Non-alcoholic steato-hepatitis (NASH) is a common disease of liver inflammation and scarring, which may progress to cirrhosis or liver cancer. While type 2 diabetes causes a higher rate of NASH and more rapid NASH progression the reasons for this are not clear. We have developed a novel animal model of NASH with diabetes added to dietary induced obesity. We show that a growth factor is elevated in the affected livers. We plan to block the growth factor to see if we can prevent NASH worsening.
Activin Type II Receptor Antagonists: Mechanism Of Action And Biological Applications
Funder
National Health and Medical Research Council
Funding Amount
$507,270.00
Summary
Activin is a member of the TGF- family of growth and differentiation factors. Over-expression in mice leads to muscle and liver wasting, scarring during wound healing, disturbances to the reproductive system and various endocrine disorders. Activin's biological activity is promoted by its binding in series to two receptors termed Type I and II. Previous studies by this investigator have shown that selective modification of activin's protein structure can result in activin forms (in this instance ....Activin is a member of the TGF- family of growth and differentiation factors. Over-expression in mice leads to muscle and liver wasting, scarring during wound healing, disturbances to the reproductive system and various endocrine disorders. Activin's biological activity is promoted by its binding in series to two receptors termed Type I and II. Previous studies by this investigator have shown that selective modification of activin's protein structure can result in activin forms (in this instance called activin-M108A) which bind to Type II receptors but fail to promote binding to the Type I receptor. This has led to the hypothesis that activin-M108A may compete for native activin binding to Type II receptors and thus prevent activin's recruitment of the Type I receptor with the consequence that activin's biological activity is inhibited. It is proposed to test this hypothesis by producing sufficient amounts of activin-M108A and testing its inhibitory effects in several mouse models of liver damage, muscular degeneration and ovarian and testicular disease. If activin-M108A, or related modified forms of activin, decrease the morbidity and mortality associated with these murine diseases, then we envisage that these activin type II receptor antagonists will also be beneficial for the treatment of related human conditions.Read moreRead less
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
Dietary Fats As Drivers Of Obesity-related Inflammation
Funder
National Health and Medical Research Council
Funding Amount
$336,767.00
Summary
Obesity leads to diabetes and heart disease but not all body fat seems to be bad. Increased fat around the waist (especially the visceral fat around the intestine and internal organs) is particularly bad. Visceral fat secretes a lot of inflammatory molecules. This research aims to understand how visceral fat becomes inflamed and how we might use diet and other methods to reduce both the amount of visceral fat and its level of inflammation; thus reducing both obesity and its health consequences.
The Relationship Between Non-Alcoholic Fatty Liver Disease And Type 2 Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$133,351.00
Summary
Non alcoholic Fatty Liver Disease (NAFLD) threatens to become a major public health problem. Its increasing prevalence is associated with parallel increases in obesity and diabetes. This study aims to understand the mechanisms involved in progression to liver failure and liver cancer in the setting of diabetes and the impact of NAFLD on blood sugar levels and diabetes complications (esp. cardiovascular). Using a recently developed animal model of type 2 diabetes and fatty liver, it will better d ....Non alcoholic Fatty Liver Disease (NAFLD) threatens to become a major public health problem. Its increasing prevalence is associated with parallel increases in obesity and diabetes. This study aims to understand the mechanisms involved in progression to liver failure and liver cancer in the setting of diabetes and the impact of NAFLD on blood sugar levels and diabetes complications (esp. cardiovascular). Using a recently developed animal model of type 2 diabetes and fatty liver, it will better define a novel therapeutic agent.Read moreRead less
Mechanisms Of The Insulin-sensitising Effects Of AMPK Activation In Liver And Muscle.
Funder
National Health and Medical Research Council
Funding Amount
$454,500.00
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). Insulin resistance is closely associated with obesity, dyslipidemia, hypertension and cardiovascular diseases (Syndrome X) as well as diabetes. A high caloric intake (particularly with a high fat content) and a sedentary lifestyle are extremely important environmental contributors to Syndrome X and diabetes. One of the m ....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). Insulin resistance is closely associated with obesity, dyslipidemia, hypertension and cardiovascular diseases (Syndrome X) as well as diabetes. A high caloric intake (particularly with a high fat content) and a sedentary lifestyle are extremely important environmental contributors to Syndrome X and diabetes. One of the most exciting developments in the past few years has been the discovery that an enzyme, AMP kinase (AMPK), normally activated by exercise, may be involved in its beneficial effects. We have contributed to this exciting field by showing in an animal model that one dose of AICAR, a chemical agent which can activate AMPK, ameliorates the effects of insulin resistance in muscle and liver. Further very recent work has linked AMPK with various drugs (particularly glitazones and metformin) and hormones which can enhance insulin sensitivity. The goal of the experiments in this project is to determine the overall mechanism by which AMPK has ameliorating effects on counteracting insulin resistance. We hypothesize that the mechanism for this involves an effect of AMPK to reduce fat molecules accumulating within muscle and liver cells, and our studies will examine this hypothesis. Our studies should lead to a better understanding of how exercise and pharmacological activators of AMPK help in management of diabetes and insulin resistant states. In addition because AMPK activation enhances glucose metabolism by a separate pathway to insulin, it offers promise of developing compounds able to bypass metabolic steps impaired by insulin resistance. Our studies should help in the design of new therapeutic agents which can counteract insulin resistance.Read moreRead less
Correction Of Diabetes In An Autoimmune Model Using Insulin-secreting Liver Cells.
Funder
National Health and Medical Research Council
Funding Amount
$472,500.00
Summary
Type I diabetes mellitus is caused by the autoimmune destruction of the beta cells of the pancreas that secrete insulin. The problems of the chronic complications of diabetes and the lack of donor tissue for transplantation, could theoretically be overcome by engineering from the patient's own cells, an artificial beta cell, i. e. a non-islet cell capable of synthesising, storing and secreting mature insulin in response to metabolic stimuli, such as glucose. The ultimate goal of this technology ....Type I diabetes mellitus is caused by the autoimmune destruction of the beta cells of the pancreas that secrete insulin. The problems of the chronic complications of diabetes and the lack of donor tissue for transplantation, could theoretically be overcome by engineering from the patient's own cells, an artificial beta cell, i. e. a non-islet cell capable of synthesising, storing and secreting mature insulin in response to metabolic stimuli, such as glucose. The ultimate goal of this technology is to deliver the insulin gene directly to a patient's own liver cells which would regulate insulin secretion in response to glucose and other substances that stimulate insulin secretion, controlling blood glucose without the need for immunosuppression. To accomplish this it must be possible to deliver the insulin gene efficiently to primary liver cells (cells derived from an animal's or human's body). Results from our laboratory using a non-pathogenic viral delivery system indicate that we can reverse diabetes in chemically induced diabetic rats by expression of insulin and a beta cell transcription factor NeuroD. The aim of this study is to repeat this in an auto-immune model of diabetes the nonobese diabetic mouse, which mimicks very closely the development of diabetes in humans. We will determine if we can reverse diabetes in these animals and determine if their response to glucose is normal over an extended period of time, with no attack by the factors of the immune system that stimulate the development of diabetes in man. The results from this research proposal should result in the delivery of the insulin gene to large numbers of primary liver cells that will then synthesise, store and secrete insulin in response to glucose. These cells would control blood glucose levels in patients without the need for immunosuppression.Read moreRead less