None listed
Conditions
Brief summary
Hormones called “incretins” are released from the gut in response to meal ingestion and greatly enhance postprandial insulin secretion (the “incretin effect”), thereby playing a critical role in limiting the rise in blood glucose concentrations. Glucose-dependent insulinotropic polypeptide (GIP) was the first incretin discovered in 1973. While its capacity to stimulate insulin secretion appears to be diminished in people with type 2 diabetes (T2DM), recent studies suggest that this loss of effect is reversible if good blood glucose control is regained. A second incretin, glucagon-like peptide-1 (GLP-1), was discovered in 1987 and has risen to prominence, in part because drugs that mimic its effects have been developed and are used to treat T2DM, with great success. Incretin-based therapies are attractive because they only stimulate insulin secretion when blood glucose concentration elevated, so unlike insulin injections, they entail a low risk of hypoglycaemia. The role of GIP has been neglected, in part because we have lacked an antagonist suitable for human experiments to block the action of GIP. One factor that enabled GLP-1 to be developed into a drug was the availability of a GLP-1 antagonist, exendin9-39, that was suitable for use in humans. In collaboration with Prof Jens Holst from University of Copenhagen, who has recently identified a GIP antagonist, GIP(3-30)NH2, that can be used in human research, we can now for the first time to identify exactly what role GIP plays in insulin secretion and blood glucose control. In the current proposal, we will employ this novel human GIP antagonist and the GLP-1 antagonist, exendin9-39, to determine in healthy humans whether GIP and GLP-1 together account for the entire incretin effect, or whether there is a “third incretin”.
Interventions
Following a screening visit, each subject will be studied on 4 occasions, separated at least 7 days, in a double-blind randomised crossover design.
On each study day, a silicone rubber catheter will be inserted through an anaesthetised nostril into the stomach, and be positioned with the infusion port located 12 cm below to the pylorus (in the duodenum). The correct positioning of the catheter will be monitored continuously by measurement of the transmucosal potential difference in the stomach (
Following a screening visit, each subject will be studied on 4 occasions, separated at least 7 days, in a double-blind randomised crossover design. On each study day, a silicone rubber catheter will be inserted through an anaesthetised nostril into the stomach, and be positioned with the infusion port located 12 cm below to the pylorus (in the duodenum). 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 and filled with sterile saline as a reference electrode. An intravenous cannula will be placed into a vein of each forearm for hyperglycaemic clamping and infusion of the GIP and/or GLP- antagonist, and blood sampling, respectively. After that, a hyperglycaemic clamp will be maintained at 5 mmol/L above fasting blood glucose from t = 0 to 270 min. This is achieved by intravenous administration of an initial bolus of 25% dextrose, followed by a 25% dextrose infusion at a rate adjusted according to blood glucose concentrations measured every 5 min. Concurrently, a solution of 100 units of insulin, made up to 500 ml with Gelofusine to yield a final concentration of 0.2 IU/ml, will also be infused intravenously at rates according to a sliding scale used in previous similar studies. An IV infusion of the GIP antagonist GIP(3-30)NH2 at the rate of 800 pmol/kg/min and/or the GLP-1 antagonist exendin9-39 at the rate of 600 pmol/kg/min, or saline control, will run from t = 30 to 270 min. Intraduodenal glucose will be infused at 3 kcal/min from t = 90 to 190 min.
Sponsors
The 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 40 Years
Healthy volunteers
Yes
Inclusion criteria
• Healthy male and females aged from 18 to 40 years, without a family history of T2DM in any 1st degree relative • Body mass index (BMI) from 19 to 28 kg/m2 • 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 less than 90 mL/min or abnormal liver function tests (greater 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