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Hemodynamic and metabolic changes in muscle in relation to insulin action

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Mahajan, H (2005) Hemodynamic and metabolic changes in muscle in relation to insulin action. PhD thesis, University of Tasmania.

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Abstract

It is widely accepted that insulin increases total blood flow to muscle. This lab has
demonstrated in a number of studies that insulin also recruits capillary flow in muscle by
an unknown mechanism. This hemodynamic response to insulin is linked to its metabolic
effects as it increases the access of glucose and insulin to muscle cells. It is possible that
insulin may act on endothelial or vascular smooth muscle cells to release a vasodilator
(NO, adenosine, prostaglandins or endothelium-dependent hyperpolarizing factor)
causing capillary recruitment.
The aim of this thesis was to look at possible mechanisms underlying insulin’s
hemodynamic and metabolic action in muscle. This was examined during
hyperinsulinemic euglycemic clamps in anesthetized rats. To test the agents affecting
insulin action at the local muscle level, a novel technique was developed wherein the
epigastric artery (a branch of the femoral artery) was cannulated and test substances were
infused into one leg to avoid any systemic effects; the contralateral leg served as control.
Femoral artery blood flow and metabolism of exogenously infused 1-methylxanthine (1-
MX) as an index of capillary recruitment were measured in both legs for comparison.
There is some evidence that insulin’s hemodynamic action on muscle is mediated by
nitric oxide-cGMP pathway. T-1032, a phosphodiesterase-5 inhibitor, was infused
systemically, to see whether NO-dependent insulin-mediated capillary recruitment in
muscle could be enhanced by inhibiting cyclic GMP degradation. T-1032, however,
produced an acute insulin resistance. In addition, NO production was enhanced using two
endothelium-dependent nitro-vasodilators methacholine and bradykinin. Methacholine
infused systemically caused MAP to fall and blood glucose to rise, resulting in a lower
GIR. Local infusion of methacholine but not bradykinin in one leg significantly increased
capillary recruitment and insulin-mediated glucose uptake.
Furthermore, a NOS inhibitor, L-NAME, infused locally in one leg had no effect on
insulin action in muscle. Systemic L-NAME infusion partially blocked the insulinmediated
capillary recruitment without any effect on insulin-mediated glucose uptake. On
the other hand, local infusion of calcium-dependent potassium channel (KCa) blocker TEA
in one leg, almost completely blocked insulin’s effects on capillary recruitment and
attenuated insulin-mediated glucose uptake.
Collectively these findings indicate that the action of insulin on muscle is the net
result of a combination of effects. There is evidence for involvement of systemic NO and
local KCa channels in insulin-mediated capillary recruitment. Hence, modulation of either
of these components could potentially alter the hemodynamics and metabolism in muscle.

Item Type: Thesis (PhD)
Copyright Information:

Copyright 2005 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).

Date Deposited: 09 Sep 2015 00:07
Last Modified: 11 Mar 2016 05:54
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