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Regulation And Effect Of The Growth Hormone, IGF-I, And IGF-Binding Protein Response To Acute Exercise
Funder
National Health and Medical Research Council
Funding Amount
$367,197.00
Summary
The body's ability to respond to physiological stress is vital to survival. This series of studies aims to examine the hormonal responses to physical exercise. In studies recently completed to determine how to detect Growth Hormone (GH) abuse in the Olympics, we have discovered a new system of hormones that respond to exercise. These Insulin-like Growth Factors (IGF) and their IGF-Binding Proteins (IGF-BP) are normally controlled by GH. The IGF-IGF-BP system normally acts to control of many cell ....The body's ability to respond to physiological stress is vital to survival. This series of studies aims to examine the hormonal responses to physical exercise. In studies recently completed to determine how to detect Growth Hormone (GH) abuse in the Olympics, we have discovered a new system of hormones that respond to exercise. These Insulin-like Growth Factors (IGF) and their IGF-Binding Proteins (IGF-BP) are normally controlled by GH. The IGF-IGF-BP system normally acts to control of many cellular and organ functions in many different tissues of the body. For example they stimulate protein accumulation and muscle growth, and have actions to control blood glucose in conditions like diabetes. Little is known about what regulates the production of the IGF and IGF-BPs in response to physical exercise. We aim to examine whether GH, either as an acute pulse as occurs naturally, or a direct effect of exercise that is not GH-mediated, is responsible for the increase in IGF and IGFBPs. This may uncover a new means of controlling this powerful hormonal system. In addition, we will examine whether GH or IGF-I, alone and together, influence the body's ability to respond to the stress of exercise (e.g., controlling fuel use, cardiovascular and kidney responses). Such information will allow greater understanding of this important hormonal system, so that in novel therapies may be developed for conditions such as normal ageing, the wasting states that accompany severe surgical or infectious stress, or conditions with abnormal blood glucose regulation such as diabetes. In addition, this information will permit greater sophistication in the detection of GH and related compounds in elite athletes. Unfortunately, GH is also being abused by non-elite athletes and high-school children. We believe our efforts will asist in the detection and prevention of these more general societal health issues.Read moreRead less
Investigation Of Transgenic Mouse Models Of Type 2 Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$412,200.00
Summary
Type 2 diabetes is a common condition characterised by high blood glucose, that afflicts 700,000 Australians. It causes blindness, kidney failure and an increased risk of heart attack and stroke. despite intensive study over many years, the reasons for the elevated blood glucose in this condition are not fully understood. Several abnormalities can contribute to the high glucose and different researchers have proposed different defects as the initial cause. It has proven difficult to unravel the ....Type 2 diabetes is a common condition characterised by high blood glucose, that afflicts 700,000 Australians. It causes blindness, kidney failure and an increased risk of heart attack and stroke. despite intensive study over many years, the reasons for the elevated blood glucose in this condition are not fully understood. Several abnormalities can contribute to the high glucose and different researchers have proposed different defects as the initial cause. It has proven difficult to unravel the sequence of events in the evolution of the syndrome because high glucose can cause insulin resistance and a defect in insulin secretion, both of which can lead to high blood glucose. One approach to study the consequences of specific defects is to genetically engineer them. The aims of this project are to: 1. make a mouse with reduced ability to store glucose in muscle. 2. test the metabolic consequences of a defect in the manufacture of glycogen (starch) in muscle. 3. study the effects of combining a defect in glucose storage with one that results in an oversupply of glucose. 4. study the effects on a mouse with a genetic predisposition for failure of beta cells (insulin making cells) of a defect in muscle glucose storage and over production of glucose. A successful completion of this grant will greatly enhance our understanding of how blood glucose is increased in Type 2 diabetes.Read moreRead less
Gestational Diabetes: Treatment With Metformin Compared To Insulin
Funder
National Health and Medical Research Council
Funding Amount
$257,400.00
Summary
Gestational diabetes (GDM) is diagnosed when women have elevated blood sugar levels detected in pregnancy. Treatment aims to keep the mother's blood sugar normal and to prevent extra sugar transferring to the baby, as this can lead to elevated insulin levels, and subsequent complications, in the baby. Initial treatment is by diet, but more than 30% of women need further treatment with insulin injections. Metformin, which can be taken by as a tablet, is an alternative to insulin that is used wide ....Gestational diabetes (GDM) is diagnosed when women have elevated blood sugar levels detected in pregnancy. Treatment aims to keep the mother's blood sugar normal and to prevent extra sugar transferring to the baby, as this can lead to elevated insulin levels, and subsequent complications, in the baby. Initial treatment is by diet, but more than 30% of women need further treatment with insulin injections. Metformin, which can be taken by as a tablet, is an alternative to insulin that is used widely outside pregnancy for people with diabetes. There are good data to support the safety of metformin in pregnancy. We plan to test that metformin is not only safe but also an effective alternative to insulin for women with GDM. Metformin works by reducing resistance to insulin, which is a key factor for the development of GDM and also for high blood pressure complications. We hope to demonstrate a reduction in these complications with metformin treatment. Metformin is associated with less weight gain than insulin and we hope to demonstrate an associated reduction in the risk of diabetes following pregnancy in women with GDM treated with metformin. It is likely that metformin crosses the placenta, and if so, it may reduce elevated insulin levels in the baby. The study will measure insulin levels in the cord blood, hoping to demonstrate that more babies have normal insulin levels in pregnancies treated with metformin.Read moreRead less
Structure And Function Of The AMPK Glycogen-binding Domain
Funder
National Health and Medical Research Council
Funding Amount
$538,764.00
Summary
The AMP-activated protein kinase (AMPK) is an enzyme responsible for coordinating metabolism in response to energy supply (diet) and energy demand (exercise). Research into this kinase can increase our understanding of how diet and exercise are so important for maintaining health. The kinase acts either by sensing when cellular energy levels become too low for normal functioning or when the body tells it by sending a chemical messenger (hormone) that overall energy levels are low. This results i ....The AMP-activated protein kinase (AMPK) is an enzyme responsible for coordinating metabolism in response to energy supply (diet) and energy demand (exercise). Research into this kinase can increase our understanding of how diet and exercise are so important for maintaining health. The kinase acts either by sensing when cellular energy levels become too low for normal functioning or when the body tells it by sending a chemical messenger (hormone) that overall energy levels are low. This results in activation of energy-producing pathways and inhibition of energy-consuming pathways, allowing cells to match supply with demand to ensure their survival. The AMPK comprises of three proteins that together form a functional enzyme. I have previously found that AMPK localizes to a source of cellular energy called glycogen (sugar stores) via one part that I have called the glycogen-binding domain. In this application I aim to obtain a thorough understanding of the molecular basis of how the glycogen-binding domain affects AMPK function in muscle and heart following exercise. In addition this research may lead to the identification of new molecules, similar to glycogen, that are important for AMPK regulation and may lead to the development of a new class of drugs for Type 2 Diabetes. Research into AMPK promises to dramatically increase our knowledge of how to reduce the risk of cardiovascular and neurodegenerative diseases, diabetes and obesity and provide an understanding of the reasons these diseases develop.Read moreRead less
Metformin In Gestational Diabetes: Follow-up Of Mothers And Offspring: Body Composition, Insulin Resistance, Development
Funder
National Health and Medical Research Council
Funding Amount
$630,142.00
Summary
Children born to women with gestational diabetes are at increased risk of later obesity and diabetes. This study will help to assess if giving such women during their pregnancy the cheap oral diabetes drug metformin rather than insulin injections can safely reduce this risk, measuring growth, fatness and blood glucose-insulin in the children at 2 and 5 years of age, as well as assessing the mothers. If so, such treatment might help to reduce the worldwide burden of disease related to obesity.
Evolution And Targeting Of Polysaccharide Biosynthesis In Leishmania Parasites
Funder
National Health and Medical Research Council
Funding Amount
$449,484.00
Summary
Leishmania are parasitic protozoa that cause devastating diseases in humans. This proposal will identify the enzymes involved in the biosynthesis of an unusual carbohydrate reserve material that accumulates in pathogenic stages of these parasites. Information on the structure and mode of action of these enzymes will be used to develop novel drugs that will be tested for anti-parasite activity.
Regulation Of Protein Kinases And Their Substrates
Funder
National Health and Medical Research Council
Funding Amount
$582,000.00
Summary
Western communities are experiencing an obesity epidemic with up to half the population being overweight. Sedentary life styles and high caloric intake are the cause and will contribute to the development of age onset diseases including obesity, diabetes, cardiovascular disease, stroke and neurodegeneration. This project is investigating an enzyme that plays a pivotal role in controlling the body s response to exercise and diet. The key enzyme involved in this process is called the AMP-activated ....Western communities are experiencing an obesity epidemic with up to half the population being overweight. Sedentary life styles and high caloric intake are the cause and will contribute to the development of age onset diseases including obesity, diabetes, cardiovascular disease, stroke and neurodegeneration. This project is investigating an enzyme that plays a pivotal role in controlling the body s response to exercise and diet. The key enzyme involved in this process is called the AMP-activated protein kinase. This work will increase our understanding of the health benefits of diet and exercise. This new knowledge will play a vital role in developing new therapies for promoting exercise and mitigating the effects of diet that will improve health during the ageing process.Read moreRead less
Nuclear Receptor 4A3 Signalling In Skeletal Muscle
Funder
National Health and Medical Research Council
Funding Amount
$475,745.00
Summary
Nuclear receptors regulate hormonal control of reproduction, endocrine physiology, and metabolism, and are very important in human health. NR4A3 function in peripheral tissues remains illusive. However, it is expressed in skeletal muscle, a tissue that (i) modulates blood lipids, insulin sensitivity and energy balance, and (ii) has an imortant role in diabetes and obesity. Understanding NR4A3 function in metabolism provides a potential platform for therapeutic intervention.
The Role Of Circadian Rhythm Genes In The Regulation Of Energy Balance And Substrate Metabolism In Muscle And Liver
Funder
National Health and Medical Research Council
Funding Amount
$349,263.00
Summary
Obesity is increasing at an alarming rate worldwide and as the standard of living increases in developing countries such as India and China, the incidence of obesity and its related diseases of diabetes, cardiovascular disease and cancer will become the major health problem of the 21st century. The epidemic of obesity appears to be due to a complex interaction between genetic background and changes in the environment such as reduced physical activity and increased availability and consumption of ....Obesity is increasing at an alarming rate worldwide and as the standard of living increases in developing countries such as India and China, the incidence of obesity and its related diseases of diabetes, cardiovascular disease and cancer will become the major health problem of the 21st century. The epidemic of obesity appears to be due to a complex interaction between genetic background and changes in the environment such as reduced physical activity and increased availability and consumption of high energy food. The accumulation of excess body fat in most individuals is not a precipitous event that occurs over a few days or weeks. Obesity actually occurs insidiously over a period years and is essentially the cumulative result of small differences in daily energy balance. In humans and animals energy balance is subject to diurnal or day-night variations in body temperature, feeding behaviour and physical activity (sleep-wake cycles). Recent research has determined that all tissues in the body have the same genes that regulate circadian (daily) rhythms in the brain. It has also become clear that the expression of these gene cycles over 24 hours in muscle liver and fat tissue the same way that they do in the brain. What is not understood is the extent to which these circadian genes control energy metabolism pathways such as glucose and fat utilisation and storage in liver and muscle. The aim of this grant is to test the effects of changing diet, feeding times and circulating hormones on metabolism and gene expression in muscle and liver to determine the extent to which circadian rhythm genes regulate the normal diurnal metabolism of glucose and fat and whether dysregulation of these systems contributes to metabolic disease.Read moreRead less
Mechanistic Studies Of C-Cbl - A Modulator Of Energy Homeostasis.
Funder
National Health and Medical Research Council
Funding Amount
$454,500.00
Summary
Obesity has become one of the most serious health care problems in the world. It is a problem not just because more people are getting fatter. It is a problem because obesity is a major risk factor for many other diseases including Type 2 diabetes and heart disease. While many consider the solution to be straight forward, ie eat less, this is obviously not an effective solution because the problem is accelerating at lightning speed around the world. At the Garvan Institute we have recently ident ....Obesity has become one of the most serious health care problems in the world. It is a problem not just because more people are getting fatter. It is a problem because obesity is a major risk factor for many other diseases including Type 2 diabetes and heart disease. While many consider the solution to be straight forward, ie eat less, this is obviously not an effective solution because the problem is accelerating at lightning speed around the world. At the Garvan Institute we have recently identified a new mouse model bearing a disruption in one single gene. This mouse eats 30% more food than its siblings but has half the body fat. This exciting discovery constitutes the foundation for the present proposal.Read moreRead less