The Role Of The Endothelium In Insulin's In Vivo Action Upon Skeletal Muscle Metabolism.
Funder
National Health and Medical Research Council
Funding Amount
$451,500.00
Summary
A number of studies using novel techniques developed in association with our USA collaborators, indicate that insulin has a major stimulatory effect on blood flow within muscle in both animals and humans to improve access for itself as well as nutrients such as glucose. As much as 50% of the glucose taken up by muscle in vivo during continual exposure to insulin may be attributed to this effect. Moreover, this haemodynamic effect of insulin in muscle is impaired in a number of animal models and ....A number of studies using novel techniques developed in association with our USA collaborators, indicate that insulin has a major stimulatory effect on blood flow within muscle in both animals and humans to improve access for itself as well as nutrients such as glucose. As much as 50% of the glucose taken up by muscle in vivo during continual exposure to insulin may be attributed to this effect. Moreover, this haemodynamic effect of insulin in muscle is impaired in a number of animal models and in obese humans when insulin mediated muscle glucose uptake is also impaired. What is not known is how insulin mediates this haemodynamic effect of recruiting capillary blood flow. Thus in the present study a number of aspects are to be explored, with particular focus on the cells that line the blood vessels and constitute the capillaries, the so called endothelium. First, we will explore the specific role of the endothelium in insulin's action by using the novel approach of attaching insulin to a large molecule that prevents it leaving the lumen of the blood vessel. This will mean that insulin will be confined to interacting only with insulin receptors on the muscle endothelium. Similarly, non activating anti insulin receptor antibody will be used in the presence of insulin to selectively prevent activation of the endothelial insulin receptors. In addition, we will investigate whether homocysteine, an amino acid found to impair endothelial dependent vasodilatation, impairs the haemodynamic effects of insulin. The impact that normal insulin release after a meal has upon the haemodynamic actions in muscle and the role this has in muscle glucose uptake will also be investigated by using the techniques developed in the first part of the project. Our over riding hypothesis is that the endothelium plays a key role in controlling insulin and possibly glucose access to muscle cells and thus a significant proportion of insulin mediated metabolic events in muscle.Read moreRead less
Anti-atherosclerotic Effects Of Angiotensin Fragments & Non-AT1 Receptors: Validation As Innovative Therapeutic Targets
Funder
National Health and Medical Research Council
Funding Amount
$512,065.00
Summary
In Australia the largest cause of death is coronary heart disease (CHD) leading to heart attacks or stroke and claiming a staggering 28,000 lives a year. Atherosclerosis is one of the leading causes of cardiovascular disease, with diseased vessels not able to fully dilate and the plaque that has built up inside these vessels impeding blood flow and possibly rupturing, resulting in heart attacks and stroke. One of the major players in the development and progression of atherosclerosis is the horm ....In Australia the largest cause of death is coronary heart disease (CHD) leading to heart attacks or stroke and claiming a staggering 28,000 lives a year. Atherosclerosis is one of the leading causes of cardiovascular disease, with diseased vessels not able to fully dilate and the plaque that has built up inside these vessels impeding blood flow and possibly rupturing, resulting in heart attacks and stroke. One of the major players in the development and progression of atherosclerosis is the hormone, angiotensin II. Angiotensin II has been found to trigger many factors that cause thickening of the vessel wall, inflammation and imbalances in vasodilator capacity (e.g. oxidative stress and endothelial dysfunction), all of which contribute to atherosclerosis. Clinical trials with drugs that inhibit the formation of angiotensin II (ACE inhibitors), or block the action of angiotensin II (angiotensin receptor antagonists), have demonstrated a significant decrease in mortality in patients with high risk for cardiovascular disease. However their mechanism(s) of action are not fully understood as the circulating levels of shorter fragments of angiotensin II (such as Ang IV and Ang (1-7)) are raised in the blood when these drugs are used and may contribute to the protective effects of these drugs. Importantly, we have found that both Ang IV and Ang (1-7) have protective effects in atherosclerotic blood vessels. Therefore, we hypothesise that fragments of angiotensin II (such as Ang IV and others) exert anti-atherogenic effects via distinct binding sites that oppose the effects caused by angiotensin II, and that these may be partly responsible for the cardio-protective effects of the ACE inhibitors and angiotensin receptor antagonists. Thus, information gained in our study will be useful in directing future prescription practices in clinical management of CHD and stroke, and for designing new therapeutic compounds for the management of atherosclerosis.Read moreRead less
Molecular Characterisation Of Adiponectin Receptors: Implications For Adiponectin Action And Resistance
Funder
National Health and Medical Research Council
Funding Amount
$95,137.00
Summary
Adiponectin is a hormone secreted by fat cells with anti-inflammatory, anti-atherogenic and insulin sensitising properties. Adiponectin levels and actions are compromised in obesity and type 2 diabetes. Adponectin mediates its effects via two receptors but the mechanisms are poorly understood. This proposal aims to define the underlying mechanisms with the ultimate goal of identifying novel therapeutic strategies to improve adiponectin's actions.
The Role Of Estrogen-receptor Alpha (ERa) In The Pathogenesis Of Diabetes And Cardiovascular Disease.
Funder
National Health and Medical Research Council
Funding Amount
$374,757.00
Summary
Cardiovascular disease (CVD), including heart attack and stroke, causes more deaths in Australia than any other disease. A major risk factor for CVD is diabetes, which affects more than 1 million Australians. Therefore, treating diabetes will reduce the number of people likely to die from CVD. This project aims to investigate a recently identified role for estrogen in the protection against diabetes. If successful, findings from this project may lead to new treatments against diabetes and CVD.
Muscarinic Receptor Signalling, Transglutaminase And Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$518,210.00
Summary
Diabetes is a major and increasing cuase of death and disability in our society. This studies aims to understand the cellular and molecular mechaisms controlling insulin secretion from the pancreas, since defects in this secretion are involved in causing diabetes. The proposed studies are of relevance to both juvenile and adult-onset diabetes, and may lead to new treatment modalities, as well as potentially being relevant to the use of pencreatic islet cell transplantation in the treatment of di ....Diabetes is a major and increasing cuase of death and disability in our society. This studies aims to understand the cellular and molecular mechaisms controlling insulin secretion from the pancreas, since defects in this secretion are involved in causing diabetes. The proposed studies are of relevance to both juvenile and adult-onset diabetes, and may lead to new treatment modalities, as well as potentially being relevant to the use of pencreatic islet cell transplantation in the treatment of diabetes.Read moreRead less
Insulin Resistance In Peripheral Artery Disease: Clinical Significance And Therapy
Funder
National Health and Medical Research Council
Funding Amount
$316,449.00
Summary
This project seeks to improve our understanding and treatment of peripheral artery disease – a condition caused by narrowing/blockages in arteries that supply the legs. Peripheral artery disease affects ~15% of adults >40 years and often causes severe, disabling leg pains during walking. Building on recent findings that peripheral artery disease shares some similar characteristics to type 2 diabetes (“insulin resistance”), a common anti-diabetes drug will be trialled as a potential new strate ....This project seeks to improve our understanding and treatment of peripheral artery disease – a condition caused by narrowing/blockages in arteries that supply the legs. Peripheral artery disease affects ~15% of adults >40 years and often causes severe, disabling leg pains during walking. Building on recent findings that peripheral artery disease shares some similar characteristics to type 2 diabetes (“insulin resistance”), a common anti-diabetes drug will be trialled as a potential new strategy to alleviate these leg pains.Read moreRead less
Understanding The Physiological Consequences Of Biased Signalling Mediated By The Glucagon-like Peptide-1 Receptor
Funder
National Health and Medical Research Council
Funding Amount
$636,508.00
Summary
The glucagon-like peptide 1 receptor is a major target for treatment of Type 2 diabetes and obesity. However, the development of drugs targeting this receptor is challenging as activation by different ligands can result in distinct signalling biases, a paradigm for which there is limited understanding of the physiological consequences. This project will address this critical knowledge gap and may allow for development of novel drugs with improved therapeutic outcomes.