WHO estimates suggest the global prevalence of diabetes will rise to 4.4% by 2030. In Ireland it is estimated that diabetes consumes 10% of the national healthcare budget, the predominant expenditure being on management and treatment of diabetic complications including cardiovascular disease, diabetic eye and diabetic kidney disease (diabetic nephropathy) affecting those with Type 1 and Type 2 diabetes. Diabetic nephropathy (DN) is the leading cause of end-stage renal disease worldwide and develops in 25-40% of diabetic patients.

Elevated blood glucose over long periods together with increased blood pressure leads to progressive kidney damage in susceptible individuals. These patients will eventually require dialysis and transplants. The development of DN reflects the convergence of multiple factors including elevated blood glucose and its toxic metabolites, abnormal blood lipids, hypertension and compromised renal function. Genetic variation in the risk of developing DN has been demonstrated. Despite advances in therapies that regulate blood glucose levels and blood pressure there has been an increase in the incidence of DN and associated-end stage renal disease.

Effective treatment for DN represents a significant unmet clinical need that will best be addressed by understanding the mechanisms underlying the development of this devastating disease.

Our research focuses on elucidating the molecular and genetic factors that drive the initiation, progression and potential regression of diabetic kidney disease. This research programme can identify novel targets and signaling pathways for therapeutic intervention, novel therapies that may reverse the development of the disease and markers that can be used to diagnose disease susceptibility and or disease progression.

To date we have investigated genes whose expression is changed in response to high glucose or to other mimics of the diabetic state in specific types of kidney cells and in diabetic animals. We have investigated whether expression of such genes is similarly changed in patients with DN and from patients with non-diabetic kidney disease.

Importantly, we see a strong correlation between these approaches and this allows us to use our cell-based investigations to model the molecular basis of DN and establish the regulatory networks of genes that drive DN. These data have uncovered several novel targets for therapeutic intervention that we are currently exploring. Furthermore, in collaboration with Professor Peter Maxwell and Dr David Savage at Belfast City Hospital and Queen’s University Belfast we have uncovered novel candidate ‘DN-susceptibility’ genes.

Our ongoing work at The UCD Diabetes Research Centre will continue to exploit our relatively unique combination of approaches and technologies: cell models, animal models, human biopsy samples and genomic resources and, coupled to our collaborative efforts with pharma companies including Wyeth and with academic researchers, we believe that we are uniquely positioned to accelerate progress towards discoveries that will result in improved treatment and diagnosis of DN.

Our research programme involves a network of clinical collaborators including the Mater University Hospital, St Vincent’s University Hospital, Beaumont Hospital, University College Hospital Galway and Cork University Hospital and a European-wide consortium of clinicians.

Our basic science research programme includes collaboration with Prof Jochen Prehn’s group at RCSI and researchers in the US, Netherlands, UK and Chile. To date our research programme is funded by The Health Research Board Ireland, The Wellcome Trust, Science Foundation Ireland, The Government of Ireland Programme for Research in Third Level Institutions and The EU.

Diabetic eye disease is the major cause of blindness in the young and middle aged. Recent epidemiological studies show a significant increase in the prevalence of diabetes, particularly Type 2 diabetes. Since Type 2 diabetes is often not diagnosed until the individual has had the disease for many years the microvascular complications of diabetes, eye disease (diabetic retinopathy), kidney disease and disorders of the nervous system may already be present.

Although the incidence of diabetic retinopathy within the population of diagnosed diabetics may be decreasing because of aggressive risk factor reduction, any gains achieved are likely to be undermined by the large increase in the incidence of Type 2 diabetes in the population owing to the increases of childhood and adolescent obesity. The WHO estimated that in 2002 there were 37 million blind people worldwide. In Ireland, there were 6862 adults registered blind in 2003, representing an increase of 37% since 1996.

There has been a 120% increase in those registered blind in Ireland due to diabetic retinopathy over the past six years

Diabetic retinopathy is characterised by a decrease in oxygen supply to the eye and a corresponding adaptive response that involves growth of new blood vessels (angiogenesis) in the retina. The growth, function and support of these vessels is inappropriately regulated causing loss of vision.

Treatment of such conditions may require laser photocoagulation, which destroys areas of the retina, but preserves central vision. Because this is an inherently destructive approach, research at The UCD Diabetes Research Centre focuses on understanding the molecular mechanisms underlying the development of diabetic retinopathy with a view to discovering novel targets and endogenous mediators that may be amenable to therapeutic intervention.

To date our investigations at The UCD Conway Institute have characterised the response of retinal cells to elevated levels of glucose and to oxygen deprivation, conditions that mimic the diabetic milieu. Oxygen deprivation frequently reflects the formation of mini-clots within the vessels as a result of activation of platelets.

We are currently using advanced proteomics technologies to define the substances which are released from such activated platelets. We have discovered that oxygen deprivation activates expression of a panel of genes not previously known to regulate angiogenesis. These changes in gene expression parallel those observed in diabetic animals. We are currently exploring the potential of these findings in the context of targets against which novel therapeutics might be directed to limit retinal angiogenesis and biomarkers which may be released from activated platelets in patients with diabetic retinopathy.

Our research programme involves collaborators at The Mater University Hospital, Dublin City University, The Royal Victoria Eye and Ear Hospital and researchers at Queen’s University Belfast and in the US. To date our research is funded by the Health Research Board, The Government of Ireland Programme for Research in Third Level Institutions and the National Council for the Blind in Ireland (NCBI).

Contact: Professor Colm O’Brien / cobrien@mater.ie

Type 2 diabetes, the most common form of diabetes, is caused by a gradual decline in the efficiency with which the body uses insulin. The incidence of Type 2 diabetes is spiralling as this is the type of diabetes which is strongly associated with obesity. In Ireland the incidence of obesity has increased from 11 % of the adult population in 1999 to 18 % in 2001 whereas in the case of children, clinical obesity increased from 5% in 1999 to 11% in 2005.

Monitoring the rate of change of overweight and obesity in Ireland is an essential piece of research which UCD covers through the collaborative national nutrition surveys and through the National Nutrition Surveillance Centre at UCD directed by Prof. Cecily Kelleher. These initiatives also cover the development of evidence-based dietary guidelines for the population for optimising nutrition in the context of public health.

Defining the relationship between human genetic make up, the type of dietary fat consumed and the risk of developing diabetes is critical to tackling Type 2 diabetes

Understanding the biology of how obesity leads to impaired insulin function is also a major part of the research of the UCD Centre for Food and Health. Lipgene, a major EU funded programme, is coordinated through the centre. This study is examining the relationship between human genetic make-up, the type of dietary fat consumed and the risk of developing insulin resistant type of diabetes.

Not everyone who gains weight goes on to develop insulin resistance which would suggest a genetic role and existing research would suggest that the type of dietary fat may also play a major role in this area. How these two factors interact is the key objective of the Lipgene project.

At The UCD Diabetes Research Centre we are pioneering studies in applying the new technology of metabolomics to the study of diet and health and in particular, diet and Type 2 diabetes. Metabolomics is the new science of creating a metabolic signature based on the simultaneous identification of many hundreds of metabolites in blood. Each individual has a unique metabolic “fingerprint” which can be measured using new pattern recognition technologies. Individuals who have disorders such as Type 2 diabetes all tend to have metabolic fingerprints which cluster together in pattern recognition analysis.

By tracking these metabolic signatures from the peak of health to the development of diabetes in populations, databases will be created which will allow an individual to be diagnostically placed somewhere on that trajectory and through dietary management, to be returned to the health end of the spectrum. The long term hope would be to combine an individual’s unique metabolic signature with their unique genetic code to personalise their optimal diet bringing to reality the old maxim that “one man’s meat is another man’s poison”. Additionally these technologies have been successfully applied to investigating nutrient stimulation of insulin secretion in failing beta cells, a model of Type 2 diabetes.

Whereas 10 years ago, diet and health was synonymous with nutrients and health, today the vital role of the non-nutrient components of food are being recognised and we have a major research interest in this area. These compounds are mainly found in plants and can have very powerful effects on metabolism including the ability of the body to handle glucose which is central to Type 2 diabetes.

Screening native Irish plants for compounds that could be used as ingredients in functional foods is a very important part of the research interests of UCD food science. UCD has created a campus-wide initiative, the UCD Food and Health Programme, which will create a multi-disciplinary environment for the study of diet and health and diabetes and the metabolic syndrome, will be central to the programme.

This research programme involves collaboration with investigators in University College Cork, Trinity College Dublin, The University of Ulster, USA, Brazil, UK and mainland Europe. The programme is funded from multiple sources including the EU, The Department of Agriculture FIRM programme, The Health Services Executive, Enterprise Ireland, The Wellcome Trust, The Government of Ireland Programme for Research in Third Level Institutions and The Health Research Board.

Contact:

• Professor Mike Gibney / mike.gibney@ucd.ie
• Dr Lorraine Brennan / lorraine.brennan@ucd.ie
• Dr Philip Newsholme / philip.newsholme@ucd.ie

Quality of life (QoL) is a concept that takes account of the multidimensional nature of a person’s well-being, reflecting the physical, psychological and social dimensions of health described by the World Health Organisation. QoL is influenced by the clinical disease state, the individual’s personal beliefs, behaviours, experiences and expectations as well as their social and environmental milieu.

The clinical syndrome of diabetes and its associated complications have a negative impact on QoL.

We have demonstrated that patients with diagnosed diabetes report significantly poorer scores using diverse indices of health status involving a multidimensional profile of QoL, by comparison with the general Irish population. This is apparent in physical function, physical role, general health and emotional role scales. Progression to diabetic nephropathy and renal dialysis results in a further marked decline in QoL across all dimensions.

Ongoing research in the UCD Diabetes Research Centre includes: validation and development of self-reported measures of function and QoL in diabetes; laboratory and clinical measurement of the sensory, motor and functional impairments associated with diabetic neuropathy; monitoring of physical activity levels in people with diabetes and the promotion of exercise for glycaemic control, cardiovascular risk reduction and optimisation of physical function.

This research programme has been funded by The Irish Kidney Association and The Health Research Board, The Government of Ireland Programme for Research in Third Level Institutions

Contact: Dr. Catherine Blake / catherine.blake@ucd.ie

Despite advances in therapeutic and the clinical care of patients with diabetes, diabetes continues to cause premature death and debilitating disease.

Our current work focuses on identifying and validating predictors of cardiovascular disease that can be measured in body fluids (blood and urine) from patients with diabetes. This work draws on existing repositories of samples from patients with diabetes (both Type 1 and Type 2) whose cardiovascular status has been established.

This work involves a range of approaches. One is a discovery approach where we are using nuclear magnetic resonance spectroscopy to identify patterns of small metabolites that predict cardiovascular disease (this is termed metabonomics). The other approach involves the systematic evaluation and validation of a large battery of markers that laboratory studies already suggest as potential markers – such as markers of inflammation.

In collaboration with investigators in the USA we are seeking to identify genetic variation that contributes to cardiovascular disease and its intermediates, including cholesterol metabolism, in patients with Type 1 diabetes. Related to this other studies are being established with clinical colleagues that take forward previous work on abnormalities in lipoprotein metabolism that may contribute to the elevated risk of cardiovascular disease in diabetes. We are especially interested in therapeutic interventions to reduce cardiovascular disease in diabetes.

Previous work has included large scale clinical trial evaluation of statin (cholesterol lowering) therapy in Type 2 diabetic patients. Importantly this has resulted in changing the clinical guidelines for cardiovascular disease prevention. Our ongoing work at The UCD Diabetes Research Centre is exploring non–cholesterol lowering effects of statin drugs that may further contribute to their effects on cardiovascular disease.

We have investigated the basis for the elevated incidence of diabetes in various ethnic groups including South Asians. Current work focuses on developing and using admixture mapping approaches to identify the gene variants that contribute to ethnic differences of several diseases including Type 2 diabetes. Diabetic nephropathy is a major contributor to cardiovascular disease and increased mortality in diabetes and our genetic studies include large scale association and family based association studies of diabetic nephropathy and retinopathy. These investigations include the examination of the role of variants in genes identified by our colleagues in their investigations of gene expression patterns in cell and animal models.

Our research programme involves collaborators in the USA and Europe and is funded from multiple sources including the EU, The US Department of Health and Public Services and The Government of Ireland Programme for Research in Third Level Institutions

Contacts:

• Professor Helen Colhoun / helen.colhoun@ucd.ie
• Professor Paul McKeigue / paul.mckeigue@ucd.ie