GRETEL - GastRic EmpTying acceleration after fast and slow hypoglycaEmic cLamp

Each participant will be evaluated on 3 separate occasions, separated by at least 3 days in a randomised single blind crossover design. On each study day, participants will be exposed to (1) euglycaemia (baseline blood glucose level (BGL)) – 6.0mmol/L, (2) acute hypoglycaemia (reducing BGL from 6.0 to 2.8mmol/L in 15 min), and (3) gradual hypoglycaemia – (reducing BGL from 6.0 to 2.8mmol/L in 2 hours). Hypoglycaemic clamp: - Glycaemic conditions will be achieved by co-administration of intra-venous glucose and insulin infusions, termed a "hypoglycaemic clamp". This method has been well described previously (Amiel SA, Simonson DC, Tamborlane WV, DeFronzo RA, Sherwin RS. Rate of glucose fall does not affect counter-regulatory hormone responses to hypoglycemia in normal and diabetic humans. Diabetes. 1987; 36: 518-22.) and has been used extensively by our research group to achieve target glycaemic conditions. - On euglycaemic clamp study days, participants will have their BGL titrated with the clamp to maintain a BGL of 6.0mmol/L for 3 hours (time point 0 - 180 minutes). - On slow hypoglycaemic clamp study days, participants will have their BGL titrated with the clamp to induce hypoglycaemia (BGL 2.8mmol/L) over a period of 2 hours (time point 0 to 120 minutes), and then maintained at 2.8mmol/L for a further 1 hour (time points 120 minutes to 180 minutes). - On fast hypoglycaemic clamp study days, participants will have their BGL maintained at 6.0mmol/L for 1 hour and 45 minutes (time point 0 to 105 minutes) and then acutely titrated to 2.8mmol/L (time point 105 minutes to 120 minutes), and then maintained at 2.8mmol/L for a further 1 hour (time point 120 minutes to 180 minutes). Hypoglycaemia will only ever be maintained for a maximum duration of 60 minutes on any study days. A study meal at the end of the study day will restore euglycaemic conditions. Glucose monitoring: Glycaemic conditions will be monitored in several ways for protocol adherence and to generate results. - a YSI (2950D rapid biochemistry analyzer) will be used for near continuous BGL monitoring. The YSI will be used to retrieve BGL values every 5 minutes to allow titration of clamping conditions. - blood samples will be obtained every 30 minutes to yield lab-based plasma glucose levels. This will confirm clamping conditions were achieved when reporting results. - Many participants may have continuous glucose monitoring (CGM) devices as part of their standard care. These CGM devices will have their alarms paused on study days only (to maintain blinding), however their data recording will continue and be retrieved to correlate with YSI and plasma glucose levels. All CGM alarms will recommence at conclusion of study days. - Hypoglycaemia awareness instruments will be administered during the study to monitoring for symptoms: participants will self-administer a visual analog scale instrument every 30 minutes, and research staff will administer a separate instrument at the onset of target hypoglycaemia (time point 120 minutes) and at the end of study days (time point 180 minutes) Study meals: - A standardised high-protein, low-carbohydrate 100g radio-labelled beef patty meal will be ingested by all participants. - This meal will be administered at time point 120 minutes, to coincide with the onset of hypoglycaemia (2.8mmol/L) in both acute and slow hypoglycaemia arms, with the same time time point used in the euglycaemic control arm as a comparator. - participants will ingest the meal within 5 minutes Strategies to monitor adherence: Appropriately qualified and experienced research staff will be available to ensure and monitor adherence to the study protocols. Senior research staff with extensive experience in hypoglycaemic clamp studies will carry out a supervisory role to ensure study procedures are carried out appropriately. A case-report form will log 5-minute BGL on study days to monitor adherence to hypoglycaemic clamp protocols. This will also allow frequent titration of insulin-glucose infusions to achieve the desired clamping conditions. A dedicated research staff member will administer the glucose-insulin infusion and perform titrations to achieve the necessary clamping conditions. Separate staff will perform the other study activities, including blood sampling, administration of hypoglycaemia awareness tools, preparation and assistance with study meals, and performance of scintigraphy.