Mediation Pathways For The Receptor For Advanced Glycation End Products In Diabetic Nephropathy
Funder
National Health and Medical Research Council
Funding Amount
$333,812.00
Summary
Excess sugar in the blood from diabetes is detrimental and can accelerate a process where sugar attaches itself to proteins, fats and DNA. Although facilitated by high sugar, the reaction occurs happily in the presence of low sugar with high levels of free oxygen radicals. These complexes are called advanced glycation end products or AGEs. In addition, we ingest vast volumes of AGES from our diet which are taken into the blood. These AGEs are known to be involved in the development of kidney dis ....Excess sugar in the blood from diabetes is detrimental and can accelerate a process where sugar attaches itself to proteins, fats and DNA. Although facilitated by high sugar, the reaction occurs happily in the presence of low sugar with high levels of free oxygen radicals. These complexes are called advanced glycation end products or AGEs. In addition, we ingest vast volumes of AGES from our diet which are taken into the blood. These AGEs are known to be involved in the development of kidney disease in diabetic subjects. AGEs exert most of their effects on the body by binding to specific proteins, the most common and nasty of which is the receptor for advanced glycation end products, RAGE. RAGE is a known participant in other serious diseases such as Alzheimer's disease and evidence is mounting for its central role in the development of kidney disease in diabetic subjects. There is not much known about the processes which mediate RAGE which is why this is the aim of this proposal. This will enable us to stop the relentless progression of kidney disease in diabetes.Read moreRead less
Characterisation Of Novel AGE Binding Proteins: Implications For Diabetic Vascular Complications.
Funder
National Health and Medical Research Council
Funding Amount
$210,990.00
Summary
This project will explore a process known as advanced glycation and in particular how this may lead to organ injury in diabetes. Diabetes is characterised by sustained elevation of blood glucose levels which interact with proteins to generate products known as advanced glycation end-products (AGEs). These AGEs bind to other proteins some of which have been isolated and are considered receptors. Our own group has identified a new family of proteins known as ERM proteins which bind to AGEs. This i ....This project will explore a process known as advanced glycation and in particular how this may lead to organ injury in diabetes. Diabetes is characterised by sustained elevation of blood glucose levels which interact with proteins to generate products known as advanced glycation end-products (AGEs). These AGEs bind to other proteins some of which have been isolated and are considered receptors. Our own group has identified a new family of proteins known as ERM proteins which bind to AGEs. This is a highly novel finding which now needs to be examined in more detail. The ERM proteins which include ezrin, radixin and moiesin are found at many sites of diabetic complications including the kidney, retina and blood vessel wall. They have a number of functions including effects on cell adhesion and cell structure. This is important in diabetes where changes in cells including altered structure have been observed. This grant will characterise the interactions between AGEs and ERM proteins at the molecular and cellular level. It will define how AGEs influence cells via interactions with ERM proteins. These studies have the potential to lead to treatments that may modulate the AGE-ERM interactions, thereby retarding or preventing diabetic vascular complications. These complications are of important clinical significance since they are the major cause of morbidity and mortality in the diabetic population. Furthermore, diabetes is a major cause of premature atherosclerosis in our community, diabetic kidney disease is the leading cause of end-stage renal failure in the Western world and diabetic retinopathy (eye disease) is the main cause of blindness in the working age population.Read moreRead less
The Role Of The Thioredoxin System In Angiogenesis And Impaired Neovascularisation In Diabetes Mellitus
Funder
National Health and Medical Research Council
Funding Amount
$306,501.00
Summary
For many sufferers of heart disease who suffer from blocked coronary arteries, current treatments (e.g. bypass surgery or angioplasty) are unable to offer relief from the debilitating effects of occluded arteries. This is particularly true of patients with diabetes who have more aggressive blockages. We plan to study a newly identified mechanism to facilitate growth of new blood vessels to sites affected by vascular disease . Ultimately, this may result in new treatments for heart disease.
An Autoantibody In Type 1 Diabetes That Mediates Autonomic Complications
Funder
National Health and Medical Research Council
Funding Amount
$254,591.00
Summary
Type 1 diabetes is a chronic autoimmune disease characterised by destruction of insulin producing cells in the pancreas. One of the most common and serious complications of type 1 diabetes is disruption of the autoimmune nervous system, and once symptoms appear the 5-year mortalityrate is approximately 50%. Symptoms of autonomic dysfunction can be extensive, and involve the stomach, intestine, bladder, heart and reproductive organs. Currently, the management of autonomic dysfunction remains prim ....Type 1 diabetes is a chronic autoimmune disease characterised by destruction of insulin producing cells in the pancreas. One of the most common and serious complications of type 1 diabetes is disruption of the autoimmune nervous system, and once symptoms appear the 5-year mortalityrate is approximately 50%. Symptoms of autonomic dysfunction can be extensive, and involve the stomach, intestine, bladder, heart and reproductive organs. Currently, the management of autonomic dysfunction remains primative due to our poor understanding of the mechanisms underlaying the disease. Recent work from our group has identified an excitatory autoantibody (an antibody against the self) to calcium channels in patients with type 1 diabetes. The anti-calcium channel autoantibody profoundly disrupts gut and bladder function by interfering with autonomic regulation of smooth muscle within these organs. The anti-calcium channel autoantibody is the first functional autoantibody to be detected in type 1 diabetes, and represents a conceptual advance in our understanding of immune mechanisms in this disease. Using animal models and a panel of novel, functional assays of colon, stomach and bladder we will investigate how the anti-calcium channel autoantibodies contribute to autonomic dysfunction in type 1 diabetes. Understanding the mechanisms by which this autoantibody effects autonomic regulation of organ function will enable the development of new therapeutic strategies for better management of patients.Read moreRead less
Chronic Gastrointestinal Symptoms And Diabetes Mellitus: Risk Factors And Mechanisms
Funder
National Health and Medical Research Council
Funding Amount
$271,527.00
Summary
Why many people with diabetes mellitus are afflicted by gastrointestinal (GI) symptoms remains uncertain. Irreversible damage to the nerves controlling the gut (autonomic neuropathy) is often considered to be important. An alternative cause of increased GI symptomatology in diabetics is poor glucose control. Some studies have shown that acute shifts in glucose levels induce changes in the gut relevant to the onset of GI symptoms. For example, high glucose levels acutely cause slower stomach empt ....Why many people with diabetes mellitus are afflicted by gastrointestinal (GI) symptoms remains uncertain. Irreversible damage to the nerves controlling the gut (autonomic neuropathy) is often considered to be important. An alternative cause of increased GI symptomatology in diabetics is poor glucose control. Some studies have shown that acute shifts in glucose levels induce changes in the gut relevant to the onset of GI symptoms. For example, high glucose levels acutely cause slower stomach emptying times, leading to feelings of fullness. Though the effects of chronic glucose levels are yet to be properly explored, population data show that poor control in the long-term is related to an increase in symptoms. The aim of this prospective study is to determine the roles played by both autonomic neuropathy and glucose control in the development of GI symptoms among diabetics. All past research has been cross-sectional, and so cannot tell us if one or both of these factors cause GI problems in diabetes. For example, it is possible that autonomic neuropathy causes an increase in GI symptoms such as nausea and fullness, which in turn induces poor glucose control though lack of appetite or inadequate stomach emptying. Upon study inclusion, all study participants will undergo a series of autonomic tests. At 3 month intervals for a period of 30 months, they will be asked to complete a 2-week diary card detailing their GI symptoms and glucose readings, and also supply blood and urine samples for analysis twice each year. Two years from the study outset, participants will again complete the autonomic test series. Psychiatric co-morbidity will be investigated using the Composite Diagnostic Interview (CIDI-Auto) at the autonomic testing time points. The study will be undertaken at the Gastroenterology Research Unit at Nepean Hospital, in collaboration with the Royal Adelaide Hospital, centres with proven track records in diabetes investigation.Read moreRead less
The Role Of Angiotensin Converting Enzyme 2 In Diabetic Complications
Funder
National Health and Medical Research Council
Funding Amount
$453,144.00
Summary
Most heart attacks and strokes arise from narrowing of the arteries. This process is regulated by a number of hormonal pathways. One of the most important is the renin angiotensin system. Our group has demonstrated important changes in this pathway which play a pivotal role in regulating the development of atherosclerosis and its response to treatment. It is predicted that these studies will provide critical information to develop innovative treatment strategies for cardiovascular disease.
A Computer Simulation Model For The Evaluation Of Interventions For The Management Of Type 2 Diabetes In Austral
Funder
National Health and Medical Research Council
Funding Amount
$334,505.00
Summary
Diabetes imposes a heavy personal, societal and financial burden in Australia and this is predicted to increase over time. It has been estimated that one million people in Australia have diabetes and the annual cost of diabetes care is in the order of 3 billion dollars. Many studies show that the current quality of diabetes care in Australia is sub-optimal and therefore decisions must be made about prioritizing the allocation of limited resources to correct these deficiencies. This project invol ....Diabetes imposes a heavy personal, societal and financial burden in Australia and this is predicted to increase over time. It has been estimated that one million people in Australia have diabetes and the annual cost of diabetes care is in the order of 3 billion dollars. Many studies show that the current quality of diabetes care in Australia is sub-optimal and therefore decisions must be made about prioritizing the allocation of limited resources to correct these deficiencies. This project involves building a computer simulation model to inform clinicians and assist policy makers in the efficient allocation of resources to improve the quality of diabetes care in Australia.Read moreRead less
Culturally Appropriate Diabetes Care In Mainstream General Practice For Urban Aboriginal And Torres Strait Islander People
Funder
National Health and Medical Research Council
Funding Amount
$381,291.00
Summary
Main study objectives are to determine the enablers and barriers for urban Indigenous people to access mainstream primary care services, in particular diabetes chronic care services. This knowledge of critical access and acceptability factors will guide the development of a culturally approirate diabetes care intervention for Indigenous patients. This adpated intervention, to be delivered in mainstream general practices, will be pilot-tested for cultural appropriateness in Indigenous patients.
Aldosterone Inhibition And Diabetic Retinopathy: Treatments And Mechanisms Of Action
Funder
National Health and Medical Research Council
Funding Amount
$511,294.00
Summary
The World Health Organization predicts that by 2030, more than 360 million people will have diabetes. Despite almost all patients developing retinopathy, current treatments do not prevent disease progression. One strategy being evaluated is blockade of a hormone called angiotensin II. We have new evidence that a related system called aldosterone exists in retina and contributes to damage. This project will determine if aldosterone blockade is a potential treatment for diabetic retinopathy.