Baldeweg, Stefanie Elisabeth; (2002) Insulin resistance, endothelial function and non-esterified fatty acids in health and type 2 diabetes. Doctoral thesis (M.D), UCL (University College London).

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Abstract

Type 2 diabetes has been established as a serious cardiovascular risk factor. Insulin resistance plays a major role in its pathogenesis. Associated with insulin resistance is a cluster of metabolic abnormalities- the "insulin resistance syndrome". An unresolved issue is whether there is a single underlying cause. Recent data suggest that endothelial dysfunction may be intrinsic to the syndrome. Endothelial dysfunction could represent the impact of subclinical disturbance of metabolism. Alternatively, the presence of a common cellular defect could influence both endothelial function and insulin mediated glucose disposal. This work had two aims: Firstly, to study the relationship between insulin resistance and non-esterified fatty acids (NEFA); Secondly, to assess the relationship between insulin resistance and endothelial function in diabetes. It was hypothesised that a common antecedent links insulin resistance with endothelial dysfunction, cytokines and NEFA being likely candidates. A large healthy cohort, part of a multicentre project, and 38 patients with uncomplicated type 2 diabetes were studied. Insulin resistance was measured in all subjects using the hyperinsulinaemic clamp technique. In the diabetic cohort endothelial function was assessed with venous-occlusion plethysmography and circulating endothelial cell products. A strong association between NEFA and insulin resistance was observed with different links in fasting and hyperinsulinaemic states. Insulin resistant subjects had evidence of several components of the insulin resistance syndrome. No evidence for a relationship between insulin resistance and endothelial dysfunction was observed on plethysmography. However, measurement of endothelial cell products showed a significant association between tissue plasminogen activator levels (tPA) and insulin resistance. The association between insulin resistance and tissue plasminogen activator levels was strongly influenced by NEFA metabolism and to a much lesser extent by cytokine concentrations. The results point towards NEFA as a putative signal linking insulin resistance with endothelial dysfunction in diabetes.

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