Novel Metabolic Actions Of HDL With Therapeutic Potential For Type 2 Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$559,471.00
Summary
Our proposal investigates a novel approach to treat type 2 (late onset) diabetes. We have identified an important link between HDL (good) cholesterol and glucose metabolism. The current proposal is to conduct studies in humans to determine whether therapies which increase HDL result in sustained reduction of blood glucose. Given the escalating global prevalence of obesity and type 2 diabetes, this work is potentially of great significance.
Brown fat protects animals against obesity and diabetes. Humans with abundant brown fat are metabolically healthy. Identification of medication that boosts brown fat function may lead to novel treatment of metabolic disorders. This proposal will examine the role of such a medication, which is modeled on a factor (called FGF21) released from brown fat. The project will also search for other factors released by human brown fat, which may become future targets of obesity treatment.
Understanding Sphingolipid Mediators Of Insulin Resistance
Funder
National Health and Medical Research Council
Funding Amount
$643,447.00
Summary
Sphingolipids are a class of lipid metabolites that have a variety of functions within cells. It has been known for some time that an accumulation of excess lipid, including certain sphingolipids, can adversely impact insulin action and glucose metabolism in cells. In this project we will a combination of strategies to test the hypothesis that the sphingolipid profile can be manipulated to have favourable effects on metabolism.
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
Targeting Ceramide Metabolism To Improve Lipid-induced Insulin Resistance
Funder
National Health and Medical Research Council
Funding Amount
$604,327.00
Summary
We have shown that the buildup of ceramide in muscle plays a key role in the inhibition of normal insulin action when the body is exposed to excessive amounts of fat, which leads to poor control of blood sugar levels and Type 2 diabetes. Using mass spectrometry we will now measure different ceramide types, to investigate which contribute to defects in insulin action. We will also examine whether enzymes involved in ceramide formation or degradation can be targeted to improve insulin responses.
Novel Interplay Of Oestrogen And Growth Hormone In Regulating Lipid Metabolism
Funder
National Health and Medical Research Council
Funding Amount
$673,045.00
Summary
These studies provide insights into the mechanisms and role of oestrogen in regulating whole body and liver fat metabolism. Oestrogen-related medications that modify the action or tissue availability of oestrogen are widely used therapeutics and can predispose to obesity and fat accumulation in the liver. Whether the effect is direct or through interplay with other metabolic hormones is unknown. This proposal examines their metabolic consequences and impact on obesity and liver health.
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
Inosine-5' Monophosphate Dehydrogenase (IMPDH) is an enzyme responsible for providing a form of energy to cells, so that they may undertake their correct functions. Recently, we have demonstrated that IMPDH also has a role in the formation of fat droplets within cells, when they are exposed to excessive nutrients. In mammals, excess consumed energy is stored as fat droplets within all cells. In fat cells, the energy is stored in very large droplets, and we see this as extra body fat. This is som ....Inosine-5' Monophosphate Dehydrogenase (IMPDH) is an enzyme responsible for providing a form of energy to cells, so that they may undertake their correct functions. Recently, we have demonstrated that IMPDH also has a role in the formation of fat droplets within cells, when they are exposed to excessive nutrients. In mammals, excess consumed energy is stored as fat droplets within all cells. In fat cells, the energy is stored in very large droplets, and we see this as extra body fat. This is sometimes associated with an alteration in the hormone production of the cells, leading to problems such as diabetes. In other cells, the excess energy is stored as tiny fat droplets (lipid bodies) that can adversely affect the function of the cell. We have shown that blocking the action of IMPDH can interfere with the accumulation of fat in both fat cells and other types of cell. This suggests that IMPDH has an important role in the development of obesity and associated problems such as diabetes. In this study we aim to investigate in detail the role of IMPDH in the accumulation of fat droplets in cells. We will do this by looking at the effects of different forms of IMPDH in different cell types, including human fat cells. We will also study cells and animals with increased or decreased amounts of IMPDH, and investigate the effects of this on the development of increased fat stores and insulin resistance. These studies will increase our understanding of the role of IMPDH in the development of obesity, and may lead to identification of new avenues of treatment for obesity and type 2 diabetes.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