Assessment of beta-cell function and insulin sensitivity in established non-insulin dependent diabetes mellitus - The influence of diet and sulphonylurea therapy.

This thesis reports on studies validating a modification of 'minimal' model analysis of the FSIVGTT to measure insulin resistance specifically in NIDDM subjects and its use along with a mixed meal test incorporating measurement of specific insulin and proinsulin concentrations to quantify changes in beta-cell function and insulin resistance following two years of diet or sulphonylurea treatment in established NIDDM. All NIDDM subjects displayed severe beta-cell dysfunction (post-prandial insulinopenia and hyperproinsulinaemia) and insulin resistance when compared to age and sex matched normals. Therapeutic interventions failed to normalise either of these abnormalities. Dietary therapy resulted in improved glycaemic control, weight loss and improved insulin sensitivity but most especially improved beta-cell function (increased post-prandial insulin secretion, reduced proinsulin concentrations) at the one year assessment. Two years post-diagnosis post-prandial proinsulin concentrations continued to fall whilst insulin concentrations mirrored those at the time of presentation. Sulphonylurea therapy also resulted in improved glycaemic control but with significant weight gain. Insulin sensitivity tripled over the two year period and beta-cell function also improved after initial increases in both post-prandial insulin secretion and proinsulin concentrations at the one year assessment Reduced 'glucose toxicity' appeared to be a major factor affecting the changes in the measured parameters in both groups of subjects. For diet treated individuals, it is suggested that this reduction rapidly maximises beta-cell function and insulin sensitivity to a predetermined level. Maintenance of glycaemic control subsequently is dependent of factors more difficult (diet, exercise, weight) or impossible to control (time). For sulphonylurea treated subjects, reduction in 'glucose toxicity' was important in improving beta-cell function and insulin sensitivity but the drugs themselves exerted an independent effect, especially on sustained increases in insulin secretion. It is suggested that the continuous use of sulphonylureas may play a causal role in the ultimate deterioration in glycaemic control frequently seen in patients who initially appear to benefit from their effects.