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
Identification Of Novel Genes Influencing Development Of Type 2 Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$558,920.00
Summary
Type 2 diabetes is usually associated with obesity and is often part of a wider disturbance affecting an individual's energy metabolism. The number of affected people with type 2 diabetes has trebled since 1981 in Australia and is still increasing. Apart from individual suffering, this presents a major public health burden for the country (approx $3 billion annually). Currently available lifestyle based and pharmaceutical therapies are inadequate to control the increasing numbers of affected ind ....Type 2 diabetes is usually associated with obesity and is often part of a wider disturbance affecting an individual's energy metabolism. The number of affected people with type 2 diabetes has trebled since 1981 in Australia and is still increasing. Apart from individual suffering, this presents a major public health burden for the country (approx $3 billion annually). Currently available lifestyle based and pharmaceutical therapies are inadequate to control the increasing numbers of affected individuals. Unfortunately the cause of disease is poorly understood, although genetic factors are known to be important, in other words it runs in the family. This project proposes to identify some of these factors (genes) and how they contribute to the disease. Using molecular flags on the DNA (like DNA fingerprinting) we have previously found that a small region on chromosome 12 is likely to carry one or more of these disease genes. But there are over 100 genes in the region. To help choose the most likely candidates first for testing, we have developed an automated computer database searching program ranked the genes based on what is already known about them. We have also taken a large number of physiological measures in a large group of people. Some of these measures are controlled by the same chromosome 12 region - thus to improve our chances of finding the genes quickly we will look at those that change the most between people with diabetes and people without diabetes. In this project we shall investigate the 20 genes most likely affect diabetes based on changes in physiological measures and what is already known about them. A successful finding means we will know more about the mechanism of disease development and be able to better develop new therapies for treatment and prevention. If none of these genes are the culprit, we would continue examination of the next set of genes likely to be involved and so on until we are successful.Read moreRead less