Defining The Insulin-signalling Defect In Human Insulin Resistance And Type 2 Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$94,280.00
Summary
Problems with the way insulin removes glucose from the circulation contribute to developing type 2 diabetes. Despite research to date, controversy remains regarding the nature of known defects in insulin action and their relevance to humans. We plan to measure molecules involved in insulin action in muscle of people with insulin resistance, which is linked to diabetes. These studies will define new defects that cause insulin resistance and type 2 diabetes in humans.
Bone Fragility: The Neglected Role Of Cortical Porosity
Funder
National Health and Medical Research Council
Funding Amount
$620,381.00
Summary
Cortical (outer shell) or compact bone constitutes 80% of the skeleton. It is not solid as implied by its name but made of inter-connected canals resembling a network of roads. We recently discovered that most of the bone loss with age occurs from these canals, not from t rabecular bone as currently believed. This suggests to know why and how bone breaks requires the study of the morphology of these canals and how they change with age. This is what we propose to do. It has never been done.
MALE OSTEOPOROSIS: A POPULATION-BASED STUDY IN GEELONG
Funder
National Health and Medical Research Council
Funding Amount
$432,645.00
Summary
Osteoporosis is a term used to indicate that bones have become thin and fragile. During the ageing process bone fragility increases and fractures occur more easily and more often. Fractures may also occur during normal daily activities, with fractures of the spine, forearm and hip being common. However, many other sites may fracture. This is a serious problem because fractures cause pain, disability and, sometimes, death. Although previously overshadowed by its effect in women, osteoporosis is i ....Osteoporosis is a term used to indicate that bones have become thin and fragile. During the ageing process bone fragility increases and fractures occur more easily and more often. Fractures may also occur during normal daily activities, with fractures of the spine, forearm and hip being common. However, many other sites may fracture. This is a serious problem because fractures cause pain, disability and, sometimes, death. Although previously overshadowed by its effect in women, osteoporosis is increasingly being recognised in men. In Australia, 39% of all fractures occur in men and prognosis for fracture in men is worse than in women. A consequence of increasing male longevity is that osteoporosis will affect a growing number of Australian men. It is anticipated that between 1996 and 2051, the number of men with fracture will double, with a 4-fold increase in the number of male hip fractures. Unless the problem of osteoporosis in men is addressed and effective interventions are implemented, the substantial health burden imposed by age-related fractures will continue to escalate. In this case-control study of fracture risk in men, men with fractures (cases) will be identified prospectively for 3 years from radiological reports. Controls will be selected concurrently, at random from electoral rolls. Anticipated number of cases and controls are 800 and 1400, respectively. Cases and controls will be characterised for risk factors for fracture: bone density and bone geometry will be measured, serum samples collected, and diet, lifestyle and medical history documented by questionnaire. The advantage of this type of data is that information from patients with fracture will be used to tell us about the risk of fracture in healthy, unaffected men and about the characteristics of the Australian male population at risk for fracture. The information can be used in decision making for the individual and in policy making for the whole population.Read moreRead less
Dilinoleoyl Phosphatidic Acid As A Novel Mediator Of Insulin Resistance In Muscle
Funder
National Health and Medical Research Council
Funding Amount
$504,097.00
Summary
We have identified a novel fat molecule in muscle which may play an important role in causing insulin resistance during obesity, a major factor in the development of Type 2 diabetes. We will now examine whether depletion of this molecule, dilinoleoyl-phosphatidic acid, can improve insulin action in muscles and in obese mice, and investigate the mechanisms by which it may act. This work may indicate new strategies for the treatment of diabetes.
NR1F (ROR) Nuclear Hormone Receptors And Metabolism: Insights Into The Control Of Lipid Homeostasis.
Funder
National Health and Medical Research Council
Funding Amount
$581,892.00
Summary
ROR is a member of a gene family, that regulates reproduction, endocrine physiology, and metabolism, and are important in human health. ROR function remains illusive. However, it is expressed in liver, fat and muscle, tissues that (i) modulate blood lipids, insulin sensitivity and energy balance, and (ii) have an important role in diabetes and obesity. Understanding ROR function in metabolism provides the opportunity for the discovery of new pathways that ameliorate metabolic disease.
A Novel Mechanism For Manipulation Of Peripheral Glucose Utilization In Patients With Type 2 Diabetes Mellitus.
Funder
National Health and Medical Research Council
Funding Amount
$283,500.00
Summary
Significance: Over 600,000 Australians have type 2 diabetes (approximately half are undiagnosed) and it is estimated that this number will increase substantially to 10% of the adult population over the next 10 years. At the conclusion of this grant we expect to understand whether specific signalling molecules might plausibly represent the basis of a novel therapeutic approach to control blood glucose. If successful, this work could contribute to improved metabolic control and prevention of diabe ....Significance: Over 600,000 Australians have type 2 diabetes (approximately half are undiagnosed) and it is estimated that this number will increase substantially to 10% of the adult population over the next 10 years. At the conclusion of this grant we expect to understand whether specific signalling molecules might plausibly represent the basis of a novel therapeutic approach to control blood glucose. If successful, this work could contribute to improved metabolic control and prevention of diabetic complications through new blood glucose lowering agents. Hypotheses: Muscle is the major site of glucose disposal in the body and the two most relevant stimuli for glucose uptake into muscle are insulin and muscle contraction (exercise). The insulin pathway is impaired in patients with type 2 diabetes leading to high blood glucose and complications. Glucose uptake in response to exercise however appears to be normal in patients with type 2 diabetes. Indeed we have evidence to suggest that this pathway may compensate for impaired insulin action in type 2 diabetes. We hypothesise that molecules activated by contraction (exercise) may be useful as therapies to improve resting glucose control in type 2 diabetic patients. Aims: We plan a series of three studies to examine whether glucose uptake may be improved both acutely and chronically at rest by an agent implicated in exercise mediated glucose uptake.Read moreRead less
Molecular Regulation Of Metabolism And Body Composition By Ski Via Crosstalk With Nuclear Hormone Receptor Signalling.
Funder
National Health and Medical Research Council
Funding Amount
$558,441.00
Summary
Obesity is a common and burdensome health problem in the community which leads to diabetes and heart disease. A number of factors, including hormones play important roles in determing risk of obesity. This study proposes to investigate whether the Ski gene which is a regulatory factor for many hormones affects metabolism in transgenic mouse models of altered Ski function. The proposed studies may identify Ski as a target for therapy for obesity and improvement in sketal muscle metabolism.
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
Osteoporosis is a major health burden resulting from bone fractures in older men and women due to progressive loss of bone and weakening of the skeleton. Although there are currently therapies to reduce bone loss, no current treatment effectively reconstructs lost bone. In this project, which is designed to identify new genes that may in the future be targeted by drugs to reverse osteoporosis, we have identified specific sets of genes that appear to work together to increase bone formation. This ....Osteoporosis is a major health burden resulting from bone fractures in older men and women due to progressive loss of bone and weakening of the skeleton. Although there are currently therapies to reduce bone loss, no current treatment effectively reconstructs lost bone. In this project, which is designed to identify new genes that may in the future be targeted by drugs to reverse osteoporosis, we have identified specific sets of genes that appear to work together to increase bone formation. This proposal is aimed at characterising these genes and the ways in which they work to determine whether they may be good targets for new osteoporosis treatments. We will examine the patterns of these genes in bone. We will also use cell cultures in which bone forming cells develop and function, to determine when the genes are expressed and how they function. We will test the ability of the candidate genes to cause an increase in the amount of bone forming activity in these cell cultures. An increase in bone formation may be caused by an increase in the number bone-forming cells, an increase in the activity of the cells, a decrease in cell death, or a combination of these changes. Each possibility will be tested. This research is important because of the need for new osteoporosis therapies to repair weakened bones. The knowledge resulting from this proposal has the potential to provide an important contribution to skeletal health and thus aged health worldwide.Read moreRead less
Investigation Of COX-2 Regulation Of Bone Turnover And Mechanically Induced Bone Formation By Genetic Overexpression.
Funder
National Health and Medical Research Council
Funding Amount
$440,750.00
Summary
This project is important because it uses novel experimental models to advance our knowledge of prostaglandin biology in normal and pathological bone remodelling, and the response of the skeleton to increased physical activity. We expect that a genetic modification in mice to increase the normal production of key prostaglandin enzymes, cyclooxygenase-2 (COX-2), in bone cells will increase the number of cells that remove bone (osteoclasts), and increase bone loss and the rate of bone turnover whe ....This project is important because it uses novel experimental models to advance our knowledge of prostaglandin biology in normal and pathological bone remodelling, and the response of the skeleton to increased physical activity. We expect that a genetic modification in mice to increase the normal production of key prostaglandin enzymes, cyclooxygenase-2 (COX-2), in bone cells will increase the number of cells that remove bone (osteoclasts), and increase bone loss and the rate of bone turnover when compared to normal mice. We believe this will occur via the effect of prostaglandins on expression of genes that control osteoclast formation. This will be tested by examining the structure of the skeleton, and the expression of certain genes, in transgenic mice at different ages from 2-8 months. These effects may be exacerbated in conditions of increased bone turnover, such as postmenopausal bone loss. This will be tested by examining the bone structure and gene expression in adult mice following removal of their ovaries. Due to the role of COX-2 in adaptation of bone to mechanical loading, we also expect the load-bearing skeleton to be more sensitive to increased weight-bearing activity. We will investigate this hypothesis by applying mechanical loads to the tibiae of mice in a controlled manner and then analysing the bone structure. Knowledge of specific pathways by which bone formation can be stimulated is important for developing novel approaches to induction and augmentation of osteogenesis in skeletal diseases associated with ageing or disability, or for maintenance of new bone around implants. The discovery that COX-2 is a key enzyme in mechanotransduction and osteoclastogenesis in bone, and a pharmacological target for modulating inflammation, has considerable clinical significance. Exploiting this knowledge requires precise knowledge of the role of this enzyme in bone remodelling and adaptation and our experiments will contribute significantly to that knowledgeRead moreRead less