Effects of small intestinal quinine (bitter agonist) on gut function and blood glucose in healthy, lean volunteers.

The intervention in this study consists of the intraduodenal infusion of a quinine or control solution over a 60 minute period during which the measurement of gut motility, blood glucose, gut hormone concentration, insulin concentrations, appetite perceptions and energy intake during a buffet meal will be measured. Subjects enrolled into the study will receive, in randomized, double-blind fashion (i) 0.625mg/min quinine, (ii) 1.25mg/min quinine, (iii) 3.75mg/min quinine. (iv) saline (control) each occurring at separate visits. Each visit will last 3-6hrs in duration, and will be separated by 3-7 days. Visits will be carried out in the clinic room facility of the Discipline of Medicine, University of Adelaide by staff members trained in the required techniques, and will be conducted on an individual basis. Subjects will be asked to consume a standardised dinner meal the night before each visit by no later than 6pm, After fasting for 14 hrs overnight and refraining from exercise and alcohol for 24 hrs, subjects will arrive at the laboratory at 8am . Upon arrival, subjects will be intubated with a 17-channel manometric catheter that will be inserted through an anaesthetised nostril and allowed to pass through the stomach and into the duodenum by peristalsis. The manometric catheter consists of 16 side holes spaced at 1.5 cm intervals, measuring pressures in the antrum, pylorus, and duodenum (APD pressures). An additional channel (with the side hole positioned approx 14 cm distal to the pylorus when the catheter is in position) is used for intraduodenal infusions. The correct positioning of the catheter will be maintained by continuous measurement of the transmucosal potential difference (TMPD) between the most distal antral channel and the most proximal duodenal channel. All manometric channels will be perfused with degassed, distilled water, except for the two TMPD channels, which will be perfused with degassed 0.9% saline, at 0.15 ml/min. An intravenous cannula will be placed into a right forearm vein for regular blood sampling to measure plasma hormone concentrations. Once the catheter has been positioned correctly, fasting motility will be monitored continuously, and immediately after the end of phase III activity of the fasting migrating motor complex (MMC), during a period of motor quiescence (t=-15 - 0 min), a 10 ml venous blood sample (baseline) will be taken, and the subject will complete a visual analogue scale questionnaire (VAS) to assess appetite-related perceptions (fullness, hunger, etc.) and gastrointestinal symptoms (nausea and bloating). At t = 0 min (during phase I of the MMC), the 60-min intraduodenal infusion (either (i), (ii), or (iii) as outlined above) will commence . APD pressures will be measured continually over the 60-min period. Blood samples will be collected and VASs completed every 15 min from t = 0 to 60 min. At t = 60 min, the manometric catheter will be removed and subjects will be presented with a cold, buffet-style meal. Subjects will be allowed 30 min to freely consume food until they are comfortably full. At t = 90 min, a final blood sample will be taken, and VAS administered. The intravenous cannula will then be removed and subjects will be allowed to leave the laboratory. A total of 70 ml of blood will be taken on each study day (280 ml over all study visits). In addition, on one further occasion, oral detection thresholds for bitter taste will be assessed using 3-Alternative Forced Choice procedure, an established technique for the quantification of oral taste detection thresholds. Samples for the assessment of bitter taste will be prepared using quinine dissolved in deionised water. All samples will be presented at room temperature, under a red light to minimise visual cues. Participants will wear nose-clips to ensure detection of differences is not due to smell, and will be asked to rinse their mouths with water after each set of samples. There will be 1 min between presentations of sample sets. A set of samples will be presented as three trays of three samples, each tray containing one sample of the quinine concentration being tested and two samples of deionised water. The subject will taste the samples from left to right on each tray and choose the one sample that tastes ‘odd’ compared to the other two. If the subject does not choose the three samples containing quinine in that set, they will be presented with the next set of samples at a higher concentration. Once the subject selects the three correct samples containing quinine, this will be recorded as their detection threshold.