Investigating the impact of glucagon timing and protein replacement on metabolism

INTERVENTION: Following an initial screening visit, participants will attend the NIHR Imperial Clinical Research Facility for a 4‐day inpatient stay, where they will undergo a 72‐hr intravenous infusion. Participants will be allocated to the following groups in a cross‐over design and receive intravenous infusions for 72 hours with a washout period: Group 1. Continuous infusion of glucagon Group 2. Continuous infusion of placebo Group 3. Daytime infusion of glucagon (0800h to 2000h) and night‐time infusion of saline (2000h to 0800h) Group 4. Continuous infusion of glucagon with dietary protein supplementation Participants allocated to receive glucagon (continuous or daytime) will receive increasing doses on study days 2 and 3, prior to discontinuation of the infusion on the morning of study day 4. Doses of glucagon administered as an intravenous infusion will be as follows: Day 1 glucagon dose: 6 ng/kg/min, Day 2 glucagon dose: 12.5 ng/kg/min, Day 3 glucagon dose: 25 ng/kg/min, Day 4: Infusion discontinued. Participants will be randomised to groups and a follow up visit will be arranged after completion of the four inpatient visits. CONDITION: Overweight/obesity ; Nutritional, Metabolic, Endocrine PRIMARY OUTCOME: 1. Circulating amino acids and lipids will be measured using mass spectrometry prior to infusion commencement, during the daytime and nighttime.; 2. Energy expenditure will be measured using indirect calorimetry at baseline and at steady state during the infusion SECONDARY OUTCOME: 1. Appetite will be measured using visual analogue scales before and after each meal.; 2. Glucose will be monitored using continuous glucose monitoring, over the 72 hour infusion period. INCLUSION CRITERIA: 1. Aged 18‐65 years 2. Male or female 3. Glycated haemoglobin (HbA1C) <48 mmol/mol 4. BMI 25‐45 kg/m², stable weight for >3 months