whole-Premilovac-thesis-2012.pdf (1.86 MB)
Microvascular dysfunction and the development of muscle insulin resistance
thesisposted on 2023-05-26, 00:25 authored by Dino PremilovacDino Premilovac
Defects in microvascular perfusion, which is important for nutrient exchange in skeletal muscle, contribute to insulin resistance associated with obesity and hypertension. One factor that may link this microvascular dysfunction in these conditions is the renin angiotensin system (RAS). The primary objective of this thesis was to address these issues using rat models of obesity and altered RAS activity. Two different models of insulin resistance were analysed for the involvement of microvascular dysfunction. Rats were fed either a high fat or a high salt diet for 4 weeks to develop insulin resistance. The hyperinsulinaemic, euglycaemic clamp and 1-methyl xanthine techniques were used to investigate insulin sensitivity and microvascular recruitment, respectively. Despite different origins of insulin resistance, both animal models had markedly impaired insulin-mediated microvascular recruitment in muscle. The contribution of increased angiotensin II (AngII) activity to microvascular dysfunction in both animal models was examined. Hindleg vascular AngII sensitivity (assessed using both the perfused rat hindlimb technique and locally infused AngII in vivo) was enhanced in the high salt but not the high fat-fed rat. Thus, although both models developed microvascular insulin resistance, only the high salt-fed rats exhibited increased vascular AngII activity. There is conflicting evidence as to whether RAS dysregulation also contributes to insulin resistance or type 2 diabetes associated with obesity. The obese Zucker rat (a model of type 2 diabetes) has impaired insulin-mediated microvascular recruitment, and has been reported to have a dysregulated RAS, but represents a later stage of insulin resistance than the high fat-fed rat. To determine whether RAS inhibition enhances insulin sensitivity, high salt-fed and obese Zucker rats were treated with an angiotensin converting enzyme inhibitor (quinapril) for 4 weeks. Inhibition of ACE significantly improved insulin sensitivity and augmented insulin-stimulated microvascular perfusion in high salt-fed rats, but not in obese Zucker rats. The data from this thesis demonstrate that the origin of microvascular insulin resistance is multifactorial. Dysregulation of the RAS is important in some but not all forms of microvascular insulin resistance. Therefore inhibition of RAS may not always be effective at treating insulin resistance and may only be beneficial during earlier stages of insulin resistance rather than later stages such as type 2 diabetes.
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