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
Regulation Of Insulin Signalling And Glucose Homeostasis By Protein Tyrosine Phosphatases
Funder
National Health and Medical Research Council
Funding Amount
$542,462.00
Summary
A common feature of type 2 diabetes is high blood glucose due to peripheral insulin resistance. Protein tyrosine phosphatases (PTPs) that antagonise insulin signalling might be important targets for therapeutic intervention in type 2 diabetes; inhibition of specific PTPs may allow for enhanced IR signalling to alleviate insulin resistance. This proposal will examine the roles of PTPs and in particular TCPTP in insulin signalling and glucose homeostasis.
The Role Of Grb10 In The Regulation Of Muscle Metabolism
Funder
National Health and Medical Research Council
Funding Amount
$624,960.00
Summary
Obesity increases the risk of metabolic diseases such as type 2 diabetes. Muscle is a key tissue for balancing whether energy is used or stored as fat and as we age, muscle mass normally decreases making maintaining a healthy metabolism even more difficult. We have discovered that removing the Grb10 gene from mice produces bigger muscles. This project will investigate the mechanisms of this effect so that strategies can be developed to regulate muscle mass and improve metabolic health
Muscarinic Receptor Signalling, Transglutaminase And Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$518,210.00
Summary
Diabetes is a major and increasing cuase of death and disability in our society. This studies aims to understand the cellular and molecular mechaisms controlling insulin secretion from the pancreas, since defects in this secretion are involved in causing diabetes. The proposed studies are of relevance to both juvenile and adult-onset diabetes, and may lead to new treatment modalities, as well as potentially being relevant to the use of pencreatic islet cell transplantation in the treatment of di ....Diabetes is a major and increasing cuase of death and disability in our society. This studies aims to understand the cellular and molecular mechaisms controlling insulin secretion from the pancreas, since defects in this secretion are involved in causing diabetes. The proposed studies are of relevance to both juvenile and adult-onset diabetes, and may lead to new treatment modalities, as well as potentially being relevant to the use of pencreatic islet cell transplantation in the treatment of diabetes.Read moreRead less
Regulation Of Insulin Sensitivity By Reactive Oxygen Species
Funder
National Health and Medical Research Council
Funding Amount
$564,644.00
Summary
In morbid obesity and type 2 diabetes chronic levels of reactive oxygen species (ROS) are detrimental and diminish insulin's ability to maintain normal blood glucose levels. Paradoxically, ROS also promote insulin action by inhibiting enzymes known as protein tyrosine phosphatases (PTPs). This proposal will determine whether the promotion of ROS for the inhibition of PTPs early in the progression of type 2 diabetes may be of therapeutic benefit.
Novel Gp130 Receptor Ligands To Treat Metabolic Disease
Funder
National Health and Medical Research Council
Funding Amount
$708,267.00
Summary
Over the past decade work from our group has identified that a group of cytokines termed the gp130 receptor cytokines can lead to weight loss in animals and humans. Unfortunately, due to side effects, clinical trials using peptides analogues of these cytokines have failed. We believe that we know why this has occurred and we think we have developed new peptides that will alleviate these side effects. This application will test the efficacy of these novel peptides in mammals in vivo.
Mitogenic And Metabolic Signalling Via The Insulin Recptor Isoform-A
Funder
National Health and Medical Research Council
Funding Amount
$533,541.00
Summary
A novel mechanism of stimulating cancer cell survival and growth has been identified which involves insulin and insulin-like growth factor-II acting via the insulin receptor isoform A. This proposal will identify the mechanisms by which these ligands stimulate growth rather than metabolism via the insulin receptor-A. This information will be used in future design of novel molecules to inhibit cancer growth without interfering with insulin's normal metabolic functions.
Regulation Of Insulin Signalling & Glucose Homeostasis By Protein Tyrosine Phosphatases
Funder
National Health and Medical Research Council
Funding Amount
$503,776.00
Summary
Type 2 diabetes has reached epidemic proportions afflicting roughly 6% of the adult population in Western society. Although the underlying genetic causes and the associated pathological symptoms are heterogenous, a common feature is high blood glucose due to peripheral insulin resistance. The molecular basis of insulin resistance is believed to be attributable to defects in insulin receptor (IR) signalling. The IR is a protein tyrosine kinase that phosphorylates itself and downstream substrates ....Type 2 diabetes has reached epidemic proportions afflicting roughly 6% of the adult population in Western society. Although the underlying genetic causes and the associated pathological symptoms are heterogenous, a common feature is high blood glucose due to peripheral insulin resistance. The molecular basis of insulin resistance is believed to be attributable to defects in insulin receptor (IR) signalling. The IR is a protein tyrosine kinase that phosphorylates itself and downstream substrates on tyrosine in response to insulin. Protein tyrosine phosphatases (PTPs) that dephosphorylate the IR and its substrates might be important targets for therapeutic intervention in type 2 diabetes; inhibition of specific PTPs may allow for enhanced insulin-induced signalling to alleviate insulin resistance. This proposal will examine the roles of PTPs and in particular TCPTP in IR signalling in vivo. Our studies will shed light on the molecular mechanisms of IR regulation and function and may provide important insights into novel strategies for enhancing insulin sensitivity in type 2 diabetes.Read moreRead less
Obesity And Infertility: Effects Of Diet-induced Insulin Resistance On Oocyte Quality.
Funder
National Health and Medical Research Council
Funding Amount
$533,510.00
Summary
The health of an embryo (and subsequently child) is largely determined by the health of the mother. It is well documented that women who have poor pre-pregnancy health due to obesity are more likely to have difficulty conceiving due to irregular ovulations and early embryo loss. My research using obese mice has found that these fertility problems are partly due to alterations in the oocytes (eggs) within the ovary. Its surrounding cells and fluid provide the oocyte with all of its required nutri ....The health of an embryo (and subsequently child) is largely determined by the health of the mother. It is well documented that women who have poor pre-pregnancy health due to obesity are more likely to have difficulty conceiving due to irregular ovulations and early embryo loss. My research using obese mice has found that these fertility problems are partly due to alterations in the oocytes (eggs) within the ovary. Its surrounding cells and fluid provide the oocyte with all of its required nutrients. I hypothesize that this follicular environment is altered in females that are obese leading to inappropriate nutritional signals and suboptimal development of the oocyte. The goals of my research are to use obese mice to 1) pinpoint exactly which metabolic alterations lead to decreased oocyte development; 2) determine how these metabolic alterations change the oocyte and the cells surrounding it; 3) use the information gained to analyse ovarian cells of women and see if these same alterations occur in women who are obese. The findings will be highly significant because they will 1) provide a greater understanding of how the maternal environment communicates nutritional information to the oocyte, which ultimately forms the developing embryo. 2) expand our knowledge of the optimal nutritional conditions for oocyte and early embryo development. 3) identify biological mechanisms that are altered during obesity and lead to decreased female fertility. 4) aid in the development of improved agents for use at fertility clinics, for instance the development of solutions most closely mimicking the critical components of the normal ovarian environment, for use in the culture of oocytes and embryos. 5) provide a strong public health message to women of reproductive age: to achieve and maintain a healthy body weight prior to becoming pregnant.Read moreRead less
Insulin Resistance In Polycystic Ovary Syndrome And The Role Of Skeletal Muscle And Adipose Tissue
Funder
National Health and Medical Research Council
Funding Amount
$416,115.00
Summary
11% of women have polycystic ovarian syndrome(PCOS), characterised by insulin resistance, irregular periods and infertility. These women are prone to obesity, diabetes and potentially, heart disease. Treatments include lifestyle modifications +-- medical therapy. Lifestyle is first line, yet the best diet-exercise prescription is unclear. This study will provide insights into the cause of PCOS, will inform on the role of exercise in therapy and may identify targets for future therapies.