The Role Fructose-1,6-bisphosphatase On The Regulation Of Hepatic Gluconeogenesis
Funder
National Health and Medical Research Council
Funding Amount
$212,485.00
Summary
Type 2 or adult onset diabetes is a disease characterised by high blood sugar that causes damage to the kidneys, eyes and to the circulation and many patients die from heart attack or stroke. There is an increase in the prevalence of diabetes in Australia and a substantial portion of the health budget is utilised by caring for people with diabetes. Determining what exactly causes the increase in blood sugar levels is critical in the treatment of the disease. It is known that the sugar produced a ....Type 2 or adult onset diabetes is a disease characterised by high blood sugar that causes damage to the kidneys, eyes and to the circulation and many patients die from heart attack or stroke. There is an increase in the prevalence of diabetes in Australia and a substantial portion of the health budget is utilised by caring for people with diabetes. Determining what exactly causes the increase in blood sugar levels is critical in the treatment of the disease. It is known that the sugar produced and released by the liver is an important contributor to the high blood sugar levels found in patients with diabetes. The main biochemical pathway responsible for this is called gluconeogenesis, a complex arrangement of enzymes, which convert amino acids and fat into sugar. Although it is known that this pathway is overactive in patients with diabetes, the exact reason for this is not clearly understood. The aim of this proposal is to produce a transgenic mouse that has an increase in liver sugar production as a result of an increase in gluconeogenesis, and to study its effects on blood sugar levels. Furthermore, studies will be performed to understand the regulation of this pathway by infusing the transgenic mice with insulin, the hormone that inhibits gluconeogenesis. The mechanism of action of insulin will be determined by the measurement of key enzymes that regulate gluconeogenesis. The significance of this grant is to identify possible sites for the development of new drugs or gene therapy that will lead to a decrease in the production of sugar by the liver. This will lead to better control of blood sugar levels and slow down or even prevent the onset of diabetes complications.Read moreRead less
Obesity is an important cause of disease, including liver disease. Obesity-associated liver disease occurs when the liver becoming resistance to the effects of insulin, the hormone that controls blood sugar (glucose). In muscle and fat, insulin causes glucose to be taken into the tissues and stored. Glucose is made in the liver and the actions of insulin here are to turn off the release of glucose into the circulation and increase uptake and storage of glucose. Insulin resistance occurs in a num ....Obesity is an important cause of disease, including liver disease. Obesity-associated liver disease occurs when the liver becoming resistance to the effects of insulin, the hormone that controls blood sugar (glucose). In muscle and fat, insulin causes glucose to be taken into the tissues and stored. Glucose is made in the liver and the actions of insulin here are to turn off the release of glucose into the circulation and increase uptake and storage of glucose. Insulin resistance occurs in a number of situations but the most important of these is obesity, particularly when there is accumulation of fat inside the abdominal cavity. Although the liver has a central role in co-ordinating the bodies response to insulin, the mechanisms of insulin resistance in human liver are unknown. One prominent hypothesis is that fat molecules released by intra-abdominal fat deposits are responsible. Intra-abdominal fat stores are important because fatty acids from these deposits can travel directly to the liver with the blood supply from the gut. However the precise effects of these on insulin action in the liver are unknown. Fat tissue is actively involved in the regulation of metabolism and releases a number of regulatory proteins. One of these, adiponectin, appears to have an important role in improving insulin sensitivity in the liver. The production of adiponectin decreases as obesity increases, providing another link between obesity and insulin resistance in the liver. This project will examine insulin action and the signalling molecules responsible for this in human liver tissue. The project aims to determine the effect of obesity, particularly intra-abdominal fat deposits, on insulin responses in liver tissue. The studies also aim to confirm (or otherwise) the role of free fatty acids and adiponectin on insulin action in human liver. The data from these studies will contribute to our understanding of insulin resistance and obesity-related liver disease.Read moreRead less
Monocytes/macrophages In Chronic Liver Diseases: Cross-talk With Hepatocytes And Nonparenchymal Cells And Role In Progressive Liver Injury
Funder
National Health and Medical Research Council
Funding Amount
$598,645.00
Summary
More than 170 million people world-wide are chronically infected with the hepatitis C virus. Approximately 10-15% of chronically infected subjects develop cirrhosis with its attendant risks of liver failure and hepatocellular carcinoma. The objective of this important project is to examine the mechanisms by which monocytes and macrophages (cells of the immune system) enhance or impair the progression of liver disease and response to antiviral treatment in patients with chronic hepatitis C.
Hepatocyte Replicative Arrest, Hepatic Progenitor Cells And The Ductular Reaction In Hepatic Fibrogenesis
Funder
National Health and Medical Research Council
Funding Amount
$527,683.00
Summary
Chronic liver diseases such as hepatitis C and obesity-related fatty liver can be associated with scarring that eventually results in cirrhosis and liver failure. We are unsure why this scarring occurs, but as hepatitis and fatty liver are becoming more common it is necessary to understand this process so that effective therapies can be developed. This study looks at one possible mechanism to explain the development of liver scarring. We believe that the normal repair mechanisms of the liver lea ....Chronic liver diseases such as hepatitis C and obesity-related fatty liver can be associated with scarring that eventually results in cirrhosis and liver failure. We are unsure why this scarring occurs, but as hepatitis and fatty liver are becoming more common it is necessary to understand this process so that effective therapies can be developed. This study looks at one possible mechanism to explain the development of liver scarring. We believe that the normal repair mechanisms of the liver lead to the production of liver cells to replace those that have died, but in some circumstances also produce small bile ducts that drain bile from the hepatocytes. These small bile ducts may have a previously unsuspected role in stimulating the scar formation. The study will see if the small bile ducts are produced in a range of liver diseases in humans, and will use rodent models to find the factors responsible for stimulating the scarring. When the process is understood more clearly, it could lead to the development of new or more effective therapies to reduce or even reverse liver scarring.Read moreRead less
Obesity-related Inflammation And Insulin Resistance In Chronic Liver Disease: Exercise And Diet As Treatment Options
Funder
National Health and Medical Research Council
Funding Amount
$540,509.00
Summary
The two most common types of liver disease in Australia are chronic hepatitis C (Hep C) and fatty liver disease and both result in more severe liver injury when the person is overweight. We propose to test if weight loss through lifestyle changes such as improving diet or increasing exercise are suitable treatment alternatives for people living with liver disease. This will help doctors better advise patients as to what they can do themselves to improve the health of their liver.
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
Factors Controlling Lipid Accumulation In Non-adipose Tissues
Funder
National Health and Medical Research Council
Funding Amount
$463,500.00
Summary
The fat cells of the body are designed to store excess fuel for use when supply from the diet is low, or in situations like exercise, demand is high. Fat also accumulates to some extent in the cells of other tissues types, but in some people the accumulation is excessive. This can have a number of serious effects. In the liver and muscle it can interfere with the ability of insulin to properly regulate the amount of glucose present in the blood, contributing to the development of diabetes. In th ....The fat cells of the body are designed to store excess fuel for use when supply from the diet is low, or in situations like exercise, demand is high. Fat also accumulates to some extent in the cells of other tissues types, but in some people the accumulation is excessive. This can have a number of serious effects. In the liver and muscle it can interfere with the ability of insulin to properly regulate the amount of glucose present in the blood, contributing to the development of diabetes. In the liver, fat accumulation can also lead to cirrhosis and liver failure. Cardiovascular complications, resulting in premature death, are also likely. However despite these devastating consequences it is not clear what the underlying cause of the over-accumulation of fat is not known. In this project we will investigate in detail several aspects of fat metabolism that we think are important in controlling how tissues take up fat from the circulation and whether it is subsequently stored or burnt for energy. We will study the amount of fat that is taken up by different tissues of the body under a range of conditions including fed, and short- and long-term fasting. We will also use drugs to inhibit or promote the amount of fat that is burnt, to see if this changes the rate at which fat is taken up by different tissues. In addition we will accelerate, by genetic manipulation, the rate at which some key enzymes of fat metabolism are produced, to determine their effect on the amount of fat that is stored by different tissue types. Our aim is to determine the metabolic processes that influence fat accumulation in those adversely affected tissues such as liver, heart and skeletal muscle. The identification of the most important processes will contribute significantly to the targeting of therapies aimed at preventing excess fat accumulation and its associated diseases.Read moreRead less
Therapeutic Regulation Of Hepatic Steatosis And Lipid Transport In The Metabolic Syndrome
Funder
National Health and Medical Research Council
Funding Amount
$522,435.00
Summary
Obesity is an increasing problem in Australia. Elevated fat levels in the liver and blood are associated with obesity and increased risk for heart disease. In this project, we will demostrate new mechanisms of action of Pioglitazone (an insulin-sensitizing agent) and Omacor (fish oils) that will complement the favourable efect of weight loss in the treatment of elevated blood fats and reduction in risk of heart disease in an important groups of subject in the population.
Long Acting Insulin: Drug Design, In Vitro Activity Through To Animal Model Efficacy
Funder
National Health and Medical Research Council
Funding Amount
$445,011.00
Summary
This research will develop novel insulins that possess improved stability and activity for diabetic patients. The improved pharmacological actions of the modified insulins offer increased treatment options for patients eg. enabling less frequent or invasive medication. Our cross-disciplinary team will (i) design and synthesise insulin derivatives, (ii) explore the activity of the modified insulins by biophysical activity profiles in vitro, (iii) evaluate the in vivo stability and clinical effect ....This research will develop novel insulins that possess improved stability and activity for diabetic patients. The improved pharmacological actions of the modified insulins offer increased treatment options for patients eg. enabling less frequent or invasive medication. Our cross-disciplinary team will (i) design and synthesise insulin derivatives, (ii) explore the activity of the modified insulins by biophysical activity profiles in vitro, (iii) evaluate the in vivo stability and clinical effects.Read moreRead less
Transcription-based Identification Of Insulin Resistance Subtypes
Funder
National Health and Medical Research Council
Funding Amount
$341,883.00
Summary
A key feature of type 2 diabetes is the failure of metabolic tissues such as muscle and fat to respond to normal levels of insulin. This 'insulin resistance' is caused by a number of mechanisms. We will use cutting-edge technology to identify small sets of genes that define each variety of insulin resistance. These gene sets will be used to diagnose sub-types of insulin resistance and will facilitate the development of personalised therapies to effectively treat individuals with type 2 diabetes.