Technical Annex for the establishment of a COST Action on Insulin resistance, obesity and diabetes mellitus in the elderly

A. Introduction

A.1. Today's status Diabetes mellitus 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. Diabetes is a leading cause of blindness, renal failure, and lower limb amputations in adults, and is a major risk factor for cardiovascular disease and stroke. 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.

Although the pathogenesis of diabetes mellitus is not clear, several metabolic abnormalities have been identified which contribute to hyperglycemia. These include impaired insulin secretion, elevated rates of hepatic glucose production and insulin resistance. Since diabetes mellitus is not a homogenous entity, different causal mechanisms may exist in separate diabetes patient groups. However, based on a variety of experimental approaches, it is clear that insulin resistance is a prominent characteristic in these patients and the contribution of insulin resistance to the manifestation of diabetes in the elderly needs thorough investigations in order to develop new therapeutic strategies.

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 insulin receptor substrate-I to VI (IRS-I to IRS-VI), resulting in the activation of a cascade of serine kinases, lipid kinases as well as serine- and tyrosine-phosphatases. Binding of insulin to its receptor also activates the MAP-kinase pathway and in addition to its metabolic effects the hormone exerts key functions at the level of gene expression. The signalling specificity between the insulin receptors and other tyrosine kinase receptors, the role of specific insulin signalling pathways in different tissues as well as their relevance to specific biological actions of insulin is rather poorly defined.

Obesity is a major risk factor leading to the development of NIDDM. Recent cloning of the ob-gene product, leptin and its receptor has provided important insights to the molecular pathways regulating food intake and energy expenditure leading to a considerable progress in understanding the pathogenesis of obesity. The increasing research activities in the leptin field strongly require a concerted European action to encourage, coordinate and help the national efforts in this important and promising area.

Diabetes mellitus has strong genetic determinants as shown by high concordance for the disease in monozygotic twins and familial histories. The disease is polygenic 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 were examined. Efficient differential screening methods have been also developed resulting in the discovery of several diabetes-related genes, such as MODY1, MODY2 and MODY3, IRS-2, Rad, PED/PEA-15, etc.

Diabetes mellitus of the aged people is most often described as non-insulin depedent diabetes mellitus (NIDDM). However, detailed studies have established other (sub-)classes, such as maturity onset diabetes of the young (MODY), and demonstrated that an improved classification of diabetic patients is urgently required.

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 downstream signalling is very much incomplete. Similarly, the role of leptin and other exogenous factors which in combination with a certain genetic background, predispose to the development of diabetes need also further clarification.

A.2. Why the Cooperation should be Carried out within the Context of COST?

The proposed Action is a logical consequence of COST Action B5 (1994-1999). During COST Action B5 it became clear that diabetes mellitus of the aged people is a more diverse disease as previously thought and can not be properly described by the single term non-insulin dependent diabetes mellitus (NIDDM). Besides insulin and IGF-signalling, leptin-dependent signalling mechanisms became also important in the etiology of diabetes. Examination of numerous candidate-genes emphasized the importance of differential screening methods in further identification of diabetes-related genes. Therefore a significant extension, total reformulation and restructuring of research in the field became necessary. This urgent need is excellently served by the present proposal. In parallel, the need and willingness for an all-European cooperation in the area has significantly increased since 1994. COST can serve this need excellently.

The proposed research action requires expertise in markedly different areas of diabetes research and in different techniques, such as

 This diverse expertise can be found and efficiently utilized only via international cooperation. 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 frames of a COST action would serve these needs excellently.

A.3. How the proposed Action is related to other international scientific programmes

During our project we will cooperate with the following related projects:
  1. COST Action 918 on "Body weight and energy expenditure: functional foods". The cooperation will utilize the different approaches taken by the two Actions for the examination and extension of obesity-related genes. (Mutual invitation to each other's meetings and information exchange is planned.)
  2. BIOMED 2 programme "Search for NIDDM genes" (two members of the Steering Committee of the BIOMED 2 programme were also involved in the formulation of the present proposal; joint meetings and continuous information exchange are planned).
  3. International Institute on Ageing (United Nations, La Valetta, Malta; information exchange is planned).
The precedessor of the present Action, COST B5 was a rich source of 5th Framework applications and collaboration. However, the present COST Action does not result in a parallel activity of the 5th Framework program for the following reasons:
  1. the present Action will be highly informal, flexible and interdisciplinary
  2. there will be numerous countries involved in the Action, e.g. those from Eastern and Southern Europe which are not often participating in 5th Framework programmes
  3. the involvement of the new Action in obesity and aging research together with diabetes research will by itself ensure an interdisciplinary approach a usual 5th Framework programme can not provide and
  4. the involvement of local experts of others fields adds a further "interdisciplinary element" to the Action.

B. Objectives and benefits

B.1. General objectives

Diabetes mellitus of aged people is a considerable health burden of western societies. At present no widely established 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. The ongoing research of candidate genes as well as various differential screening methods will be coordinated with the new Action.

Various steps of insulin action will be studied starting from the insulin receptor and following insulin action till it reaches the cell nucleus with special emphasis on the investigation of pathological changes of the molecular mechanism of insulin action in insulin resistance, obesity and NIDDM of the aged people. This research acitivity is thought to lead to the development new drug-candidates for the curing-easing of the consequences of this diverse disease.

B.2. Secondary objectives

The following steps of insulin action will be studied to gain a better understanding of the etiology of insulin resistance, obesity and NIDDM of the aged people, in hope to develop drug-candidates and a reliable screening method to detect the individuals with inherited risk for the disease. The list of secondary objectives is open for amendments incorporating the specific aims of new goups willing to participate in the concerted action. To join to the proposed research action an expertise in insulin (leptin, insulin-like growth factor) dependent signal transduction, insulin resistance/obesity-related physiological changes and/or in structural studies of insulin resistance/obesity-related genes is required.

C. Scientific programme

To help and ensure the efficient information exchange and scientific research cooperation between the participating research groups the following activities are planned in the Action: A network will facilitate fast information exchange by electronic mail, by a web-site on the Internet or by FAX. The web-site will contain an open forum for "hot topics" and technical as well as theoretical discussions. Conferences, workshops, working group meetings and seminars will be advertised in the scientific community of the host country and will be open for interested members to join. This will serve as a way to give direct information on the Action and to popularize the idea of European collaboration in frame of COST. Original results will be disseminated for the scientific community by participating in international meetings of the network and organized by other bodies and by communications in recognized scientific journals. The Action will seek the possibilities to transfer the appropriate results of the investigations to other networks and programmes such as the 5th Framework programme or EUREKA. A partnership network will be organized involving European companies in the field.

D. Organization and timetable

D.1. 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 Coordinator who will be responsible for coordinating acitivities of the three to five working groups (Genetics, Signalling, Glucose transport, Obesity, Ageing) and ensuring that the Action meets the overall objectives. 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.

D.2. 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. Economic dimension

in thousand ECU-s/year

E.1. Estimated personnel costs:

category A (50 scientists) 1.500
category B (25 technicians) 500
category C (40 students, secretaries) 500

E.2. Estimated running costs 1.940

E.3. Coordination costs 60

E.4. Total costs 4.5 mECU-s/year

Items E.1. and E.2. of the budget is covered from national sources in the participating countries. E.3. is sought to be provided by the Commission.