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Abstract

Type 2 diabetes is a disease characterised by a decrease in the sensitivity to insulin. Recently evidence has suggested an involvement of the microvasculature in the development of type 2 diabetes. Microvascular perfusion is increased by insulin and impairment of this response may contribute to muscle insulin resistance by limiting insulin and glucose delivery to skeletal muscle myocytes. This thesis focuses on the involvement of the microvascular perfusion in the development of insulin resistance.
Two different models were used to assess the impact of the microvascular perfusion on the insulin-mediated glucose disposal. Firstly, 4 weeks of high-fat diet (HFD model) feeding to rats was used as a pre-diabetic model of insulin resistance. Secondly, partial blockage of skeletal muscle microvascular beds with 15 μm diameter latex microspheres (MS model) was used to assess the effect of decreased muscle microvascular perfusion on insulin sensitivity.
In each model, insulin sensitivity was determined during hyperinsulinaemic isoglycaemic clamps in anaesthetized rats. Femoral arterial blood flow (FBF) and microvascular perfusion (assessed by the hindleg metabolism of infused 1-methylxanthine) were measured. Hindleg glucose uptake was determined from arteriovenous difference and FBF and muscle glucose uptake from [\(^{14}\)C]-2-deoxyglucose uptake.
Insulin-mediated increases in femoral blood flow and glucose uptake were blunted in the HFD rats compared to those on the normal diet, while insulininduced microvascular perfusion was completely abolished. To see whether contraction responses were intact on the HFD, the functional response to electrical stimulation in the HFD rats was explored. The contraction-mediated increase in microvascular perfusion and glucose uptake was unaffected by the HFD.
In the MS model, microsphere occlusion of hindleg muscle microvasculature diminished microvascular perfusion as well as insulin-mediated glucose uptake, thus causing a vascular-derived acute state of insulin resistance. Next, the long-term effect of microsphere occlusion was assessed. Surprisingly, insulin responses following chronic microsphere occlusion were restored by 2 weeks of recovery post-injection. This may be explained by a rapid angiogenic response in occluded muscle vasculature.
Collectively, this thesis demonstrates two key findings that highlight the potential role of the microvasculature in the development of skeletal muscle insulin resistance: (i) that insulin- but not contraction-mediated microvascular responses are impaired in a pre-diabetic model of insulin resistance, and (ii) that acute physical reduction of microvascular flow impairs muscle insulin sensitivity. This furthers our understanding of the aetiology of type 2 diabetes and emphasizes the microvasculature as an interesting therapeutic target for the management of type 2 diabetes.

Item Type:	Thesis - PhD
Authors/Creators:	St-Pierre, P
Keywords:	Insulin resistance, Diabetes
Additional Information:	Thesis (PhD)--University of Tasmania, 2010. Includes bibliographical references. Introduction -- Materials and methods -- Insulin-mediated microvascular recruitment is impaired in pre-diabetic state -- Contraction-mediated effects on microvascular recruitment in the pre-diabetic state -- Acute microsphere occlusion induced vascular insulin resistance -- Chronic effect of microsphere occlusion -- Discussion -- References
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