Objectif
A.General Background
Non-insulin dependent diabetes mellitus (NIDDM) or Type II diabetes is a frequent disease affecting about 3% of individuals in western populations. Its incidence increases regularly with age since it affects 10% of sixty years old individuals and 20% of eighty years old individuals. Its mortality and morbidity is a considerable health burden of our society. To control it, it is necessary to detect the persons who are predisposed in the population and thus, to prevent the disease by adopting healthy and dietetic actions.
Short Description of Previous Research and Today's Status
Although the pathogenesis of Type II diabetes (NIDDM) is not clear, several metabolic abnormalities have been identified which contribute to hyperglycaemia. These include impaired insulin secretion, elevated rates of hepatic glucose production and insulin resistance. Since NIDDM is not a homogenous entity, different causal mechanisms may exist in separate NIDDM patient groups. However, based on a variety of experimental approaches, it is clear that insulin resistance is a prominent characteristic in obese subjects and in virtually all patients with Type II diabetes mellitus.
The cellular mechanisms underlying insulin resistance have received intensive study during the two last decades as our knowledge in the mechanism of insulin action is increasing. The action of insulin is initiated by its interaction with a specific transmembrane receptor tyrosine kinase. The receptor is well-characterized,
however, the immediate consequences of its activation remain poorly defined. In one model, the activation of the receptor-kinase leads to the tyrosine-phosphorylation of several substrates, such as the recently identified insulin receptor substrate-I (IRS-I), resulting in the activation of a cascade of serine kinases as well as serine- and tyrosine-phosphatases. Binding of insulin to its receptor also activates G-proteins, as well as glucose transport.
NIDDM has strong genetic determinants as shown by high concordance for the disease in monozygotic twins and familial histories. The disease is unlikely to be monogenic as its inheritance does not follow a Mendelian pattern. The search for genes implicated in the pathogenesis of insulin resistance has been possible as various candidate genes are cloned. However, data obtained for genes coding for the insulin receptor and the glucose transporters have been inconclusive or limited to a small fraction of the population.
In spite of all these information, our knowledge of the relationship between structure and function of the insulin receptor, as well as the molecular mechanisms of its interactions with substrates is very much incomplete. We do not know how the insulin-induced signal propagates to the cell nucleus and there is little information about the molecular changes in insulin signalling leading to NIDDM and in ageing.
Why the Co-operation should be Carried out within the Context of COST?
The proposed research action requires expertise in markedly different areas of diabetes research and in different techniques, such as
-the enzymology of protein phosphorylation and dephosphorylation;
-structure/function relationships of insulin/IGF-1 receptors and their substrates;
-characterization of glucose transporters and G-proteins;
-antibody production;
-analysis of mutations of insulin receptor and insulin-related genes;
-search for genetic markers of NIDDM;
-clinical studies; insulin action on monocytes and in ageing, etc.
This diverse expertise can be found and efficiently utilized only via international co-operation. The fast development of the research action requires a regular exchange of new scientific results/ideas and sharing of research material and research techniques. This intensive multilateral collaboration exceeds the forms of usual, informal collaborative research and requires new, organized forms. The framework of a COST Action would serve these needs excellently.
How the Proposed Action Relates to Other International Scientific Programmes
To the best of current knowledge no other international scientific programme deals with the insulin- and insulin-like growth factor-dependent signal transductions as well as with the etiology of non-insulin dependent diabetes mellitus (NIDDM). During the Action co-operation will take place with the following related projects:
-Protein phosphatases in malignant transformation (BMH1-CT-92-1074)
-Aetiology of childhood diabetes on an epidemiological basis (BMH1-CT-92-0043)
-Alterations of extracellular matrix components in diabetic nephropathy (BMH1-CT-92-1766)
-Treatment of diabetes (Type I) by islet cell transplantation (BMH1-CT-92-0805)
-The European nicotinamide diabetes intervention trial
B.-C.Objectives of the Proposed Action - Scientific Programme
General Objectives
Non-insulin dependent diabetes mellitus (NIDDM) or Type II diabetes is a considerable health burden of western societies. At present no reliable screening method is available to detect the persons who are predisposed in the population and due to our incomplete knowledge on the molecular mechanisms leading to NIDDM we have very few means to influence the onset and development of this diverse disease.
Various steps of insulin action will be studied starting from the insulin receptor and following insulin action till it reaches the cell nucleus. A search of genetic markers characteristic of NIDDM is also planned in hope to develop a reliable screening method to detect the individuals with inherited risk for NIDDM. In the second phase of the studies outlined the investigation of pathological changes of the molecular mechanism of insulin action in NIDDM is planned hoping to develop new drug-candidates for the curing-easing of the consequences of this diverse disease.
Secondary Objectives
The following steps of insulin action will be studied to gain a better understanding of the etiology of non-insulin dependent diabetes mellitus:
1.Search for genetic markers of insulin resistance in NIDDM and rare syndromes of insulin resistance, such as in leprechaunism, Type A syndrome of insulin resistance, Acanthosis Nigricans and lipoatrophic diabetes
1.1.search for molecular alteration in the insulin receptor (IR) gene in patients with leprechaunism, Type A syndrome and Acanthosis Nigricans;
1.2.sequential study of the implementation of candidate genes (genes coding for proteins involved in the mechanism of insulin action) in NIDDM and rare syndromes of insulin resistance;
1.3.search for differential expression of various genes in insulin resistant patients;
2.Studies on insulin receptor function (or disfunction)
2.1.role of the juxtamembrane domain and the C terminal segment of insulin receptor in the insulin-dependent signal transduction;
2.2.role of serine/threonine phosphorylation in regulating insulin receptor tyrosine kinase activity in normal state and in NIDDM;
2.3.characterization of differences in the structure/function of insulin and IGF-1 receptor in extreme insulin resistance and NIDDM;
3.Studies on the intracellular mechanism of insulin action in normal and pathological states
3.1.mechanism of the interactions between insulin receptor and its substrates;
3.2.molecular characterization of GLUT4 translocation in normal and insulin-resistant states;
3.3.identification of the major insulin-induced nuclear phosphoproteins. Differences between the actin of insulin and IGF-1 in the cell nucleus;
3.4.possible involvement of the nuclear forms of insulin-induced protein kinases/phosphatases such as casein kinase II and protein phosphatase 1 in insulin-induced nuclear signalling;
3.5.identification of insulin-response element binding proteins, the role of cytoplasmic and nuclear chaperons in insulin-dependent gene expression;
3.6.characterization of insulin action on monocytes from healthy people and from patients with NIDDM;
3.7.evaluation of the functional role of insulin receptor-coupled G-proteins.
3.8.identify mRNA's exhibiting altered expression in insulin resistance and NIDDM using mRNA differential display system and sequencing, and search for genetic marker(s) among the genes coding for the proteins involved in the intracellular pathways of insulin in these conditions.
The list of secondary objectives is open for amendments incorporating the specific aims of new groups willing to participate in the concerted action. To join to the proposed research action an expertise in insulin (insulin-like growth factor) dependent signal transduction and/or in structural studies of insulin related genes is required.
COST Co-operation will provide the necessary framework for the intensive and fast exchange of new scientific data in form of phone/FAX/mail and E-MAIL communications, as well as in regular workshops organized by the participants. Exchange of scientific research material (such as antibodies, nucleotide probes, isolated proteins, peptides, etc.) is also planned on a regular basis between the groups. Short- and long-term visits are planned between the participating laboratories and joint research experiments will be performed. The exact schedule and topics of these activities will be determined by the Management Committee on a yearly basis.
D. Timetable
The project is planned to last for five years. It is anticipated that the research described in Section B will be investigated in parallel, building upon existing work in several countries. Specific time schedule and list of tasks (including the organization of workshops) will be established on a yearly basis by the Management Committee.
E.Organization and management
A Management Committee will be set up following the signing by the appropriate number of Signatories to the Memorandum of Understanding. This Committee will work out its rules of operation at its first formal meeting in accordance with existing COST regulations.
The partners will appoint an Action Co-ordinator who will be responsible for co-ordinating activities and ensuring that the Action meets the overall objectives. A network will facilitate fast information exchange by electronic mail or by FAX. Original results will be disseminated for the scientific community by participating in international meetings and by communications in recognized scientific journals. Annual reports will be produced for the COST Senior Officials, and a detailed Final Report will be written at the end of the five year period.
F.Economic dimension of the action.
Current status
One of the major goals is to promote the exchange of ideas, approaches, skills, techniques and scientific materials in the field of NIDDM research via scientific collaborations. So far Danish-English, German-Hungarian, German-Slovakian, Hungarian-Spanish bilateral co-operations have been established within the frame of the Action. Preparation of other bi-, and multilateral collaborations is in progress.
The Management Committee has so far established three working groups :
Working Group '- Insulin Signalling in Muscle'; Co-ordinator : Dr. P. Shepherd (UK)
Working Group ' Glucose Transport'; Co-ordinator : Dr. C. Reynet (DK)
Working Group ' Genetics of NIDDM'; Co-ordinator : Dr. T. Maasen (NL)
Work planned
The network will continue to organise the collaboration for the better understanding of the etiology of non-insulin dependent diabetes mellitus (NIDDM) on a European level. We will focus our efforts on the following areas :
genetics of NIDDM ("high-risk genes", potential screening methods)
signal transduction in NIDDM (development of new drugs acting on the influence of insulin signalling)
glucose transport in NIDDM (one of the most important metabolic changes in diabetes)
changes in muscle biochemistry and physiology in NIDDM (muscle is one of the most important tissues utilising insulin and human muscle biopsies are one of the very few model systems involving human tissues).
Besides joint conferences, Working Group meetings and seminars, collaboration also extends to the exchange of scientific materials, Short-Term Scientific Missions, training courses and to joint scientific and drug-development projects.
Programme(s)
Programmes de financement pluriannuels qui définissent les priorités de l’UE en matière de recherche et d’innovation.
Programmes de financement pluriannuels qui définissent les priorités de l’UE en matière de recherche et d’innovation.
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Les appels à propositions sont divisés en thèmes. Un thème définit un sujet ou un domaine spécifique dans le cadre duquel les candidats peuvent soumettre des propositions. La description d’un thème comprend sa portée spécifique et l’impact attendu du projet financé.
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Procédure par laquelle les candidats sont invités à soumettre des propositions de projet en vue de bénéficier d’un financement de l’UE.
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Régime de financement (ou «type d’action») à l’intérieur d’un programme présentant des caractéristiques communes. Le régime de financement précise le champ d’application de ce qui est financé, le taux de remboursement, les critères d’évaluation spécifiques pour bénéficier du financement et les formes simplifiées de couverture des coûts, telles que les montants forfaitaires.
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Coordinateur
1049 Brussels
Belgique
Les coûts totaux encourus par l’organisation concernée pour participer au projet, y compris les coûts directs et indirects. Ce montant est un sous-ensemble du budget global du projet.