Analysis Of The Role Of Vesicle Docking/Fusion Proteins In Trafficking Of The Glut4 Glucose Transporter In Adipocytes
Funder
National Health and Medical Research Council
Funding Amount
$212,036.00
Summary
The objective of these studies is to understand the molecular mechanisms that are involved in the control of blood glucose levels by the hormone insulin. Elevated blood glucose levels following a meal stimulate the pancreas to release insulin into the circulation. Insulin acts to reduce blood sugar levels by stimulating the uptake of glucose into fat and muscle and suppressing glucose production by the liver. Defects in insulin action in these tissues are the primary cause of Type II diabetes. T ....The objective of these studies is to understand the molecular mechanisms that are involved in the control of blood glucose levels by the hormone insulin. Elevated blood glucose levels following a meal stimulate the pancreas to release insulin into the circulation. Insulin acts to reduce blood sugar levels by stimulating the uptake of glucose into fat and muscle and suppressing glucose production by the liver. Defects in insulin action in these tissues are the primary cause of Type II diabetes. The debilitating effects of Type II diabetes, the dramatic increase its incidence, and the expense of treating the symptoms of diabetic complications have lead to the realization that the disease represents a major health problem requiring substantial research and development efforts. The project will focus on insulin regulation of glucose uptake in fat cells. Insulin promotes glucose uptake into fat by activating an intracellular signaling pathway that triggers the translocation of a unique glucose transporter protein (Glut4) from storage sites inside the cell to the cell surface. Glut4 translocation is mediated by small membrane vesicles that function to sequester the glucose transporter inside cells in the absence of insulin, and to shuttle Glut4 to the cell surface in response to the hormone. Despite the central importance of this event to the maintenance of normal blood glucose levels, it is poorly understood. The studies will be directed towards investigating the cellular machinery involved in the latter stages of insulin-stimulated glucose uptake- the vesicle-mediated delivery of Glut4 to the cell surface. The objective of these studies is to better understand the molecular basis for Glut4 translocation, and regulation by the insulin signaling cascade. Accomplishment of this goal may suggest potential drug intervention strategies aimed at enhancing insulin-stimulated Glut4 translocation and promoting improved control of blood glucose levels in Type II diabetes.Read moreRead less
Cellular And Molecular Mechanisms Of The Profibrogenic Effect Of Leptin In The Liver.
Funder
National Health and Medical Research Council
Funding Amount
$166,500.00
Summary
Cirrhosis of the liver in the 7th leading cause of death. Regardless of the underlying cause of liver injury (virus, alcohol, or in affluent countries non-alcoholic steatohepatitis -NASH), the liver repairs damage by forming scar tissue in a pocess similar to wound healing. All chronic liver diseases are associated with repeated rounds of wound-healing leading inevitably to progressive fibrosis and cirrhosis of the liver. Obesity, in addition to being linked to type II diabetes and cardiovascula ....Cirrhosis of the liver in the 7th leading cause of death. Regardless of the underlying cause of liver injury (virus, alcohol, or in affluent countries non-alcoholic steatohepatitis -NASH), the liver repairs damage by forming scar tissue in a pocess similar to wound healing. All chronic liver diseases are associated with repeated rounds of wound-healing leading inevitably to progressive fibrosis and cirrhosis of the liver. Obesity, in addition to being linked to type II diabetes and cardiovascular diseases, is an independent risk factor for liver injury. It is the clinical setting for NASH, the most common liver disorder in western countries. Also the severity of hepatic fibrosis and the risk of progression to fibrosis in most forms of liver diseases (regardless of their cause) are dramatically increased in overweight (>60%) and obese (20% of adult Australian) patients. Leptin is an hormone that primarily controls food intake and energy balance in the body. In addition, leptin has many other functions. It is a modulator of the immune and inflammatory system, it is involved in skin wound healing and increases sclerosis in the kidney. We recently showed that leptin is necessary for fibrosis to develop in the liver and that increased levels of leptin increases the severity of liver fibrosis. It appears that leptin is a fundamental player in the biological processes of hepatic fibrosis. As increased serum levels of leptin is a feature of obesity, leptin is likely to be the missing link between obesity and increased hepatic fibrosis. By understanding the mechanisms by which leptin acts on liver cells to increase fibrosis, this work will lead to new strategies to prevent fibrosis in obese patients and to reverse scarring in the liver. With the endemic obesification in developed countries, prevention and treatment of obesity-associated liver disease will be the main challenge for the hepatologist in the next decades.Read moreRead less
Understanding The Cause And Consequence Of Impaired Insulin Secretion In The NZO Mouse A Model Of Diabetes.
Funder
National Health and Medical Research Council
Funding Amount
$711,224.00
Summary
Type 2 diabetes is a major health problem affeting over 1 million Australians. A key feature of this disease is reduced secretion of the pancreratic hormone insulin which results in high blood sugar levels. We are using a naturally occurring animal model of diates called the NZO mouse to understand why the pancreas secretes less insulin and the consequences of this defect. This project has the potential of providing better therapeutic strategies for patients with Type 2 diabetes.
Mechanisms Of Insulin Resistance And Diabetes Susceptibility
Funder
National Health and Medical Research Council
Funding Amount
$633,783.00
Summary
The two main forms of diabetes - types 1 (T1D) and 2 (T2D) - pose a major problem. It is difficult to identify what causes diabetes. Recently, people at risk of T1D were found to have insulin resistance, a condition thought typical only of T2D. Excitingly, we discovered that the best T1D animal model also shows insulin resistance, and we used it to map important genes. We will now identify these genes. This will help us understand the disease process and to develop better treatments for it.
Mitochondrial Energy Metabolism And Insulin Action
Funder
National Health and Medical Research Council
Funding Amount
$380,558.00
Summary
Obesity and type 2 diabetes are two major health conditions associated with abnormal energy metabolism. In this proposal I will investigate the role of important metabolic proteins in regulating energy expenditure and insulin action in skeletal muscle and adipose tissue, two crucial tissues for whole-body energy metabolism. These studies will provide critical insight into the factors leading to obesity and type 2 diabetes and will assist in identifying possible therapeutic targets.
Ciliary Neurotrophic Factor: A Novel Theraputic Agent For The Prevention Of Muscle Insulin Resistance
Funder
National Health and Medical Research Council
Funding Amount
$602,673.00
Summary
In 1995 leptin was discovered and scientists world-wide hoped that this was the great panacea in the treatment of obesity related disorders. Alas, from 1995-1997 the identification of a novel cytokine inducible compound termed suppressor of cytokine signaling (SOCS) that negatively regulated leptin signalling and lead to leptin resistance, quashing hopes for a viable anti-obesogenic drug. Recently, however, work from our group has demonstrated that the neuropoietic cytokine, ciliary neurotrophic ....In 1995 leptin was discovered and scientists world-wide hoped that this was the great panacea in the treatment of obesity related disorders. Alas, from 1995-1997 the identification of a novel cytokine inducible compound termed suppressor of cytokine signaling (SOCS) that negatively regulated leptin signalling and lead to leptin resistance, quashing hopes for a viable anti-obesogenic drug. Recently, however, work from our group has demonstrated that the neuropoietic cytokine, ciliary neurotrophic factor (CNTF), can act in an anti-obesogenic fashion in a manner similar to leptin. However, unlike leptin, when we place rodents on a high fat diet, the effects of CNTF persist and override induction SOCS proteins. This project will examine the biochemical pathways that allow the actions of CNTF to persist in the presence of diet-induced obesity. This is of major significance because in completing this work, the potential for the development of peripheral tissue drug targets for the treatment of obesity related diseases are both tangible and realistic.Read moreRead less
Regulation Of Pancreatic Beta-cell Number And Function By Adipocyte-released Hormones, Free Fatty Acids And Ghrelin.
Funder
National Health and Medical Research Council
Funding Amount
$256,500.00
Summary
The disease diabetes mellitus comprises a heterogeneous group of disorders all characterised by high blood glucose levels. Beta-cells in the pancreas, which secrete insulin, are central to the pathophysiology of the disease. Type 1 or insulin-dependent diabetes mellitus results from an absolute deficiency of insulin due to auto immunological destruction of the pancreatic beta cell, and accounts for 5-10% of total diabetes mellitus. In the more common type 2 or non-insulin-dependent diabetes mell ....The disease diabetes mellitus comprises a heterogeneous group of disorders all characterised by high blood glucose levels. Beta-cells in the pancreas, which secrete insulin, are central to the pathophysiology of the disease. Type 1 or insulin-dependent diabetes mellitus results from an absolute deficiency of insulin due to auto immunological destruction of the pancreatic beta cell, and accounts for 5-10% of total diabetes mellitus. In the more common type 2 or non-insulin-dependent diabetes mellitus, liver, muscle and fat cells are resistant to the action of insulin and compensatory mechanisms that are activated in the beta-cell to increase insulin secretion are not sufficient to maintain normal blood glucose levels. In Western countries including Australia, type 2 diabetes currently affects around 2% of the whole population and about 6% of adults (10% of over 60-y) and continues to grow at around 6% per annum. Type 2 diabetes often occurs in obese patients and a direct link between obesity and type 2 diabetes has been strongly suggested by research to date. It has also been found that a progressive loss of beta-cell function throughout the course of the disease results in the reduction of insulin secretion. The contribution of excessive fat tissue in obese patients to the progress of type 2 diabetes is not clear. Certain hormones from fat cells, metabolic regulatory hormone, and fatty acids have been demonstrated to influence the function of beta-cells in previous studies, including our own. We now aim to investigate in detail the effect of these on cultured beta-cells with molecular and cell biology techniques. We expect to identify a factor or factors which stimulate or inhibit the progress of beta-cell dysfunction, with the potential to identify therapeutic targets in the treatment of type 2 diabetes.Read moreRead less