The Regulation Of Insulin Action In Liver And Skeletal Muscle By Protein Kinase C Epsilon
Funder
National Health and Medical Research Council
Funding Amount
$647,604.00
Summary
We have identified an enzyme, protein kinase C epsilon, which has a major negative impact on the control of blood glucose levels. We will now examine the mechansisms by which it affects insulin action in liver and muscle, two major target tissues of the hormone responsible for glucose disposal. This work is expected to validate PKCepsilon or its downstream effectors as therapeutic targets in the treatment of the insulin resistance which accompanies obesity and Type 2 diabetes.
Role Of Impaired Insulin Signalling In Fatty Acid-induced Muscle Insulin Resistance In Vivo
Funder
National Health and Medical Research Council
Funding Amount
$481,500.00
Summary
Type 2 diabetes represents an escalating global health problem. In Australia 7.5% of the population has diabetes and another 16% insulin resistance (impaired action of insulin in tissues). As well as diabetes, insulin resistance is closely associated with obesity, dyslipidaemia, hypertension and cardiovascular diseases (Syndrome X). While genetic factors play a role, a high caloric intake (particularly with a high fat content) and a sedentary lifestyle are extremely important environmental contr ....Type 2 diabetes represents an escalating global health problem. In Australia 7.5% of the population has diabetes and another 16% insulin resistance (impaired action of insulin in tissues). As well as diabetes, insulin resistance is closely associated with obesity, dyslipidaemia, hypertension and cardiovascular diseases (Syndrome X). While genetic factors play a role, a high caloric intake (particularly with a high fat content) and a sedentary lifestyle are extremely important environmental contributors to Syndrome X and diabetes. From evidence that we and others have obtained over the last few years it is now evident that an important mediator of insulin resistance is the quantity of fat molecules which accumulate in muscle and liver. This project examines mechanisms whereby this fat accumulation can disrupt the signalling mechanism normally causing increased glucose metabolism in response to insulin. While basic experiments in cell systems have identified some candidates, a need exists to demonstrate whether they actually cause the insulin resistance in the whole animal or human, or are merely associated with it. We will combine metabolic-physiological studies with a novel technique we have recently established in our laboratory for introducing DNA into skeletal muscle of laboratory animal models. We now aim to exploit this approach to obtain more definitive data about the importance of insulin signalling changes to insulin resistance. Two major steps in insulin signalling will be investigated, involving the insulin receptor substrate proteins and the kinase Akt-PKB, both strongly implicated in lipid-induced insulin resistance. This knowledge will be invaluable in improving strategies to lessen or prevent lipid-associated insulin resistance, a major contributor to the metabolic derangement in Type 2 diabetes and Syndrome X.Read moreRead less
Defining The Insulin-signalling Defect In Human Insulin Resistance And Type 2 Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$94,280.00
Summary
Problems with the way insulin removes glucose from the circulation contribute to developing type 2 diabetes. Despite research to date, controversy remains regarding the nature of known defects in insulin action and their relevance to humans. We plan to measure molecules involved in insulin action in muscle of people with insulin resistance, which is linked to diabetes. These studies will define new defects that cause insulin resistance and type 2 diabetes in humans.
Dilinoleoyl Phosphatidic Acid As A Novel Mediator Of Insulin Resistance In Muscle
Funder
National Health and Medical Research Council
Funding Amount
$504,097.00
Summary
We have identified a novel fat molecule in muscle which may play an important role in causing insulin resistance during obesity, a major factor in the development of Type 2 diabetes. We will now examine whether depletion of this molecule, dilinoleoyl-phosphatidic acid, can improve insulin action in muscles and in obese mice, and investigate the mechanisms by which it may act. This work may indicate new strategies for the treatment of diabetes.
The Clinicial Centre Of Research Excellence At The Jean Hailes Foundation: For The Study Of Women's Health
Funder
National Health and Medical Research Council
Funding Amount
$2,000,000.00
Summary
The major health issues affecting women from the mid-reproductive years include depression, disorders of mood and sexual function, and breast cancer, with cardiovascular disease, osteoporosis, and osteoarthritis becoming increasingly prevalent with age. Linking each of these are their known or probable causal associations with oestrogens and androgens. This Centre will provide an opportunity for comprehensive and multidisciplinary research into the role of oestrogens and androgens in these disor ....The major health issues affecting women from the mid-reproductive years include depression, disorders of mood and sexual function, and breast cancer, with cardiovascular disease, osteoporosis, and osteoarthritis becoming increasingly prevalent with age. Linking each of these are their known or probable causal associations with oestrogens and androgens. This Centre will provide an opportunity for comprehensive and multidisciplinary research into the role of oestrogens and androgens in these disorders.Read moreRead less
NR1F (ROR) Nuclear Hormone Receptors And Metabolism: Insights Into The Control Of Lipid Homeostasis.
Funder
National Health and Medical Research Council
Funding Amount
$581,892.00
Summary
ROR is a member of a gene family, that regulates reproduction, endocrine physiology, and metabolism, and are important in human health. ROR function remains illusive. However, it is expressed in liver, fat and muscle, tissues that (i) modulate blood lipids, insulin sensitivity and energy balance, and (ii) have an important role in diabetes and obesity. Understanding ROR function in metabolism provides the opportunity for the discovery of new pathways that ameliorate metabolic disease.
A Novel Mechanism For Manipulation Of Peripheral Glucose Utilization In Patients With Type 2 Diabetes Mellitus.
Funder
National Health and Medical Research Council
Funding Amount
$283,500.00
Summary
Significance: Over 600,000 Australians have type 2 diabetes (approximately half are undiagnosed) and it is estimated that this number will increase substantially to 10% of the adult population over the next 10 years. At the conclusion of this grant we expect to understand whether specific signalling molecules might plausibly represent the basis of a novel therapeutic approach to control blood glucose. If successful, this work could contribute to improved metabolic control and prevention of diabe ....Significance: Over 600,000 Australians have type 2 diabetes (approximately half are undiagnosed) and it is estimated that this number will increase substantially to 10% of the adult population over the next 10 years. At the conclusion of this grant we expect to understand whether specific signalling molecules might plausibly represent the basis of a novel therapeutic approach to control blood glucose. If successful, this work could contribute to improved metabolic control and prevention of diabetic complications through new blood glucose lowering agents. Hypotheses: Muscle is the major site of glucose disposal in the body and the two most relevant stimuli for glucose uptake into muscle are insulin and muscle contraction (exercise). The insulin pathway is impaired in patients with type 2 diabetes leading to high blood glucose and complications. Glucose uptake in response to exercise however appears to be normal in patients with type 2 diabetes. Indeed we have evidence to suggest that this pathway may compensate for impaired insulin action in type 2 diabetes. We hypothesise that molecules activated by contraction (exercise) may be useful as therapies to improve resting glucose control in type 2 diabetic patients. Aims: We plan a series of three studies to examine whether glucose uptake may be improved both acutely and chronically at rest by an agent implicated in exercise mediated glucose uptake.Read moreRead less
Molecular Regulation Of Metabolism And Body Composition By Ski Via Crosstalk With Nuclear Hormone Receptor Signalling.
Funder
National Health and Medical Research Council
Funding Amount
$558,441.00
Summary
Obesity is a common and burdensome health problem in the community which leads to diabetes and heart disease. A number of factors, including hormones play important roles in determing risk of obesity. This study proposes to investigate whether the Ski gene which is a regulatory factor for many hormones affects metabolism in transgenic mouse models of altered Ski function. The proposed studies may identify Ski as a target for therapy for obesity and improvement in sketal muscle metabolism.