Cellular Mechanisms And Physiological Roles Of GLUT12 Mediated Glucose Transport In Glucose Homeostasis
Funder
National Health and Medical Research Council
Funding Amount
$499,000.00
Summary
Diabetes affects almost one million Australians, although only 50% are aware they have the disease. Type 2 diabetes accounts for about 90% of diabetes and usually occurs after the age of 40. As a leading cause of death, adult blindness, lower limb amputation, kidney failure, stroke and heart attack, diabetes has huge economic and social consequences and has been designated an Australian National Health priority. A clinical feature of Type 2 diabetes is high blood glucose levels. This occurs beca ....Diabetes affects almost one million Australians, although only 50% are aware they have the disease. Type 2 diabetes accounts for about 90% of diabetes and usually occurs after the age of 40. As a leading cause of death, adult blindness, lower limb amputation, kidney failure, stroke and heart attack, diabetes has huge economic and social consequences and has been designated an Australian National Health priority. A clinical feature of Type 2 diabetes is high blood glucose levels. This occurs because insulin does not effectively stimulate the transfer of glucose from the blood into muscle and fat. The reasons for this are not fully understood. Insulin normally works to move glucose transporter (GLUT) proteins to the surface of muscle and fat cells. One GLUT that has been studied extensively in muscle and fat is GLUT4. GLUT4 moves to the cell surface in response to insulin and this response is one of the defects that is known to occur in Type 2 diabetes. Glucose then accumulates in the blood, leading to many of the complications of diabetes. We have discovered a novel glucose transporter, GLUT12, that is also present in muscle and fat. We have shown that GLUT12, like GLUT4, responds to insulin. GLUT12 could therefore be a critical backup for GLUT4. We have also found that GLUT12 responds to glucose itself, suggesting a unique role in controlling blood glucose levels. We will explore how GLUT12 acts in muscle and fat cells to find whether GLUT12 can act as a backup for GLUT4. We will also study GLUT12 in tissue from normal animals and in animals with features of Type 2 diabetes. To determine the role of GLUT12 in maintaining normal blood glucose levels, we will produce mice with an inactive GLUT12 gene. Our research could identify novel ways of increasing GLUT12 activity. The eventual goal will be to find a pharmaceutical compound that can improve glucose transport into muscle, reduce high blood glucose levels and thus the complications of Type 2 diabetes.Read moreRead less
Obesity and diabetes are increasing in our community at an alarming rate. When one considers that Diabetes is a major cause of heart disease, stroke and kidney disease these diseases represent one of the most threatening for the future health of our nation. At the heart of these diseases is a disorder known as insulin resistance, or the inability of insulin to function correctly. The explosion in biological outcomes over the past decade has brought us closer than ever before to solving some of t ....Obesity and diabetes are increasing in our community at an alarming rate. When one considers that Diabetes is a major cause of heart disease, stroke and kidney disease these diseases represent one of the most threatening for the future health of our nation. At the heart of these diseases is a disorder known as insulin resistance, or the inability of insulin to function correctly. The explosion in biological outcomes over the past decade has brought us closer than ever before to solving some of the key questions associated with this problem. This proposal represents an exciting step forward in this area because our recent research combined with information from our international colleagues have led us to propose a new concept concerning the mechanism of insulin action. In this proposal we have formulated a series of molecular experiments to test this hypothesis which if correct will both change the way we think about this problem and provide new prospects for therapeutic design.Read moreRead less
Insulin resistance (the inability of ordinarily insulin-sensitive tissues such as muscle and adipose tisse to respond to insulin) contributes to a number of diseases including diabetes and obesity. A key metabolic step in these tissues is the uptake of glucose from the blood stream. This step is accelerated by insulin thus allowing efficient clearance of glucose from the bloodstream after a meal. Our laboratory has played a major role in showing that insulin regulates glucose uptake into muscle ....Insulin resistance (the inability of ordinarily insulin-sensitive tissues such as muscle and adipose tisse to respond to insulin) contributes to a number of diseases including diabetes and obesity. A key metabolic step in these tissues is the uptake of glucose from the blood stream. This step is accelerated by insulin thus allowing efficient clearance of glucose from the bloodstream after a meal. Our laboratory has played a major role in showing that insulin regulates glucose uptake into muscle and adipose tissue by stimulating the movement of a glucose transport protein from inside the cell to the cell surface. The purpose of this proposal is to dissect the molecular mechanisms by which this glucose transporter can be held inside the cell in the absence of insulin and then allowed to be released from this site moving to the surface in the presence of insulin. Our studies over the past 5 years have brought us much closer to understanding this process in detail. The identification of the molecules responsible for this regulatory step will not only aid our understanding of this process but it will also provide a valuable target for development of therapeutic agents that can be used to combat insulin resistance.Read moreRead less
Dissection Of Insulin Regulated Phosphorylation In The Adipocyte
Funder
National Health and Medical Research Council
Funding Amount
$303,510.00
Summary
Obesity and diabetes are increasing at an alarming rate throughout the world. These diseases are part of a constellation of disorders that includes cardiovascular disease and kidney disease, which are collectively referred to as the metabolic syndrome. A disorder referred to as insulin resistance is at the heart of the metabolic syndrome. This represents the inability of insulin to function correctly in target cells like muscle and fat. In this project we are attempting to undertake a large scal ....Obesity and diabetes are increasing at an alarming rate throughout the world. These diseases are part of a constellation of disorders that includes cardiovascular disease and kidney disease, which are collectively referred to as the metabolic syndrome. A disorder referred to as insulin resistance is at the heart of the metabolic syndrome. This represents the inability of insulin to function correctly in target cells like muscle and fat. In this project we are attempting to undertake a large scale effort to understand the complex circuitry that gets turned on within cells when they become exposed to insulin. This project involves a collaboration between the Garvan Institute and the University of New South Wales Mass Spectrometry Facility allowing us to bring a combination of very sophisticated technologies to bear on this very significant health care problem. This project will provide major new insights into our understanding of insulin action yielding new possibilities for therapeutic development.Read moreRead less