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
Therapeutic Strategies And Screening Methods For PKC Epsilon Antagonists In The Treatment Of Type 2 Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$157,375.00
Summary
Type 2 diabetes is a chronic disease affecting over a million Australians and hundreds of millions of people worldwide. Its prevalence is rising due to several factors such as an increase in caloric intake, the aging of the population, and the common sedentary lifestyle of Western civilization. Type 2 diabetes occurs when the pancreas is unable to produce enough insulin for the body to cope with rising blood glucose levels after a meal, and has been strongly linked to obesity. We have now shown ....Type 2 diabetes is a chronic disease affecting over a million Australians and hundreds of millions of people worldwide. Its prevalence is rising due to several factors such as an increase in caloric intake, the aging of the population, and the common sedentary lifestyle of Western civilization. Type 2 diabetes occurs when the pancreas is unable to produce enough insulin for the body to cope with rising blood glucose levels after a meal, and has been strongly linked to obesity. We have now shown that an enzyme found in the pancreas becomes inappropriately activated under conditions of fat oversupply, and plays an important role in the development of defects in insulin release from the pancreas in response to glucose. Excitingly, we have also shown that inhibition of this enzyme can partly reverse these defects once they have been established. We now intend to further validate this enzyme as a drug target by determining the optimum dosing regimen for the treatment of type 2 diabetes in a mouse model, and testing whether this approach can be used in conjunction with previously-developed drugs which promote insulin action, to improve bood glucose handling better than either treatment alone. This would promote the enzyme as a therapeutic strategy in the treatment of Type 2 diabetes. We also plan to develop a high throuhput screen to identify novel inhibitors of the enzyme, which will further increase the attractiveness of the project to pharmaceutical companies, who are better able to implent full commercialization of our findings.Read moreRead less
Muscarinic Receptor Signalling In The Control Of Insulin Secretion
Funder
National Health and Medical Research Council
Funding Amount
$425,250.00
Summary
The project is aimed at a better understanding of the way in which nerves control the release of insulin from the pancreatic beta cells of the islets of Langerhans. Nerves release chemicals called neurotransmitters, one of which, acetylcholine, stimulates insulin release in conjunction with a rise in blood glucose immediately after a meal. Acetylcholine binds to receptors on the surface of the beta cells, and triggers signalling pathways inside the cell. We have discovered novel features of thos ....The project is aimed at a better understanding of the way in which nerves control the release of insulin from the pancreatic beta cells of the islets of Langerhans. Nerves release chemicals called neurotransmitters, one of which, acetylcholine, stimulates insulin release in conjunction with a rise in blood glucose immediately after a meal. Acetylcholine binds to receptors on the surface of the beta cells, and triggers signalling pathways inside the cell. We have discovered novel features of those signalling pathways and plan to explore them further. These include a novel route of generation of the intracellular sigalling compound, diacylglycerol, insights into the way that the intracellular messenger Ca2+ enters the cell, and a better understanding of the way in which enzymes known as protein kinases act.Read moreRead less
The Role Of Phospholipase D In Regulating Insulin Secretion
Funder
National Health and Medical Research Council
Funding Amount
$509,267.00
Summary
Insulin, secreted appropriately by the b-cell of the pancreatic islets of Langerhans, regulates blood glucose levels through its effects on various tissues throughout the body. Precise control of insulin secretion from the pancreatic b-cell into the blood is therefore vital for accurate glucose homeostasis. Type II Diabetes Mellitus is caused by the inability of pancreatic b-cells to respond adequately to changes in blood glucose. In the last 18 months we have determined that the enzyme phosphol ....Insulin, secreted appropriately by the b-cell of the pancreatic islets of Langerhans, regulates blood glucose levels through its effects on various tissues throughout the body. Precise control of insulin secretion from the pancreatic b-cell into the blood is therefore vital for accurate glucose homeostasis. Type II Diabetes Mellitus is caused by the inability of pancreatic b-cells to respond adequately to changes in blood glucose. In the last 18 months we have determined that the enzyme phospholipase D (PLD) plays an essential role in distally coordinating signals leading to accurately regulated insulin secretion from the pancreatic b-cell. Through this proposal we now aim to define the signalling pathways upstream of PLD and identify the mechanism downstream that allows PLD activity to regulate insulin secretion. We aim to use a combination of established and novel, biochemical and cell biological, approaches to characterize the role PKC alpha and beta isoforms and the small GTPase cdc42 may have in controlling PLD mediated insulin release. We will also use a variety of cell biological approaches to identify why, where, and when PLD activation is required for appropriate insulin secretion. We will also correlate these observations with the role the cell cytoskeleton may have in mediating PKC, cdc42 and-or PLD effects. In particular we aim to use a state-of-the-art microscope facility recently established at the Garvan Institute to achieve these aims. In doing this we will gain new insights into the pathways determining how insulin is released into the bloodstream, further define cellular processes common to all vesicular trafficking events and also identify potential targets for pharmacological intervention in the disease Diabetes.Read moreRead less
Alterations In Secretion And Gene Expression In Pancreatic Beta Cells Exposed To Lipid.
Funder
National Health and Medical Research Council
Funding Amount
$425,250.00
Summary
The project is aimed at a better understanding of the way in which fats control gene expression in the pancreatic beta cells of the islets of Langerhans. Because changes in gene expression are to likely to explain why exposure of these cells to fat disrupts their ability to release insulin, identification of these genes could explain why only some obese people develop Type 2 diabetes.
Mechanisms Of Fatty-acid Mediated Destruction Of Pancreatic Beta Cells
Funder
National Health and Medical Research Council
Funding Amount
$510,476.00
Summary
Type 2 diabetes is associated with obesity, but not all obese individuals develop the disease. Non-diabetic obese subjects are able to compensate for diminished sensitivity to insulin (a general feature of obesity) by enhanced output of insulin from the pancreatic beta-cells of the islet of Langerhans. In diabetics this compensatory mechanism is disrupted. Obesity and Type 2 diabetes are also associated with elevated levels of fatty acids (FAs) in the bloodstream. These can be taken up by the be ....Type 2 diabetes is associated with obesity, but not all obese individuals develop the disease. Non-diabetic obese subjects are able to compensate for diminished sensitivity to insulin (a general feature of obesity) by enhanced output of insulin from the pancreatic beta-cells of the islet of Langerhans. In diabetics this compensatory mechanism is disrupted. Obesity and Type 2 diabetes are also associated with elevated levels of fatty acids (FAs) in the bloodstream. These can be taken up by the beta-cells where they exert both short and long-term effects. In the longer term FAs can be toxic to beta-cells and this is thought to be important in the failure of beta-cell compensation. The project is aimed at a better understanding of the manner by which different types of FAs influence the susceptibility of beta-cells to destruction. It builds on our preliminary results suggesting that the capacity of the beta-cell to convert saturated FAs to unsaturated FAs helps protect them from destruction. Our aim is to examine the mechanisms underlying this protection.Read moreRead less
Influence Of TNF And TGF-beta On Langerhans Cell Mobilisation From Regressor And Progressor Skin Tumours
Funder
National Health and Medical Research Council
Funding Amount
$227,036.00
Summary
Skin cancer is the most common type of cancer in humans. It is caused by the ultraviolet wavelengths found in sunlight. Australia has the highest incidence of skin cancer in the world, due to the large amount of sun exposure experienced by Australians during work and leisure. Considerable research needs to be directed towards this disease to understand how it forms and how it can be treated. Skin cancer can be controlled by the immune system, which in some cases is able to destroy the cancer, so ....Skin cancer is the most common type of cancer in humans. It is caused by the ultraviolet wavelengths found in sunlight. Australia has the highest incidence of skin cancer in the world, due to the large amount of sun exposure experienced by Australians during work and leisure. Considerable research needs to be directed towards this disease to understand how it forms and how it can be treated. Skin cancer can be controlled by the immune system, which in some cases is able to destroy the cancer, so that it disappears, or regresses. Other skin tumours fail to be destroyed by the immune system and therefore grow progressively. Differences between progressor and regressor tumours can help define why the immune system is able to destroy some but not other tumours. The cell of the immune system that is responsible for initiating immune responses against skin cancer is called the Langerhans cell. This cell migrates between the cancer and the local lymph node, where it activates lymphocytes to leave the lymph node and destroy the cancer. Our studies have shown that a major difference between progressor and regressor skin tumours is the ability of Langerhans cells to migrate from these tumours. Skin tumours produce cytokines (hormone like molecules) which enhance or inhibit Langerhans cell mobilization from the tumour. We have identified some of the cytokines involved, and plan to study how these cytokines interfere with this process and whether they do this by increasing the production of other factors, or by having a direct influence on the Langerhans cells. This knowledge would increase our ability to utilize these cells for treatment of cancer. This study will also further basic understanding of the biological factors which regulate the movement of this important cell from our tissues to the draining lymph node, which is of fundamental importance in the development of immunity.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
Investigating The Novel Role Of SEPS1 In The Prevention Of Islet Beta Cell Failure And Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$535,804.00
Summary
SEPS1 is an important glucose-regulated protein whose function is to protect tissues from oxidative stress. Inhibition of SEPS1 by hyperglycaemia, is a mechanism for progression of Type 1 and Type 2 diabetes once hyperglycaemia supervenes. The overall aim of the project is to investigate the function of the novel SEPS1, using transgenic and knockout approaches.
Defining The Mechanisms That Control Exocytosis And Cell Signalling In Health And Disease.
Funder
National Health and Medical Research Council
Funding Amount
$473,477.00
Summary
This research focuses on pathways regulating nervous communication and hormone release. It centres on proteins that regulate this process and on the function of specific endocrine cells in health and disease. It uses unique research tools developed in this laboratory enabling the study of mechanisms regulating cell signalling. Through this research I aim to identify how the cells in our body communicate with each other and how this relates to diseases such as type 2 diabetes.