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
Does Loss Of Melanocortin Glucose Sensing Contribute To Obesity Induced Diabetes?
Funder
National Health and Medical Research Council
Funding Amount
$617,531.00
Summary
Diabetes is a failure to properly regulate blood glucose levels. Escalating rates of diabetes are a major health problem. Melanocortin neurons in the brain detect blood sugar levels and usually regulate glucose production and utilization, but in obese animals they do not. We have developed a possible therapeutic, which appears to reverse the glucose insensitivity, and rapidly reduces blood glucose in diabetic mice. This project will determine how melanocortins act to regulate glucose levels
Gastric Counter-regulation Of Hypoglycaemia: Studies In Health And Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$357,193.00
Summary
Insulin injections are often needed to treat diabetes, but they can cause low blood sugar levels (hypoglycaemia), which are usually distressing, and sometimes fatal. The stomach is important in regulating blood sugar; in response to hypoglycaemia, it empties food much more rapidly, allowing carbohydrate to be absorbed faster to normalise blood sugar levels. The proposed studies will explore this important area, in order to develop better ways of preventing and treating hypoglycaemia.
In Australia over 7% of the population have type 2 diabetes. This epidemic represents a major health problem. The majority of overweight individuals do not develop diabetes because their insulin-secreting pancreatic beta-cells adequately compensate with over-secretion. It is the failure of this so called, beta-cell compensation, that is fundamental to the development of diabetes. We propose that in susceptible individuals, a gradual rise in blood glucose levels resulting from obesity and insulin ....In Australia over 7% of the population have type 2 diabetes. This epidemic represents a major health problem. The majority of overweight individuals do not develop diabetes because their insulin-secreting pancreatic beta-cells adequately compensate with over-secretion. It is the failure of this so called, beta-cell compensation, that is fundamental to the development of diabetes. We propose that in susceptible individuals, a gradual rise in blood glucose levels resulting from obesity and insulin resistance leads to beta-cell failure and overt diabetes. This project will investigate the mechanisms responsible for beta-cell failure in a mouse model with a similar time-dependent progression to obesity and type 2 diabetes as that seen in humans. C57BL-KsJ db-db mice progress from a pre-diabetic phase of insulin over-secretion, obesity and insulin resistance to a diabetic state characterised by the appearance of high blood glucose and lipid levels and the loss of insulin secretory capacity. With age, there are also a reduced number of beta-cells because of increased cell death. db-db mice will be studied at different stages in their natural progression to diabetes to fully characterise the secretory dysfunction and the changes in beta-cell phenotype over the time-course of diabetes development. The use of laser capture microdissection will allow us to study selectively the actual beta-cells without contamination from the other cells of the pancreas. The mice will also be treated with an agent that lowers blood glucose levels without affecting lipids to test the influence of hyperglycaemia itself in the development of beta-cell dysfunction. We will also test if the changes observed in the mice are regulated independently by high glucose levels in cell culture systems. The role of one candidate protein called ID-1 will be investigated as a potential link between hyperglycaemia and the development of beta-cell dysfunction.Read moreRead less