The role of endothelial function and oxidant stress in a model of insulin resistance
Abstract
Type 2 diabetes mellitus affects over 100 million people worldwide. It is characterized by
various metabolic abnormalities such as insulin resistance, aberrant insulin secretion,
hyperglycaemia and a cluster of cardiovascular risk factors, including increased oxidative
stress. It is associated with microvascular complications and increased potential of
macrovascular disease. The aim of the studies described in this thesis was to test the
hypothesis that oxidant stress contributes to an altered vascular function and impaired
insulin regulation in a pre-diabetic animal model- the obese Zucker rats.
The first objective was to develop new methods to measure endothelial function in animal
disease models. Firstly, without autonomic control - the in situ perfused hindquarters, and
secondly, with autonomic control - the in vivo Doppler ear blood flow.
The obese Zucker rat was shown to have increased oxidative stress, as measured by plasma
8-epi-PGF2a,. It also had high insulin and glucose levels and impaired glucose disposal.
Obese rats also had increased agonist-induced nitric oxide-dependent endothelial responses;
these were further enhanced by insulin in a macrovascular preparation, but were impaired
by insulin in a resistance vessel bed.
Following dietary treatment with the antioxidants, the obese plasma insulin/glucose ratio
was improved. However, vitamin E blunted the enhanced endothelial-dependent vasodilator
responses, and decreased plasma levels of 8-epi-PGF2a. In contrast, pro-oxidant treatment
with hydroquinone and buthionine-sulphoximine impaired the plasma insulin/glucose ratio,
abolished endothelial hyperactivity but increased plasma 8-epi-PGF2a levels. Interestingly,
fructose protected against pro-oxidant-induced increases in plasma 8-epi-PGF2a levels and
further increases in glucose-induced plasma insulin.
In summary the redox status in obese Zucker rats was modified with antioxidant and prooxidant
treatment. This resulted in compensatory changes in glucose disposal and
endothelial function. Impaired endothelial function may initiate "damage" especially in
those individuals susceptible to syndrome X, leading to insulin insensitivity and vascular
dysfunction in type 2 diabetes
Authors
Andrews, Tara JaneCollections
- Theses [4122]