Type 2 diabetes represents an escalating global health problem. In Australia 7.2% of the population has diabetes but an additional 16% have difficulty handling glucose, a problem which frequently precedes the development of diabetes. Resistance of tissues to the action of insulin is an essential pre-requisite for type 2 diabetes but is also closely associated with the syndrome of obesity, dyslipidaemia, hypertension and cardiovascular diseases (Syndrome X). Genetic factors combined with a high c ....Type 2 diabetes represents an escalating global health problem. In Australia 7.2% of the population has diabetes but an additional 16% have difficulty handling glucose, a problem which frequently precedes the development of diabetes. Resistance of tissues to the action of insulin is an essential pre-requisite for type 2 diabetes but is also closely associated with the syndrome of obesity, dyslipidaemia, hypertension and cardiovascular diseases (Syndrome X). Genetic factors combined with a high caloric intake and a sedentary lifestyle are together responsible for the development of insulin resistance. From evidence that we and others have obtained in recent years it is evident that an important mediator of insulin resistance is the amount of fat which accumulates in muscle and liver. One way in which this abnormality seems to cause insulin resistance is through interference with the normal signalling mechanism which causes increased glucose metabolism in response to insulin. While experiments in cell systems have identified some candidate molecules that may be involved, a need exists to demonstrate whether their dysregulation actually causes the insulin resistance in the whole animal or human, or are merely associated with it. We will use novel techniques to manipulate the levels of one of these candidate genes, protein kinase B-Akt, and its regulators in the muscle of rodents. We will then examine the effects of these manipulations on insulin resistance using a combination of metabolic and molecular tests. Building upon earlier work we will also determine how important different subtypes of this molecule are for both normal and abnormal insulin-glucose metabolism, and whether these molecules or others in the pathway are more important in insulin resistance. This knowledge will be invaluable in tailoring specific novel treatment strategies or drugs for prevention or treatment of insulin resistance, and thus reducing the burden of type 2 diabetes and Syndrome X.Read moreRead less
Defining The Insulin-signalling Defect In Human Insulin Resistance And Type 2 Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$94,280.00
Summary
Problems with the way insulin removes glucose from the circulation contribute to developing type 2 diabetes. Despite research to date, controversy remains regarding the nature of known defects in insulin action and their relevance to humans. We plan to measure molecules involved in insulin action in muscle of people with insulin resistance, which is linked to diabetes. These studies will define new defects that cause insulin resistance and type 2 diabetes in humans.
Characterization Of The Phosphoinositide 5-phosphatase SKIP.
Funder
National Health and Medical Research Council
Funding Amount
$505,523.00
Summary
Growth factors and insulin stimulate a complex array of signals inside the cell, which are important for both cell survival and metabolism. A central intracellular signaling enzyme that initiates lipid messages that promote glucose uptake into the cell and promote cell survival is that generated by the PI3-kinase. This enzyme has increased activity in many cancers, and is also important in diabetes when the enzyme may be suppressed. Our grant proposes to investigate the function of another enzym ....Growth factors and insulin stimulate a complex array of signals inside the cell, which are important for both cell survival and metabolism. A central intracellular signaling enzyme that initiates lipid messages that promote glucose uptake into the cell and promote cell survival is that generated by the PI3-kinase. This enzyme has increased activity in many cancers, and is also important in diabetes when the enzyme may be suppressed. Our grant proposes to investigate the function of another enzyme called SKIP which acts within the cell to oppose the functions of the PI3-kinase. Several lines of evidence indicate SKIP may be important in both development and cancer. SKIP has been identified as a putative candidate gene for a developmental disorder known as Miller Dieker syndrome. This disease is associated with facial and significant brain abnormalities. In addition the SKIP gene is located on a chromosome that is frequently deleted in breast and colon cancer. SKIP is an enzyme that functions to remove phosphate molecules from PI3-kinase signaling molecules. SKIP has been shown to prevent glucose uptake into the cell by breaking down PI3-kinase signals. We have recently demonstrated SKIP phosphatase activity can be inhibited by binding to another protein called suppressor of death domains (SODD). We plan to investigate the effects this complex has on SKIP enzyme activity, and how this complex plays a role in regulating PI3-kinase signals that promote glucose uptake. Secondly, we plan to investigate the function of SKIP in an intact animal by making mice which lack SKIP(knock out mice). Given SKIP is implicated in a developmental syndrome and insulin signaling, we can delineate the functional significance of SKIP and the molecular pathways regulated by this enzyme.Read moreRead less
Trafficking Mechanisms Governing Receptor Availability For Signalling
Funder
National Health and Medical Research Council
Funding Amount
$526,978.00
Summary
Receptors on the cell surface allow cells to respond to their environment. We have recently discovered a new pathway for controlling the amount of receptors displayed on the cell surface, errors within which will lead to defects in development and diseases like cancer. We are studying how this new pathway controls the balance between how much receptors are destroyed after being activated and how much are recycled back for re-use.
Physiological Effects Of Manipulating AMP-activated Kinase Genes
Funder
National Health and Medical Research Council
Funding Amount
$351,110.00
Summary
The AMP-activated protein kinase is a metabolic stress sensing protein kinase responsible for matching the supply of energy to the body's functions. During vigorous exercise it senses metabolic stress (reduction in energy) caused by muscle contraction and stimulates glucose uptake and burning of fat to provide energy. The AMP-activated protein kinase also regulates the production of nitric oxide that is important in controlling blood pressure and blood clotting. Reduced caloric intake activates ....The AMP-activated protein kinase is a metabolic stress sensing protein kinase responsible for matching the supply of energy to the body's functions. During vigorous exercise it senses metabolic stress (reduction in energy) caused by muscle contraction and stimulates glucose uptake and burning of fat to provide energy. The AMP-activated protein kinase also regulates the production of nitric oxide that is important in controlling blood pressure and blood clotting. Reduced caloric intake activates the AMP-activated protein kinase to suppress energy consuming activities and modify the expression of genes. Many of the conditions that activate the AMP-activated protein kinase (exercise, reduced caloric intake) are associated with a healthy life style, increased longevity and resistance to age onset diseases including cardiovascular disease (atherosclerosis, hypertension), obesity, neurodegeneration and diabetes. By manipulating the gene for the AMP-activated protein kinase in mice we expect to learn more about its key physiological roles and give new insight into the control of age onset diseases.Read moreRead less
The immune system usually rapidly responds to eradicate infectious pathogens. However patients with mutations in the gene PI3KCD, which is important for delivering messages within immune cells, are unable to control infections with some bacteria and viruses. We will study the effects of these mutations on B cells, the immune cells produce antibodies that bind to and remove pathogens from our body. This will explain some of the clinical features of this disease and reveal potential new treatments
Sphingosine Kinase As A Target For Anti-cancer Therapy
Funder
National Health and Medical Research Council
Funding Amount
$590,785.00
Summary
Sphingosine kinase is a protein involved in the development and progression of numerous types of solid tumors and leukaemias. We have recently made a major break-through by identifing how the cancer-inducing activity of sphingosine kinase is controlled. In this study we will target these control mechanisms to develop potential new anti-cancer therapies.