An analysis of insulin- and non-insulin-stimulated glucose transport in rat skeletal muscle

James, Declan Jonathan (2002) An analysis of insulin- and non-insulin-stimulated glucose transport in rat skeletal muscle. PhD thesis, University of Glasgow.

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Skeletal muscle plays a crucial role in the insulin-mediated post-prandial disposal of blood glucose. Insulin resistance, that is a reduction in insulin's ability to stimulate glucose uptake, is of major pathogenic importance in several prevalent human disorders, including type 2 diabetes, hypertension and obesity. Interestingly, there is good evidence to suggest that in insulin-resistant individuals exercise-stimulated glucose uptake is unaffected. In an effort to explore these two mechanisms, I have examined insulin- and 5-aminoimidazole-4-carboxamide 1-beta-D-ribonucleoside (AICAR)-stimulated glucose uptake in isolated skeletal muscle from the insulin-resistant stroke-prone spontaneously hypertensive rat (SHRSP) and the obese Zucker diabetic fatty rat (ZDF), a model of type 2 diabetes. The data presented here will show that while the stroke-prone spontaneously hypertensive rat (SHRSP) and Zucker diabetic fatty rat display reduced insulin-stimulated glucose transport, their response to AICAR is unimpaired with respect to their insulin-sensitive controls, the Wistar Kyoto (WKY) and lean Zucker rats, respectively. Importantly, the observed insulin-resistance is also maintained in skeletal muscle cells cultured from SHRSP and ZDF rats, implying that the defect does not arise as a consequence of the tissue environment, but rather is a genetic characteristic of the muscle cells. The expression and function of key molecules in the insulin-signalling cascade was also examined in these strains. Intriguingly, the total cellular expression levels of caveolin and flotillin, key proteins implicated in insulin signal transduction and compartmentalisation, are increased in the skeletal muscle from SHRSP compared to WKY but are unchanged between ZDF and lean Zucker rats. On the other hand the insulin-dependent activation of protein kinase B is markedly impaired in ZDF skeletal muscle with respect to lean Zucker rats, but is not different between SHRSP and WKY. Taken together these results indicate that an inherent defect, at the level of skeletal muscle, is responsible for the observed insulin resistance. Moreover, this defect is confined to an insulin-specific step in the activation of glucose transport and is not a consequence of generalised resistance in the mechanism(s) of glucose transport. In addition, this underlying defect may be different between SHRSP and ZDF rats. Finally, the molecular mechanism by which hyperglycaemia impairs insulin action was investigated in ZDF rats. Hyperglycaemia impairs insulin-stimulated glucose transport in lean Zucker muscle cells but does not lead to further impairment in the ZDF rat. The anti-diabetic drug, Rosiglitazone, was found to increase the basal glucose uptake by approximately two-fold but had no effect on insulin-stimulated glucose transport in lean or ZDF muscle cells cultured under normoglycaemic or hyperglycaemic conditions. These data are discussed within the context of present theories on the aetiology of insulin resistance.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Physiology.
Colleges/Schools: College of Medical Veterinary and Life Sciences
Supervisor's Name: Gould, Professor Gwyn
Date of Award: 2002
Depositing User: Enlighten Team
Unique ID: glathesis:2002-73237
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 14 Jun 2019 08:56
Last Modified: 26 Aug 2022 15:25
Thesis DOI: 10.5525/gla.thesis.73237
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