalase mediated protection against FFA toxicity, indicating that formation of oxygen free radicals contributes to lipotoxicity.
- The antioxidant enzyme catalase mediated protection against FFA toxicity, indicating that formation of oxygen free radicals contributes to lipotoxicity.
- A SREBP1 null mouse was used to characterise the role of this transcription factor for beta cell adaptation to prolonged exposure to high glucose, a condition that prevails in T2D. It was observed that enhanced lipid synthesis mediated by SREBP1c-dependent genes is required for the adaptive changes in islet gene expression and insulin secretion in the presence of chronic exposure to high glucose.

The STREP offers to the public a freely accessible webpage of the project at http://www.savebeta.eu which contains contact information of the project coordinator office in Brussels, title and detailed aims of the project, a list of all partners and an internal site (accessible only for members of the consortium) where relevant administrative information are posted on a regular basis. Array analysis made by members of the consortium are posted on an open access website of the Beta Cell Gene Expression Bank, an initiative coordinated by D.L. Eizirik, coordinator of SAVEBETA.

As a whole, the meetings organised (including a public meeting attended by more than 200 participants), the open access websites of SAVEBETA and the Beta Cell Gene Expression Bank, and the continuous publication of data generated by members of the SAVEBETA consortium in high impact journals (43 original publications, mostly in high impact journals, plus 13 reviews in the course of the project) assured excellent dissemination of the knowledge generated in the project.

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UNIVERSITÉ LIBRE DE BRUXELLES
BRUSSELS
Belgium
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