Mitochondrial Sirtuins, Energy Metabolism And Insulin Action
Funder
National Health and Medical Research Council
Funding Amount
$582,925.00
Summary
Post-translational modification of lysine residues has a major influence on protein function. Many mitochondrial proteins are affected by lysine modifications and recent work has described a role for sirtuin enzymes in regulating these processes. This proposal will investigate whether targeted increases in sirtuin activity can improve mitochondrial function and insulin action in mouse models of obesity and insulin resistance.
The proposal focuses on a novel angle explaining how pancreatic beta cells normally match their insulin synthesis, storage and secretion in response to an enhanced demand as occurs during obesity, and how this fails in the progression to Type 2 diabetes. In particular we will expand our discovery that glucose rapidly enhances the synthesis of a novel factor regulating gene transcription. This will generate basic knowledge that will potentially help design of novel therapies for Type 2 diabetes.
Ceramide Metabolism And ER Stress In Fatty-acid Mediated Destruction Of Pancreatic Beta Cells
Funder
National Health and Medical Research Council
Funding Amount
$549,092.00
Summary
The underlying cause of Type 2 diabetes is the failure of pancreatic beta cells to secrete sufficient insulin to overcome the insulin resistance that is associated with obesity. Beta cell failre is associated with both defective insulin secretion and loss of beta cell mass. This proposal focuses on the cellular mechanisms and stress pathways whereby too much fatty acid promotes beta cell death.
Investigation Of The Mechanism By Which Medium Chain Fatty Acids Prevent The Development Of Obesity And Insulin Resistance - What Role For GPR84?
Funder
National Health and Medical Research Council
Funding Amount
$512,541.00
Summary
Medium chain fatty acids do not induce the same degree of obesity and insulin resistance as long chain fatty acids and this is due to changes in metabolism in skeletal muscle and adipose tissue. In this proposal we will investigate whether medium chain fatty acids induce their beneficial effects by interacting with a specific G protein-coupled receptor named GPR84. This receptor may be a new therapeutic target for the treatment of metabolic diseases.
Molecular Determinants Of Amino Acid-dependent Signalling By The Calcium-sensing Receptor
Funder
National Health and Medical Research Council
Funding Amount
$566,035.00
Summary
Amino acids are the building blocks of proteins and an alternative energy source to carbohydrate and fat. Proteins are major structural components of our bodies. They also fulfil an amazing diversity of cellular and bodily functions acting, for example, as enzymes (biological catalysts), receptors, molecular chaperones and biological machines. Thus, amino acids are key nutrients and the human body has developed mechanisms for tightly regulating cellular responses depending upon their levels in b ....Amino acids are the building blocks of proteins and an alternative energy source to carbohydrate and fat. Proteins are major structural components of our bodies. They also fulfil an amazing diversity of cellular and bodily functions acting, for example, as enzymes (biological catalysts), receptors, molecular chaperones and biological machines. Thus, amino acids are key nutrients and the human body has developed mechanisms for tightly regulating cellular responses depending upon their levels in blood. Identifying amino acid sensing molecules and identifying the mechanisms they use to control cellular responses is thus a key issue in human biology. The applicant identified the calcium-sensing receptor as an amino acid sensor and has shown that this receptor provides a means by which fluctuations in amino acid levels regulate the secretion of the key calcium-regulating hormone, PTH. In the current proposal, the mechanisms that link amino acid activation of the calcium-sensing receptor to its key cellular responses will be determined.Read moreRead less
Type 2 diabetes represents an escalating global health problem. In Australia 7.2% of the population has diabetes but an additional 16% have difficulty handling glucose, a problem which frequently precedes the development of diabetes. Resistance of tissues to the action of insulin is an essential pre-requisite for type 2 diabetes but is also closely associated with the syndrome of obesity, dyslipidaemia, hypertension and cardiovascular diseases (Syndrome X). Genetic factors combined with a high c ....Type 2 diabetes represents an escalating global health problem. In Australia 7.2% of the population has diabetes but an additional 16% have difficulty handling glucose, a problem which frequently precedes the development of diabetes. Resistance of tissues to the action of insulin is an essential pre-requisite for type 2 diabetes but is also closely associated with the syndrome of obesity, dyslipidaemia, hypertension and cardiovascular diseases (Syndrome X). Genetic factors combined with a high caloric intake and a sedentary lifestyle are together responsible for the development of insulin resistance. From evidence that we and others have obtained in recent years it is evident that an important mediator of insulin resistance is the amount of fat which accumulates in muscle and liver. One way in which this abnormality seems to cause insulin resistance is through interference with the normal signalling mechanism which causes increased glucose metabolism in response to insulin. While experiments in cell systems have identified some candidate molecules that may be involved, a need exists to demonstrate whether their dysregulation actually causes the insulin resistance in the whole animal or human, or are merely associated with it. We will use novel techniques to manipulate the levels of one of these candidate genes, protein kinase B-Akt, and its regulators in the muscle of rodents. We will then examine the effects of these manipulations on insulin resistance using a combination of metabolic and molecular tests. Building upon earlier work we will also determine how important different subtypes of this molecule are for both normal and abnormal insulin-glucose metabolism, and whether these molecules or others in the pathway are more important in insulin resistance. This knowledge will be invaluable in tailoring specific novel treatment strategies or drugs for prevention or treatment of insulin resistance, and thus reducing the burden of type 2 diabetes and Syndrome X.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
The Differential Innervation Of Fat - Potential To Target Visceral Adiposity
Funder
National Health and Medical Research Council
Funding Amount
$486,818.00
Summary
Levels of abdominal fat are closely correlated with metabolic syndrome. We propose experiments to identify unique characteristics (neurotransmitters or receptors) of neurons deep in the brain that project specifically to this type of fat or other less harmful subcutaneous fat. We can then test the functional significance of these unique elements in animal experimets involving gene knockdown or pharmacological approaches to modify their function and test the effect on fat distribution
The Metabolic Effects Of Oestrogens And SERMs: Regulatory Interactions With The GH-IGF-system In Health And Disease
Funder
National Health and Medical Research Council
Funding Amount
$379,142.00
Summary
This project extends work aimed at understanding how GH and sex hormones work together to optimise physical health in women and men. It addresses the benefits and safety of oestrogen compounds in relation to their effects on body fat and muscle (body composition). Oestrogen compounds are among the most widely used medicines and include tradition oestrogens (female hormone) and synthetic oestrogens called SERMs. Oestrogens are used in young women as oral contraception and in the postmenopause for ....This project extends work aimed at understanding how GH and sex hormones work together to optimise physical health in women and men. It addresses the benefits and safety of oestrogen compounds in relation to their effects on body fat and muscle (body composition). Oestrogen compounds are among the most widely used medicines and include tradition oestrogens (female hormone) and synthetic oestrogens called SERMs. Oestrogens are used in young women as oral contraception and in the postmenopause for replacement therapy. Body composition is an important determinant of fitness and health. Obesity reduces fitness and increases the risk of diabetes and heart attacks while muscle loss causes weakness and frailty. GH is a major regulator of body composition; it acts by breaking down fat and building muscle mass. We discovered that oestrogens, when taken as a tablet interferes with the action of GH and causes detrimental changes in body composition. On the positive side, we have exploited the GH blocking action to treat acromegaly. This is a debilitating disease of excessive GH production from a pituitary tumour and for which available drug treatments are very expensive and require injection. The effects of SERMs on body composition are unknown. SERMs are interesting compounds because they act like oestrogens in some but as oestrogen blockers in other tissues. These are widely used in the treatment of breast cancer and osteoporosis. The extent to which they interfere with the action of GH has not been studied. They may exert additional effects because they act on the pituitary gland to reduce the secretion of GH. They may also prove to be effective in acromegaly which could extend their usefulness to men. In summary, the work will provide important information on the long-term benefits of SERMs in patient groups that tend to be frail. It may also prove to be a simple and inexpensive treatment for acromegaly.Read moreRead less