DIA MAP
s t t r r a t t e g i i c p l l a n f f o r r d i i a b e t t e s r r e s e a r r c h

Note: this is a short overview of the full DIAMAP road map report, which can be found on www.DIAMAP.eu where the searchable DIAMAP Research and Funding databases can also be accessed. Readers are encouraged to consult the full report for more complete explanation of the road maps and recommendations.
Executive summary…………………………………………………………………………………….……… 3
Short guide to the road map……………………………………………………………………………….… 5
Introduction to reading the road maps……………………………………………………………….……. 6
Chapter 1. Genetics and epidemiology………………………………………………………………..…... 9
Goal 1.1. Develop novel prevention strategies for type 1 diabetes……………………………………….. 9
Goal 1.2. Develop overall type 2 diabetes prevention strategies………………………………………….. 10
Goal 1.3. Develop novel personalised type 2 diabetes prevention strategies through studying the aetiology and prediction of disease……………………………………………………………….. 11
Goal 1.4. Develop approaches to the prevention of the complications of type 2 diabetes……………… 12
Goal 1.5. Develop novel personalised diabetes treatment strategies through studying the aetiology and prediction of complications……………………………………………………..…. 13
Roadblocks Chapter 1………………………………………………………………………………………….. 14
Chapter 2. Islets ………………………………………………………………………………………………. 15
Overarching Goal 2.0. Cure and prevent diabetes by restoring and preserving beta cell function……. 15
Goal 2.1. Guide development of novel therapies based on understanding beta cell function and its regulation……………………………………………………………………………………….... 16
Goal 2.2. Guide the development of novel therapies based on an understanding of mechanisms controlling beta cell mass………………………………………………………………….………. 17
Goal 2.3. Guide development of novel therapies based on understanding beta cell specific phenotypic characteristics related to regulation of defence/repair……………………………. 18
Goal 2.4. Guide development of novel therapies based on understanding the role of tissue interactions in regulating beta cell function and mass………………………………………….. 19
Roadblocks Chapter 2………………………………………………………………………………………..... 20
Chapter 3. Pathophysiology, metabolism and integrative physiology…………………………....... 21
Goal 3.1. Understand tissue-to-tissue communication in diabetes pathogenesis………………………. 21
Goal 3.2. Identify pathways controlling energy balance and weight regulation to develop targetted therapeutic intervention for obesity and diabetes……………………………………………….. 22
Goal 3.3. Identify and validate biological indicators (biomarkers) predicting an individual’s risk of developing type 2 diabetes (prediabetic phenotype) beyond routine measurements............ 23
Goal 3.4. Develop lifestyle intervention strategies with individualised diet and exercise approaches to prevent type 2 diabetes and obesity based on specific genetic traits………………………… 24
Roadblocks Chapter 3…………………………………………………………………………………………. 25
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Chapter 4. Clinical science and care
incorporating a European Platform for Clinical Research in Diabetes (EPCRD)…………………… 26
Goal 4.1. Create a European Platform for Clinical Research in Diabetes (EPCRD) to facilitate and enhance research for improved care and treatment of people with diabetes throughout Europe …………………………………………………………………………………. 26
Goal 4.2. Achieve comparable outcomes for people with diabetes regardless of socio-economic status and diversity…………………………………………………………………………………. 28
Goal 4.3. Improve outcomes for people with diabetes in hospital or institutional settings……….…….. 29
Goal 4.4. Achieve remission of diabetes and improvement of quality of life for obesity-related diabetes 30
Goal 4.5. Achieve normal ageing in diabetes with preserved quality of life………………….………….. 31
Goal 4.6. Improve metabolic and psychological endpoints in paediatric diabetes……………………… 32
Goal 4.7. Prevent pregnancy-related acute and long-term diabetes complications in both mother and child…………………………………………………………………………………..… 34
Goal 4.8. Relate islet function to clinical outcomes and clinical care…………………………………….. 35
Goal 4.9. Prevent and/or reduce cognitive impairment and psychopathology in diabetes…………….. 36
Goal 4.10. Develop new strategies to minimise the risk of hypoglycaemia (including technologies)….. 37
Goal 4.11. Improve prognosis and quality of life by developing strategies to achieve clinical targets in different dysglycaemic populations …………………………………………………………… 38
Roadblocks Chapter 4……………………………………………………………………….…………..….…. 39
Chapter 5. Microvascular complications………………………………………………………………..… 41
Goal 5.1. Develop and validate new pathogenetic treatments for diabetic microangiopathy……….... 41
Goal 5.2. Identify early organ-specific predictors of high-risk, accelerated course, or protection from microvascular complications…………………………………………………………..……. 42
Goal 5.3. Define efficacy and safety of new therapeutic strategies to prevent blindness…………..…. 43
Goal 5.4. Develop strategies to prevent the need for dialysis and define appropriate timing for transplantation………………………………………………………………………………..……. 44
Goal 5.5. Prevent diabetic autonomic neuropathy…………………………………………………..….…. 45
Goal 5.6. Reduce end-stage neuropathic foot ulcers and Charcot neuroarthropathy…………..…….. 46
Goal 5.7. Understand the impact of microvascular disease on cardiovascular endpoints……..…...... 47
Roadblocks Chapter 5………………………………………………………………………………..…….….. 48
Chapter 6. Macrovascular complications………………………………………………………..……….. 49
Goal 6.1. Understand why cardiovascular disease develops early in people with diabetes: molecular, genetic and environmental bases………………………………………………….... 49
Goal 6.2. Establish early diagnosis of cardiovascular disease in diabetes and identify patients at high risk…………………………………………………………………………………………...… 50
Goal 6.3. Develop personalised therapy related to the stage of cardiovascular disease in diabetes.. 51
Goal 6.4. Understand prevention of cardiovascular disease in diabetes………………………..…..….. 52
Roadblocks Chapter 6………………………………………………………………………………..…..…… 53
Chapter 7. Horizontal Issues ……………………………………………………………………..……….. 54
Major recommendations and suggestions………………………………………………………………….. 55
The future of DIAMAP and European Diabetes Research: the European Diabetes Academy…. 57
Academic teams and staff…………………………………………………………………………..……… 58
EURADIA: Alliance for European Diabetes Research………………………………………..….......... 62
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Background
Diabetes mellitus is a major health challenge of the 21 st
century. This chronic disease has reached epidemic proportions in all regions of the world and the prevalence of diabetes in both its major forms is expected to continue to rise inexorably if nothing is done to prevent it.
Today, there is no cure for diabetes; while new drugs and a holistic approach to treatment have improved the prognosis for individuals with diabetes and their quality of life, the menace, morbidity and increased mortality from micro- and macrovascular complications remain.
The challenge of curing diabetes and preventing its onset will only be met through increased research. Europe is well placed to play a leading role in this research effort in terms of existing expertise. However, success will depend not only on increased funding but also on more rational use of research funds and better coordination of research across the region. DIAMAP is the first European research road map of its kind in any disease area.
Major Goals
The aim of DIAMAP, a project funded by the
European Commission (FP7 HEALTH
200701), was to chart the future of diabetes research in Europe for the benefit of the person with diabetes. In support of this innovative mission a survey was carried out of the European diabetes research landscape, and a strategic road mapping exercise for diabetes research in Europe was undertaken.
The DIAMAP report comprising strategic maps and reports from seven sub-groups is intended to guide investment in diabetes research in
Europe for the period 2010-2019 and to suggest means for improved coordination. The two public DIAMAP databases provide insight into the current landscape of European diabetes research, with information on research activities and funding.
Methods
Diabetes research was considered in its broadest sense embracing, where possible, all aspects of this complex field, from molecules, cells and tissues, to whole animal studies, and clinical science and care. The project took a multi-disciplinary/multi-professional approach and involved over 50 experts from all areas of diabetes research. Individuals with diabetes were represented on the Steering Committee, alongside researchers from academia and industry. Demographic trends and lifestyle factors were taken into consideration as well as ageing of the European population. Ethical issues as well as research in health economics and public health also feature across the various road maps. Information in the databases (summarised in the full DIAMAP report) is based on questionnaires returned by investigators and major funding agencies
(public and non-profit) across Europe. All data aside from essential contact details were anonymised prior to aggregation.
Results
Road maps and reports: DIAMAP provides the first ever blueprint for future diabetes research in Europe. The entry point to each road map track is based on major advances in the given field of research in the past 10 years or so. The tracks then progress along several milestones to reach a common endpoint, an over-arching goal considered of particular importance for improved treatment or prevention of diabetes and its complications.
The groups were also invited to consider the feasibility of milestones and to identify roadblocks preventing smooth progress along a track, as well as the specific opportunities for
European science, whether in an academic or industrial setting. Tracks or milestones considered particularly opportune for immediate investment are flagged as priorities.
The road maps from each sub-group are not independent but part of a whole, stressing the need for crosscutting, interdisciplinary research. Basic research proposed by the specialist groups is translated into clinical studies (see Chapter 4 Clinical science and care incorporating the creation of a European
Platform for Clinical Research in Diabetes).
Chapter 7 (Horizontal Issues) suggests ways to overcome generic roadblocks common to many road maps as well as addressing major obstacles to competitive research in Europe, including training and mobility.
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DIAMAP proposes the creation of a European
Platform for Clinical Research in Diabetes
(EPCRD: see Goal 4.1). This major European collaborative resource would allow centralisation of information, with increased involvement of people with diabetes and improved sharing of data and samples.
DIAMAP further recommends cross-fertilisation between the academic world and the private sector, comprising biotechnology, pharmaceutical and also food industries, as well as bridging the gap between researchers, people with diabetes and healthcare providers.
There must also be some way to ensure that the European diabetes research effort is coordinated. This can best be achieved by the creation of a central entity, the European
Diabetes Academy (Chapter 7).
Databases: There are two freely accessible databases. The Research Database, which provides information regarding who
(investigators) is doing what type of diabetes research (keyword search for topics and technology/methodology) and where (country, city, academic institution) in Europe. With over
1200 entries, this is the first searchable database of its kind ever developed for
European diabetes research. The Funding
Database and accompanying report provide a best estimate of total funding for diabetes research in Europe by public agencies and non-profit foundations as well as information on unrestricted grants from industry.
Future perspectives
Aside from the primary goal of using the road maps to guide choice of research areas for future funding and to ensure coordination of such research, in the longer term this innovative project cannot succeed unless there is constant monitoring of progress. It will also be essential to evaluate the impact of this innovative research strategy in terms of development of new therapies and improved quality of life for individuals with diabetes. The databases must be maintained and constantly updated. It will thus be critical to sustain
DIAMAP in order to capitalise fully on the initial investment in this unique endeavour.
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To our knowledge, this is the first attempt to prepare a road map for diabetes research in
Europe and indeed DIAMAP may be the first project of its kind in Europe in any disease area. However, DIAMAP is set in the context of previous diabetes road maps charted in the
United States where the Juvenile Diabetes
Research Foundation (JDRF) Research Task
Force ‘mapped’ potential approaches to curing type 1 diabetes and its complications (1996-
97) [1]. In 1999 the National Institutes of
Health (NIH) looked at ways to prevent the development of type 1 and type 2 diabetes and their complications [2]. These successful strategic exercises have been repeated several times in the United States, while in
Europe individual countries have used a similar process [3] to identify research opportunities at a national level.
At the European level and with a more general scope, the European Strategy Forum on
Research Infrastructures (ESFRI) has used a strategic mapping process for a large-scale, long-term plan embracing all scientific areas regardless of location ‘to develop the scientific integration of Europe and to strengthen its international outreach’ [4]. The European
Medicines Agency (EMA) is also in the process of consulting on its draft road map document
(at the time of this report) that will set out its research strategy to 2015 [5].
With such research road maps in mind,
DIAMAP seeks to ensure that diabetes research priorities can engage with both national plans and with larger-scale more general strategic approaches to funding and coordination.
The inspirational and practical tone, and nontechnical but specific language, is intended to attract attention from non-scientists who will be using DIAMAP, while still allowing specialists to benefit from it. The road maps are clearly oriented towards what can be achieved by the research community, while health care policy and care delivery are not addressed unless they can be specifically impacted by the research strategy.
Strategy for developing the road maps
Guided by the Steering Committee and staff, sub-groups of experts were invited to develop the road maps using a common strategy. First, they identified the major scientific advances in their field in the past five or so years that still impacted on science today; these advances served as entry points for developing the research tracks. The groups then decided on important overarching research goals for their field as the endpoint of each track, with identification of the interim research milestones along each track towards the goals.
Roadblocks to research were considered to be factors that prevent progression of research and that cannot be resolved by research alone but by engaging with groups or individuals possibly external to the research community to allow a goal to be reached. The Horizontal
Issues group then addressed any roadblocks common to several research tracks as well as other crosscutting and generic issues relevant to diabetes research, such as ethics and communication.
Synergistic points of intersection between research areas have been identified with cross-referenced milestones in the road map diagrams.
The mapping process was developed first in a diagrammatic ‘map’ format and then elaborated in accompanying narrative text for ease of reference.
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The general layout of the maps is described in Figure 1.
The following seven chapters consist of six road maps from sub-groups 1-6 and the
Horizontal Issues report from sub-group 7.
These cover all of the major areas of diabetes research, although it is acknowledged that many details will not have been included for reasons of space, group preferences and practicality. The maps are intended to be flexible and open to new ideas as the research progresses.
Each of the individual maps begins with the road map diagram that makes the progress of the research tracks towards the goal easy to follow. The diagram also makes it easier to track research progress as individual milestones are achieved, as well as to appreciate the points of cross-linkage between maps. The accompanying narrative connects to the diagram and provides an overview of the
overarching research goal (the endpoint of each map) and the roadblocks that hinder the research being carried out.
The ultimate and unifying overarching research goal of diabetes research is to cure or prevent diabetes. However, this was considered such an overwhelming task for individual sub-groups that their overarching goals are those that would naturally progress towards this final objective within their individual fields. Goals are kept specific to ensure that a clear research pathway is charted within each field, although there are intersections and crosslinks between groups along the way (indicated in the text and the diagrams).
The research goals were drawn up with a very broad picture of research in mind, much larger than one specific scientific project. The authors of the report were creative in their thinking but as a guide they were given an approximate 10-year time frame to achieve the goals, although it is acknowledged that one single research advance could achieve the objective much more quickly and that advance could come from a direction not considered within this map.
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Along each research track towards the goal are the research milestones. Again, the milestones are much broader than a single research project and it could be envisaged that each milestone covers a series of initiatives or large projects. Although reference is made to biology, physiology and pathophysiology to provide context and explanation, the maps are mainly presented in a practical action-oriented non-scientific language to indicate that
DIAMAP is intended as a practical tool and not an academic exercise constrained by traditional research disciplines.
Prioritisation
DIAMAP did not originally intend to prioritise tracks. However, it was felt to be in the interest of those consulting the report and seeking guidance for future investment in European diabetes research to provide a limited degree of prioritisation. The sub-groups were therefore invited to identify a small number of overarching goals or specific milestones that were considered particularly important for advancement in the field and where today’s
European know-how and state-of-the-art technology would allow optimal and rapid return for investment. Goals and Milestones considered a priority are indicated with a broken line in the diagram (in green when printed in colour).
The goals and milestones have been developed with the objective of addressing the
‘person with diabetes’ and the disease itself and not the academic research process. Often the goals and milestones will necessitate the development of new research tools. With this in mind it is intended that these maps will inspire research agendas and funding from many different sources, not necessarily always from the classical diabetes agencies. There is no particular geographic limitation on the location of research, but the maps have been written keeping in mind the infrastructure and expertise currently available within Europe.
Roadblocks and Horizontal Issues
Research roadblocks are indicated when possible in red circles within each road map and listed immediately underneath.
Roadblocks are issues that impede progress or completely inhibit achieving the research goals such as: lack of research networks, infrastructure, resources, specific training, biosample collections, and so on. These roadblocks must be addressed with urgency to allow smooth progress along any given track.
The Horizontal Issues group was also asked to indicate major, generic roadblocks that could be overcome with appropriate and rapid funding or action, thereby accelerating progress in a large number of research tracks.
The Horizontal Issues group considered a much wider and less focussed field than the other groups. These issues are not necessarily specific to diabetes research but do have an impact upon the field.
Ethical issues, professional training and education, research governance, funding policies and funding instruments are also addressed within the Horizontal Issues report.
Strategies are proposed to reduce regulatory and administrative roadblocks to the conduct of research alongside policies and frameworks needed to promote research across Europe.
It is acknowledged that the Horizontal Issues report, just as for the other reports, cannot address every single issue in detail. The broad approach taken in the overall strategy is intended to provide a practical and workable framework for those in the diabetes research and funding communities.
Contributors to the DIAMAP research road maps and a list of staff and committees are noted at the end of this publication.
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References
1. Research Task Force (1996-7) Juvenile
Diabetes Research Foundation (personal communication)
2. NIH Conquering Diabetes: a strategic plan for the 21st century (1997) Report of the
Congressionally Established Diabetes
Research Working Group. http://www.niddk.nih.gov/federal/dwg/dwgmain.
htm
3. Department of Health and Medical Research
Council (UK). Research Advisory Committee on Diabetes (2002) Current and future research on diabetes. http://www.dh.gov.uk/en/Publicationsandstatisti cs/Publications/PublicationsPolicyAndGuida nce/DH_4091473
4. European Commission (2009) European
Strategy Forum on Research Infrastructures
(ESFRI) European Roadmap for Research
Infrastructures Implementation Report. http://ec.europa.eu/research/infrastructures/ind ex_en.cfm?pg=esfri
5. European Medicines Agency (2009) The
European Medicines Agency Road Map to
2015: The Agency’s Contribution to Science,
Medicines, Health. Draft for Public
Consultation http://www.ema.europa.eu/
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Roadblock 1. Ethical challenges of preventive trials in children
Short guide to road map 1.1
Patients with type 1 diabetes present acutely There has been considerable progress in and at the time of clinical presentation already have such marked destruction of the insulinproducing beta cells that intervention at this point in the disease process is unlikely to understanding the genetic basis of type 1 diabetes, yet the descriptive epidemiology of the condition suggests that major environmental factors must play a key role in modify the underlying disorders that have caused the disease. In order to target early interventions on appropriate individuals and on appropriate pathophysiological pathways, we need to develop better understanding of these pathways. Achieving this goal requires the determining why the incidence of the disease is rising on the background of stable genetic predisposition. These environmental factors remain unclear, and enhanced understanding is a necessary prerequisite for the design of future primary prevention strategies. The development and validation of novel biomarkers of the type 1 diabetes process and better proxy outcomes to facilitate the study of pathogenesis. This topic is clearly also of relevance to Chapter 2, which discusses islet cell research in greater detail. design of studies to investigate how genetic, epigenetic and environmental factors operate together to bring about disease will require multi-disciplinary large-scale prospective studies.
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Roadblock 2. Reluctance of policymakers to evaluate policy
Roadblock 3. Intellectual schism between disease prevention and health promotion strategies
Short guide to road map 1.2
The rising prevalence of type 2 diabetes is a major public health problem. Although individually focussed approaches to prevention in high-risk sub-groups are effective, these need to be balanced by the development of strategies aimed at tackling this problem at a population level. Developing greater understanding of the determinants of population-level dietary and physical activity behaviour will change the focus away from individual approaches to prevention towards more integrated strategies that acknowledge the wider societal determinants of these lifestyles. This public health focus requires a multi-disciplinary approach bringing together strategies for understanding population behaviour together with the evaluation of planned and natural experiments, and enhanced disease surveillance. Many of the issues prominent in these milestones are also of relevance to Chapters 3, 4, and 7.
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Roadblock 4. Willingness of scientists to play individual small role in larger activity
Short guide to road map 1.3
The variation in the prevalence of type 2 diabetes around the world suggests that this disease arises from an interaction between innate susceptibility (either arising from genetic or early developmental programming) and potentially modifiable environmental factors that include diet and physical activity as well as socio-economic position. Progress has been made in defining the association of common genetic variants with diabetes, but little is yet known about the interaction of these variants with lifestyle behavioural factors. Future work will determine the role of rare variants, copy number variation and epigenetic factors in determining diabetes risk. The use of this genetic and epigenetic understanding to describe the different pathways leading to disease will produce opportunities for subclassifying this disorder and potentially for moving away from non-specific strategies to a more individualised approach to prevention.
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Roadblock 5. Ethical issues about use of routine data for aetiological investigation
Short guide to road map 1.4
Previous randomised controlled trials of therapies in people with type 2 diabetes have demonstrated that many of the complications of diabetes are preventable. However, such therapies are generally applied to all people with diabetes with no current understanding about how interventions might be tailored to the individual.
Developments in understanding the genetic basis of complications and the response to therapy will increase the ability to tailor therapeutic interventions. While understanding of the role of diabetes and the underlying state of hyperglycaemia in determining micro- and macrovascular disease is reasonably well established, the role of these factors in other clinical outcomes, such as cancer and cognitive function, for other purposes. is less clear. The development of public health models that estimate the likely impact on all health outcomes of changes in the population distribution of glucose levels is important as it will inform the development of public health strategies to deal with this issue. A balanced view is needed of the impact of strategies that target interventions only on people with established disease - with alternative approaches aimed at the entire population.
This necessitates public health modelling as such information will not be obtained from individual clinical trials. In turn, this may require the use of routinely collected clinical, demographic and other data, and the possibility of linkage of databases established
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Short guide to road map 1.5
There is heterogeneity in the rate of change in the underlying pathophysiological processes that are driving hyperglycaemia among people with established diabetes. This heterogeneity may be explained by genetic, developmental and environmental factors.
Understanding these factors could lead to targeting of therapy at these specific pathways, to individualised treatment and improved health outcomes.
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Roadblock 1. Ethical challenges of preventive trials
in children
The peak age of incidence of type 1 diabetes is in childhood, and since most of the complications of diabetes are duration-dependent, preventive strategies for type 1 diabetes have the greatest potential for health benefit in younger people. However, this is the very group in which prevention, particularly with invasive interventions, is most challenging from an ethical perspective (see also Goal 4.6).
Roadblock 2. Reluctance of policymakers to evaluate
policy
Many of the major interventions that will impact on diabetes incidence operate at the policy level. In order to develop sustainable understanding of what is (and what is not) effective at this level there needs to be a greater emphasis on ‘evidence-based policy making’, a development analogous to the change in approach in clinical practice. The production of information about policy effectiveness needs a change in culture among policy makers to embrace the notion of evaluation, including, where possible, the introduction of not only observational approaches but also more experimental designs.
Roadblock 3. Intellectual schism between disease
prevention and health promotion strategies
The discussion about the balance between population- and individual-level approaches to the prevention of diabetes is essentially an example of the contrast between a health promotion model and one more clinically focussed on disease prevention. It is imperative that there is a harmonisation of these two approaches, which can sometimes be erroneously presented as mutually exclusive alternatives. In reality, there needs to be the development of a balanced approach but to achieve this there is an important initial roadblock of narrowing the intellectual gulf between them.
Roadblock 4. Willingness of scientists to play individual small role in larger activity and the need for methods for determining output of European scientists giving credit for collaboration in larger activities
Many contemporary issues in epidemiology and particularly genetic epidemiology are not resolvable by single cohort studies and require the combination of data from multiple studies. This requires scientists to work together in large consortia where their individual chance of prominence is lessened, but the resulting scientific discoveries are more likely to be valid. This requires a cultural change from the scientists but may also need to be encouraged by research funders and academic employers who have, in the past, judged scientific performance on authorship position that could become an outdated method for large collaborative projects.
Roadblock 5. Ethical issues about use of routine data
for aetiological investigation
Many classical aetiological studies are based around special cohort studies designed for that purpose.
Individuals provide informed consent and the information collected both at baseline and at follow-up is standardised and often obtained specifically for the cohort study without clinical care. The increasing ability to collect data in more standardised ways in routine clinical practice, and the ever-increasing need for greater sample sizes, coupled with the spiralling costs of the construction and maintenance of special studies, creates an imperative to utilise data routinely collected in everyday clinical practice for aetiological investigations. This creates many operational issues, but foremost amongst them is the challenge of using routinely collected data for such studies where it is not possible to obtain specific consent (see also Goal 4.1).
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The overarching goal of the islet research area is to cure and prevent type 1 and type 2 diabetes by restoring and preserving beta cell function and mass. Four road maps (2.1-2.4), each with one major goal reflecting the particular strategic approach, lead to this overarching goal.
The strategy will depend upon deeper understanding of molecular mechanisms underlying beta cell function, survival and regeneration, and how they are impacted by the fundamental disease process in both type
1 and type 2 diabetes. This will provide the knowledge fundament to guide development of new therapies by employing translational methodologies of drug discovery and development.
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Roadblock 1. Limited access to human beta cells/islets/pancreatic tissue
Short guide to road map 2.1
The central role of the beta cell and insulin secretion in metabolic regulation is well established. Although the normal regulation of insulin secretion is fairly well understood, we still only have fragmentary knowledge about the processes that culminate in impaired beta cell function and insufficient insulin secretion in type 2 diabetes and in the pathways required to restore and maintain normal beta cell function in beta cell replacement therapies for type 1 diabetes. Achieving this goal will depend upon a multidisciplinary team approach to discover molecular mechanisms that can be used as targets for novel antidiabetic medicines superior to those currently available.
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Roadblock 1. Limited access to human beta cells/islets/pancreatic tissue
Roadblock 2. Lack of beta cell-specific surface ligands
Roadblock 3. Lack of a unified European Union stem cell strategy
Roadblock 4. Ethical and regulatory issues
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Short guide to road map 2.2
An adequate functional beta cell mass is essential to ensure normal blood glucose regulation, and we now know that an absolute or relative beta cell deficiency characterises diabetes phenotypes in type 1 and type 2 diabetes respectively. To normalise functional beta cell mass as a treatment or cure for diabetes, it is not only important to understand how beta cells are born during fetal development and regenerate in adult life, but also how beta cell replication and death are controlled. Detailed knowledge from basic pancreatic and beta cell developmental biology is envisioned to translate into ex vivo production of therapeutic beta cells from stem cells. Optimal and safe conditions for beta cell replacement and regenerative therapy need to be developed.
This road map comprises a large number of interconnected tracks. Its complexity reflects the magnitude of the challenge. The lower track (Milestones 2.2.18-21) seeks to understand in fine detail the disease process leading to the absolute (type 1 diabetes) or relative (type 2 diabetes) destruction of beta cells. Major milestones will include understanding and thereby combating the initial triggers to such destruction, autoimmune disease in type 1 diabetes and most probably inflammation in type 2 diabetes. Many of the later events may be common to both types of diabetes. For type 1 diabetes, understanding the mechanism of autoimmune destruction of beta cells and thereby how to prevent it will be of fundamental importance not only for preventing the disease but also to ensure survival of new (replaced or regenerated) beta cells.
The testing of novel therapies targetting restoration of the beta cell functional mass has been greatly hampered by the lack of understanding of the precise relationship between beta cell mass and function. It is unclear if insulin secretory capacity compensatory to increased physiological demands in non-diabetic individuals is met by increasing function of an existing mass, by increasing the mass of beta cells without increasing the function per beta cell or both. In diabetes, where beta cell mass is reduced, this relationship becomes even more important to monitor therapies aimed at restoring beta cell mass.
Roadblock 1. Limited access to human beta cells/islets/pancreatic tissue
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Short guide to road map 2.3
Genome-wide association studies point to discrete genes predisposing to type 1 and 2 diabetes that seem to be responsible for regulating beta cell function, apoptosis and replication. Although many of these genes are expressed in beta cells, this does not mean that they are not also expressed in other cells.
Indeed, some genes associated with an increased diabetes risk are associated with reduced risk of developing certain cancers and vice versa.
This finding illustrates the need to understand fully the specific beta cell phenotypic characteristics relative to other cell types and also to understand why beta cells are so susceptible to destruction in diabetes. All cells are thus equipped with specific methods for defending themselves against damage caused by stress or inflammation for example. It is thought that the beta cell may be particularly vulnerable to such damage because of its peculiar phenotypic characteristics. It would be necessary to explore this relationship between beta cell phenotype and defence in order to identify novel targets for improved protection of beta cells in the early stages of both type 1 and type 2 diabetes.
Roadblock 5. Methods of maintaining myotubes, neuronal cells and intestinal tissue in culture
Short guide to road map 2.4
Beta cells release insulin that affects the function of almost all tissues of the body.
Conversely, they receive a rich input via the circulation (hormones and metabolites, growth factors/cytokines) and via nerve terminals
(neurotransmitters). This cross-talk between the beta cell, its immediate environment within the islet and the rest of the body is far more extensive than thought previously.
It seems possible that disturbances in this cross-talk may contribute to impaired insulin secretion. The aim here is to explore this aspect of the regulation of beta cell function and mass, with a special focus on communication from the major insulin-sensitive tissues and possible novel factors from the gut.
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Roadblock 1. Limited access to human beta cells/islets/pancreatic tissue from diabetic and nondiabetic (and obese and pregnant) individuals
Human islet cells differ from their rodent counterparts. It is important, building on the firm knowledge base provided by studies in cell lines and rodent models, to characterise the human beta cell. The ability to interpret correctly the genetic association and expression data that are now emerging depends critically on accurate information about gene expression in pure fractions of human beta cells. Currently, human islets are obtained from organ donors. Given the major advances in modern endoscopic techniques, it is conceivable that safe and ethical bioptic methodologies for obtaining functional pancreatic tissue could be developed.
Roadblock 2. Lack of beta cell specific surface ligands and safe labels of such ligands that have sufficient tissue signal penetration
Lack of beta cell specific surface ligands that allow clinical imaging with sufficient resolution is an obstacle to prospective non-invasive imaging of islet and beta cell mass.
Roadblock 3. Lack of a unified European Union stem
cell strategy
Many European Union Member States now allow experimental research with human embryonic stem (hES) cells, but there is still need for coordinated and harmonised ethical policies across Europe
Roadblock 4. Ethical and regulatory issues
In order to translate novel therapeutic targets from multiple biochemical pathways into the clinic, which no doubt will require a combinatorial approach, there is an urgent need for facilitated processes to promote clinical trials testing combinations of therapy. This will pose demands on ethical and regulatory authorities and on funding agencies and industry.
Roadblock 5. Methods of maintaining myotubes, neuronal cells and intestinal tissue in culture
Methods are established, but scientific advances in this area will critically depend on the ability to study neuronal, hormonal and other humoural signals and responses in human specimens. This could be linked to a European pancreas and islet procurement network.
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Roadblock 1. Testing of promising new drugs is too slow
Roadblock 2. Collaboration among researchers in related fields
Roadblock 4. Synergy between academia and food industry
Roadblock 5. Lack of biobanks of readily accessible human material
Roadblock 7. Lack of appropriate models that mimic the human condition
Short guide to road map 3.1
Nearly all tissues of the body are involved in the development of insulin resistance and type
2 diabetes. A major challenge in the development of successful diabetes treatments is to identify the complex network of communication between the various tissues.
Future work should be expanded beyond the classical tissues that are currently recognised as playing a key role in the control of glucose and energy homeostasis as well as inflammation, to include the role of the brain in blood glucose homeostasis and feeding behaviour, as well as the role of the taste and smell centres, sensation perception and chemical recognition. This research track interconnects with both Chapter 1 Genetics and epidemiology and Chapter 2 Islets. There is great interest from SMEs and the pharmaceutical industry to learn about these mechanisms and their dysregulation in metabolic disease in order to identify new drug targets. The role of the food industry and fastfood chains is clearly implicated since nutritional factors can be linked to insulin sensitivity and energy homeostasis. Thus, synergy between academic and industry research efforts may present an opportunity to stimulate progress in diabetes care and treatment.
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Roadblock 1. Testing of promising new drugs is too slow
Roadblock 2. Collaboration among researchers in related fields
Roadblock 3. Collaboration between academia and industry (biotechnology, pharmaceutical)
Roadblock 6. Lack of available in vivo methodology and imaging techniques
Roadblock 7. Lack of appropriate models that mimic the human condition
Roadblock 8. Ethical issues related to application of biomarkers and genetic markers
Short guide to road map 3.2
These tracks exploit and extend established research lines addressing the control of energy balance and weight regulation, with an essential focus on the translation into therapy to benefit the person with diabetes. This is important because current therapies are insufficient to normalise both blood glucose and energy balance and/or body weight. There is a need for appropriate models that mimic the human condition (especially neurobehavioural aspects). These studies will enhance understanding of the (patho)physiological regulation and treatment strategies to control energy balance and weight regulation. Direct access to pathways of fat oxidation, mitochondrial function, and fat tissue (trans-) differentiation and functionality in humans is mandatory but despite most recent developments there are still technical and methodological limitations to be overcome.
Intensive synergistic efforts between experimental and clinical researchers both at academic and industry levels will be necessary for this perfect model of translational research to be successful.
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Roadblock 5. Lack of biobanks of readily accessible human material
Roadblock 8. Ethical issues related to application of biomarkers and genetic markers
Short guide to road map 3.3
It will be important to identify ‘prediabetic’ individuals who are at high risk of developing type 2 diabetes and suitable for early intervention towards prevention. While research to enhance prediction of diabetes is described in Chapter 1, here the aim is to use a holistic ‘systems biology’ approach for identification of novel predictive biomarkers.
Aside from the established risk factors associated with type 2 diabetes, simple markers to identify disease risk are lacking and improved methods would be needed for their validation. Special effort should be taken to develop inexpensive assays suitable for largescale screening using proteomics or metabolomics. Recent advances in the genetics of type 2 diabetes have indicated that large prospective population-based studies, including thousands of subjects, are needed to estimate the role of genetic variants as risk factors for type 2 diabetes. Therefore, pan-
European resources are needed to fund large population-based studies gene and gene-lifestyle interactions. Crucial information on ethnic-specific differences will also be required. This research track will emphasise molecular and cellular studies and will synergise with the clinical studies described in Chapter 1. having similar protocols to reach numbers needed to test biomarkers including genetic markers for gene-
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Roadblock 3. Collaboration between academia and industry (biotechnology, pharmaceutical)
Roadblock 4. Synergy between academia and food industry
Roadblock 5. Lack of biobanks of readily accessible human material
Roadblock 6. Lack of available in vivo methodology and imaging techniques
Roadblock 7. Lack of appropriate models that mimic the human condition
Roadblock 8. Ethical issues related to application of biomarkers and genetic markers
Short guide to road map 3.4
The increased incidence of poor health associated with insulin resistance constitutes a major threat to global health. A cluster of clinically distinct, but metabolically related disorders, including type 2 diabetes and obesity, constitutes a syndrome that ultimately results in premature death. Physical exercise training is among the most powerful of these approaches. The specific genes and pre- and postnatal environmental factors that influence the efficacy of exercise- and nutrientinduced improvement in insulin sensitivity, and individual variations in metabolic health will therefore need to be understood to allow for more effective intervention strategies.
Emphasis should also be placed on the ageing physiological interventions known to maintain insulin sensitivity. Moreover, accumulating evidence suggests that proper diet and nutrition can also have a positive impact in this same regard. However, there seem to be great differences between individuals in the efficacy population to understand the molecular mechanisms for the long-term health benefits of regular physical exercise. Moreover, the link between diabetes and non-classical diseases including cancer, Alzheimer’s disease, and sleep apnoea should be considered.
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Roadblock 1. Testing of promising new drugs is too
slow
New ways are needed to promote synergy between industry and academia for accelerated testing of promising new drugs in the prevention of insulin resistance and type 2 diabetes, and to bring such drugs to market. Identification and validation of new targets in the inflammatory pathway with chemistry and highthroughput screening is an expensive, time-consuming line of research for academics and would be better conducted as a collaborative effort with industry. Industry is better equipped for drug development and possesses tools not usually available in academia.
Roadblock 2. Collaboration among researchers in
related fields
Integrated research environments with multiple levels of expertise in basic and clinical research and approaches in diabetes and metabolism should be fostered to gain a better understanding of the pathological processes involved.
Roadblock 3. Collaboration between academia and
industry (SMEs, pharmaceutical)
Academia-industry interaction and collaboration with experts in all research fields to translate basic and clinical research discoveries into prevention, treatment and care of diabetes do not have to be considered as blocks but rather opportunities. Interactions could be fostered among all key stakeholders (such as academia, industry,
SMEs, government organisations, regulatory authorities).
A recent model is the Innovative Medicines Initiative, which shows this type of collaboration is feasible.
Roadblock 4. Synergy between academia and food industry
Synergy between academia and the food industry is necessary to develop functional foods. Indeed, it is the task of the food industry to modify food to make it appropriate and palatable to human needs.
Roadblock 5. Lack of biobanks of readily accessible human material
The availability of readily accessible human material
(biobanks of human tissues and samples for example from well-characterised subjects at rest and after physical training or diet interventions) is necessary to allow the transition from clinical physiology to cell biology in humans as effectively as possible.
Roadblock 6. Lack of available in vivo methodology and imaging techniques
Cellular and whole body imaging technology needs to be developed in order to study intact cells and human individuals under physiological conditions, such as exercise and dietary intervention, and their effects on metabolism, as well as gene/environment interactions.
Roadblock 7. Lack of appropriate models that mimic the human condition
Since molecular studies often require genetically modified cellular or animal models, the challenge will be to closely align these models with distinct characteristics of human physiology. This will require humanised animal models.
Roadblock 8. Ethical issues related to application of biomarkers and genetic markers
Increased awareness of ethical issues and privacy is needed whenever working with human material, biomarkers and especially genetic markers (DNA analysis).
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Introduction
This group considered all aspects of clinical science and research devoted to improved, evidence-based diabetes care. This road map translates basic science proposed elsewhere in DIAMAP into clinical studies for the direct benefit of individuals with diabetes and also considers the needs of special populations or those in specific institutional settings. In keeping with the mission of DIAMAP to improve coordination of European diabetes research and delivery to patients, this group also proposes the creation of an innovative coordinating structure, the European Platform for Clinical Research in Diabetes (EPCRD).
Roadblock 1. Ethical guidelines: in particular regarding data sharing and transfer, collection and use of biological materials including DNA
Roadblock 2. Variation, lack of standardisation or international consensus across Europe in laboratory conditions, measurement techniques, sample handling and clinical diagnoses and practice
Short guide to road map 4.1
Throughout Europe there are increasing numbers of adults and children with diabetes.
Despite guidelines and consensus statements related to approaches, targets and therapies, there remains huge variation across European
Union Member States in the quantity and quality of diabetes-related clinical research and in care available for people with diabetes. This variability in research activity and service delivery is a consequence of many factors, the most significant being the social and cultural differences among countries, differences in clinical governance, and lack of structured networks of interested parties with commonly agreed goals. In proposing the European
Platform for Clinical Research in Diabetes
(EPCRD) DIAMAP seeks to address these issues as well as other more generic obstacles towards clinical research for the benefit of individuals with diabetes Europe.
Aims and objectives
The aims of the European Platform for Clinical
Research in Diabetes (EPCRD) are to:
•
facilitate and enhance clinical diabetes research with the purpose of improving care and treatment for people with diabetes.
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•
facilitate access to data and biological samples by providing a uniform agreed and ethically approved infrastructure to permit sample and data sharing across multiple national and international security barriers.
•
improve access to structured education and training for European diabetes researchers and healthcare professionals engaging in research activity, and for people living with diabetes.
•
create centrally determined governance structures in line with current ethical guidelines.
•
facilitate access to information and online databases of clinical studies and trials, thus encouraging participation by interested volunteers (with diabetes and without). The closer dialogue between professionals and research participants is intended to encourage greater understanding of the science.
•
streamline the processes for dissemination of research findings through a dedicated communication channel including a consultation process with people with diabetes and the public.
•
encourage investment by and participation of industry, facilitating access to a large number of research subjects and to scientists from sub-specialties. Funding of industry-initiated trials could be standardised across Europe supporting the concept of the ‘European diabetes patient’.
The use of such a market approach to clinical research has the potential to drive down costs to increase the competitiveness of Europe as a clinical trial location.
Advantages of an EPCRD
A large population of people with diabetes with variations in genetic and ethnic background
(and family members) could be made accessible to clinical (and basic) researchers and the sponsors of research by participation in a network with a centralised point of entry.
The DIAMAP road maps have repeatedly mentioned as roadblocks the need for registries of people with diabetes, networks of specialist researchers, access to biobanks and human biological material (especially in relation to the rarer complications) and the need for more standardised treatment guidelines. The majority of roadblocks are addressed within the Horizontal Issues report by engaging with organisations or individuals external to the research community. However, it was felt strongly that diabetes research would be enhanced if the clinical research community itself could drive a collaborative initiative as it deals with the consequences of research upon treatment and care delivery
(this goal is linked with many goals and milestones throughout the road maps).
European clinical research has limitations compared with the United States in that access to large numbers of people with diabetes and healthy volunteers with specific characteristics in single centres is difficult. Clinical research, from small studies to large-scale pharmaceutical trials, or research into health service provision is more laborious and less representative than it could be because of the number of countries, languages and organisational cultures. The EPCRD would facilitate research in such situations.
Limitations of an EPCRD
The roadblocks list the limitations of an
EPCRD, mainly concerning privacy of data and difficulties of data and sample transfer across borders. Also, participation is likely to vary in different countries, which may cause a cultural imbalance. The establishment of an EPCRD should ideally be piloted in a small number of locations, with operations directed from a central office, before any wider scale network could be envisaged.
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Roadblock 3. Practical and ethical challenges of locating research participants among diverse groups
Short guide to road map 4.2
There are now many European studies indicating links between prevalence of diabetes and socio-economic status, with lower income groups being disproportionately affected by type 2 diabetes. These lower income groups are also likely to have high immigrant populations. They are also likely to have a higher incidence of obesity (of which type 2 diabetes is a consequence). Deprived populations such as these are also less likely to be well educated, less likely to take up available health services, and appear to be less likely to even locate those services. Many deprived populations may also be older adults with restricted incomes, mobility and social standing. It has been noted with regards to diabetes management that such deprived populations are less likely to have accurate medical records documenting HbA1c, cholesterol and smoking status although the reasons for this disparity with higher income groups are not clear. Deprived populations also tend to have more micro- and macrovascular disease – especially retinopathy and cardiovascular disease – and many present with higher HbA1c levels than national averages.
Many European countries are experiencing economic and budgetary constraints, with higher unemployment; as a consequence, the economic burden of care for diabetes and its complications is expected to rise substantially. This has been recognised recently by the World Health Organization
(WHO), which has indicated the growing negative impact of chronic diseases, such as diabetes, in terms of national social and economic wealth.
The importance of addressing such problems early, before expensive complications drain health services and affect European productivity, is crucial. It is also noted that research approaches likely to succeed in tackling these issues are those that involve all major agencies and, most importantly, the targetted populations through a focussed strategy involving people with diabetes and the public.
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Roadblock 2. Variation, lack of standardisation or international consensus across Europe in laboratory conditions, measurement techniques, sample handling and clinical diagnoses and practice
Roadblock 4. Lack of birth cohorts and registries with repeated examinations for long-term follow-up studies over the life-course
Roadblock 6. Fragmented electronic medical records, even within a single institution
Roadblock 8. Gap in professional skills
Roadblock 10. Resistance to implementation of large-scale clinical research in the setting of usual care and fragmentation of usual clinical care from the tradition of clinical research
Short guide to road map 4.3
This road map focusses on people with diabetes who are in hospital or in institutional settings, including long-term care (for the elderly), psychiatric hospitals, prisons and other chronic care facilities. Taken together, this group of people constitutes a particularly vulnerable population, whose outcomes are worse often since ‘diabetes diagnosis’ can be lost or ignored because of the effects of comorbidities or other clinical complexities. If diabetes is neglected or hidden behind another illness, metabolic outcomes are likely to be sub-optimal, and costs and complications likely to increase. The overall goal of this map is to harness research to improve the outcomes for such vulnerable people, including morbidity, mortality, length of stay, costs and quality of life.
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Roadblock 3. Practical and ethical challenges of locating research participants among diverse groups
Roadblock 7. Lack of specific bioinformatic software to analyse and integrate multiple data on biological (genetic), psychological, lifestyle and social factors
Roadblock 9. Lack of appropriate professional training and education
Short guide to road map 4.4
Bariatric surgery is the most effective treatment for obesity resulting in long-term weight loss and amelioration of obesityassociated co-morbidities, particularly type 2 diabetes. Surgical therapies, apart from offering morbidly obese patients the best hope for substantial and sustainable weight loss, may lead to a reduction in morbidity and mortality. Metabolic benefits of bariatric surgery occur rapidly and independently of the weight loss and are correlated with the particular anatomical restructuring of the surgery.
Understanding the mechanisms mediating the beneficial outcomes of bariatric surgery could result in new non-surgical treatment strategies for obesity and type 2 diabetes.
The physiological issues associated with bariatric surgery and diabetes remission have yet to be clarified, and insight gained from such research would be useful for the development of new pharmacotherapy for the treatment of obesity and diabetes.
The number of morbidly obese patients
40) requesting surgical treatment is increasing.
While new surgical procedures are being developed there is the need to ensure a low post-operative mortality rate, that quality of life is enhanced and that the treatment is costeffective. Bariatric surgery needs to be developed as a cost-effective and sustainable treatment that can be supported by national health services especially as obesity is more prevalent in underdeveloped countries and affects more people at lower socioeconomic levels.
BMI ≥
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Roadblock 3. Practical and ethical challenges of locating research participants among diverse groups
Roadblock 4. Lack of birth cohorts and registries with repeated examinations for long-term follow-up studies over the life-course
Roadblock 7. Lack of specific bioinformatic software to analyse and integrate multiple data on biological (genetic), psychological, lifestyle and social factors
Short guide to road map 4.5
Europe has a rapidly growing ageing population with increased mean life expectancy. These older individuals become much more prone to a range of chronic diseases, including diabetes, especially type 2 diabetes. There is a well-documented gap in life expectancy between people who develop diabetes and healthy people of similar age.
Diabetes itself can be considered a disease of premature ageing, specifically of the cardiovascular system and also of other tissue and organ systems, at least in a substantial proportion of patients. However, some patients appear to be protected against this accelerated ageing process, and the underlying mechanisms of these protective processes remain unclear.
A European research strategy for ageing and diabetes is likely to include: experimental studies in animals to investigate biomedical aspects of the normal ageing process, as well as in diabetes; studies in non-diabetic people; studies in people with diabetes of short, intermediate and long duration to investigate the process of ageing in different organs. The impact of diabetes treatments specifically on these ageing processes is also a research priority. Thus, specific studies are required of biological and molecular ageing in patients treated with the traditional oral hypoglycaemic agents and insulins, as well as the wide range of newer agents. The risk of cancer (an agerelated phenomenon in general) in relation to diabetes is an area of growing interest as diabetes itself as well as some drugs used for the treatment of diabetes may also impact on cancer risk and the modification of this risk.
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Roadblock 5. Lack of large European diabetes networks
Roadblock 7. Lack of specific bioinformatic software to analyse and integrate multiple data on biological (genetic), psychological, lifestyle and social factors
Roadblock 11. Drug regulatory issues: paediatric drug approvals lag behind adult decision-making
Roadblock 12. Partnerships between academia and industry (both pharmaceutical and other industry) are needed
Roadblock 13. Huge differences in structure, process, quality and delivery of diabetes care between European countries
Roadblock 14. Advances in diabetes treatment or new drugs or new devices can only be implemented if society is able to support such treatments
Short guide to road map 4.6
Adolescents with type 1 and type 2 diabetes are particularly prone to poor metabolic and psychosocial outcomes due to the potentially long diabetes duration being faced. At the same time the study of the effect of diabetes in this age group provides an opportunity to study early vascular ageing without other concomitant diseases. Normal ageing with diabetes starts in childhood as many processes leading to debilitating complications later in life have their onset then. This offers a unique opportunity to identify potential factors that are important to delay accelerated biological ageing in diabetes. Also, preventive strategies that prove effective in childhood and adolescence are likely to be particularly cost-effective as most of the healthcare cost is incurred for the treatment of late complications.
There is a predicted 70 percent increase in prevalence of diabetes by 2020 with more and more young children being affected.
These children show a more rapid decrease in beta cell function and have less residual insulin production than adolescents or adults.
The average metabolic outcomes of children with diabetes as judged by international cohort studies of HbA1c were found to be significantly worse than in the adult population, with those of adolescents being the worst. Also, studies with new technologies such as continuous glucose monitoring have shown a less favourable effect in youth compared to adults.
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Successful implementation of this road map would improve the situation for children with diabetes in Europe and ensure that all children have the right to participate fully in all the experiences of childhood and adolescence, regardless of whether they have diabetes and wherever they live. Also it would reduce the effects of accelerated vascular ageing imposed by the diabetic state and provide the basis for a long-term participation in professional and family life without or with delayed debilitating long-term diabetes complications.
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Roadblock 2. Variation, lack of standardisation or international consensus across Europe in laboratory conditions, measurement techniques, sample handling and clinical diagnoses and practice (including GDM)
Roadblock 3. Practical and ethical challenges of locating research participants among diverse groups
Roadblock 4. Lack of birth cohorts and registries with repeated examinations for long-term follow-up studies over the life-course
Roadblock 13. Huge differences in structure, process, quality and delivery of diabetes care between
European countries
Roadblock 15. Lack of appropriate animal models to study fetal programming, fetopathy and embryopathy
Short guide to road map 4.7
Gestational diabetes mellitus (GDM) occurs in
5-15 percent of pregnancies and is increasing in prevalence. Women with a history of GDM have a very high risk of developing type 2 diabetes (80 percent within 5-10 years following pregnancy) and are also at increased risk for cardiovascular disease. However, prevention trials have shown that diet and exercise as well as pharmacological intervention can diminish the risk substantially
(by 50 percent). In addition to acute pregnancy-associated complications (diabetic fetopathy) the offspring of mothers with diabetes also have increased risk of obesity and metabolic syndrome in childhood and adolescence. Genetic predisposition, but also fetal programming and metabolic imprinting may contribute to these long-term risks in offspring. Genes and other factors contributing to fetal programming and metabolic imprinting, and predisposing the offspring to obesity and diabetes in adulthood, are currently unknown as are factors underlying the different vulnerability of male and female offspring.
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Roadblock 1. Ethical guidelines: in particular regarding data sharing and transfer, collection and use of biological materials, including DNA
Roadblock 2. Variation, lack of standardisation or international consensus across Europe in laboratory conditions, measurement techniques, sample handling
Roadblock 4. Lack of birth cohorts and registries with repeated examinations for long-term follow-up studies over
the life-course
Roadblock 12. Partnerships between academia and industry (both pharmaceutical and other industry) are needed
Short guide to road map 4.8
Islet dysfunction is an early event in the cascade of metabolic defects leading to diabetes (see Chapter 2). Temporal progression of the metabolic disorder is manifested by inadequate islet cell responsiveness (in the face of insulin resistance) by the time a susceptible individual has attained impaired glucose tolerance.
Preventing islet deterioration is a major goal for the prevention or cure of diabetes, and for the prevention of further deterioration of preexisting diabetes. Understanding the causes of islet impairment, developing simple methods to measure impaired islet function, and improved strategies for intervention are critical to helping people with diabetes better manage their own condition and live a healthier life. This area of research is of great interest to the biotechnology and pharmaceutical industries as it directly applies to the development of therapies.
The road maps for islet biology research (see
Chapter 2) describe mostly in vitro studies to understand beta cell function, destruction and regeneration as a platform for novel therapy. In a complementary fashion, this clinical road map focusses on research within the ‘intact’ person in order to design more effective, simpler tests of islet function performed in the whole body and, ultimately, to develop and evaluate interventions to restore islet function.
This section focusses goal is to relate the restoration and then maintenance of islet function (through various strategies, whether pharmacological or cellbased) to clinical outcomes. on techniques of biomedical engineering and mathematical modelling in diabetes research to better understand complex multi-organ pathophysiologic processes. The overarching incorporating
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The overarching goal of this road map will be to prevent and/or reduce cognitive impairment and psychopathology in diabetes, by stimulating research into: specific (molecular) mechanisms that lead to the development of cognitive impairment and psychopathology, specifically in people with diabetes; identify people at the highest risk of developing these conditions; develop and validate interventions for prevention and cure of these conditions.
Roadblock 3. Practical and ethical challenges of locating research participants among diverse groups
Roadblock 16. Barriers in the multi-disciplinary approach to guiding people with diabetes through health care structures (e.g. referral from primary to hospital care and back)
Short guide to road map 4.9
Cognitive impairment and psychopathologies including depression, anxiety and eating disorders, occur more frequently in people with diabetes relative to their non-diabetic peers.
Cognitive impairment and psychopathology reduce quality of life and affect long-term outcomes. Barriers to research in this field have included uncertainty regarding the causal relationships between diabetes and cognitive impairment/psychopathology; lack of knowledge regarding the diabetes-specific effects on these conditions; lack of information about prevalence; methodological issues in diagnosis, measurement and classification.
Cognitive impairment and psychopathology can in turn worsen glycaemic control and outcomes. Novel research approaches will be needed to address these important areas of uncertainty.
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Roadblock 1. Ethical guidelines: in particular regarding data sharing and transfer, collection and use of biological materials, including DNA
Roadblock 7. Lack of specific bioinformatic software to analyse and integrate multiple data
Roadblock 10. Resistance to implementation of large-scale clinical research in the setting of usual clinical care
Roadblock 12. Partnerships between academia and industry (both pharmaceutical and other industry)
Roadblock 13. Huge differences in structure, process, quality and delivery of diabetes care between European countries
Roadblock 14. Advances in diabetes treatment or new drugs or new devices can only be implemented if society is able to support such treatments
Short guide to road map 4.10
Despite advances in the technology of insulin delivery, self-monitoring of interstitial and blood glucose and structured patient education, hypoglycaemia (low blood glucose) remains an important consideration for people with diabetes and for healthcare professionals. The consequences of even a single episode of hypoglycaemia can range from a minor nuisance to major disruption in the daily life for people living with diabetes. Consequently, some individuals resist attempts by the diabetes team to intensify insulin therapy leading to poor control and diabetes complications. Regular episodes of hypoglycaemia can limit employment, normal socio-professional activities, driving and educational attainment, and shorten life. There is also decreased awareness of hypoglycaemia with increasing number of episodes. The socioeconomic costs of dealing with severe hypoglycaemia are considerable.
The goal is therefore to minimise the risk of hypoglycaemia in people with diabetes.
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Roadblock 1. Ethical guidelines: in particular regarding data sharing and transfer, collection and use of biological
Materials including DNA
Roadblock 2. Variation, lack of standardisation or international consensus across Europe in laboratory conditions, measurement techniques, sample handling and clinical diagnoses and practice
Short guide to road map 4.11
There is increasing recognition that general guidelines and treatment algorithms for diabetes are difficult to fit into clinical practice.
Furthermore, treatment algorithms have come under criticism recently for their lack of foundation on an evidence base. Particularly for type 2 diabetes, the heterogeneity is so wide that it is difficult and unscientific to generalise treatment recommendations (see also Chapter 1). The long natural history of type 2 diabetes, and its gradual progression run in parallel with the life-course of the patient, and with other co-morbidities. All of these components of temporal evolution of diabetes in the setting of the life of the individual call for a greater focus on personalised treatment – and a lesser reliance on general guidelines that may not ‘fit’ the needs of the individual.
Recent evidence shows that certain groups of people with diabetes may face increased risks
(for example, for cardiovascular events) at
HbA1c below 7.5%. Thus, there is a need for better staging of patients according to diabetes phenotype, duration of disease, stage of life and the presence or absence of complications.
Glucose targets (and other treatment targets) probably need to be different for these different sub-groups. Thus, early diagnosis and early treatment to near-normal glucose target in people with newly diagnosed diabetes (prior to the onset of complications) is likely to yield excellent long-term outcomes, as has been shown by analysis of the United Kingdom
Prospective diagnosed
Diabetes or silent) may whether increase cardiovascular risk and risk of mortality.
Studies in new large population cohorts will be necessary to support this research strategy, and prospective studies are now needed to address these questions.
Study (UKPDS).
However, aggressive treatment to target in older people with longer-duration disease (and cardiovascular complications,
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Roadblock 1. Ethical guidelines: in particular regarding data sharing and transfer, collection and use of biological materials including DNA
Guidelines on data privacy are extremely complex and many are highly restrictive. Individual countries are likely to have different approaches to data handling and patient confidentiality.
Roadblock 2. Variation, lack of standardisation or international consensus across Europe in laboratory conditions, measurement techniques, sample handling and clinical diagnoses and practice
Lack of standardisation in laboratory assays (such as
HbA1c, insulin and lipids) and in clinical practice means the same clinical picture can be managed differently in both quantitative (because of laboratory variability) and qualitative terms thus impacting on validation of clinical research in different settings. In diabetic pregnancy there is also no international consensus for the diagnosis of gestational diabetes mellitus or standardised oral glucose tolerance test for such cases.
Roadblock 3. Practical and ethical challenges of locating research participants among diverse groups
Locating research participants is challenging among socially diverse groups (including: ethnicity, older age or early ageing, low socio-economic status, psychopathology and cognitive dysfunction, overweight and obesity). Barriers exist at several levels: limited literacy means potential participants are unaware of projects, and then of research implications. Individuals in such groups often have sub-optimal health care service delivery. Unintentional labelling and stigmatisation caused by participation could impose negative attitudes towards changing behaviour. New strategies should be developed in order to increase participation, especially if barriers exist related to social background,
Roadblock 4. Lack of birth cohorts and registries with repeated examinations for long-term follow-up studies over the life-course
In diabetes in pregnancy, childhood, normal ageing and chronic conditions such as diabetes there is a lack of diabetes registries (national and international). With diabetes of long duration (50-60 years) this also means that people already diagnosed with diabetes can ‘lose’ this diagnosis when admitted to hospital or long-term care, resulting in confusion and inappropriate treatment.
Cost effectiveness and application to health care policy requires such long term data, e.g. morbidity from gestational diabetes mellitus is often mild and treatment expensive. The long-term benefits to mother and child are difficult to calculate and need follow-up of up to 20 years.
Roadblock 5. Lack of large European diabetes networks
There is a lack of diabetes networks focussing on clinical aspects of diabetes treatment; those that do exist are mainly supported by pharmaceutical companies. This means there is a lack of reference centres, and experts in specialities such as paediatrics.
Roadblock 6. Fragmented electronic medical records, even within a single institution
Alongside the fragmented electronic records system is the lack of integration of the laboratory record (which may prove the presence of undiagnosed diabetes) with the main clinical record.
Roadblock 7. Lack of specific bioinformatic software to analyse and integrate multiple data on biological
(genetic), psychological, lifestyle and social factors
New bioinformatic approaches (e.g. Google Health) have the potential to revolutionise the way that medical data are stored and transferred; however, they are not available to benefit children with a chronic disease.
Roadblock 8. Gap in professional skills
The skill gap between generalists, who provide most of the care to patients with diabetes in hospitals and institutional settings, and diabetes specialists, who work mostly in ambulatory care is a research roadblock.
Roadblock 9. Lack of appropriate professional training and education
Lack of professional training for physicians and health care professionals providing treatment and care in specialised treatment centres and referring patients from general health care settings.
Roadblock 10. Resistance to implementation of largescale clinical research in the setting of usual clinical care and fragmentation of usual clinical care from the tradition of clinical research
This includes difficulties with ethics approval, intellectual property, language, culture and simple logistics. This results in fragmentation of usual clinical care from the tradition of clinical research with a lack of awareness of research issues.
Roadblock 11. Drug regulatory issues: paediatric drug approvals lag behind adult decision-making in the regulatory pathway
The EMA needs to have sufficient paediatric scientific input to put promising drugs and technological advances on an accelerated pathway without compromising safety to make them available also for the young age group and pregnant women at the earliest possible stage.
Requirements for European drug approval are not sufficient to provide the necessary data and 50-90 percent of paediatric medicines have not been tested and evaluated, including many existing diabetes medicines.
Therefore, the EMA is asking for a Paediatric
Investigation Plan as the basis for the development and authorisation of a medicinal product for the paediatric population subsets and rewards this with patent extension etc. However, not all questions with paediatric diabetes medicine development can be covered by this approach. Thus, sufficient resources for testing new drug development in different age groups need to be allocated, as it is likely that the drugs will not be of equal effectiveness in young children, adolescents or young adults. On the other hand ethical issues of intervention studies in children and differences in national regulatory procedures require a continued European approach for paediatric diabetes medicines regulations.
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Roadblock 12. Partnerships between academia and industry (both pharmaceutical and other industry) are needed
Such partnerships are necessary for the development and bringing to market of new drugs and devices, especially in the area of paediatrics where they are still limited. Additional incentives and support are needed.
Roadblock 13. Huge differences in structure, process, quality and delivery of diabetes care between European countries - especially in specialties such as paediatrics and obstetrics and in particular sub-groups
Such differences must be taken into account when researching and testing interventions in the clinical setting.
Roadblock 14. Advances in diabetes treatment or new drugs or new devices can only be implemented if society is able to support such treatments
In particular discrimination against children with diabetes and lack of support in school and the peer-group environment make it very difficult for families to implement advanced therapies such as multiple injection regimens, insulin pumps or continuous glucose monitors during time outside of the immediate family environment.
Many countries in Europe do not have appropriate measures to enable schools to support children with diabetes. As a consequence, children with diabetes are often not allowed to take part in normal school activities, such as sport. There are examples of very young children being asked to leave the school because of their diabetes. This has serious consequences for the quality of life for the children, but also for their families and prohibits implementation of medical advances in paediatric patients.
Roadblock 15. Lack of appropriate animal models to study fetal programming, fetopathy and embryopathy
There are ethical issues in studying these processes in pregnant women because of the risk of harm to the developing fetus, and thus only observational studies can be undertaken.
Roadblock 16. Barriers in the multi-disciplinary approach to guiding people with diabetes through health care structures (e.g. referral from primary to hospital care and back)
Collaboration is required for joint studies of diabetes and cognitive/psychological diseases and is particularly challenging for inter-disciplinary research that will require major commitment of resources and joint structures.
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Roadblock 1. Assumption that nephropathy in type 2 diabetes is the same as in type 1 diabetes
Roadblock 2. Lack of access to human tissue through large accessible biobanks
Roadblock 5. Lack of animal models to sufficiently mirror human disease
Short guide to road map 5.1
Chronic diabetes results in progressive damage to a number of different organs, including the eyes, the kidneys and the nerves.
Fundamental to all such microvascular complications of diabetes is the loss of the ability to regulate and maintain healthy glucose levels in the blood. However, the mechanisms by which poor glucose control as well as other factors are able to mediate functional changes that initiate and sustain tissue damage are poorly understood. This road map specifically focusses on defining these mechanisms.
The ultimate aim is to develop and validate new treatments for diabetic microangiopathy.
Understanding the underlying basic molecular mechanisms is intended to facilitate the identification of new drug targets. The primary procedure comprises validation in animal models that are as close as possible to early human disease. A novel prerequisite for validation is secondary intervention (treatment when the complication is already present), which is mostly neglected in the development of drugs for complications. Studies along these tracks may also shed light on possible differences in the aetiology, pathophysiology and clinical outcomes in microvascular complications in type 1 compared with type 2 diabetes.
41

Roadblock 1. Assumption that nephropathy in type 2 diabetes is the same as in type 1 diabetes
Roadblock 2. Lack of access to human tissue through large accessible biobanks
Roadblock 3. Lack of large-scale European research networks to generate large international studies
Roadblock 4. Lack of multi-disciplinary collaboration
Roadblock 5. Lack of animal models to sufficiently mirror human disease
Short guide to road map 5.2
It is crucial to develop early markers able to identify people with diabetes at high risk of developing microvascular complications, given that the best results are obtained when the complications are treated at very early stages of the disease. The availability of early markers/predictors would allow the high-risk patients to be treated intensively with currently available therapies as well as with new agents.
When the complications are established and advanced, current strategies can only partially impact on the progression towards end-organ failure.
42

Roadblock 2. Lack of access to human tissue through large accessible biobanks
Roadblock 3. Lack of large-scale European research networks to generate large international studies
Roadblock 4. Lack of multi-disciplinary collaboration
Short guide to road map 5.3
Diabetic retinopathy progresses through definite stages of increasing severity and deteriorating visual function ultimately leading to blindness. The various currently available therapeutic options employed at each stage are essentially the same - early and regular detection of high-risk groups, control of glycaemic status and other contributing systemic factors, laser therapy, intraocular injections, surgery, and rehabilitation by low vision aids - but the proportion in which they are employed varies. Also, these therapeutic options serve primarily to arrest rather than reverse the progression of diabetic retinopathy and, hence, visual deterioration. The present approach is designed to redefine and refine existing therapies, as well as discover and invent novel therapies capable of reversing progression and restoring vision. It is important to note that with each progressive stage, the therapeutic options increase in number, cost, multiplicity of sessions and in particular, profile of side effects. Particular attention must be paid to any side effects that may be more vision-threatening than the disease process itself.
43

Roadblock 1. Assumption that nephropathy in type 2 diabetes is the same as in type 1 diabetes
Roadblock 2. Lack of access to human tissue through large accessible biobanks
Roadblock 3. Lack of large-scale European research networks to generate large international studies
Roadblock 4. Lack of multi-disciplinary collaboration
Roadblock 5. Lack of animal models to sufficiently mirror human disease
Short guide to road map 5.4
Diabetic nephropathy is the leading cause of end-stage renal disease in developed as well as in developing countries. Currently available therapeutic strategies, such as glucose and blood pressure control, are effective in preventing the development and in halting/slowing the progression in the early stages of diabetic kidney disease. Once the renal damage is advanced and overt diabetic nephropathy (characterised by the presence of proteinuria) is present, the decline in renal function towards end-stage renal disease can only be slowed; indeed, in most patients with advanced renal disease the need for renal replacement therapy is inevitable. The ultimate goal is to define optimal strategies to reduce the burden of diabetic kidney disease.
Early referral to speciality services, education and planning for renal replacement therapy improves outcomes in patients with chronic kidney disease. The particular clinical needs of diabetic patients, who have higher co-morbidity and risk, have not been explored in any comprehensive way.
44

Roadblock 2. Lack of access to human tissue through large accessible biobanks
Roadblock 3. Lack of large-scale European research networks to generate large international studies
Roadblock 4. Lack of multi-disciplinary collaboration
Short guide to road map 5.5
Diabetic autonomic neuropathy is associated with markedly reduced quality of life and poor prognosis. Its manifestations cause multiple symptoms involving among others the cardiovascular and respiratory systems, gastrointestinal and genitourinary tracts.
Progress in this area has been frustratingly slow and this map focusses on developing new treatments based on studies of the natural history of diabetic autonomic neuropathy as well as a better understanding of the underlying pathological process(es).
Significant investment in a multi-disciplinary, regional approach is favoured.
45

Roadblock 2. Lack of access to human tissue through large accessible biobanks
Roadblock 3. Lack of large-scale European research networks to generate large international studies
Roadblock 4. Lack of multi-disciplinary collaboration
Short guide to road map 5.6
The aim of this road map is to focus on research for the primary, secondary and tertiary prevention of diabetic foot ulcers and/or amputations. Foot ulcers are very common in people with diabetes, and it is estimated that people developing diabetes have a 25 percent chance of developing a foot ulcer at some time during their remaining lifetime. Up to 50 percent of older people with type 2 diabetes have risk factors for foot ulcers, and despite the huge economic burden of diabetic foot disease, no interventions to date (including educational programmes) have been shown to reduce the risk of developing first or recurrent ulcers. Neuropathic foot ulcers should be entirely preventable but once a patient has had one, there is up to a 50 percent annual recurrence rate. Recurrent ulcers increase the risk of ultimately undergoing lower limb amputation, and up to 90 percent of amputations are preceded by foot ulcers.
Thus, a reduction in the incidence of foot ulcers would be followed by a reduction in lower extremity amputation.
Diabetes is now the most common cause of
Charcot neuroarthropathy in the western world.
Charcot neuroarthropathy can be described as a progressive condition affecting the bones and joints of the foot and is characterised by joint dislocation and pathological factors of the foot in patients with diabetic neuropathy. This may result in a debilitating deformity and eventually lead to amputation. Charcot neuroarthropathy tends to occur at a younger age than foot ulceration and as it is relatively rare, there have been few studies that accurately describe the pathogenesis and management of this condition, despite its impact on quality of life.
46

Roadblock 2. Lack of access to human tissue through large accessible biobanks
Roadblock 3. Lack of large-scale European research networks to generate large international studies
Roadblock 4. Lack of multi-disciplinary collaboration
Short guide to road map 5.7
It is widely accepted that high concentrations of glucose impact on the microcirculation (the capillaries situated downstream to large vessels constituting the circulation) in a causal relationship. However, the relationship between risk for cardiovascular disease and hyperglycaemia is different from that regarding risk for microvascular disease for several reasons. While a causal relationship between high blood glucose and microvascular disease is well evidenced by clinical trials, this is still questionable for cardiovascular disease. One possibility is that benefit only becomes manifest over the longer term as suggested by the Diabetes Control and Complications Trial
(DCCT) and UK Prospective Diabetes Study
(UKPDS).
Furthermore, inflammation and/or sclerosis are involved in the development of both cardiovascular and microvascular diseases that are thus entangled from epidemiological, mechanistic, and therapeutic viewpoints. It will therefore be of great interest to examine whether the status of microvascular disease affects the response to insult on large vessels
(prognosis following myocardial infarction, stroke, or peripheral vascular disease) as well as the response to preventive measures.
47

Roadblock 1. Assumption that nephropathy in type 2 diabetes is the same as in type 1 diabetes
This assumption has prevented further investigations on the aetiology, pathophysiology, diagnosis and treatment of renal disease in patients with type 2 diabetes. Given that the mechanisms underlying renal dysfunction are likely to be different in type 1 and type 2 diabetes, this assumption has led to the use of inadequate early markers and delays in diagnosis. Also, prognosis and response to treatment are likely to be different between the two patient groups. The need to understand better the differences in nephropathy in type 1 vs type 2 diabetes is addressed in part in the research section (see
Milestones 5.1.05, 5.1.06 and 5.4.04).
Roadblock 2. Lack of access to human tissue through large accessible biobanks
Biobanks containing tissue samples from a large number of well-documented patients with representative inclusion criteria could significantly hasten research and help to confirm that markers are associated with tissue damage.
This could be achieved through the European Platform for Clinical Research in Diabetes (EPCRD) proposed in
Chapter 4. Alternative systems are of only limited value.
Cell culture is limited in exposure time and may thus only represent early, transient transcriptional changes. The use of cell lines often ignores specific cell propensities, and macrovascular endothelial cells are not representative of microvascular alterations.
Roadblock 3. Lack of large-scale European research networks to generate large international studies
No single centre can expect to conduct appropriate intervention trials for new therapies or assess whether abnormal tests in asymptomatic patients are predictive of the symptomatic manifestations. The rarity of some manifestations of microvascular complications means that sufficient numbers of people with the condition can only be accessed through a European-wide platform such as the EPCRD that would also facilitate the longterm studies essential to much of the research strategy outlined in this road map.
Roadblock 4. Lack of multi-disciplinary collaboration
Current research approaches are often subjective for the rarer conditions and dependent on views and experience of individuals. Large-scale collaboration is needed, through networks, to overcome this problem, allowing for consensus on classification and coordinated study of these less common conditions.
Roadblock 5. Lack of animal models to sufficiently mirror human disease
Since animal models do not develop advanced diabetic complications it is difficult to understand the mechanisms of progression of complications and to test new treatments. The need for such animal models would be somewhat mitigated if there was greater access to adequate amounts of human material (see Roadblock 2).
For some microvascular complications, animal models are not representative and care needs to be exercised when trying to translate results from conditions in experimental models to conditions in man. The need to develop robust animal models is addressed in part in the research section (see Milestone 5.4.02).
48

Roadblock 1. Biobanks and biosample collections
Roadblock 2. Registries of people with diabetes
Roadblock 4. Academic and industry collaboration
Short guide to road map 6.1
Diabetes creates specific conditions (a high glucose concentration with multiple metabolic effects) for macrovascular complications to develop that are characterised by atherosclerosis appearing earlier and at a more advanced stage than in people without diabetes. However, it has not been established if cardiovascular disease (CVD) in diabetes has specific features (e.g. biochemical changes within the vessel wall), which may differentiate it from that in patients without diabetes. A deeper understanding of pathogenic mechanisms is a prerequisite for an improvement in early diagnosis and treatment, as well as eventually preventing
CVD in diabetes. As CVD develops during the early stages of diabetes, frequently even before diagnosis, it should be investigated also in the prediabetic state and in the metabolic syndrome. Epidemiological studies evaluating risk factors should similarly be carried out in individuals with diabetes and prediabetes.
Development of CVD in diabetes may be influenced by interactions between genetic and metabolic risk factors, as well as those that facilitate functional (e.g. endothelial dysfunction) and morphological
(atherosclerotic plaques) changes of the vascular wall. All of these factors may be modified by sex and ethnic differences. The early stage of vascular disease is mostly asymptomatic, and the patient is without any problems. However, CVD develops progressively and, therefore, it needs to be discovered as early as possible.
49

Roadblock 1. Biobanks and biosample collections
Roadblock 3. Large-scale research networks
Short guide to road map 6.2
Macrovascular disease presented by ischaemia in the heart, brain and lower limbs is manifested when advanced changes of the vascular wall are already developed. Its manifestation is frequently asymptomatic, and the patient may not visit a physician for some time. Diagnosis may then be made at a time that is too late for treatment to be successful, and it limits the likelihood of preventing organ failure. Late diagnosis of macrovascular disease is thus a major cause of premature death of people with diabetes; early diagnosis, before development of vascular changes, is therefore an important goal. The patient can be intensively handled both pharmacologically and non-pharmacologically when morphological changes in the vessel wall have not yet developed, and this may slow or prevent atherosclerosis.
Early diagnosis depends on being able to evaluate markers that indicate either predisposition to development of atherosclerosis (genetic markers) or the presence of specific initial vascular wall activation which is characterised by molecules associated with and produced by endothelial cells (biomarkers). Identification of such novel biomarkers will enable development of an algorithm for early diagnosis of diabetic cardiovascular disease.
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Roadblock 3. Large-scale research networks
Roadblock 4. Academic and industry collaboration
Short guide to road map 6.3
Successful diabetes treatment needs to approach the physiological regulation of metabolism and to normalise blood glucose concentrations, as well as to eliminate the risk factors that contribute to macrovascular disease. This cannot be achieved by currently available treatment strategies, making it important to develop new and more effective ones. This goal will include both pharmacological and non-pharmacological interventions to improve the quality of life and prognosis of people with diabetes by preventing or diminishing development of atherosclerosis. New strategies must take into account individual responsiveness to treatment regimens, leading to personalised therapy.
By combining efficient pharmacological/ technical and non-pharmacological interventions, focussed on the stage of cardiovascular disease, more effective results can be achieved. Personalised therapy for diabetic cardiovascular disease may also have positive effects on other risks and comorbidities.
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Roadblock 5. Patient and/or provider education campaigns
Short guide to road map 6.4
Development of chronic vascular complications causes major problems to people with diabetes and presents a huge challenge to health care professionals involved in their treatment and care. Complications worsen the clinical status of the patient, and therefore quality of life and life expectancy are impaired. Progressive disturbance of the vessel wall ultimately leads to organ failure with increasing disability; even successful treatment fails to improve the situation over the long term. As an example, chronic heart failure causes repeated hospitalisations with worsening of breathing, fluid retention (oedema), loss of appetite and diminished interest in usual daily life activities.
Therefore, prevention of atherosclerosis is the ultimate aim not only in patients with no current signs of macrovascular disease (secondary prevention) but also in patients with established atherosclerosis (tertiary prevention). Prevention may delay or diminish the development of vascular disease and also its progression.
Preventive procedures can be divided into changes to lifestyle and pharmacological intervention. These two research tracks in combination may be more effective than only one route alone; however, further research is required to provide the hard data necessary to validate effective prevention strategies for cardiovascular disease in diabetes.
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Roadblock 1. Biobanks and biosample collections
No large biobanks at national or international level are available for extended genetic analyses, which are necessary to determine gene-related causes of cardiovascular disease in diabetes. This could be remedied by the European Platform for Clinical Research in Diabetes (EPCRD – Chapter 4). It is supposed that multiple genes and their different combinations (as various gene mixtures) participate in development of macrovascular complications. Lack of data from large studies with adequate statistical power prevents clinicians from considering and using genetic information in clinical decisions for proper treatment.
Roadblock 2. Registries of people with diabetes
Large cross-sectional and follow-up clinical trials evaluating development of cardiovascular disease in people with diabetes need to have registries at national level. Identification of people with particular characteristics (such as genetic characteristics, risk factors) would allow for proper selection of individuals in such trials, thereby limiting heterogeneity in studied cohorts and increasing the significance of the results of these trials. Such registries would facilitate research and simplify the organisation of large cohorts with particular signs or properties (sub-groups). No such registries currently exist but they could be established in the context of the EPCRD.
Roadblock 3. Large-scale research networks
Although research networks do exist they are not sufficiently large to support national and international studies and clinical trials. Such networks would also support academic collaborations between experts and could best be set up under the auspices of the EPCRD.
Roadblock 4. Academic and industry collaboration
Scientific development needs to create focussed collaboration between academic investigators and industry that will help to apply research developments and improve the speed to which they can be put to use in the clinical environment. Independent (outside) evaluation of the results gained in academic-industry collaboration may bring more and earlier data on side effects of drugs. This includes collaboration of pharmaceutical companies in large and long-lasting clinical trials for cardiovascular endpoints, which would have to be evaluated especially if novel drugs were introduced.
Roadblock 5. Patient and/or provider education campaigns
Achieving the goals and transferring the knowledge to individuals may be hindered by the lack of education of people with diabetes and/or health care providers. This may slow further development in research activity. More information on the research goals will be necessary in the diabetes community when creating groups for clinical trials. In addition, there is lack of knowledge on the importance of physical activity and dietary regimen, which may significantly modify results of treatment. The potential to improve the prognosis of the patient, including macrovascular disease, could be enhanced through education campaigns targetted at people with diabetes and providers.
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This Chapter considers issues that span the breadth of diabetes research Europe-wide, so as to improve the efficiency of research and its translation to benefit the individual. Also addressed are the overarching roadblocks identified by the discipline-specific sub-groups, along with strategies and recommendations to overcome them. A matrix approach was used for acquisition of information from the various sub-groups, with “Horizontal Issues” bridging disciplines and fields of study to make recommendations in key areas summarised below.
Priorities of the Horizontal Issues group focus upon policy, human resources, infrastructure, funding, societal and ethico-legal issues.
Recommendations are provided with examples of key opportunities to improve the efficiency, competitiveness and impact of diabetes research Europe-wide, noting the communication and education strategies for implementation.
Policy at a pan-European level, within the context of health-related research must
54 embrace action to address the diabetes epidemic, which is in part a consequence of escalating obesity but also reflects a disturbing increase in type 1 diabetes. Diabetes research should be more inclusively represented in
European policies affecting all aspects of relevant health research and public health messaging. Coordination of the European diabetes research effort could best be assured by a European Diabetes Academy of subject specialists that would also facilitate evaluation and delivery of across Europe.

Human resources are vital, recognising the need to retain research talent in Europe and facilitate interchange at all levels of scientific and clinical endeavour through appropriate recognition and adjustment of equivalent career structures between countries.
Infrastructure will require the orientation of and accessibility to registries of people with diabetes, high-risk groups, biobanks and repositories, and clinical research networks that stretch Europe-wide. Ethical and legal issues need conformity to facilitate this approach towards international research collaboration. The proposed European
Platform for Clinical Research in Diabetes
(EPCRD) (Goal 4.1) will provide essential services in this regard. Communication between researchers and the European
Commission and national research agencies could be best managed by an international group of experts (European Diabetes
Academy).
Funding sources mostly operate independently with few pan-European collaborations. Proposals to improve cohesion and integration of national funding structures require urgent consideration.
1. Policy
Roadblocks
Differences between national scientific and healthcare structures
Lack of integration of national scientific and healthcare research across Europe
Limited integration within and between research in disciplines closely linked to diabetes
Lack of large independent multi-national clinical studies
Dialogue between industry, academia, healthcare and non-governmental research organisations as well as government-funded bodies will be essential to optimise discovery, development and application of new medicines. International convergence of the regulatory framework for healthcare products would facilitate this process.
Societal and economic impact: the diabetes epidemic will have a catastrophic effect on healthcare provisions, which will pervade families, communities, cultures and economies, particularly impacting vulnerable groups. Initiatives to improve public health awareness are essential for effective implementation of recommendations from research.
Communication and education between scientists and healthcare professionals at an international level, and engagement of the general public and people with diabetes to empower personal decision-making are key implementation pathways for this diabetes research road map.
Recommendations
European Union further enhances integration of scientific and clinical research, e.g. using
European Commission Research Framework
Programmes to overarch national differences in guidelines and policy
Create a European Diabetes Academy to encourage national bodies to subscribe to
European disease road map recommendations
Create association of biomedical research associations to address generic issues
Funding for investigator-initiated multi-national studies
55

2. Human resources
Roadblocks Recommendations
Differences between national scientific and clinical career structures and remuneration
Integration of basic and clinical research
Europe-wide; e.g. European Directive to consider harmonising scientific and clinical career structures across Europe
Attraction and retention of best scientific talent Equivalent remuneration and recognition of achievement within scientific and clinical career structures Europe-wide
3. Funding
Roadblocks
Insufficient funding for large or long-term international projects
Insufficient innovation funds
Insufficient funding of clinical research
Recommendations
Optimise industrial-academic research partnerships and not-for-profit sources; allow outstanding projects to receive sustained
European Union support
Provide incentives for collaboration with biotechnology sector, e.g. protection of intellectual property and extension of patent life
Encourage national healthcare initiatives for primary and secondary care
4. Infrastructure improvement/development
Roadblocks
Insufficient large information databases and tissue repositories
Lack of electronic conformity
Disconnect between research activities and public health needs
Mismatch of communication between the research community and the European
Commission
Recommendations
Develop European registries of people with diabetes and tissue repositories with wide but rigorously regulated access through the
European Platform for Clinical Research in
Diabetes (EPCRD)
Ensure simplicity and compatibility of electronic operating procedures for clinical networks
Incorporate research into public health initiatives Europe-wide and monitor adoption of
DIAMAP under the guidance of the European
Diabetes Academy
Create an overarching diabetes research infrastructure of subject specialists (European
Diabetes Academy) to facilitate policy and delivery of diabetes research across Europe
5. Societal issues
Roadblocks
Lack of information regarding minority and vulnerable groups including migrants and particular ethnic populations
6. Ethical and legal
Roadblocks
National differences in ethical and legal systems
Lack of Europe-wide guidelines for pre-clinical and clinical studies outside of regulatory requirements
Recommendations
Targetted research to include special at-risk groups and health economics analyses; support for research on type 1 diabetes
Recommendations
Greater conformity of documentation for ethical issues
Position statements routinely updated for scientific procedures including trials, use of animals and stem cells and other controversial issues that divide regions of Europe
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7. Communication and education
Roadblocks
Insufficient public awareness of diabetes research
Major electronic communication advances remain under-utilised for knowledge dissemination
Regulatory issues
Recommendations
Requirement of grant awarding bodies that grant awardees engage with public.
Wider involvement of all stakeholders in public events including policy makers and journalists where appropriate.
Support to make key scientific information readily available through electronic formats e.g. telehealth, email and texting.
Issues
Regulatory
Pharmaceutical
Suggestions
Reconsider patent life and international harmonisation of regulatory requirement for new medicines
Recognise role of basic and early translational research as platform for drug development
Clarify health claims attributed to some foods Food
Many of the recommendations mentioned in the DIAMAP report depend upon successful coordination of the European diabetes research effort and improved communication between all stakeholders. This can best be achieved by creation of an overarching entity, the European Diabetes Academy as mentioned in the major recommendations above. This Academy would also be involved in overseeing implementation of the DIAMAP strategy across Europe and ensuring rational, synergistic but non-overlapping investment in specific research tracks, integrating national and international efforts while encouraging national specificity that capitalises on local expertise.
Return for investment in DIAMAP will only be realised if the impact of the project is monitored and quantified during the implementation phase following the end of existing FP7 funding. The European Diabetes
Academy must be funded to monitor success of DIAMAP in terms of advancement of research, improved regional research competitiveness and most importantly benefit to individuals with diabetes.
57

DIAMAP, funded by the European Commission (FP7 HEALTH 200701), was coordinated by
EURADIA (Alliance for European Diabetes Research) and overseen by a Project Steering
Committee (PSC) with one representative from the academic research community, one from industry and one lay person representing individuals with diabetes. The mapping and writing of the scientific reports was undertaken by seven sub-groups, with the Chair of each of these groups comprising an Expert Advisory Board (EAB). The DIAMAP project was managed by the DIAMAP staff.
Chair and DIAMAP Coordinator
Philippe A. Halban,
Department of Genetic Medicine and Development, CMU
Geneva, Switzerland
Veikko A. Koivisto
Lilly Deutschland GmbH
Diabetes Medical Affairs, Europe
Bad Homburg, Germany
Steve Hitchins
Juvenile Diabetes
Research Foundation (JDRF)
London, UK
Emmanuel Van Obberghen
Medical School, University of Nice-
Sophia-Antipolis
University-INSERM Laboratory
Clinical Chemistry
University Hospitals
Nice, France
Chair: Nicholas J. Wareham
MRC Epidemiology Unit
Institute of Metabolic Science
Addenbrooke's Hospital
Cambridge, UK
Knut Borch Johnsen
Steno Diabetes Center, Gentofte, Denmark
Helen Colhoun
University of Dundee, Biomedical Research
Institute, Ninewells Hospital and Medical School,
Dundee, UK
Leif C. Groop
Lund University, Department of Clinical Science,
University Hospital Malmö, Malmö, Sweden
Mikael Knip
Hospital for Children and Adolescents,
University of Helsinki, Helsinki, Finland
Chair: Thomas Mandrup-Poulsen
Hagedorn Research Institute
Gentofte, Denmark
University of Copenhagen
Copenhagen, Denmark
Karolinska Institute
Stockholm, Sweden
Marc Y. Donath
University Hospital Zürich, Division of
Endocrinology/Diabetology, Zürich, Switzerland
Ole Dragsbæk Madsen
Hagedorn Research Institute, Gentofte, Denmark
Olle Korsgren
Uppsala University, Department of Oncology,
Radiology and Clinical Immunology, Rudbeck
Laboratory C11, Uppsala, Sweden
Patrik Rorsman
University of Oxford, Oxford Centre for Diabetes,
Endocrinology and Metabolism, Churchill Hospital,
Oxford, UK
58

Chair: Juleen R. Zierath
Karolinska Institute
Department of Molecular Medicine and Surgery, Integrative Physiology
Stockholm, Sweden
Markku Laakso
University of Eastern Finland and Kuopio
University Hospital, Department of Medicine,
Kuopio, Finland
Yannick Le Marchand-Brustel
INSERM U895, C3M, Batiment Universitaire
Archimed, Nice, France
Michael Roden
Institute for Clinical Diabetology, German Diabetes
Center, Düsseldorf, Germany
Michael Stumvoll
University of Leipzig, Medizinische Klinik III,
Leipzig, Germany
Chair: John J. Nolan
St. James's Hospital
Trinity College Dublin
Metabolic Research Unit
Clinical Medicine
Dublin, Ireland
Thomas Danne
Kinderkrankenhaus auf der Bult,
Diabetes Centre for Children and Adolescents,
Hannover, Germany
Michaela Diamant
VU University Medical Center, Diabetes Center,
Department of Internal Medicine, Amsterdam,
The Netherlands
Gillian Hood
Barts and The London Hospital, Barts and The
London School of Medicine and Dentistry, London,
UK
Alexandra Kautzky-Willer
Allgemeines Krankenhaus, Medical University of
Vienna, Innere Medizin III, Vienna, Austria
David Kerr
Bournemouth Diabetes and Endocrine Centre,
Royal Bournemouth and Christchurch Hospitals,
Dorset, UK
Asimina Mitrakou
National and Kapodistrian University of Athens,
Department of Clinical Therapeutics, Athens,
Greece
Peter M. Nilsson
Lund University, Department of Medicine,
Malmö University Hospital, Malmö, Sweden
Giovanni Pacini
Istituto di Ingegneria Biomedica del CNR,
Metabolic Unit, Padova, Italy
59

Chair: Paola Fioretto
University of Padova
Clinica Medica I
Department of Medical and Surgical
Sciences
Padova, Italy
Francesco Bandello
University Vita Salute, Scientific Institute San
Raffaele, Department of Ophthalmology,
Milano, Italy
Andrew J. M. Boulton
Manchester Royal Infirmary, Department of
Medicine, Manchester, UK
Mark Cooper
JDRF Albert Einstein Centre, Division of Diabetes and Metabolism, Melbourne, Australia
Hans-Peter Hammes
V. Medical Clinic, University Hospital Mannheim,
Department of Endocrinology,
Mannheim, Germany
Michel Marre
Hôpital Bichat, Diabetology, Endocrinology and
Nutrition, Paris, France
Merlin Thomas
JDRF Albert Einstein Centre, Division of Diabetes and Metabolism, Melbourne, Australia
Dan Ziegler
Institute for Clinical Diabetology, German Diabetes
Center, Düsseldorf, Germany
Chair: Jan Skrha
Charles University
Faculty of Medicine 1
Department of Internal Medicine 3
Prague, Czech Republic
Antonio Ceriello
Institut d'Investigacions, Biomediques August Pi i
Sunyer (IDIBAPS), Barcelona, Spain
Anselm K. Gitt
Herzzentrum Ludwigshafen, Institut für
Herzinfarktforschung, Ludwigshafen, Germany
Didac Mauricio
Hospital Arnau de Vilnova, Department of
Endocrinology, Lleida, Spain
Bart Staels
Département d'Athérosclérose, U545 INSERM,
Université de Lille 2, Institut Pasteur, Lille, France
Krzysztof Strojek
Silesian Medical University, Department of Internal
Diseases, Diabetology and Nephrology,
Zabrze, Poland
Ivan Tkac
Safarik University, Faculty of Medicine,
Department of Internal Medicine 4, Kosice,
Slovakia
60

Chair (year 2): Clifford J. Bailey
Diabetes Research
Life and Health Sciences
Aston University
Birmingham, UK
Chair (year 1): Peter E. Schwarz
Medizinische Klinik und Poliklinik III
University Clinic Carl Gustav Carus
Dresden, Germany
Magdalena Annersten Gershater
Universitetssjukhuset, Fakulteten för Hälsa och
Samhälle, Malmö, Sweden
Anne-Marie Felton
President, Federation of European Nurses in
Diabetes, London, UK
Stephan Matthaei
Diabetes-Zentrum Quakenbrück, Fachabteilung für Diabetologie, Stoffwechsel und Endokrinologie,
Quakenbrück, Germany
Bernhard Paulweber
Universitätsklinik für Innere Medizin I,
Stoffwechselerkrankungen und Medizinische
Molekularbiologie, Salzburg, Austria
Markku Peltonen
National Institute for Health and Welfare, Diabetes
Prevention Unit, Helsinki, Finland
Thomas Pieber
Medical University Graz, Department of Internal
Medicine, Diabetes and Metabolism, Graz, Austria
Johan Wens
University of Antwerp, Department of General
Practice, Interdisciplinary Health Care and
Geriatrics, Antwerp, Belgium
Sarah A. Hills
Project Manager
Michelle A. Cissell
Special Advisor and scientific support for the research road mapping
Regina Sautter
Administration Manager
Lara Lütke-Spatz
Research Assistant
During the first six months Ulf Smith was a member of the Project Steering Committee and Joan Davis
Nagel served as Scientific Project Manager.
Nathalie Vercruysse
Scientific Officer
European Commission
DG RTD-F02
Brussels, Belgium
61

EURADIA is a unique alliance of major European diabetes research stakeholders. The following non-governmental organisations and companies are members of the Alliance:
EASD (European Association for the Study of Diabetes)
FEND (Federation of European Nurses in Diabetes)
IDF-Europe (International Diabetes Federation-Europe)
ISPAD (International Society for Paediatric and Adolescent Diabetes)
JDRF (Juvenile Diabetes Research Foundation International)
PCD Europe (Primary Care Diabetes Europe)
AstraZeneca
Bayer Health Care
Eli Lilly and Company
GlaxoSmithKline
Merck Sharp & Dohme (MSD)
Novartis
Novo Nordisk
Sanofi-Aventis
Members of EURADIA have not contributed directly to the DIAMAP project. Individuals working for DIAMAP did so in a personal capacity and not as a representative of a member organisation or company, in order to avoid any potential conflict of interest in the coordination of DIAMAP by
EURADIA.
EURADIA e.V.
Rheindorfer Weg 3
40591 Düsseldorf
Germany www.EURADIA.org
EURADIA e.V. is a Non-Profit-Association, registered at the County Court Düsseldorf, Registry Number: VR 9885
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