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
Overweight and obesity are at epidemic proportions in Australia, reflecting the pattern in the developed and developing world. The main cause appears to be an energy mismatch, with excessive caloric consumption. One response of the body to excessive nutrient supply is energy storage in fat tissue and to aid in this the body also generates new fat tissue, termed adipogenesis (also known in cells as fat cell differentiation). In many people who gain excess body weight, fat tissue is abnormal and d ....Overweight and obesity are at epidemic proportions in Australia, reflecting the pattern in the developed and developing world. The main cause appears to be an energy mismatch, with excessive caloric consumption. One response of the body to excessive nutrient supply is energy storage in fat tissue and to aid in this the body also generates new fat tissue, termed adipogenesis (also known in cells as fat cell differentiation). In many people who gain excess body weight, fat tissue is abnormal and does not respond well to the chemical insulin, thus causing insulin resistance. This insulin resistant fat tissue is especially present in a central body (visceral) site. Insulin resistance related to this visceral fat predisposes to both diabetes and premature death from cardiovascular disease. Understanding how fat tissue develops and how it might cause insulin resistance is thus important in human health. One of the factors in fat that prevents normal development of fat tissue and which induces insulin resistance is transforming growth factor- (TGF- ). We have generated new data showing that two proteins which are increased by TGF- , termed connective tissue growth factor (CTGF) and insulin like growth factor binding protein-3, (IGFBP-3), prevent adipogenesis. We have shown this in cultured cells, and have found that CTGF and IGFBP-3 are increased in visceral fat in animal models of obesity and insulin resistance. Our preliminary work has further indicated how CTGF and IGFBP-3 might each work in the fat cell to prevent adipogenesis. This proposal will determine if TGF- works through CTGF and IGFBP-3 to block adipogenesis, and it will define how CTGF and IGFBP-3 have their inhibitory effects on fat cell differentiation. Cells in culture will be utilised and an animal model of dietary induced obesity and insulin resistance will help to define whether CTGF and IGFBP-3 prevent adipogenesis in vivo, furthering our understanding in how abnormal fat tissue may develop.Read moreRead less
RCAN1 IS A MASTER REGULATOR OF BETA CELL FUNCTION AND INSULIN SECRETION
Funder
National Health and Medical Research Council
Funding Amount
$446,610.00
Summary
Type 2 diabetes affects over 1.5 million Australians and is caused by insufficient insulin release by beta cells in the pancreas. We have discovered a new regulator of insulin secretion called RCAN1 and we now aim to understand how this regulation occurs. We also believe RCAN1 may be responsible for the transition from healthy to dysfunctional beta cell in Type 2 diabetes and this project will identify whether this is the case.
Adiponectin - Multimerization, Secretion And Action
Funder
National Health and Medical Research Council
Funding Amount
$478,844.00
Summary
Adiponectin is a hormone produced by fat tissue. It functions to control blood glucose levels and acts to prevent damage to blood vessels associated with heart disease and stroke. Adiponectin levels in the blood are low in subjects with obesity, diabetes and heart disease, and in animals with these conditions, additional adiponectin is of benefit. It has recently been recognised that adiponectin is produced in different forms - a low weight form made up of a small number of adiponectin molecules ....Adiponectin is a hormone produced by fat tissue. It functions to control blood glucose levels and acts to prevent damage to blood vessels associated with heart disease and stroke. Adiponectin levels in the blood are low in subjects with obesity, diabetes and heart disease, and in animals with these conditions, additional adiponectin is of benefit. It has recently been recognised that adiponectin is produced in different forms - a low weight form made up of a small number of adiponectin molecules and a higher weight form (HMW adiponectin) made up of large numbers of adiponectin molecules complexed together. We and others have shown that the HMW adiponectin is particularly beneficial. This projects aims to understand the processes regulating the production of differing types of adiponectin by fat cells. It will also examine how the different types of adiponectin have their effects in different tissues such as liver and muscle. The information gained will increase our understanding of how illnesses such as diabetes are associated with obesity. It may also lead to the development of treatments aimed at increasing adiponectin levels - particulalry HMW adiponectin - which may be of benefit in patients with diabetes and cardiovascular disease.Read moreRead less
Ceramide Metabolism And ER Stress In Fatty-acid Mediated Destruction Of Pancreatic Beta Cells
Funder
National Health and Medical Research Council
Funding Amount
$549,092.00
Summary
The underlying cause of Type 2 diabetes is the failure of pancreatic beta cells to secrete sufficient insulin to overcome the insulin resistance that is associated with obesity. Beta cell failre is associated with both defective insulin secretion and loss of beta cell mass. This proposal focuses on the cellular mechanisms and stress pathways whereby too much fatty acid promotes beta cell death.
FUNCTIONAL ANALYSIS OF IGF-BINDING PROTEIN-2 MOLECULAR INTERACTIONS IN EARLY DEVELOPMENT AND DISEASE
Funder
National Health and Medical Research Council
Funding Amount
$551,328.00
Summary
Early development involves complex regulation of cell and organ growth. Cell migration and invasion are critical components of epithelial-mesenchymal transition (EMT) essential for early developmental, as well as injury repair and cancer. Common to these events is a highly expressed protein, insulin-like growth factor binding protein-2 (IGFBP-2), which appears to play a critical role in regulating the processes of cell migration and invasion. The underlying mechanisms of cellular regulation by I ....Early development involves complex regulation of cell and organ growth. Cell migration and invasion are critical components of epithelial-mesenchymal transition (EMT) essential for early developmental, as well as injury repair and cancer. Common to these events is a highly expressed protein, insulin-like growth factor binding protein-2 (IGFBP-2), which appears to play a critical role in regulating the processes of cell migration and invasion. The underlying mechanisms of cellular regulation by IGFBP-2 are major focus of this proposal, which brings together four major groups focussed on early development, neural injury repair, and cancer biology. We will use a range of in vitro and in vivo approaches to determine the underlying mechanisms of action of this critical protein. This project has the potential to point to novel therapeutic modalities in development, repair and cancer.Read moreRead less