Effect of exogenous glucose-dependent insulinotropic polypeptide (GIP) on urinary glucose excretion in type 2 diabetes

Following enrolment, each participant will be studied on 2 occasions, separated by at least 7 days, in a double-blinded, randomised, crossover design. On the evening preceding the study day (~1900h), participants will be given a standardised evening meal. 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 Clinical Research Facility (CRF) of the Adelaide Health and Medical Science (AHMS) building at ~0800h. On each study day, participants will be instructed to defer any morning dose of prescribed medications until the end of the investigation, and an intravenous cannula will be placed into a vein of each forearm for intravenous (IV) dextrose and GIP infusions, and for blood sampling, respectively. A hyperglycaemic clamp will be maintained at 15 mmol/L from t = 0 to 210 min. This will be achieved by intravenous administration of an initial bolus of 25% dextrose (volume calculated to elevate blood glucose to 15 mmol/L from baseline, followed by a 25% dextrose infusion at a rate adjusted according to blood glucose concentrations measured every 5 min using a glucose analyser (Yellow Springs Instrument (YSI) 2500, YSI Life Science Inc, Ohio, USA). Concurrently, an IV infusion of GIP (4 pmol/kg/min; intervention) or 0.9% saline (control) will be administered. Following an initial 30 min of stabilisation of the hyperglycaemic clamp, participants will be asked to empty their bladder at t = 30 min. Subsequently, participants will consume 250 mL water at t = 30, 60, 90, 120, 150 and 180 min respectively, each within 2 min. Urine samples will be collected every 60 min between t = 30-210 min. The glucose levels in the urine will be measured immediately using a YSI analyser. Urine samples will also be collected for urinary electrolytes (including sodium and potassium). “Arterialised” venous blood will be sampled every 30 min, kept warm with a heat pad, between t = 0 and 210 min for measurement of plasma insulin, C-peptide and glucagon. Serum creatinine will be measured and used for calculating the estimated Glomerular Filtration Rate (eGFR) by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula. Renal and superior mesenteric artery blood flow will be measured using ultrasound at baseline, and at t = 120 and 210 min. Blood pressure will be monitored every 15 min from t = 0-210 min. After a final blood sample is collected, participants will be served a light lunch, and once the blood glucose concentration has stabilised above 5 mmol/L, they will be free to leave the laboratory. The total amount of blood drawn during the screening and 2 study visits will be ~200 mL.