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Title: Aspects of insulin secretion and action in non-insulin-dependent diabetes mellitus
Author: Whitelaw, Donald C.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1999
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In a cross-sectional survey of coronary risk factors in subjects with recently diagnosed NIDDM I confirm the high prevalence of individual risk factors described by others, and show a broadly normal distribution pattern for the clustering of risk factors forming Reaven's Syndrome X, in contrast to that reported in other populations. I suggest that hyperinsulinaemia and hypertriglyceridaemia are the best markers of high coronary risk and note the association of obesity and other risk factors. In a study to examine the effects of the new oral hypoglycaemic drug A4166 in NIDDM I confirm its major effect as an insulin secretagogue but find limited effects on intermediary metabolism when assessed during and intravenous glucose tolerance test. Any enhancement of glucose clearance appears to be secondary to the increase in insulin secretion. If hypertriglyceridaemia exacerbates insulin resistance in NIDDM, then its treatment may reverse this process. In a randomised study comparing the fibrate drug gemfibrozil with placebo I show that reduction in serum triglyceride concentrations with gemfibrozil is associated with improved insulin sensitivity to non-esterified fatty acid (NEFA) and ketone metabolism but not to glucose metabolism, when assessed using a low-dose incremental insulin infusion technique. In established diabetes (NIDDM) the contribution of body fat to insulin resistance is less clear than among non-diabetic subjects. In a group of NIDDM subjects I show no consistent effects of body fat on insulin resistance using the low-dose incremental insulin infusion, and no relation between body fat indices and euglycaemic clamp measures of insulin sensitivity. From the insulin infusion data I show that fasting glucose concentration has the greatest impact on insulin resistance, suggesting that hyperglycaemia or perhaps glucose toxicity has an effect overwhelming that of other factors. Using the data from the body fat studies described, I compare measures of insulin resistance derived from insulin infusions, euglycamic clamps and homeostatic modelling (HOMA-R) in NIDDM, and discuss uses and limitations of these techniques. In a concluding chapter I attempt to summarise the findings from these studies and draw together a discussion of the results obtained in the context of the existing published literature.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available