Mechanisms Of Insulin Resistance And Diabetes Susceptibility
Funder
National Health and Medical Research Council
Funding Amount
$633,783.00
Summary
The two main forms of diabetes - types 1 (T1D) and 2 (T2D) - pose a major problem. It is difficult to identify what causes diabetes. Recently, people at risk of T1D were found to have insulin resistance, a condition thought typical only of T2D. Excitingly, we discovered that the best T1D animal model also shows insulin resistance, and we used it to map important genes. We will now identify these genes. This will help us understand the disease process and to develop better treatments for it.
Regulation Of Insulin Signalling And Glucose Homeostasis By Protein Tyrosine Phosphatases
Funder
National Health and Medical Research Council
Funding Amount
$542,462.00
Summary
A common feature of type 2 diabetes is high blood glucose due to peripheral insulin resistance. Protein tyrosine phosphatases (PTPs) that antagonise insulin signalling might be important targets for therapeutic intervention in type 2 diabetes; inhibition of specific PTPs may allow for enhanced IR signalling to alleviate insulin resistance. This proposal will examine the roles of PTPs and in particular TCPTP in insulin signalling and glucose homeostasis.
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
The Role Of Vitamin D In Beta Cell Function, Glucose Tolerance And Diabetes Mellitus.
Funder
National Health and Medical Research Council
Funding Amount
$102,820.00
Summary
A significant proportion of Australians are deficient in Vitamin D, a vitamin obtained from sunlight exposure and to a lesser extent from food. Vitamin D deficiency has been associated with increased risk of Type 2 diabetes. This study aims to demonstrate the mechanisms through which vitamin D affects the insulin-producing cells of the pancreas and to determine whether deficiency affects the body's handling of glucose and subsequent risk of Type 2 diabetes and diabetes in pregnancy.
Understanding The Cause And Consequence Of Impaired Insulin Secretion In The NZO Mouse A Model Of Diabetes.
Funder
National Health and Medical Research Council
Funding Amount
$711,224.00
Summary
Type 2 diabetes is a major health problem affeting over 1 million Australians. A key feature of this disease is reduced secretion of the pancreratic hormone insulin which results in high blood sugar levels. We are using a naturally occurring animal model of diates called the NZO mouse to understand why the pancreas secretes less insulin and the consequences of this defect. This project has the potential of providing better therapeutic strategies for patients with Type 2 diabetes.
Expansion, Differentiation And Functional Analysis Of In Vitro Derived Pdx1+ Pancreatic Progenitors
Funder
National Health and Medical Research Council
Funding Amount
$540,075.00
Summary
Type 1 diabetes is a condition that arises when the body's immune system destroys insulin-producing beta cells within the pancreas. Recent studies have shown that normal glucose control can be restored by replacing the missing beta cells by transplantation of cells from deceased donors. However, the demand for transplant material outweighs supply. The work described in this application seeks to define how insulin-producing beta cells can be derived in the laboratory from embryonic stem cells .
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
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
L-amino Acid Sensing By The Extracellular Calcium-sensing Receptor: Molecular, Cellular And In Vivo Studies
Funder
National Health and Medical Research Council
Funding Amount
$362,545.00
Summary
Recent work by Dr Conigrave and colleagues demonstrates for the first time that protein and calcium metabolism are linked at the molecular level by the widely distributed calcium-sensing receptor. The project will aim to demonstrate the physiological significance of this finding by testing whether L-amino acids, the building blocks of body protein, exert receptor-dependent control over the secretion and blood levels of hormones that regulate body calcium levels. It will further test the hypothes ....Recent work by Dr Conigrave and colleagues demonstrates for the first time that protein and calcium metabolism are linked at the molecular level by the widely distributed calcium-sensing receptor. The project will aim to demonstrate the physiological significance of this finding by testing whether L-amino acids, the building blocks of body protein, exert receptor-dependent control over the secretion and blood levels of hormones that regulate body calcium levels. It will further test the hypothesis by determining whether amino acids exert receptor-dependent control over the proliferation of bone forming cells and urinary excretion of calcium.Read moreRead less