Studies on the metabolic effects of chloroquine and mepacrine in non-insulin dependent diabetes mellitus & an assement of the hyperinsulinaemic euglycaemic clamp & isotope dilution techniques
The studies detailed in this dissertation were instigated primarily to confirm an effect and determine the mechanism of action of chloroquine and mepacrine on insulin, glucose and lipid metabolism in patients with non-insulin dependent diabetes mellitus (NIDDM). This work included an assessment of the errors inherent in the hyperinsulinaemic euglycaemic clamp and isotope dilution techniques and investigated the effect of novel modifications designed to improve this methodology. The results demonstrate that chloroquine has several modes of action. There was a) an improvement in glycaemia due to increased peripheral glucose disposal without alteration in hepatic glucose output, b) a striking reduction in receptor mediated plasma insulin clearance, c) an increase in pancreatic insulin secretion, and finally, d) a reduction in fasting plasma total cholesterol, LDL cholesterol and apolipoprotein B. A preliminary trial of mepacrine resulted in a marked reduction in fasting total cholesterol, LDL cholesterol, apolipoprotein B, apolipoprotein A-I and apolipoprotein A-II without significant change in glucose, insulin or c-peptide levels. In vitro studies failed to show any significant effect of chloroquine or mepacrine on insulin stimulated lipogenesis in isolated rat adipoctyes suggesting that the effect of chloroquine to promote peripheral glucose disposal is mediated via an increase in tissue insulin levels rather than a direct effect on insulin action at a cellular level. An assessment of the hyperinsulinaemic euglycaemic clamp and isotope dilution techniques demonstrate that these produce reproducible measurements, with the exception of hepatic glucose output, when performed sequentially in the same individuals with NIDDM. In addition, novel modifications to the isotope dilution technique, designed to minimise errors inherent in the methodology, produced values for hepatic glucose output which, in contrast to the established literature, indicate that the liver is resistant to insulin in NIDDM.