Can loss of response to the gut hormone, glucose-dependent insulinotropic polypeptide (GIP), be reversed in type 2 diabetes?

Following enrolment (within 1-2 weeks), each subject will commence 12 weeks treatment with capsules containing sitagliptin (100 mg daily) in an open label design, supplied via the Royal Adelaide Hospital Pharmacy. During each of weeks 1 and 12, they will attend the laboratory twice for intraduodenal infusion studies, 2-5 days apart. On the evening preceding the study day (~1900h), participants will be given a standardised evening meal (~591 kcal, 55% carbohydrate, 14% protein and 31% fat). Following this meal, participants will be asked to fast from solids and liquids (other than water) until the following morning, when they will attend the CRF of the AHMS building at 0800h. 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). An intravenous cannula will be placed into a vein of each forearm for hyperglycaemic clamping and infusion of the GIP antagonist GIP(3-30)NH2 (or saline control) and blood sampling, respectively. After correct positioning of the intraduodenal catheter, a hyperglycaemic clamp will be maintained at 15 mmol/L 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, or saline control, will run from t = 30 to 270 min. Intraduodenal glucose will be infused at 2 kcal/min from t = 90 to 190 min. During the 12 week intervention, subjects will keep a daily diary for study medication, receive a fortnightly telephone call to reinforce compliance and document any adverse effects, and visit our centre in weeks 4 and 8 to return any unused medication, receive the next 4 weeks’ supply and undergo repeated physical examinations and assessment of liver and renal function.