Kidney disease is a common and serious complication of diabetes and it is associated with a greatly increased risk of heart attack and stroke.  Globally, diabetic kidney disease is now the leading cause of end stage kidney failure requiring dialysis or kidney transplant.  Up to now scientists and clinicians were aware that only some patients with diabetes will develop kidney disease but the basis of this susceptibility was not known.

The UCD Diabetes Research Centre is involved in an international consortium colalborating with investigators at the Centre for Public Health, Queen’s University Belfast, the Broad Institute of MIT/Harvard and the University of Helsinki.  This collaboration, the GENIE consortium has discovered genes associated with risk of diabetic kidney disease.

The researchers carefully analysed over two million DNA markers in the genome of each person with diabetes who participated in the gene scan. In the largest study of its kind, the investigators recruited 4,750 patients with diabetic kidney disease and almost 7,000 patients with long-standing diabetes but with no evidence of kidney disease. Their findings demonstrate that changes associated with two genes  called AFF3 and ERBB4 increase the risk of kidney disease. When the researchers experimentally altered the levels of these genes in kidney cells they were able to mimic disease. 

‘Currently available drugs cannot cure the kidney failure but may slow its progression. Knowing which patients are most at risk of kidney complications will be helpful in managing their diabetes’ commented Professor Peter Maxwell of Queen’s University, one of the principal investigators on the study.  

Professor Catherine Godson, lead investigator of the UCD group observes that  ‘these new research findings are very important as they define mechanisms that underpin the development of this devastating disease. This research helps accelerate development of new and effective therapies’. 

This work is supported by the US-Ireland research and development programme, a collaborative initiative funded by Science Foundation Ireland, the Northern Ireland R&D Office and the US National Institutes of Health.

The UCD Diabetes Research Centre consolidates multi-disciplinary and collaborative expertise to accelerate progress towards discoveries that will improve the diagnosis and treatment of diabetes and associated diseases.

The Centre brings together experts in clinical and translational medicine, genetic epidemiology, public health and molecular cell biology in the UCD Conway Institute and several UCD Schools together with UCD’s affiliated teaching hospitals and with both national and international collaborators in academia, hospitals and industry.

This multidisciplinary approach addresses the full spectrum of issues concerning Diabetes Research from molecular genetics to the physical, psychological and social dimensions of the disease.

Ongoing research programmes by School investigators include:

Diabetic Kidney Disease

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 led by Professor Catherine Godson (Director, Diabetes Research Centre at the UCD Conway Institute) 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 Prof Godson's group 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. They have investigated whether expression of such genes is similarly changed in patients with DN and from patients with non-diabetic kidney disease. Importantly, They 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 which are being explored for therapeutic intervention.  Furthermore, in collaboration with Professor Peter Maxwell and Dr David Savage at Belfast City Hospital and Queen’s University Belfast they have uncovered novel candidate ‘DN-susceptibility’ genes.

Diabetic Retinopathy

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.

Research by Professor Colm O'Brien (UCD Professor of Ophthalmology at Mater Misericordiae University Hospital) and by researchers 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. They are currently using advanced proteomics technologies to define the substances which are released from such activated platelets. The team 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. Current research explores 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.

Insulin, growth hormone (GH) and IGF-I comprise an important endocrine axis involved in regulating growth and metabolism. Dysregulation of this axis is a consistent pathogenic finding in disorders of insulin deficiency (type 1 diabets) and resistance (type 2 diabetes).

Dr Paul Crossey's research interests are focused on a family of IGF binding proteins (IGFBPs) which regulate IGF bioavailability and thus bioactivity. One of these IGFBPs, IGFBP-1, is directly regulated by insulin in a manner that suggests its plays a key role in co-ordinating the metabolic actions of IGF-I and insulin in relation to nutritional status. Reduced IGF-I bioavailability is a feature of type 1 and type 2 diabetes and there is growing evidence that this is an important factor in the pathophysiology of these disorders.

Dr Crossey's research strategy utilises in vivo methodologies in genetically modified mouse models to derive important insights into the role of IGF-I in diabetes and its sequelae and to explore if manipulation of the growth hormone/IGF-I axis may be a viable therapeutic approach for treatment of these disorders.