Diabetes mellitus is a disease reaching epidemic proprotions in the western world. Nearly one million Australians have diabetes mellitus; many of these people will suffer debilitating secondary complications, resulting in significant morbidity and mortality at considerable social and economic cost. Complications include heart attack, stroke, kidney disaease, blindness and limb amputation. There are two forms of diabetes (type I and type 2), and though there are considerable differences in their ....Diabetes mellitus is a disease reaching epidemic proprotions in the western world. Nearly one million Australians have diabetes mellitus; many of these people will suffer debilitating secondary complications, resulting in significant morbidity and mortality at considerable social and economic cost. Complications include heart attack, stroke, kidney disaease, blindness and limb amputation. There are two forms of diabetes (type I and type 2), and though there are considerable differences in their etiology, both forms result in an inability of the body to control blood sugar levels. Beta cells release the hormone insulin, which regulates blood sugar levels. Current knowledge suggests that a loss of beta cell mass is important for both diseases. For type I diabetes the beta cells are destroyed by the immune system. Though for type 2 diabetes the causes are less clear, it is apparent that the beta cells are dying. Our research is focused on understanding the molecular pathways that control beta cell survival and regulate their death. Such knowledge would help us understand the complex processes leading to the development of diabetes. Furthermore, we could use this knowledge in the design of genetic engineering strategies to create 'death-defying' beta cells, as a potential therapeutic strategy for the treatment of diabetes.Read moreRead less
Kidney fibrosis is a serious complication seen in diabetic subjects. This process is mainly controlled by transforming growth factor beta (TGF-beta). However, direct targeting of TGF-beta as a therapeutic approach is inappropriate due to its other important functions. Our preliminary data show that Cell Division Autoantigen 1 (CDA1) is critical for the disease causing activity of TGF-beta. We propose to use our recently generated unique CDA1 gene knockout mouse to demonstrate this important role ....Kidney fibrosis is a serious complication seen in diabetic subjects. This process is mainly controlled by transforming growth factor beta (TGF-beta). However, direct targeting of TGF-beta as a therapeutic approach is inappropriate due to its other important functions. Our preliminary data show that Cell Division Autoantigen 1 (CDA1) is critical for the disease causing activity of TGF-beta. We propose to use our recently generated unique CDA1 gene knockout mouse to demonstrate this important role of CDA1.Read moreRead less
Molecular Attributes And Physiological Significance Of Beta1L-adrenoceptors
Funder
National Health and Medical Research Council
Funding Amount
$754,353.00
Summary
Beta-blockers are used for the management of cardiovascular diseases including heart failure. We have discovered that one group of beta-blockers not only blocks the receptor but stimulates it. To explain this we hypothesize that human beta-adrenoceptors exist in two different 'states' , high and low. We are now determining whether 1. the low state causes progression of heart failure, 2. the molecular basis of the two states and 3. we can make new compounds to block the low state.
Contractile And Relaxant Effects Of B2- And B1-adrenoceptors In Human Heart: Blockade By A Third Generation B-blocker
Funder
National Health and Medical Research Council
Funding Amount
$136,320.00
Summary
The force and the duration of each heart beat can be modified in disease states affecting the heart. They can also be modified by chemicals which occur naturally in the body. Two of the most important naturally occurring chemicals which affect the function of the heart are (-)-noradrenaline and (-)-adrenaline. These chemicals and others which have been synthesized and optimized can also be used therapeutically. They work by activating proteins which occur on the cell surface, called b-adrenocept ....The force and the duration of each heart beat can be modified in disease states affecting the heart. They can also be modified by chemicals which occur naturally in the body. Two of the most important naturally occurring chemicals which affect the function of the heart are (-)-noradrenaline and (-)-adrenaline. These chemicals and others which have been synthesized and optimized can also be used therapeutically. They work by activating proteins which occur on the cell surface, called b-adrenoceptors. When activated, b-adrenoceptors cause an increase in the force of each heart beat and a reduction in the duration of each heart beat. This may be an advantage in conditions where the heart beat is too long. In this study we propose to map the biochemical pathways through which b-adrenoceptors affect each heart beat. The therapeutic management of heart failure has been revolutionized by the use of compounds which block b-adrenoceptors. One such drug, carvedilol is currently used in this country. The way in which it works may not be fully understood. In preliminary experiments we have identified a novel mechanism for carvedilol directly in human heart in which it may work and contribute to it's beneficial effects in the management of heart failure. Our studies will focus on this finding.Read moreRead less
Biochemical Basis Of Islet Beta-cell Compensation And Failure In Normal Pregnancy And Gestational Diabetes Mellitus
Funder
National Health and Medical Research Council
Funding Amount
$480,828.00
Summary
The factors causing the current world-wide crisis of rapidly rising diabetes prevalence remain poorly understood. Of potential major importance, however, is the hypothesis that abnormalities in the maternal metabolic environment, as occur in gestational diabetes (GDM) (diabetes that develops in pregnancy), result in abnormal development of metabolic systems in the baby resulting in higher risk of adult onset diabetes in the babies. Therefore, it is of importance to understand the mechanisms caus ....The factors causing the current world-wide crisis of rapidly rising diabetes prevalence remain poorly understood. Of potential major importance, however, is the hypothesis that abnormalities in the maternal metabolic environment, as occur in gestational diabetes (GDM) (diabetes that develops in pregnancy), result in abnormal development of metabolic systems in the baby resulting in higher risk of adult onset diabetes in the babies. Therefore, it is of importance to understand the mechanisms causing GDM, such that effective measures can be developed to counter this passing on of diabetes risk from mother to baby. It is known that a key factor causing GDM is failure of maternal pancreatic islet beta-cells to compensate for increased demands for insulin production in pregnancy. Poorly understood, however, are the cellular mechanisms of islet beta-cell compensation in normal pregnancy and failure of this compensation in GDM pregnancy. We have recently shown that there is a pathway of fat metabolism (triglyceride- free fatty acid cycle) within the islet beta-cell that has an important role in amplyfing insulin secretion necessary to maintain normal blood glucose and protecting the islets from failure in obese rats. The major focus of this project is to test the hypothesis that this pathway has a key role in the adaptation of pancreatic islets to normal pregnancy and its dysfunction contributes to the causation of GDM. Of great interest from preliminary findings is that a master regulator of glucose and fat metabolism, PGC1alpha, is markedly reduced in islets during normal pregnancy. Studies will also be directed to PGC1alpha's role in islet adaptation to pregnancy and failure in GDM. We expect that successful completion of this project will lead to the development of highly targeted counter measures to prevent GDM and to slow and reverse the current epidemic of diabetes.Read moreRead less