Effect of Glucagon and Glucagon-like Peptide-1 Co-agonism on Cardiac Function and Metabolism in Overweight Participants with Type 2 Diabetes

This is a single-centre, single-blinded pilot study designed to understand the role the GLP-1 receptor agonist, exenatide, and glucagon receptor co-agonism has on normal cardiac physiology, myocardial energetics and myocardial glucose utilisation.

Part A - Overweight participants with type 2 diabetes will act as their own control and will undergo a series of three imaging studies (in a randomised order) as detailed below:

• Cardiac positron emission tomography-magnetic resonance imaging (PET-MRI) with fluorine-18-fluorodeoxyglucose (18F-FDG) with placebo (0.9% saline) infusion
• Cardiac PET-MRI with 18F-FDG with co-infusion of exenatide and glucagon
• Cardiac PET-MRI with 18F-FDG with infusion of glucagon

Part B - Overweight participants with type 2 diabetes will act as their own control and will undergo a series of two imaging studies (in a randomised order), followed by one optional visit as detailed below:

• 7T Phosphorus (P) 31 magnetic resonance spectroscopy (MRS) (31P-MRS) with placebo (0.9% saline) infusion
• 7T 31P-MRS with co-infusion of glucagon and exenatide 3 (optional) 7T 31P-MRS with infusion of glucagon

Study outcome measures are detailed below

Inclusion criteria

• Written informed consent to participate
• Aged >18 years
• Clinical diagnosis of T2DM, either diet controlled or treated with metformin (to be withheld on the morning of the imaging visit)
• BMI ≥25kg/m2
• Current non-smoker

Exclusion criteria

• Females of childbearing potential (Part A only) / current pregnancy (all parts)
• Sustained Hypertension (sustained BP >160/100mmHg) or hypotension (systolic BP below 90 mmHg)
• Clinically significant heart disease
• Implanted heart pacemaker or implantable cardioverter defibrillator (ICD)
• Known active malignancy other than skin cancer
• Known renal failure (creatinine >150µmol/L)
• Known type one diabetes mellitus / known or clinically suspected diagnosis of a monogenic form of diabetes
• Poorly controlled blood glucose
• Current daily use of anti-diabetic medication including Insulin, GLP-1 based agonists, DPP4i or any other medication known to interact with either of the study drugs (exenatide or glucagon)
• Current involvement in the active treatment phase of other research studies, (excluding observational/non-interventional).
• Contraindication for MRI/PET scan, i.e. any reason which precludes MRI imaging according to local policy (ie internal pacemaker/defibrillator, metal fragments, claustrophobia)
• Participation in research studies in the last 3 years involving radiation (if the effective dose exceeded 10mSv). This does not include any diagnostic or therapeutic exposures which were clinically justified.
• Any other clinical reason which may preclude entry in the opinion of the investigator