Glucagon-like peptide 1 (GLP-1) for lowering plasma glucose in type 2-diabetic patients: A systematic comparison of intravenous and subcutaneous routes.

Following enrolment, each participant will be studied on two occasions, separated by 5-21 days, in a double blind randomised controlled design. They will withhold their usual long acting insulin (glargine) on the day before the study, and any premixed or prandial insulin from 1500h on that day. Any oral agents will be continued. On the evening preceding the study day (~1900h), participants will be given a standardised evening meal (2472kJ) and a piece of fruit to consume with water. 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 study site at 0800h. On each study day one SC needle and two IV cannulae (in opposite arms) will be inserted. An infusion of GLP-1 (GMP grade, sterile and pyrogen-free) in normal saline with 1% albumin to prevent adhesion of peptide to tubing will commence via an infusion pump into either the SC needle or an IV cannula, with saline and albumin alone into the alternate site, and the sites reversed on the second study visit. Each infusion will be marked only with the subject code, intended route (SC or IV), and visit number to maintain allocation concealment; the appearance of the solutions will be identical. The rate of infusion will be adjusted every 2 h, commencing at a “physiological” rate (comparable to circulating postprandial concentrations) and progressing to pharmacological concentrations, for a total 8 h infusion period on each day (t = 0 to 480 min) as follows: - 0.3, 0.6, 1.2 and 2.4 pmol/kg/min GLP-1 on the IV day, and - 1.2, 2.4, 4.8, and 9.6 pmol/kg/min GLP-1 on the SC day Blood will be sampled from the IV cannula in the arm opposite the IV infusion at baseline and then every 30min , i.e. t = -15, 0, 30, 60, 90, 120, 150, 180, 210, 240, 270, 300, 330, 360, 390, 420, 450, and 480 min, for subsequent measurement of plasma glucose, insulin, C-peptide, glucagon, and intact and total GLP-1 concentrations. Blood glucose will also be monitored using a bedside glucometer every 30 min. The total amount of blood drawn during the study will be approx. 370 mL. GI symptoms including nausea and appetite ratings will be scored using validated 100mm visual analog scales at the same intervals as blood sampling; the infusions will be terminated if nausea scores reach =50mm or vomiting occurs. Heart rate and blood pressure will be monitored every 15 min using an automated sphygmomanometer. Subjects will remain fasting throughout the infusion period, but at t=480 min will be offered a buffet meal, from which they will be given 30 min to eat until they feel comfortably full. All food items will be weighed before and after the meal to quantify energy intake. At the conclusion of the meal, the cannulae will be removed and subjects allowed to leave the facility, with instructions to resume their usual insulin therapy.