Role Of Epigenetic Mechanisms In Diabetic Vascular Complications
Funder
National Health and Medical Research Council
Funding Amount
$438,520.00
Summary
Diabetic complications including heart attacks, strokes, kidney disease and blindness appear to be related to the high glucose (sugar) level but how glucose itself induces end-organ injury remains to be fully determined. In this proposal it is suggested that the long-term damaging effects of glucose relate to its ability to damage the regulation of genes by directly affecting DNA and its covering known as histones. Specifically glucose, possibly by altering certain biochemical pathways called ox ....Diabetic complications including heart attacks, strokes, kidney disease and blindness appear to be related to the high glucose (sugar) level but how glucose itself induces end-organ injury remains to be fully determined. In this proposal it is suggested that the long-term damaging effects of glucose relate to its ability to damage the regulation of genes by directly affecting DNA and its covering known as histones. Specifically glucose, possibly by altering certain biochemical pathways called oxidation pathways, interferes with enzymes which affect the structure of DNA and related molecules resulting in altered expression of many proteins. One of these proteins known as NF kappa B is activated in diabetes, probably by mechanisms involving regulation of these enzymes which play a central role in modifying gene structure. By clarifying the exact mechanisms at a molecular level that mediate the effect of glucose on genes and proteins it will be possible to target these molecules and develop new treatments to prevent, retard or reverse the blood vessel complications that are so common in diabetes.Read moreRead less
Identification And Characterisation Of A Gene Causing Insulin Hypersecretion In A Mouse Model Of Diabetes Susceptibility
Funder
National Health and Medical Research Council
Funding Amount
$430,320.00
Summary
Diabetes is a disorder primarily characterised by the inability to produce and secrete the pancreatic hormone insulin, which regulates plasma sugar levels. This results in increased sugar levels which cause diabetic complications such as retinopathy and nephropathy. The inability to produce and secrete insulin is due to both defects in function as well as a reduction in pancreatic beta cells. Paradoxically it has been shown that some patients who are at risk of develping diabetes actually secret ....Diabetes is a disorder primarily characterised by the inability to produce and secrete the pancreatic hormone insulin, which regulates plasma sugar levels. This results in increased sugar levels which cause diabetic complications such as retinopathy and nephropathy. The inability to produce and secrete insulin is due to both defects in function as well as a reduction in pancreatic beta cells. Paradoxically it has been shown that some patients who are at risk of develping diabetes actually secrete more insulin than normal. Furthermore it has been suggested that this increase in insulin secretion actually may be associated with the decreased production and secretion of insulin characteristic of diabetes. The DBA-2 mouse is a model of reduced insulin production and secretion when exposed to high sugar levels or diabetes. However we have shown that in the normal non-stressed state DBA-2 mice actually secrete more insulin than normal and that this occurs from a very early age, suggesting that this trait is inherited. We have subsequently performed genetic studies and have identified a segment of DNA containing 10 genes associated with increased insulin secretion in DBA-2 mice. The level of one of these genes we have called Hip1 is increased 5-fold in DBA-2 mice, providing a candidate gene for increased insulin secretion in this model of diabetes susceptibility. However, whether Hip1 is also responsible for reduced insulin production and secretion in the DBA-2 mouse is not known. Therefore the overall hypothesis of this project is that the gene Hip1 which is associated with increased insulin secretion is also responsible for reduced insulin production and secretion when DBA-2 mice are exposed to high sugar or obesity. Determining why Hip1 is increased and whether it results in diabetes in DBA-2 mice may provide a reasonable candidate for the development of therapeutic interventions which may prevent the progression of diabetes in some patients.Read moreRead less
Progesterone Regulation Of Epithelial Expansion In The Normal Human Breast
Funder
National Health and Medical Research Council
Funding Amount
$556,393.00
Summary
The ovaries play a pivotal role in breast cancer. Progesterone increases breast cancer risk, and this is likely to be a subversion of its role in the normal breast, which is to participate in the normal expansion of the epithelial cells during the menstrual cycle, but how it does this is unknown. We will explore how progesterone influences cell types in the breast similar to those that become cancerous. This will uncover potential targets for prevention and treatment.
How Does Disruption Of Circadian Rhythms Induce Diabetes?
Funder
National Health and Medical Research Council
Funding Amount
$631,782.00
Summary
Increasing evidence suggests that disturbed circadian rhythms initiate and amplify metabolic and cardiovascular disease. The increasing and already high proportion of workers engaged in shiftwork, and increased frequency of disruption of these rhythms in the population more generally, implicate this body system as contributing to the growing epidemic of obesity and diabetes and related disorders in our community and world-wide. While we are now beginning to understand how our rhythms are synchro ....Increasing evidence suggests that disturbed circadian rhythms initiate and amplify metabolic and cardiovascular disease. The increasing and already high proportion of workers engaged in shiftwork, and increased frequency of disruption of these rhythms in the population more generally, implicate this body system as contributing to the growing epidemic of obesity and diabetes and related disorders in our community and world-wide. While we are now beginning to understand how our rhythms are synchronised to night and day, how this rhythmicity is linked to our organs in the normal and common disease states such as diabetes is poorly understood. The discovery of a special set of genes, called clock genes that function in all of the cells in our bodies and strongly influence the function of our organs such as the liver, pancreas and heart has been particularly important. We hypothesise that both environmentally (exogenous) and genetically (endogenous) induced disruption of circadian rhythms causes metabolic dysfunction. This is due to altered central and peripheral clock gene expression rhythms, which in turn alter metabolic rhythms and impair glucose homeostasis. This project aims to determine the impact of disrupted rhythmicity on metabolism with a particular emphasis on the possibility that the disrupted rhythmicity may be a predisposing factor for the development of diabetes.Read moreRead less
Short-term Effects Of Overfeeding On Metabolic Risk In Humans
Funder
National Health and Medical Research Council
Funding Amount
$417,196.00
Summary
The prevalence of obesity is rapidly increasing in Australia and other parts of the world. Obesity is closely associated with insulin resistance and plays a role in the development of type 2 diabetes. However, the effects of short-term periods of over nutrition in humans remain unclear. In the proposed study, we will investigate the effects of short-term weight gain by high fat feeding in lean subjects, in subjects who are overweight and in subjects who are genetically more likely to develop dia ....The prevalence of obesity is rapidly increasing in Australia and other parts of the world. Obesity is closely associated with insulin resistance and plays a role in the development of type 2 diabetes. However, the effects of short-term periods of over nutrition in humans remain unclear. In the proposed study, we will investigate the effects of short-term weight gain by high fat feeding in lean subjects, in subjects who are overweight and in subjects who are genetically more likely to develop diabetes (due to strong family history). The aims are to distinguish physiological and endocrine characteristics of individuals who store more fat in response to overfeeding. We will identify differences between these individuals and whether they have defects in upregulating machinery involved in fat oxidation and energy production in skeletal muscle that may help them adapt during to energy excess. We will look for changes in type 2 diabetes risk and we will have the potential to identify defects in factors that are involved in this response. We will also re-examine indivudals again after calorie restriction and weight loss. We also plan to confirm the role of the candidate genes involved in fat oxidation that have been identifieid in human studies by in vivo gene transfer technology in rodents. This study will determine whether overweight and lean subjects behave similarly when faced with an overfeeding challenge. We expect that individuals with a genetic predisposition for T2DM will become more IR, due to metabolic inflexibility and a decreased ability to upregulate machinery involved in fatty acid oxidation and mitochondrial function. By characterising the physiological and endocrine responses to overfeeding, we will establish quantifiable markers allowing us to distinguish those at risk and identify new targets for pharmacological or lifestyle intervention.Read moreRead less