This group will continue on their standard diabetes care. They will be required to undergo three periods of blinded continuous glucose monitoring each lasting 20-days at: baseline, 4 months and 8 months. Participants in this group will undergo a hyperinsulinaemic hypoglycaemic clamp study at baseline and 8 months. They will also complete quality of life and diabetes treatment questionnaires at baseline and 8 months.

Participants will commence on a primed insulin infusion at a constant rate of 60mU/m2/min along with a variable rate 20% glucose infusion. Participants will have their blood glucose monitored every 5 minutes. The glucose infusion will be altered to achieve the desired blood glucose plateaus of: 5mmol/l, 3mmol/l and 2.5mmol/l. Each plateau will be held for 40 minutes. During each plateau blood samples will be taken on three occasions for: glucagon, cortisol, adrenaline, noradrenaline, D2 glucose and D5 glycerol. On two occasions during each plateau participants will complete the Edinburgh hypoglycaemia scale and the following cognitive tests: trail making test, digit span test, digit symbol substitution test and four choice reaction time test. At the end of the clamp study the insulin infusion will be discontinued and the blood glucose will be allowed to rise to the normal range. Participants will consume lunch before leaving the clinical research facility.

Stepped hyperinsulinaemic-hypoglycaemic clamp study

Allows data on blood glucose to be collected without values altering the behaviour of the participant. Participants have to continue to monitor their own blood glucose while wearing the device in the blinded mode.

Blinded continuous glucose monitor

These studies will take place at the same time as the hyperinsulinaemic hypoglycaemic clamp studies. Participants will receive a priming dose of each stable isotope followed by a continuous infusion for the remainder of the clamp study.

Stable isotope studies- D2 Glucose and D5 Glycerol

This group will be placed on an automated insulin delivery system: Tandem t:slim x2 insulin pump with Control IQ technology and Dexcom G6 continuous glucose monitor. They will also be asked to follow a low-carbohydrate diet of 30-40g of carbohydrate per main meal. At baseline they will have a 20-day period of blinded continuous glucose monitoring. Participants in this group will undergo a stepped hyperinsulinaemic hypoglycaemic clamp study at baseline and 8 months. They will also complete quality of life and diabetes treatment questionnaires at baseline and 8 months.

Insulin pump with a built-in algorithm that allows it to work with a CGM device to adjust insulin delivery based on CGM readings.

Insulin pump

Continuous glucose monitoring device that sends data to the insulin pump to allow the algorithm to adjust insulin delivery. Participants are able to see the glucose data from the device when it is used in open mode.

Continuous glucose monitor

30-40g of carbohydrate per main meal portion.

Low carbohydrate diet

Insulin will be infused at a continuous rate of 60 mU∙m-2 ∙min-1 and glucose 20% will be infused at a variable rate, aiming for stable plasma glucose levels of 5.0 mmol/L. The infusion rate of glucose will be adjusted by plasma glucose levels, measured at 5-minute intervals. After 30 minutes of stable euglycaemia, plasma glucose levels will be allowed to drop gradually to 2.8 mmol/L and will be maintained at this level for 60 minutes. Then, insulin infusion and adrenergic blockade infusions will be stopped. Glucose infusion will be increased and then tapered until stable euglycaemia plasma levels are reached.

hyperinsulinaemic hypoglycaemic clamp

When euglycaemic level of 5.0mmol/L is achieved we will start the adrenergic blockade which will continue throughout euglycaemia and hypoglycaemia. The participants will be administered a bolus of phentolamine of 70µg/kg followed by a dose of 7.0µg/kg/min continuous infusion and a bolus of propranolol of 14µg/kg followed by a dose of 1.4µg/kg/min.

Propranolol Hydrochloride 1 MG/ML

Phentolamine

We aim to match our participants with each other to have comparable groups. So we aim to have the same amount of males and females.

Participants will have their glial acetate metabolism measured by carbon-13 magnetic resonance spectroscopy as well as their neuroendocrine response to hypoglycemia 3 days later.

An intravenous catheter will be placed in an antecubital vein for infusion of insulin and glucose. A second catheter will be placed retrograde in a dorsal vein of the contra-lateral hand for blood withdrawal. The hand will be placed in a heating box or pad at 70°C for arterialization of venous blood. A primed infusion of regular insulin (120 mU/min/m2) will be initiated and continued for approximately 2 hours. Beginning 20 minutes prior to the start of the insulin infusion, arterialized venous blood glucose will be measured at 5 minute intervals via a Hemocue or YSI analyzer. Following initiation of insulin infusion, blood glucose will be allowed to fall to 50 mg/dL and then maintained at this level using a variable infusion of exogenous dextrose (20% solution). Our goal is to achieve steady-state (blood glucose stabilized at 50 +/- 5 mg/dL) within the first 45 minutes following the start of insulin infusion.

hyperinsulinemic-hypoglycemic clamp

Glial metabolism will be measured via MRS utilizing a simultaneous intravenous infusion of 13C labeled acetate. An intravenous catheter will be placed in a vein of each arm, one to infuse 13C-acetate and the other to draw blood samples

단계적 고인슐린혈증-저혈당 클램프 연구, 인슐린 펌프, 연속 혈당 측정기, 저탄수화물 식단, 맹검 연속 혈당 측정기, 안정 동위원소 연구 - D2 포도당 및 D5 글리세롤

고인슐린혈증성 저혈당 클램프, 프로프라놀롤 염산염 1MG/ML, 펜톨아민

고인슐린혈증-저혈당 클램프, 13C-MRS 시술/아세트산염 주입