None listed
Conditions
Brief summary
Metformin is the first-line oral glucose-lowering medicine in almost all clinical guidelines on the management of type 2 diabetes (T2DM). It was long thought that metformin’s main action was to suppress glucose output from the liver. However, newer evidence suggests that the gastrointestinal tract is a key site of metformin action. In this study, we want to define the role of bile acids in the anti-diabetic action of metformin in type 2 diabetes. We wish to investigate whether the addition of exogenous bile will induce substantially more glucagon-like peptide-1 (GLP-1) secretion when compared to the removal of endogenous bile.
Interventions
Following an overnight fast, each subject will be studied on four occasions, separated by at least 7 days, in a double-blind, randomised fashion.
On each study day, a customised multi-lumen silicone catheter will be inserted through an anaesthetised nostril and allowed to pass into the small intestine by peristalsis. The catheter will be positioned with the small intestinal infusion port located 50 cm below to the pylorus (in the jejunum), with an inflatable self-contained balloon (5 cm in leng
Following an overnight fast, each subject will be studied on four occasions, separated by at least 7 days, in a double-blind, randomised fashion. On each study day, a customised multi-lumen silicone catheter will be inserted through an anaesthetised nostril and allowed to pass into the small intestine by peristalsis. The catheter will be positioned with the small intestinal infusion port located 50 cm below to the pylorus (in the jejunum), with 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 be used to collect endogenous bile and other proximal gut secretions during the study period). 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). Once the intraluminal catheter is correctly positioned, one of the following 4 treatments will be administered by a medically qualified investigator: (i) exclusion of endogenous bile + jejunal 0.9% saline and placebo, (ii) exclusion of endogenous bile + jejunal 0.9% saline and metformin (1 g) (iii) inclusion of endogenous bile + jejunal 0.9% saline and metformin (1 g) (iv) inclusion of endogenous bile + jejunal taurocholic acid (TCA, 4g) and metformin (1 g). At t=-6 min, metformin (1 g) dissolved in water to a volume of 50 mL or placebo (sodium chloride) will be given via intrajejunal infusion over 5 min. Intrajejunal infusion of either TCA (4 g TCA dissolved in 240 mL 0.9% saline), or 0.9% saline, will be commenced at the rate of 240 mL/hour for 30min (t=-30-0min), and reduced to the rate of 60 mL/hour for 120min (t=0-120min). At t=0min, subjects will also receive a small intestinal glucose infusion (60 g glucose dissolved in water to a total volume of 240 mL, infused over 120 minutes; i.e. 2 mL/min, and 2 kcal/min). At the end of the intrajejunal infusion (ie. at t = 120 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, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
All
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
*Type 2 diabetes (World Health Organisation (WHO) criteria), managed by diet only *Body mass index (BMI) from 25 to 35 kg/m2 *Males and females, aged from 18 to 75 years *Glycated haemoglobin (HbA1c) equal to 8.5% *Haemoglobin above the lower limit of the normal range (ie. greater than 135g/L for men and 115g/L for women), and ferritin above the lower limit of normal (ie. greater than 30ng/mL for men and greater than 20mg/mL for women)
Exclusion criteria
*Use of any medication that may influence gastrointestinal motor function, body weight or appetite (opiates, anticholinergics, levodopa, clonidine, nitrates, tricyclic antidepressants, selective serotonin re-uptake inhibitors, phosphodiesterase type 5 inhibitors, sumatriptan, metoclopramide, domperidone, cisapride, prucalopride, or erythromycin) *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 < 90 mL/min or abnormal liver function tests (> 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