Investigation Of Transgenic Mouse Models Of Type 2 Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$412,200.00
Summary
Type 2 diabetes is a common condition characterised by high blood glucose, that afflicts 700,000 Australians. It causes blindness, kidney failure and an increased risk of heart attack and stroke. despite intensive study over many years, the reasons for the elevated blood glucose in this condition are not fully understood. Several abnormalities can contribute to the high glucose and different researchers have proposed different defects as the initial cause. It has proven difficult to unravel the ....Type 2 diabetes is a common condition characterised by high blood glucose, that afflicts 700,000 Australians. It causes blindness, kidney failure and an increased risk of heart attack and stroke. despite intensive study over many years, the reasons for the elevated blood glucose in this condition are not fully understood. Several abnormalities can contribute to the high glucose and different researchers have proposed different defects as the initial cause. It has proven difficult to unravel the sequence of events in the evolution of the syndrome because high glucose can cause insulin resistance and a defect in insulin secretion, both of which can lead to high blood glucose. One approach to study the consequences of specific defects is to genetically engineer them. The aims of this project are to: 1. make a mouse with reduced ability to store glucose in muscle. 2. test the metabolic consequences of a defect in the manufacture of glycogen (starch) in muscle. 3. study the effects of combining a defect in glucose storage with one that results in an oversupply of glucose. 4. study the effects on a mouse with a genetic predisposition for failure of beta cells (insulin making cells) of a defect in muscle glucose storage and over production of glucose. A successful completion of this grant will greatly enhance our understanding of how blood glucose is increased in Type 2 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.
Comparison Between AICAR And Exercise-induced Stimulation Of Skeletal Muscle AMP-K On Fat/glucose Metabolism In Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$347,036.00
Summary
Background and Rationale: Exercise is important in the life of the diabetic. In well controlled diabetes, the rates of whole body sugar usage and energy production in skeletal muscle (SkM) in response to acute exercise are similar to non-diabetics. However in diabetics, little information is available as to how SkM processes sugar and produces energy during exercise. Insulin controls SkM sugar and energy processing in sedentary subjects. During exercise, these processes are controlled by non-ins ....Background and Rationale: Exercise is important in the life of the diabetic. In well controlled diabetes, the rates of whole body sugar usage and energy production in skeletal muscle (SkM) in response to acute exercise are similar to non-diabetics. However in diabetics, little information is available as to how SkM processes sugar and produces energy during exercise. Insulin controls SkM sugar and energy processing in sedentary subjects. During exercise, these processes are controlled by non-insulin factors. The chemical catalyst AMP activated protein kinase (AMP-K), which has been investigated only in normal exercising rats, is an important alternative regulator of acute sugar processing and energy supply for exercising SkM. No studies of AMP-K activity are available in diabetes. Our studies will focus on i) how important is the stimulation of SkM AMP-K in diabetes to efficient SkM sugar processing and energy production; ii) if the benefits of exercise can be simulated by pharmacological stimulation of AMP-K in sedentary diabetic subjects. We aim to i) compare the metabolic effects of exercise vs pharmacological stimulation of AMP-K in normal and diabetic subjects; ii) define the molecular mechanisms which trigger the AMP-K metabolic responses; iii) determine if the circulating levels of insulin, blood sugar and-or blood fat influence the AMP-K metabolic responses. Likely Outcomes: pharmacological stimulation of AMP-K will improve SkM sugar metabolism, but less so in diabetes. The associated AMP-K stimulation of SkM fat metabolism may blunt the beneficial SkM sugar responses, particularly in diabetes. This information will be used in future drug developments for diabetics which aim to simulate the beneficial AMP-K metabolic effects of exercise.Read moreRead less
Functional Effects Of Polymorphic Variation Of The Aromatase (CYP19) Gene On Enzyme Activity:relationship To Disease
Funder
National Health and Medical Research Council
Funding Amount
$237,708.00
Summary
After menopause, oestrogen synthesis changes from an ovarian to an adipose source by concersion of androgens to estrogens, a process catalyzed by aromatase, the product of the CYP19 gene. We will generate mutants of the CYP19 gene that we have previously found in humans by site-directed mutagenesis and observe the effects of these mutants on aromatase function. This research will help with diagnosis and treatment of breast and other cancers and osteoporosis in humans .
The Role Fructose-1,6-bisphosphatase On The Regulation Of Hepatic Gluconeogenesis
Funder
National Health and Medical Research Council
Funding Amount
$212,485.00
Summary
Type 2 or adult onset diabetes is a disease characterised by high blood sugar that causes damage to the kidneys, eyes and to the circulation and many patients die from heart attack or stroke. There is an increase in the prevalence of diabetes in Australia and a substantial portion of the health budget is utilised by caring for people with diabetes. Determining what exactly causes the increase in blood sugar levels is critical in the treatment of the disease. It is known that the sugar produced a ....Type 2 or adult onset diabetes is a disease characterised by high blood sugar that causes damage to the kidneys, eyes and to the circulation and many patients die from heart attack or stroke. There is an increase in the prevalence of diabetes in Australia and a substantial portion of the health budget is utilised by caring for people with diabetes. Determining what exactly causes the increase in blood sugar levels is critical in the treatment of the disease. It is known that the sugar produced and released by the liver is an important contributor to the high blood sugar levels found in patients with diabetes. The main biochemical pathway responsible for this is called gluconeogenesis, a complex arrangement of enzymes, which convert amino acids and fat into sugar. Although it is known that this pathway is overactive in patients with diabetes, the exact reason for this is not clearly understood. The aim of this proposal is to produce a transgenic mouse that has an increase in liver sugar production as a result of an increase in gluconeogenesis, and to study its effects on blood sugar levels. Furthermore, studies will be performed to understand the regulation of this pathway by infusing the transgenic mice with insulin, the hormone that inhibits gluconeogenesis. The mechanism of action of insulin will be determined by the measurement of key enzymes that regulate gluconeogenesis. The significance of this grant is to identify possible sites for the development of new drugs or gene therapy that will lead to a decrease in the production of sugar by the liver. This will lead to better control of blood sugar levels and slow down or even prevent the onset of diabetes complications.Read moreRead less
Protein Tyrosine Phosphatases In The Regulation Of Insulin Receptor Signalling And Glucose Uptake
Funder
National Health and Medical Research Council
Funding Amount
$425,250.00
Summary
The key pathological feature of type II diabetes is the lack of cellular response to normal levels of circulating insulin. Insulin binding to its cell surface transmembrane receptor initiates a cascade of events known as cellular signalling that results in amongst other things in the uptake of glucose. Protein tyrosine phosphatases (PTPs) are key negative regulators of insulin-induced signalling events and their inhibition with broad based chemical inhibitors can mimic several actions of insulin ....The key pathological feature of type II diabetes is the lack of cellular response to normal levels of circulating insulin. Insulin binding to its cell surface transmembrane receptor initiates a cascade of events known as cellular signalling that results in amongst other things in the uptake of glucose. Protein tyrosine phosphatases (PTPs) are key negative regulators of insulin-induced signalling events and their inhibition with broad based chemical inhibitors can mimic several actions of insulin and lower blood glucose levels in both normal and diabetic rats. This proposal will examine the roles of PTPs and in particular TCPTP and PTP1B in insulin receptor-mediated signalling and glucose uptake. Moreover we will explore the role of TCPTP in alternate insulin receptor-independent processes for glucose uptake. Our studies will shed light on processes important for the regulation of glucose uptake. Moreover our studies may lead to the development of drugs capable of inhibiting PTPs such as TCPTP, that may allow for enhanced glucose uptake and have therapeutic use in the treatment of type II diabetes.Read moreRead less
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
Type 2 diabetes (T2D) is threatening the health of this nation and if unchecked will cripple our health care system. There are several problems: (1) The incidence of T2D is growing and we do not fully know why; (2) T2D involves defective insulin action but how insulin works normally is still unclear; (3) much research in this area is performed in laboratory cells or animals and the translation of this research to the human disease is yet to be fully realised; and (4) current therapies and diagno ....Type 2 diabetes (T2D) is threatening the health of this nation and if unchecked will cripple our health care system. There are several problems: (1) The incidence of T2D is growing and we do not fully know why; (2) T2D involves defective insulin action but how insulin works normally is still unclear; (3) much research in this area is performed in laboratory cells or animals and the translation of this research to the human disease is yet to be fully realised; and (4) current therapies and diagnostic markers for early disease prediction are inadequate. Our goal is to make progress in each of these areas.Read moreRead less
Inhibition Of Glucose-stimulated Insulin Secretion By Protein Kinase C Epsilon
Funder
National Health and Medical Research Council
Funding Amount
$555,693.00
Summary
Type 2 diabetes is a chronic disease which occurs when the pancreas is unable to produce enough insulin for the body to cope with rising blood glucose levels after a meal, and is strongly linked to obesity. We have discovered that fat oversupply activates an enzyme in the pancreas causing defects in insulin release due to glucose. Inhibiting this enzyme helps overcome diabetes, through poorly defined mechanisms that we aim to clarify here. Our work could lead to new therapies for diabetes.
Therapeutic Regulation Of Hepatic Steatosis And Lipid Transport In The Metabolic Syndrome
Funder
National Health and Medical Research Council
Funding Amount
$522,435.00
Summary
Obesity is an increasing problem in Australia. Elevated fat levels in the liver and blood are associated with obesity and increased risk for heart disease. In this project, we will demostrate new mechanisms of action of Pioglitazone (an insulin-sensitizing agent) and Omacor (fish oils) that will complement the favourable efect of weight loss in the treatment of elevated blood fats and reduction in risk of heart disease in an important groups of subject in the population.