University of Tasmania
whole_RossReneeMartha2007_thesis.pdf (19.98 MB)

Exercise and insulin : muscle haemodynamics and metabolism

Download (19.98 MB)
posted on 2023-05-27, 17:05 authored by Renee RossRenee Ross
Insulin resistance is a disease characterised by an inability of the body to effectively respond to insulin in terms of increased glucose uptake. However, in most cases, the response to exercise to increase glucose uptake is largely unaffected in insulin resistance. This thesis focuses on the differences and similarities between these two stimuli with a view to further understanding the cause of insulin resistance and the possibility of developing new treatments for this disease. There is evidence to suggest that the ability of insulin and muscle contraction to increase muscle glucose uptake is due in part, to their ability to increase blood flow, in particular microvascular perfusion. Accordingly, the hyperinsulinaemic euglycaemic clamp technique, in conjunction with electrical stimulation to simulate exercise, was used in anaesthetised rats to examine factors which control muscle microvascular perfusion. Additionally, an assessment was made of how microvascular perfusion related to glucose uptake and insulin resistance in skeletal muscle, the main site where insulin normally acts to increase glucose uptake. This study used two techniques to measure changes in muscle microvascular perfusion. The first, an established method involving the capillary endothelial metabolism of infused 1- methylxanthine; the second, a relatively new technique, contrast enhanced ultrasound (CEU), which has been adapted from its use in measuring microvascular perfusion in heart. A component of this thesis applied model systems to validate the use of CEU to measure microvascular perfusion and showed that this was independent of changes in bulk flow, and that CEU can be used to measure changes in skeletal muscle microvascular perfusion regardless of the microvascular architecture involved. In another component, again using CEU, changes in microvascular perfusion in response to electrical stimulation were measured. The rapid increase in femoral blood flow in response to muscle contraction was found to reverse quickly, however microvascular perfusion remained enhanced up to 60 min after contraction. In addition, it was also shown that while insulinmediated vasodilation was nitric oxide-dependent and thus was indicative of the main mechanism by which insulin causes vasodilation in muscle, a local infusion (via the epigastric artery) of a nitric oxide synthase inhibitor during contraction did not block microvascular perfusion, even though it inhibited the accompanying increase limb (femoral arterial) blood flow. The nitric oxide synthase inhibitor blocked ~35% of the contraction-mediated increase in muscle glucose uptake, but by not affecting the accompanying increase in microvascular perfusion, the results suggested that a non-nitric oxide compensatory mechanism (such as adenosine, potassium ions, or neural inputs) may be involved. Interleukin-6 (IL-6) is released by muscle during exercise and thought to have a role in glucose homeostasis. Its involvement in insulin resistance is controversial and its effects on insulin-mediated changes were thus explored. The infusion of this cytokine during a hyperinsulinaemic euglycaemic clamp suppressed the insulin-mediated increase in microvascular perfusion. Interestingly, this inhibition did not result in insulin resistance as IL-6 was able to increase muscle glucose uptake through its own signalling pathway. However, it is possible that elevated plasma IL-6 when maintained over longer periods may lead to insulin resistance due to the inhibition of insulin's microvascular effects. Because chronically elevated levels of endothelin-1 (ET-1) may also be implicated in insulin resistance of muscle through actions on the microvasculature, another component of this thesis explored the acute effects ofET-1 in vivo. Infusion ofET-1 into anaesthetised rats in conjunction with insulin led to a hyperinsulinaemic state, found to be due to a decrease in insulin clearance. Muscle insulin resistance also resulted and was concluded to result from an attenuation of insulin-mediated increase in microvascular perfusion. Collectively, the findings of this thesis confirm an important role for microvascular perfusion in mediating the stimulatory responses of both insulin and exercise on muscle glucose uptake. In most cases there was a close association between increases in microvascular perfusion and glucose uptake. However, contraction-mediated microvascular perfusion was maintained even when muscle glucose uptake was blocked by infusion of a nitric oxide synthase inhibitor, suggesting a non-vascular myocyte source of nitric oxide that is involved in contractionmediated glucose uptake. ET-1 was found to play an important part in opposing the insulinmediated increases in microvascular perfusion, thus consistent with growing evidence that ET-1 may be a major contributor to insulin resistance in muscle. Finally there are data to suggest that in the short term, the body may be able to compensate for a decrease in insulinor contraction-mediated microvascular perfusion, but that the compensatory mechanisms may unsustainable in the longer term and insulin resistance may develop because of the reduced microvascular perfusion.


Publication status

  • Unpublished

Rights statement

Copyright 2007 the author - The University is continuing to endeavour to trace the copyright owner(s) and in the meantime this item has been reproduced here in good faith. We would be pleased to hear from the copyright owner(s). Thesis (PhD)--University of Tasmania, 2007. Includes bibliographical references. Ch. 1. Introduction -- Ch. 2. Materials and methods -- Ch. 3. CEU of capillary models in vitro -- Ch. 4. Contraction mediated sensitisation of skeletal muscle -- Ch. 5. Nitric oxide synthase inhibition and microvascular flow during contraction -- Ch. 6. Entothelin-1 and insulin action in vivo -- Ch. 7. Interleukin-6 and insulin action in vivo -- Ch. 8. Discussion

Repository Status

  • Open

Usage metrics

    Thesis collection


    No categories selected


    Ref. manager