Central And Peripheral Actions Of Insulin For The Control Of Muscle Capillary Recruitment
Funder
National Health and Medical Research Council
Funding Amount
$433,973.00
Summary
Type 2 diabetes is on the increase world wide and reflects the ever-increasing incidence of obesity. Whereas the likely cause of type 2 diabetes includes low physical activity and high fat diet, the primary metabolic abnormality is likely to be muscle insulin resistance. The cause of this resistance is controversial, but may stem from microvascular dysfunction where muscle becomes poorly perfused and unresponsive to the action of insulin to recruit capillary flow. In this project we will further ....Type 2 diabetes is on the increase world wide and reflects the ever-increasing incidence of obesity. Whereas the likely cause of type 2 diabetes includes low physical activity and high fat diet, the primary metabolic abnormality is likely to be muscle insulin resistance. The cause of this resistance is controversial, but may stem from microvascular dysfunction where muscle becomes poorly perfused and unresponsive to the action of insulin to recruit capillary flow. In this project we will further extend our seminal discoveries that insulin mediates capillary recruitment under normal circumstances and that in various models of insulin resistance insulin's ability to increase the perfusion of muscle is markedly impaired. We will explore the hypothesis, that insulin controls microvascular perfusion of muscle by a central neural mechanism ending at terminal arterioles on the vasculature and endeavour to identify the details of this control. We will use in-house novel techniques for examining both the role of central control mechanisms involving the brain as well as peripheral mechanisms by local infusion of various agents likely to either enhance or block insulin's microvascular action. A positive outcome will enhance our understanding of insulin action and the insulin resistance that precedes type 2 diabetes. There is also the possible outcome that important clues will be obtained leading to new therapeutic agents that could be used to treat type 2 diabetes.Read moreRead less
The impact of female sex hormones on neurodevelopment. This project aims to characterise the contribution of sex hormones to the development of emotional brain circuits in female adolescents. Puberty is associated with profound changes in emotional behaviours in females, but we know little about the underlying brain mechanisms. In particular, research has neglected to consider the role of the sex hormones for which changes are a defining feature of female puberty (eg, oestradiol). This work will ....The impact of female sex hormones on neurodevelopment. This project aims to characterise the contribution of sex hormones to the development of emotional brain circuits in female adolescents. Puberty is associated with profound changes in emotional behaviours in females, but we know little about the underlying brain mechanisms. In particular, research has neglected to consider the role of the sex hormones for which changes are a defining feature of female puberty (eg, oestradiol). This work will be the first to comprehensively advance our understanding of the unique role of sex hormones in shaping the adolescent female brain. It will provide critical understanding of how individual differences in hormonal factors increase risk for emotional problems in females, and inform treatment strategies.Read moreRead less
The critical role of kisspeptin/neurokinin/dynorphin (KNDy) neurons in gonadotropin releasing hormone (GnRH) release. The brain controls fertility through the secretion of its primary stimulatory factor, gonadotropin releasing hormone (GnRH). Brain cells producing three key peptide hormones, kisspeptin, neurokin B and dynorphin (termed KNDy cells) are vital for the control of GnRH. This project will detail the role of KNDy cells in puberty and reproduction.
Does Loss Of Melanocortin Glucose Sensing Contribute To Obesity Induced Diabetes?
Funder
National Health and Medical Research Council
Funding Amount
$617,531.00
Summary
Diabetes is a failure to properly regulate blood glucose levels. Escalating rates of diabetes are a major health problem. Melanocortin neurons in the brain detect blood sugar levels and usually regulate glucose production and utilization, but in obese animals they do not. We have developed a possible therapeutic, which appears to reverse the glucose insensitivity, and rapidly reduces blood glucose in diabetic mice. This project will determine how melanocortins act to regulate glucose levels
Masterminding Reproduction: Kisspeptin and RFamide-Related Peptide. There are a number of concerning trends in reproductive health. Women are reporting difficulty conceiving and maintaining pregnancies; while sperm count and quality are declining in men. More concerning is the increase in reproductive cancers. Gonadotropin-releasing hormone (GnRH) antagonist and agonist have been used for decades to treat reproductive cancers (such as breast cancer and prostate cancer), infertility and precociou ....Masterminding Reproduction: Kisspeptin and RFamide-Related Peptide. There are a number of concerning trends in reproductive health. Women are reporting difficulty conceiving and maintaining pregnancies; while sperm count and quality are declining in men. More concerning is the increase in reproductive cancers. Gonadotropin-releasing hormone (GnRH) antagonist and agonist have been used for decades to treat reproductive cancers (such as breast cancer and prostate cancer), infertility and precocious puberty. Kisspeptin and RF-related peptide may offer more physiological alternatives to GnRH, without detrimental side effects. We will fully explore these two newly defined and major players in reproduction and provide a physiological framework for their progression to clinical use.Read moreRead less
Type 2 Diabetic Renal Complications And Microvascular Injury: Novel Predictors Of Onset And Progression, Mechanisms Of Association With Cardiovascular Disease And The Benefits Of Fenofibrate.
Funder
National Health and Medical Research Council
Funding Amount
$84,448.00
Summary
We will investigate the mechanisms of diabetic complications related to kidney and blood vessel disease, focusing on identifying people at greater risk and ways to improve or prevent these complications. In addition, we will look at how diabetic kidney disease affects non-kidney related problems like heart disease and examine the benefit of fenofibrate on both. This greater understanding will aid further drug development in kidney and cardiovascular diseases.
This study aims to identify naturally occurring genetic variations between men which modify the impact of testosterone, the major male hormone, on men's health and medical care. This study will examine new factors which determine how much any particular man may gain benefit from testosterone exposure such as in muscle and bone development as well as suffer detrimental effects on cardiovascular and prostate diseases. This may clarify some new aspects of how men's health is determined as well as d ....This study aims to identify naturally occurring genetic variations between men which modify the impact of testosterone, the major male hormone, on men's health and medical care. This study will examine new factors which determine how much any particular man may gain benefit from testosterone exposure such as in muscle and bone development as well as suffer detrimental effects on cardiovascular and prostate diseases. This may clarify some new aspects of how men's health is determined as well as developing new, customized medical treatments for men.Read moreRead less
Genomic And Non-genomic Actions Of Androgens In Regulation Of Fat Mass And Metabolism
Funder
National Health and Medical Research Council
Funding Amount
$395,421.00
Summary
Men have lower amounts of body fat than women, but are more likely to deposit fat around the stomach and abdominal region than women. This increased abdominal fat in men significantly increases the risk of developing type 2 diabetes and heart disease. The differences between men and women suggest that there is hormonal control of fat development; however, little is known regarding how male sex hormones, androgens, control these processes. We will investigate how androgens control fat formation, ....Men have lower amounts of body fat than women, but are more likely to deposit fat around the stomach and abdominal region than women. This increased abdominal fat in men significantly increases the risk of developing type 2 diabetes and heart disease. The differences between men and women suggest that there is hormonal control of fat development; however, little is known regarding how male sex hormones, androgens, control these processes. We will investigate how androgens control fat formation, and the response of fat and muscle tissue to glucose and insulin, using mutant mouse strains. These mouse strains have a mutation in the androgen receptor, a protein which acts as a key-lock mechanism to allow tissues to respond to androgens. This mutation stops the androgen receptor from functioning, so these mice can be used to determine the function of androgens acting through the androgen receptor. We will study three strains of mutant mice: (i) in which the androgen receptor is non-functional in all tissues of the body; (ii) in which the androgen receptor is non-functional only in fat tissue, but normal in all other tissues; and (iii) in which the androgen receptor is non-functional only in skeletal muscle, but is normal in all other tissues. The aim of our research is to determine the effect of the mutations in these three different mouse lines on paramateres including the amount of fat formed, the site of fat deposition, the levels of lipids and insulin in the blood and their response to glucose. The androgen receptor is a master switch that turns on or off other genes. Therefore, we also aim to identify which genes are controlled by the androgen receptor in fat and muscle. This research will identify how androgens control fat development and function, and will identify genes that mediate these actions in fat and muscle. This will provide potential molecules that could be used therapeutically to treat obesity and prevent type 2 diabetes and heart disease.Read moreRead less
Thalassaemia is the most common blood disorder worldwide. In severe cases, life-long blood transfusions are needed to survive but complications including iron overload and bone disease can occur. Deferasirox, a drug used to treat iron overload has been linked to kidney stones and bone loss in these patients through increased loss of calcium in the urine. The purpose of this study is to investigate whether bone loss can be reversed by using a diuretic or an alternative iron chelator.