Insulin sensitivity: measurements in the whole body and in isolated tissues

As the incidence of type 2 diabetes rises exponentially in the early part of the 21st century, the global healthcare and financial burdens associated with this chronic condition rise in tandem. As such, it becomes increasingly important to characterise this disease further, and unravel the molecular mechanisms which lead to hyperglycaemia and, ultimately, premature vascular disease. Insulin resistance, while pathognomonic of type 2 diabetes, is not confined to this condition. It has become clear that insulin resistance lies at the centre of a constellation of cardiovascular risk factors, which include hypertension, obesity and dyslipidaemia. To date there are no large prospective studies that have examined the role of insulin sensitivity in the development of vascular disease, however epidemiological evidence suggests that there is a relationship. Thus, studies exploring the factors that determine insulin sensitivity are of considerable clinical importance. In this thesis, a series of studies is described which were designed to measure insulin action in the whole body and in isolated tissues. Insulin sensitivity was measured in the whole body using the hyperinsulinaemic euglycaemic clamp, though also in adipose tissue by measuring insulin-mediated suppression of lipolysis and in human resistance vessels by measuring insulin-mediated vasodilation. In association with this, the effect of activation of endogenous hormonal axes that may influence insulin sensitivity was investigated, not only in the whole body but also in individual tissues. As an overview of the experimental chapters: i) Insulin-mediated suppression of lipolysis; development and application of an assay of insulin sensitivity; ii) Dietary sodium restriction and insulin sensitivity; iii) Angiotensin II and insulin sensitivity in human adipocytes; iv) Glucocorticoids and insulin sensitivity: dissociation of insulin's metabolic and vascular actions. Conclusions. From the above experimental chapters, several conclusions were made: i) Insulin sensitivity in isolated human adipocytes is reduced in obese, though otherwise healthy, females with normal fasting plasma glucose. ii) Dietary sodium restriction is associated with a reduction in systemic insulin sensitivity. iii) Intracellular crosstalk between angiotensin II and insulin does not result in insulin resistance in human adipocytes. iv) Dexamethasone treatment is associated with a significant reduction in systemic insulin sensitivity, though no change in insulin action in the vasculature