None listed
Conditions
Brief summary
Bile acids are increasingly recognised to play a critical role in the regulation of glucose homeostasis. The proposed study extends our novel findings on the effects of exogenous bile acids and capitalises on our capacity to aspirate endogenous bile and target nutrient infusions to specific regions of the small intestine in humans, to define the role of endogenous bile acids in postprandial glucose metabolism in type 2 diabetes (T2DM), and to clarify the relative importance of exposure of different regions of the gut to bile acids. Specifically, we will evaluate the hypothesis that small intestinal exposure to endogenous bile acids will reduce postprandial glycaemic excursions, associated with augmented secretion of glucagon-like peptide-1 (GLP-1) and insulin and suppression of glucagon in patients with T2DM and that these effects will be potentiated by diversion of bile acids from the proximal to the distal small intestine.
Interventions
Following enrolment, each subject will be studied on 3 occasions, separated by at least 7 days, in a single-blind, randomized fashion.
On each study day, a silicone rubber catheter will be inserted by an experienced research officer through an anaesthetised nostril into the stomach, and allowed to pass into the small intestine by peristalsis. The catheter will be positioned with the two infusion ports (i.e. proximal and distal small intestinal infusion ports) located at 50 cm (i.e. the jejunum)
Following enrolment, each subject will be studied on 3 occasions, separated by at least 7 days, in a single-blind, randomized fashion. On each study day, a silicone rubber catheter will be inserted by an experienced research officer through an anaesthetised nostril into the stomach, and allowed to pass into the small intestine by peristalsis. The catheter will be positioned with the two infusion ports (i.e. proximal and distal small intestinal infusion ports) located at 50 cm (i.e. the jejunum) and 190 cm (i.e. the ileum) beyond the pylorus, respectively, while subjects laid in a supine position. An inflatable self-contained balloon (5 cm in length, with a maximum volume of 100 mL) situated 30 cm below the pylorus, that can be inflated as a barrier between the duodenum and the jejunum, and an aspiration channel 25 cm distal to the pylorus (to aspirate endogenous bile). The correct positioning of the catheter will be monitored continuously by measurement of the transmucosal potential difference in the stomach (~ -40 mV) and the duodenum (~ 0 mV). For this purpose, an intravenous cannula will be placed subcutaneously in the left forearm by our experienced research office rand filled with sterile saline as a reference electrode. An intravenous cannula will be placed into a vein on the dorsum of the hand, which will be kept warm with a heat pad to allow sampling of “arterialised” blood. Once the intraluminal catheter is correctly positioned, the balloon will be slowly inflated with air (~30-40 mL) until the subject reports a sensation of pressure without discomfort. An intra-balloon pressure of at least 20 mmHg (a known pressure to be sufficient to achieve full blockade) will be maintained by continuous monitoring with a pressure gauge throughout the study (t = 0 - 180 min). The aspiration channel will be connected to negative pressure drainage to allow constant aspiration of secretions from the duodenum. At t = 0 min, subjects will receive intrajejunal glucose infusion at 3 kcal/min (67.5 g glucose dissolved in water to a total volume of 180 mL, infused over 90 minutes). Meanwhile, endogenous bile will be aspirated consciously and one of the following three interventions will be conducted by one of the investigators: (i) stored separately for analysis (ii) re-perfused into the proximal jejunum (every 5 minutes, for 180 minutes) (iii) re-perfused into the ileum (every 5 minutes, for 180 minutes). The volume of bile re-perfused is whatever was aspirated in the previous 5 minutes. Sites without reperfusion of endogenous bile will be perfused with 0.9% saline to control for the volume infused. At t = 180 min, the catheter will be removed.
Sponsors
University of Adelaide
Study design
Allocation
Randomised controlled trial
Intervention model
Crossover
Primary purpose
Treatment
Masking
Blinded (masking used) (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
All
Age
18 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
(i) Patients with type 2 diabetes (World Health Organisation (WHO) criteria), HbA1c less than or equal to 8.5%, managed by diet or metformin alone, body mass index from 20 to 35 kg/m2, both males and females aged from 18 to 75 years (ii) Healthy volunteers, matched as closely as possible to the diabetic subjects for age, sex, and BMI. Additional inclusion criteria include: haemoglobin above the lower limit of the normal range (ie. more than 135g/L for men and 115g/L for women), and ferritin above the lower limit of normal (ie. more than 30ng/mL for men and 20mg/mL for women)
Exclusion criteria
Exclusion criteria • Use of any medication that may influence gastrointestinal motor function, bile acid metabolism, body weight or appetite (e.g. bile acid sequestrants, domperidone and cisapride, anticholinergic drugs (e.g. atropine), metoclopramide, erythromycin, hyoscine, orlistat, green tea extracts, Astragalus, St. John's Wort etc.) • Evidence of drug abuse, consumption of more than 20 g alcohol or 10 cigarettes on a daily basis • History of gastrointestinal disease, including significant upper or lower gastrointestinal symptoms, pancreatitis, or previous gastrointestinal surgery (other than uncomplicated appendicectomy or cholecystectomy) • Other significant illness, including epilepsy, cardiovascular or respiratory disease • Impaired renal or liver function (as assessed by calculated creatinine clearance less than 90 mL/min or abnormal liver function tests (more than 2 times upper limit of normal range)) • Donation of blood within the previous 3 months • Participation in any other research studies within the previous 3 months • Inability to give informed consent • Female participants who are pregnant or planning for pregnancy, or are lactating • Vegetarians
Outcome results
None listed