Secretion is an essential step in memory and learning, control of metabolism and reproduction and the functioning of most organs. Secretory dysfunction also underlies many diseases including type 2 diabetes. We plan experiments to test for a new model of control of insulin secretion.
The Role Of Vitamin D In Beta-cell Function And Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$554,248.00
Summary
Vitamin D deficiency is common in Australia, with the success of the 'slip, slop, slap' campaigns. Low levels of Vitamin D have been associated with diabetes. This grant aims to determine how vitamin D affects insulin release and blood glucose levels.
In Australia over 7% of the population have type 2 diabetes. This epidemic represents a major health problem. The majority of overweight individuals do not develop diabetes because their insulin-secreting pancreatic beta-cells adequately compensate with over-secretion. It is the failure of this so called, beta-cell compensation, that is fundamental to the development of diabetes. We propose that in susceptible individuals, a gradual rise in blood glucose levels resulting from obesity and insulin ....In Australia over 7% of the population have type 2 diabetes. This epidemic represents a major health problem. The majority of overweight individuals do not develop diabetes because their insulin-secreting pancreatic beta-cells adequately compensate with over-secretion. It is the failure of this so called, beta-cell compensation, that is fundamental to the development of diabetes. We propose that in susceptible individuals, a gradual rise in blood glucose levels resulting from obesity and insulin resistance leads to beta-cell failure and overt diabetes. This project will investigate the mechanisms responsible for beta-cell failure in a mouse model with a similar time-dependent progression to obesity and type 2 diabetes as that seen in humans. C57BL-KsJ db-db mice progress from a pre-diabetic phase of insulin over-secretion, obesity and insulin resistance to a diabetic state characterised by the appearance of high blood glucose and lipid levels and the loss of insulin secretory capacity. With age, there are also a reduced number of beta-cells because of increased cell death. db-db mice will be studied at different stages in their natural progression to diabetes to fully characterise the secretory dysfunction and the changes in beta-cell phenotype over the time-course of diabetes development. The use of laser capture microdissection will allow us to study selectively the actual beta-cells without contamination from the other cells of the pancreas. The mice will also be treated with an agent that lowers blood glucose levels without affecting lipids to test the influence of hyperglycaemia itself in the development of beta-cell dysfunction. We will also test if the changes observed in the mice are regulated independently by high glucose levels in cell culture systems. The role of one candidate protein called ID-1 will be investigated as a potential link between hyperglycaemia and the development of beta-cell dysfunction.Read moreRead less
Investigations Of Beta Cell Dysfunction And Death In Type 2 Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$314,433.00
Summary
Diabetes is a disease that affects 100 million people worldwide and this number is expected to double in the next twenty years. This disease is characterised by high blood sugar levels which over prolonged periods of time can affect the function of the kidneys and eyes as well as causing heart attacks and strokes. A main contributing factor to diabetes is the inability of the pancreas to secrete insulin, the hormone that is responsible for keeping blood sugar levels in the normal range. The reas ....Diabetes is a disease that affects 100 million people worldwide and this number is expected to double in the next twenty years. This disease is characterised by high blood sugar levels which over prolonged periods of time can affect the function of the kidneys and eyes as well as causing heart attacks and strokes. A main contributing factor to diabetes is the inability of the pancreas to secrete insulin, the hormone that is responsible for keeping blood sugar levels in the normal range. The reason for this inability of the pancreas to secrete enough insulin is not known. It is known however, that both genetic and environmetal factors are responsible. The aim of this investigation is to determine the biochemical and genetic reason for decreased insulin secretion from an animal model of diabetes called DBA-2J mouse. Specifically we will be studying the effects of long-term increased sugar and fat on the function of the insulin producing cells of the pancreas, in order to identify the biochemical pathway responsible for reduced insulin secretion. In parallel we will be investigating the gene or genes in DBA-2J mice that are responsible for decreased insulin secretion and pancreatic cell death. This will provide clues as to the genes that may be responsible for diabetes in humans. This project will provide crucial information on the cause of reduced insulin secretion both at the cellular and genetic level, and will lead to a better understanding of the cause of diabetes.Read moreRead less
Effect Of Oral Glutamine On GLP-1 And Insulin Secretion And Glycaemia In Humans.
Funder
National Health and Medical Research Council
Funding Amount
$397,444.00
Summary
Diabetes is an ever increasing problem with serious complications. We will investigate whether glutamine, one of the most common amino acids (protein building blocks) in the body, has a beneficial effect on blood glucose and insulin levels in the body in people who have type 2 (non-insulin dependent) diabetes. If so, glutamine supplementation may represent a novel, cheap and palatable way of improving outcomes and preventing the development of complications in people with type 2 diabetes.
The current epidemic of type 2 diabetes represents a major global health problem, with over 7% of the Australians suffering the disease. While there is a well-established relationship between obesity and insulin resistance, the majority of overweight individuals do not develop type 2 diabetes because their pancreatic beta-cells compensate with enhanced insulin secretion. It is the failure of beta-cell compensation that is fundamental to the development of diabetes. The beta-cell is a highly spec ....The current epidemic of type 2 diabetes represents a major global health problem, with over 7% of the Australians suffering the disease. While there is a well-established relationship between obesity and insulin resistance, the majority of overweight individuals do not develop type 2 diabetes because their pancreatic beta-cells compensate with enhanced insulin secretion. It is the failure of beta-cell compensation that is fundamental to the development of diabetes. The beta-cell is a highly specialised cell with a unique metabolic profile and differentiation specifically geared towards making these cells able to sense fluctuations in circulating glucose levels and secrete insulin accordingly. We propose that in susceptible individuals, a gradual rise in blood glucose (hyperglycaemia) and lipid levels resulting from increasing obesity and insulin resistance leads to a loss of the unique expression pattern of genes necessary for appropriate insulin secretion. This exacerbates hyperglycaemia, which causes further beta-cell dedifferentiation and eventually the death of beta-cells by apoptosis. We have recently found evidence in several models of diabetes that supports this hypothesis. We propose to use animal studies and cell culture systems to investigate the following hypotheses important for our understanding of beta-cell failure and progression to diabetes: 1) The loss of beta-cell phenotype (dedifferentiation) underlies the loss of insulin secretory function in failing beta-cells. 2) Hyperglycaemia plays a critical role regulating the progression to beta-cell dedifferentiation. 3) The overexpression of key candidate gene products play an integral role linking hyperglycaemia to the loss of beta-cell secretion. 4) Endoplasmic reticulum stress is necessary for beta-cell death in diabetes. Our studies will make a major contribution to our understanding of why beta-cells fail in diabetes and aim to provide novel therapeutic targets in the treatment of diabetes.Read moreRead less
Investigation Of The Roles Of Protein Kinase C Epsilon In Insulin Secretion And Insulin Clearance
Funder
National Health and Medical Research Council
Funding Amount
$627,148.00
Summary
The rise in blood insulin levels after a meal normally reduces blood sugar levels by increasing glucose uptake and storage in certain tissues, especially muscle. Type 2 diabetes is characterized in part by a failure of the pancreas to produce adequate insulin in response to increases in blood sugar. This loss of insulin secretion has been strongly linked to increases in the availability of fat, although the reasons for this are not clear. We have recently found that mice lacking a specific enzym ....The rise in blood insulin levels after a meal normally reduces blood sugar levels by increasing glucose uptake and storage in certain tissues, especially muscle. Type 2 diabetes is characterized in part by a failure of the pancreas to produce adequate insulin in response to increases in blood sugar. This loss of insulin secretion has been strongly linked to increases in the availability of fat, although the reasons for this are not clear. We have recently found that mice lacking a specific enzyme (protein kinase C epsilon) are much less susceptible to the problems in dealing with blood sugar that are caused by a high fat diet. We showed that this is due partly to improved insulin secretion, and also to a slower breakdown of insulin by the liver, which increases its availability to target tissues. The aim of this project is to investigate the mechanisms occurring in the liver and in the pancreas by which this enzyme contributes to improved insulin action. Firstly, we will examine insulin uptake in liver cells, to investigate how the enzyme controls this process. Secondly, we will determine the mechanism through which the activation of the enzyme, upon increased fat supply to pancreatic beta-cells, reduces insulin secretion in response to glucose. Finally, will assess the relative importance of these two actions of the enzyme in improving the control of blood sugar levels. This work will lead to a better understanding of the mechanisms by which fat oversupply, and hence obesity, can play a role in the development of Type 2 diabetes, so that they can be targeted both for the development of new and more effective treatments for the disorder and for prevention of its onset.Read moreRead less