Obesity, Type 2 Diabetes
Conditions
Brief summary
The study seeks to explore the cardiovascular effects of co-agonism at the glucagon and (glucagon-like peptide-1) GLP-1 receptor. Glucagon and exenatide will be intravenously infused into participants with type 2 diabetes (T2DM). Overall, the aim of the study is to further the investigator's understanding on the role these endogenous substances have on normal cardiac physiology, myocardial energetics and myocardial glucose uptake through a series of PET and MRI imaging studies
Detailed description
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: 1. Cardiac positron emission tomography-magnetic resonance imaging (PET-MRI) with fluorine-18-fluorodeoxyglucose (18F-FDG) with placebo (0.9% saline) infusion 2. Cardiac PET-MRI with 18F-FDG with co-infusion of exenatide and glucagon 3. 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: 1. 7T Phosphorus (P) 31 magnetic resonance spectroscopy (MRS) (31P-MRS) with placebo (0.9% saline) infusion 2. 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
Interventions
Part A - 0.9% saline infusion during cardiac PET-MRI scan
DRUGExenatide (50ng/min for 30 minutes loading followed by 25ng/min maintenance) and glucagon 12.5ng/kg/min
Part A - exenatide and glucagon infusion during cardiac PET-MRI scan
DRUGGlucagon 12.5ng/kg/min and 0.9% saline
Part A - Glucagon and 0.9% saline infusion during PET-MRI scan
DRUGGlucagon 12.5ng/kg/min
Part B - Glucagon infusion during 7T 31P MRS scan
Sponsors
Antaros Medical
Cambridge University Hospitals NHS Foundation Trust
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
SINGLE (Subject)
Masking description
Imaging analysis performed by Antaros Medical (blinded to infusion)
Intervention model description
Single-centre, single-blinded, physiological pilot study
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part A - Myocardial glucose uptake | Comparison between scans over a maximum period of 16 weeks | Difference in myocardial glucose uptake between 0.9% saline, glucagon:exenatide and glucagon scan as measured by 18F-FDG |
| Part A - Global longitudinal strain / global circumferential strain / global radial strain | Comparison between scans over a maximum period of 16 weeks | Difference in global longitudinal strain / global circumferential strain / global radial strain between 0.9% saline, glucagon:exenatide and glucagon scan as measured by CMR |
| Part A - Ejection fraction | Comparison between scans over a maximum period of 16 weeks | Difference in ejection fraction between 0.9% saline, glucagon:exenatide and glucagon scan as measured by CMR |
| Part A - Stroke volume | Comparison between scans over a maximum period of 16 weeks | Difference in stroke volume between 0.9% saline, glucagon:exenatide and glucagon scan as measured by CMR |
| Part A - Cardiac output | Comparison between scans over a maximum period of 16 weeks | Difference in cardiac output between 0.9% saline, glucagon:exenatide and glucagon scan as measured by CMR |
| Part B - Changes in phosphocreatine/adenosine (PCr/ATP) radio | Comparison between scans over a maximum period of 16 weeks | Changes in PCr/ATP radio between 0.9% saline, glucagon:exenatide and glucagon (optional) in the mid-interventricular septum as a measure of cardiac energy status as measured by 7T phosphorus (P) 31 magnetic resonance spectroscopy (MRS) |
| Part B - Changes in absolute concentrations of PCr and ATP defined by AHA 17- segment territory as a measure of cardiac energy status (determined by 31P-MRS) | Comparison between scans over a maximum period of 16 weeks | Changes in absolute concentrations of PCr and ATP between 0.9% saline, glucagon:exenatide and glucagon (optional) as defined by AHA 17-segment territory as a measure of cardiac energy status (determined by 7T 31P-MRS) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part A/B - Glucagon | Comparison between infusions (placebo vs drug) over a maximum period of 16 weeks | Difference in glucagon between 0.9% saline, glucagon:exenatide and glucagon |
| Part A/B - Insulin | Comparison between infusions (placebo vs drug) over a maximum period of 16 weeks | Difference in insulin between 0.9% saline, glucagon:exenatide and glucagon |
| Part A/B - C-peptide | Comparison between infusions (placebo vs drug) over a maximum period of 16 weeks | Difference in C-peptide between 0.9% saline, glucagon:exenatide and glucagon |
| Part A - End systolic/diastolic ventricular/atrial volumes | Comparison between scans over a maximum period of 16 weeks | Difference in end systolic/diastolic ventricular/atrial volumes between 0.9% saline, glucagon:exenatide and glucagon scan as measured by CMR |
| Part A/B - exenatide | Comparison between infusions (placebo vs drug) over a maximum period of 16 weeks | Difference in exenatide between 0.9% saline, glucagon:exenatide and glucagon |
| Part A/B - Total GLP-1 and total active GLP-1 | Comparison between infusions (placebo vs drug) over a maximum period of 16 weeks | Difference in GLP-1 between 0.9% saline, glucagon:exenatide and glucagon |
| Part A/B - gastric inhibitory polypeptide | Comparison between infusions (placebo vs drug) over a maximum period of 16 weeks | Difference in gastric inhibitory polypeptide between 0.9% saline, glucagon:exenatide and glucagon |
| Part A/B - fatty acids | Comparison between infusions (placebo vs drug) over a maximum period of 16 weeks | Difference in fatty acids between 0.9% saline, glucagon:exenatide and glucagon |
| Part A - Radial strain | Comparison between scans over a maximum period of 16 weeks | Difference in radial strain between 0.9% saline, glucagon:exenatide and glucagon scan as measured by CMR |
| Part A - Global systolic/diastolic longitudinal/circumferential/radial strain rate | Comparison between scans over a maximum period of 16 weeks | Difference in global systolic/diastolic longitudinal/circumferential/radial strain rate between 0.9% saline, glucagon:exenatide and glucagon scan as measured by CMR |
| Part A - Relationship between early and late filling (from mitral flow) | Comparison between scans over a maximum period of 16 weeks | Difference in early and late filling (from mitral flow) between 0.9% saline, glucagon:exenatide and glucagon scan as measured by CMR |
| Part A/B - Heart rate | Comparison between infusions (placebo vs drug) over a maximum period of 16 weeks | Difference in heart rate between 0.9% saline, glucagon:exenatide and glucagon |
| Part A/B - Blood pressure | Comparison between infusions (placebo vs drug) over a maximum period of 16 weeks | Difference in blood pressure between 0.9% saline, glucagon:exenatide and glucagon |
| Part A/B - Glucose | Comparison between infusions (placebo vs drug) over a maximum period of 16 weeks | Difference in glucose between 0.9% saline, glucagon:exenatide and glucagon |
Countries
United Kingdom
Outcome results
None listed