Mechanisms Linking Insulin-mediated Muscle Capillary Recruitment And Glucose Uptake
Funder
National Health and Medical Research Council
Funding Amount
$315,990.00
Summary
A number of studies over recent years including our own have suggested that insulin acts in normal humans and animals to improve blood supply to muscle and that a contributing factor to Type 2 diabetes is an impaired ability of insulin to achieve this effect. Our key contribution to this field is the finding that insulin acts to alter blood flow in muscle to improve access for itself and nutrients such as glucose. This discovery of blood flow redistribution in muscle was made possible by newly d ....A number of studies over recent years including our own have suggested that insulin acts in normal humans and animals to improve blood supply to muscle and that a contributing factor to Type 2 diabetes is an impaired ability of insulin to achieve this effect. Our key contribution to this field is the finding that insulin acts to alter blood flow in muscle to improve access for itself and nutrients such as glucose. This discovery of blood flow redistribution in muscle was made possible by newly developed in-house methods. Using these methods we now wish to explore (a) the mechanism by which insulin mediates this effect and (b) when this effect of insulin to improve muscle blood flow is impaired in diabetes, how it might be recovered. We expect to find that insulin-mediated capillary recruitment in muscle results from a signal substance released from muscle that permeates nearby tissue reacting with the blood vessels to improve blood flow. It is also expected that new therapeutic approaches for enhancing insulin action in muscle and targeted at the blood vessels will be identified.Read moreRead less
Cyclic GMP Phosphodiesterase Inhibitors And Facilitation Of Insulin-mediated Capillary Recruitment In Muscle
Funder
National Health and Medical Research Council
Funding Amount
$220,500.00
Summary
It would now seem clear that insulin has a major stimulatory effect on blood flow within muscle to improve access for itself as well as nutrients such as glucose. When this haemodynamic effect of insulin is impaired insulin resistance in terms of glucose uptake by muscle results and there is the potential for type 2 diabetes to develop. Our key contribution has been the development of new techniques to make this observation possible and it would be fair to say that we are the world leaders in th ....It would now seem clear that insulin has a major stimulatory effect on blood flow within muscle to improve access for itself as well as nutrients such as glucose. When this haemodynamic effect of insulin is impaired insulin resistance in terms of glucose uptake by muscle results and there is the potential for type 2 diabetes to develop. Our key contribution has been the development of new techniques to make this observation possible and it would be fair to say that we are the world leaders in this field because of these techniques. Using these methods we now wish to develop new drugs for treating type 2 diabetes based on improving muscle capillary blood flow. The approach we will use is similar to that used previously by others for the treatment of erectile dysfunction with drugs targeted at a particular enzyme controlling the metabolism of a substance (cyclic GMP) which in turn regulates blood flow to the corpus cavernosum. In our case, the drugs will be targeted at another specific isoform of the same enzyme, cyclic GMP phosphodiesterase, located at control points in the skeletal muscle microvasculature. We expect to find that insulin-mediated capillary recruitment in muscle will be enhanced by such drugs. As a consequence, insulin resistance in muscle will be lessened.Read moreRead less
Nutrient And Hormone Delivery To Muscle: Interactions Between Insulin And Exercise
Funder
National Health and Medical Research Council
Funding Amount
$304,375.00
Summary
Exercise is known to be beneficial in the treatment and prevention of Type 2 diabetes and in particular muscle insulin resistance. Also, exercise and insulin share similar acute actions on muscle. Firstly, muscle contraction has a well established action to increase glucose uptake, and secondly, both muscle contraction and insulin act to increase capillary recruitment. This latter phenomenon is thought to enhance nutrient delivery and waste product removal. There is evidence that the increase in ....Exercise is known to be beneficial in the treatment and prevention of Type 2 diabetes and in particular muscle insulin resistance. Also, exercise and insulin share similar acute actions on muscle. Firstly, muscle contraction has a well established action to increase glucose uptake, and secondly, both muscle contraction and insulin act to increase capillary recruitment. This latter phenomenon is thought to enhance nutrient delivery and waste product removal. There is evidence that the increase in capillary flow due to muscle contraction is accompanied by increases in total blood flow. For insulin action we now have preliminary data to indicate that capillary recruitment occurs within a 5-10 min application of a physiologic dose of insulin independent of a change in total blood flow suggesting a redistribution of flow. Muscle contraction also increases capillary recruitment and it raises the question of whether similar mechanisms underlie insulin- and muscle contraction-induced capillary recruitment or whether there are distinct and complementary pathways. In this project we plan to define the mechanisms responsible for contraction- and insulin-induced capillary recruitment in muscle. We hypothesize that similar mechanisms are operative, with both insulin and muscle contractions acting via NO-dependent mechanisms. Because of capillary reserve, and different initial steps of the signalling systems stimulated by insulin and exercise, capillary recruitment by combined contraction and insulin stimuli will be additive at both sub maximal and perhaps at maximal insulin pathway stimulation. Signalling mechanisms will be compared and the role of non-nutritive route as a flow reserve assessed.Read moreRead less