GRETEL - GastRic EmpTying acceleration after fast and slow hypoglycaEmic cLamp

INTERVENTION: 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 CONDITION: Metabolic and Endocrine ‐ Diabetes Metabolic and Endocrine ‐ Normal metabolism and endocrine development and function type 1 diabetes;delayed gastric emptying; ; type 1 diabetes ; delayed gastric emptying PRIMARY OUTCOME: Gastric emptying[Scintigraphy Scintigraphy will commence at the onset of hypoglycaemia (2.8mmol/L) and will continue for up to 60 minutes after ingestion of a standardised meal labelled with a radiotracer. Scintigraphy will commence 2 hours after study commencement for the slow hypoglycaemia and euglycaemia arms, and 15 minutes after the fast hypoglycaemia arm.] INCLUSION CRITERIA: Men and women with type 1 diabetes Aged 18 years and over HbA 1c lesser than or equal to 9.5 % SECONDARY OUTCOME: Humoral response[Serum assays of: adrenaline, noradrenaline, growth hormone, cortisol, glucagon, pancreatic polypeptide. These assays will be assessed as a composite secondary outcomes measure. Assays will be taken every 30 min leading up to the onset of hypoglycaemia (2.8mmol/L) and up until 60 minutes after the onset of hypoglycaemia . Sequence of time points for assays are indicated below: ; Time‐point 0: ; Plasma glucose, growth hormone, cortisol ; Noradrenaline, adrenaline ; Glucagon ; Pancreatic polypeptide ; Time‐point 30: ; Plasma glucose ; Time‐point 60: ; Plasma glucose, growth hormone, cortisol ; Noradrenaline, adrenaline ; Time‐point 90: ; Plasma glucose ; Time‐point 105: ; Plasma glucose, growth hormone, cortisol ; Noradrenaline, adrenaline ; Glucagon ; Pancreatic polypeptide ; Time‐point 120: ; Plasma glucose, growth hormone, cortisol ; Noradrenaline, adrenaline ; Glucagon ; Pancreatic polypeptide ; Time‐point 150: ; Plasma glucose ; Time‐point 180: ; Plasma glucose, growth hormone, cortisol ; Noradrenaline, adrenaline ]