Abstract
The focus of the investigations in this thesis was to assess the role of the entero-insular axis in simple, non-diabetic obesity. The first study was undertaken in vivo in obese and matched lean controls where entero-pancreatic hormone responses as well as plasma post-heparin lipoprotein lipase activity (PH-LPL) were assessed following nutrient stimulation. The idea that an overactive entero-insular axis may accentuate lipid deposition in obesity through the stimulation of adipose-tissue lipoprotein lipase activity was investigated by octreotide-mediated suppression of postprandial entero-pancreatic secretion. Plasma LPL activity was similar in lean and obese subjects following carbohydrate administration. However, plasma LPL activity was higher in obese subjects following ingestion of fat consistent with increased lipid deposition in this group. Hyperinsulinaemia as well as impaired glucose tolerance was shown in the obese group, despite which no increase in GIP or GLP-1 responses could be shown in this group. These findings do not support the hypothesis that hypersecretion of insulinotropic factors is responsible for hyperinsulinaemia in obesity. Infusion of octreotide achieved significant suppression of the enteroinsular axis, despite which no reduction in plasma LPL activity was found either in obese or lean groups. Perhaps more significantly, a marked attenuation of plasma GLP-1 response was found in the obese group especially following carbohydrate. The administration of heparin at 120 minutes following nutrient ingestion led to a decrease in GLP-1 responses in both lean and obese groups. A second study was carried out in vitro where a constant amount of heparin was added to tubes containing standard amounts of GLP-1 where the dose-response in the radioimmunoassay was assessed. The dose response curves for GLP-1 with and without heparin were similar and no evidence for an artifactual lowering of GLP-1 due to interference in the antigen-antibody binding was found. One possible reason for the lack of difference in plasma LPL between obese and lean in the earlier study following carbohydrate, namely non-individualisation of heparin dose, was investigated in vivo in obese and matched lean subjects. Indocyanine green was used to measure blood volume in all subjects and heparin dose calculated based on these measurements. Plasma LPL activity was measured following administration of this individualised dose, in the fasting state, in all subjects. The mean blood volumes as well as the calculated heparin doses were greater in the obese subjects. Despite this, fasting plasma LPL activity showed a consistent reduction in the obese group. The final study was also preformed in vivo where carbohydrate-stimulated GLP-1 responses were studied during simultaneous modulation of circulating non-esterified fatty acid (NEFA) in obese and matched lean controls. Heparin was co-administered with carbohydrate to increase serum NEFA while acipimox given 120 minutes prior to carbohydrate achieved a reduction in serum NEFA. Higher fasting levels and postprandial total integrated NEFA and glycerol responses were also observed in the obese group. GLP-1. responses were significantly lower following the increase in NEFA post-heparin and significantly higher following the decrease in NEFA post-acipimox. Despite reduction of serum NEFA post-acipimox to similar levels in lean and obese subjects, the obese group exhibited significantly lower GLP-1 responses suggestive of an intrinsic defect in GLP-1 secretion in this group. Based on these findings and the satiating properties of GLP-1 a model of short-term regulation of Food Intake is proposed. The higher fasting and postprandial NEFA in obesity may tonically inhibit nutrient mediated GLP-1 secretion and disrupt the control of food intake in obesity.