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Vascular and metabolic actions of insulin and AMPK activation in muscle


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Bradley, Eloise Alice 2010 , 'Vascular and metabolic actions of insulin and AMPK activation in muscle', Research Master thesis, University of Tasmania.

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It has been well established that both insulin and muscle contraction
increase total blood flow to skeletal muscle. A number of studies have also
demonstrated that insulin and muscle contraction increase muscle
microvascular perfusion in vivo in both humans and animals. The
haemodynamic responses to insulin have been thought to promote delivery of
glucose and hormones to the myocyte to enhance glucose disposal. In models
of insulin resistance, insulin mediated increases in blood flow (total and
microvascular) and glucose uptake are impaired. In contrast contraction
stimulated increases in blood flow and glucose uptake are generally not
impaired in insulin resistant rodents and humans. Although increases in total
blood flow, microvascular perfusion and glucose uptake in skeletal muscle
can be stimulated by either insulin or muscle contraction these processes use
different signalling pathways. The main focus of this thesis was to explore
mechanisms involved in insulin- and contraction-stimulated haemodynamics
in skeletal muscle and their impact on insulin-mediated glucose uptake.
The in vivo techniques employed in this thesis include
hyperinsulinemic euglycaemic clamps performed in anesthetised rats, arterial
blood flow measurements by Transonic®flow probes, microvascular
perfusion measurements by either metabolism of exogenously infused 1-
methylxanthine (1-MX) or contrast enhanced ultrasound (CEU). Test agents
were administered either systemically or locally into one hindlimb via the
epigastric artery. Isolated resistance arteries were used in one study to
compliment the in vivo studies.
The hypothesis that a PI3K dependant signalling pathway, leading to
activation of eNOS and the production of NO, is involved in the
hemodynamic actions of insulin in muscle was examined. Wortmannin, a
PI3K inhibitor, was infused systemically during an insulin clamp in vivo.
Wortmannin administration resulted in inhibition of the haemodynamic
effects of insulin including total flow and microvascular perfusion as well as
glucose uptake. The relationship between insulin mediated NOS activation
and microvascular perfusion was also studied. A NOS inhibitor, L-NAME,
was infused locally in one leg and attenuated insulin action in skeletal muscle
by inhibiting microvascular perfusion and blunting glucose uptake.
AMPK is a potential mediator of metabolic changes in muscle during
contraction and can be artificially activated by the compound AICAR. Acute
activation of AMPK in vivo by low dose AICAR resulted in increased
microvascular blood volume without effects on blood pressure, femoral blood
flow or hindleg glucose uptake. In addition, in isolated resistance arteries,
AICAR induced vasodilatation, which was abolished by the NO synthase
inhibitor L-NA or the AMPK inhibitor compound C. Activation of AMPK by
AICAR also sensitised smooth muscle cells to sodium nitroprusside (SNP)
mediated vasodilatation and induced vasodilatation of resistance arteries.
AMPK activation by AICAR resulted in marked enhancement of insulinmediated
microvascular perfusion and glucose uptake.
Collectively the findings in this thesis highlight the important role of
microvascular perfusion for facilitating skeletal muscle glucose metabolism
and explore some of the mechanisms which are involved. Insulin mediated
microvascular perfusion occurs via a PI3K dependant pathway and is strongly
associated with NOS activation. Activation of AMPK increases microvascular
perfusion which is also associated with NOS activation. The combination of
AMPK activation and insulin resulted in marked enhancement of insulinmediated
microvascular perfusion and glucose uptake. Improvement of
microvascular perfusion through targeting AMPK activation may provide a
potential therapeutic avenue for enhancing glucose metabolism.

Item Type: Thesis - Research Master
Authors/Creators:Bradley, Eloise Alice
Keywords: Muscles, Musculoskeletal system
Copyright Holders: The Author
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Copyright 2010 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
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Additional Information:

Available for use in the Library and copying in accordance with the Copyright Act 1968, as amended. Thesis (MMedSc)--University of Tasmania, 2010. Includes bibliographical references. !. Introduction -- 2. Materials and methods -- 3. Acute effects of Wortmannin on haemodynamic and metabolic actions of insulin in vivo -- 4. Effects of nitric oxide synthase inhibition on the actions of insulin in muscle -- 5. Acute effects of AMPK activation by AICAR on muscle microvascular perfusion in vivo & isolated muscle resistance arteries in vitro -- 6. Acute effects of AICAR on haemodynamic and metabolic actions of insulin in vivo -- 7. General discussion

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