Role Of UBL-5 In Mitochondrial Function And Glucose Metabolism
Funder
National Health and Medical Research Council
Funding Amount
$647,539.00
Summary
Type 2 diabetes is caused by insulin resistance, a condition that is characterised by the inability of insulin to elicit its normal function to lower blood sugar levels. The cause of insulin resistance is not known. In this study we will determine the role of a novel gene called UBL-5 to elicit insulin resistance in muscle and fat by generating genetically-induced models in which this gene has been deleted. By understanding the role of UBL-5 in insulin resistance, better therapeutic strategies c ....Type 2 diabetes is caused by insulin resistance, a condition that is characterised by the inability of insulin to elicit its normal function to lower blood sugar levels. The cause of insulin resistance is not known. In this study we will determine the role of a novel gene called UBL-5 to elicit insulin resistance in muscle and fat by generating genetically-induced models in which this gene has been deleted. By understanding the role of UBL-5 in insulin resistance, better therapeutic strategies can be developed to treat Type 2 diabetes.Read moreRead less
Targeting Nicotinamide Adenine Dinucleotide Biosynthesis To Improve Metabolism
Funder
National Health and Medical Research Council
Funding Amount
$844,596.00
Summary
Nicotinamide adenine dinucleotide (NAD) is a cellular metabolite that regulates many biological processes. NAD levels decline with age and also in obesity and interventions that increase NAD levels produce favourable metabolic effects. In this proposal we will utilise a range of novel experimental models to define the molecular pathways that mediate the beneficial effects of NAD.
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.
NAD+ And SIRT2 Regulation Of Mitotic Lifespan, Senescence And Healthy Ageing
Funder
National Health and Medical Research Council
Funding Amount
$617,274.00
Summary
During youth, cells in our body undergo a continual process of self-renewal, known as mitosis, where cells divide and accurately provide equal number of chromosomes into each daughter cell. During old age, dysfunctional mitosis leads to senescence, where cells no longer divide, and are unable to renew old tissue. We have uncovered a new molecular pathway involving the enzyme SIRT2 that maintains healthy mitosis, and will determine if targeting this pathway preserves health into old age, and ulti ....During youth, cells in our body undergo a continual process of self-renewal, known as mitosis, where cells divide and accurately provide equal number of chromosomes into each daughter cell. During old age, dysfunctional mitosis leads to senescence, where cells no longer divide, and are unable to renew old tissue. We have uncovered a new molecular pathway involving the enzyme SIRT2 that maintains healthy mitosis, and will determine if targeting this pathway preserves health into old age, and ultimately extends lifespanRead moreRead less
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.
Short-term Effects Of Overfeeding On Metabolic Risk In Humans
Funder
National Health and Medical Research Council
Funding Amount
$417,196.00
Summary
The prevalence of obesity is rapidly increasing in Australia and other parts of the world. Obesity is closely associated with insulin resistance and plays a role in the development of type 2 diabetes. However, the effects of short-term periods of over nutrition in humans remain unclear. In the proposed study, we will investigate the effects of short-term weight gain by high fat feeding in lean subjects, in subjects who are overweight and in subjects who are genetically more likely to develop dia ....The prevalence of obesity is rapidly increasing in Australia and other parts of the world. Obesity is closely associated with insulin resistance and plays a role in the development of type 2 diabetes. However, the effects of short-term periods of over nutrition in humans remain unclear. In the proposed study, we will investigate the effects of short-term weight gain by high fat feeding in lean subjects, in subjects who are overweight and in subjects who are genetically more likely to develop diabetes (due to strong family history). The aims are to distinguish physiological and endocrine characteristics of individuals who store more fat in response to overfeeding. We will identify differences between these individuals and whether they have defects in upregulating machinery involved in fat oxidation and energy production in skeletal muscle that may help them adapt during to energy excess. We will look for changes in type 2 diabetes risk and we will have the potential to identify defects in factors that are involved in this response. We will also re-examine indivudals again after calorie restriction and weight loss. We also plan to confirm the role of the candidate genes involved in fat oxidation that have been identifieid in human studies by in vivo gene transfer technology in rodents. This study will determine whether overweight and lean subjects behave similarly when faced with an overfeeding challenge. We expect that individuals with a genetic predisposition for T2DM will become more IR, due to metabolic inflexibility and a decreased ability to upregulate machinery involved in fatty acid oxidation and mitochondrial function. By characterising the physiological and endocrine responses to overfeeding, we will establish quantifiable markers allowing us to distinguish those at risk and identify new targets for pharmacological or lifestyle intervention.Read moreRead less
Preventing Adverse Effects Of Matrix Metalloproteinases In Diabetic Wound Healing
Funder
National Health and Medical Research Council
Funding Amount
$387,784.00
Summary
Treatment of diabetic foot ulcers presents a significant challenge to diabetic patients and the health care system. Despite concerted treatment, many ulcers do not heal and it is this failure to heal which eventually leads to deep-seated infection and amputation. For these reasons development of new therapeutic strategies to improve wound healing in diabetes is of critical importance. In this study we investigate the role of MMPs in particular MMP-9 in diabetic wounds and examine whether MMP inh ....Treatment of diabetic foot ulcers presents a significant challenge to diabetic patients and the health care system. Despite concerted treatment, many ulcers do not heal and it is this failure to heal which eventually leads to deep-seated infection and amputation. For these reasons development of new therapeutic strategies to improve wound healing in diabetes is of critical importance. In this study we investigate the role of MMPs in particular MMP-9 in diabetic wounds and examine whether MMP inhibition will improve wound healing in diabetes.Read moreRead less
Role And Mechanism Of Connective Tissue Growth Factor In Diabetic Cardiomyopathy
Funder
National Health and Medical Research Council
Funding Amount
$382,820.00
Summary
Diabetic cardiomyopathy is a condition where the heart muscle is directly damaged by diabetes. It is being recognised as a prominent cause of both acute and chronic heart failure in diabetes. It is common and occurs in up to 60% of diabetic patients . At present however, no treatments are available to directly treat the cardiomyopathy. This condition can also occur in people with diabetes who have high blood pressure and-or coronary artery disease and may combine with these problems to worsen pa ....Diabetic cardiomyopathy is a condition where the heart muscle is directly damaged by diabetes. It is being recognised as a prominent cause of both acute and chronic heart failure in diabetes. It is common and occurs in up to 60% of diabetic patients . At present however, no treatments are available to directly treat the cardiomyopathy. This condition can also occur in people with diabetes who have high blood pressure and-or coronary artery disease and may combine with these problems to worsen patient outcomes. We have generated data in experimental diabetes in rodents that strongly implicates a heart growth factor in causing diabetic cardiomyopathy. This protein, called connective tissue growth factor (CTGF), is increased in diabetic cardiomyopathy, and is elevated by high glucose and other factors in diabetes. We have published data showing that CTGF causes tissue scarring like that which occurs in cardiomyopathy, by affecting signals in cells called fibroblasts. It increases the laying down of extracellular matrix (ECM) and also inhibits the degradation of ECM by the proteins that break down matrix, known as the MMPand PAI systems. Such accumulation of ECM is thought to be a major factor leading to abnormal muscle function in cardiomyopathy. We now plan to block CTGF in this diabetic heart model to determine if we can prevent diabetic cardiomyopathy. We have generated two methods to inhibit CTGF in the animal model. Echocardiography (a heart ultrasound test), and molecular analysis of the heart tissue will determine if we can prevent the otherwise adverse functional and structural changes of diabetes in the heart. We will also study our baboon model of diabetes to determine if diabetic cardiomyopathy with increased heart CTGF is present in the primates. Cell culture studies from rat heart fibroblasts and myocytes will determine how CTGF has the effect on cells to cause cardiomyopathy and how we might further prevent this condition developing in diabetes.Read moreRead less