Healthy, Type 2 Diabetes Mellitus
Conditions
Keywords
Type 2 diabetes mellitus, lean healthy control
Brief summary
The objective of this proposal is to provide quantitative dose-response data for effects of GLP-1 on myocardial glucose uptake in healthy control subjects and obese type 2 diabetic subjects, in support of the design of later studies evaluating therapeutic applications of GLP-1 to heart disease. Aim 1: To measure the effects of GLP-1 infusion on myocardial fuel selection in lean healthy humans under fasting (fatty acid-dominant) conditions. Four groups of 10 lean healthy subjects will be studied during infusions of 0 (saline control), 0.5, 1.5, and 4.0 pmol/kg/min GLP-1 (one study per subject). Cardiac metabolism will be measured using PET, using a dual-tracer approach which allows measurement of myocardial glucose uptake (the primary endpoint) along with total oxidation rate and myocardial perfusion (secondary endpoints). In concert with measures of circulating metabolites and regulatory hormones, the investigators will produce the most comprehensive assessment of actions of GLP-1 on myocardial metabolism in humans to date. Effects of each dose will be compared to the saline control, plus the investigators will combine all data and use nonlinear curve-fitting to derive sensitivity (ED50) and maximal responses for GLP-1 effects on myocardial glucose uptake. Aim 2: To measure the effects of GLP-1 infusion on myocardial fuel selection in obese type 2 diabetic humans under fasting (fatty acid-dominant) conditions Four groups of 10 obese type 2 diabetic subjects will be studied during infusions of 0, 0.5, 1.5, and 4.0 pmol/kg/min GLP-1 as under Aim 1. Analyses will be parallel to those described under Aim 1. Results from Aims 1 and 2 will be combined to allow direct comparison of the dose-response between nondiabetic control and type 2 diabetic subjects. No literature has been published to inform dose selection in the design of clinical trials of GLP-1 for modulation of heart fuel selection. With our expertise and experience in PET measurement of heart metabolism in diabetes, the investigators are uniquely positioned to fill this gap in knowledge. These studies are a necessary preamble to further evaluation of the potential for GLP-1 based treatments in heart disease.
Interventions
DRUGGLP-1 Low Dose
0.5mmol/kg/hr GLP-1 for 12 hours prior to PET study
DRUGGLP-1 Mid-Range Dose
1.5mmol/kg/min for 12 hours prior to PET study
DRUGGLP-1 High Dose
4.0mmol/kg/min GLP-1 for 12 hours prior to PET study
DRUGSaline
Normal saline placebo infusion for 12 hours prior to PET study
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Indiana University
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
Yes
Inclusion criteria
* Age 18-60 * Lean subjects will be defined as having a BMI \<25 kg/m2, in good general health, taking no regular medications * Diabetic subjects will be obese (BMI \>30 kg/m2 but \<40 kg/m2), HbA1c 7.0-10.0%, treated with diet and exercise plus oral agents or injected insulin. All diabetic subjects will be treated with injected insulin for 2 weeks prior to study, to avoid potential confounding effects of other antidiabetic agents.
Exclusion criteria
* Chronic illnesses or infections (other than type 2 diabetes) * Known coronary artery disease or abnormal ECG on screening evaluation * Blood pressure \> 160/100 mmHg on two occasions during screening evaluations. Current use of 3 or fewer blood pressure medications with blood pressure below this cutpoint will be acceptable. * Total cholesterol \> 240 mg/dL. Current use of 2 or fewer lipid lowering agents with cholesterol below this cutpoint will be acceptable. * Diabetic subjects: Treatment with a GLP-1 agonist or DPP4 inhibitor within the past 6 months * Known intolerance to injected GLP-1 agonist * Treatment with PPAR gamma agonists currently or within the past 6 months * Recognized microvascular complications (retinopathy, nephropathy, neuropathy) * Unwillingness or inability to use injected insulin for the purposes of this study * Chronic pain or other physical conditions which limit ability to remain supine for the duration of the study protocol * History of claustrophobia, musculoskeletal or other factors which would result in an inability to comfortably remain within PET scanner gantry for the duration of the imaging protocol * Occupational, investigational or other known radiation exposure which, together with the planned radiologic studies, will result in greater than 500 mrem total exposure in a contiguous 12 month period * For female participants, current pregnancy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Myocardial Glucose Uptake. | After 12 hours of glucagon-like peptide 1 (GLP-1) exposure | Myocardial glucose uptake measured using 18FDG PET, quantified using a 3-compartment model with a lumped constant of 1.0. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Myocardial Blood Flow | After 12 hours of GLP-1 exposure | Myocardial perfusion derived from acetate kinetics |
| Myocardial Total Oxidation Rate | After 12 hours of GLP-1 exposure | MVO2 derived from acetate kinetics |
| Cardiac Index | After 12 hours of GLP-1 exposure | Impedance cardiography-derived measurement of cardiac index, assessed following 12 hour exposure to treatment condition concurrent with the PET measurements. |
| GLP-1 Concentrations | After 12 hours of GLP-1 exposure | Achieved GLP-1 concentrations at the end of the 12 hour treatment exposure |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Lean Saline 12 hour placebo (saline) infusion prior to PET study
Placebo: Saline placebo infusion for 12 hours prior to PET study | 6 |
| Lean GLP-1 0.5 Pmol/kg/Min GLP-1 Low Dose: 0.5 pmol/kg/min for 12 hours prior to PET study | 11 |
| Type 2 DM GLP-1 0.5 Pmol/kg/Min GLP-1 Low Dose: 0.5 pmol/kg/min for 12 hours prior to PET study | 1 |
| Lean GLP-1 1.5 Pmol/kg/Min GLP-1 Mid-Range Dose: 1.5 pmol/kg/min for 12 hours prior to PET study | 8 |
| Type 2 DM GLP-1 1.5 Pmol/kg/Min GLP-1 Mid-Range Dose: 1.5 pmol/kg/min for 12 hours prior to PET study | 7 |
| Lean GLP-1 4.0 Pmol/kg/Min GLP-1 High Dose:4.0 pmol/kg/min for 12 hours prior to PET study | 0 |
| Type 2 DM GLP-1 4.0 Pmol/kg/Min GLP-1 High Dose:4.0 pmol/kg/min for 12 hours prior to PET study | 0 |
| Total | 33 |
Baseline characteristics
| Characteristic | Lean Saline | Lean GLP-1 0.5 Pmol/kg/Min | Type 2 DM GLP-1 0.5 Pmol/kg/Min | Lean GLP-1 1.5 Pmol/kg/Min | Type 2 DM GLP-1 1.5 Pmol/kg/Min | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 35.5 years STANDARD_DEVIATION 10.6 | 38.0 years STANDARD_DEVIATION 6 | 42 years STANDARD_DEVIATION 0 | 46.0 years STANDARD_DEVIATION 5.8 | 45.1 years STANDARD_DEVIATION 7.9 | 42.7 years STANDARD_DEVIATION 7.9 |
| Body Mass Index (kg/m2) | 23.9 kg/m^2 STANDARD_DEVIATION 1.6 | 23.0 kg/m^2 STANDARD_DEVIATION 1.5 | 31.0 kg/m^2 STANDARD_DEVIATION 0 | 22.9 kg/m^2 STANDARD_DEVIATION 1.8 | 30.3 kg/m^2 STANDARD_DEVIATION 1.7 | 25.7 kg/m^2 STANDARD_DEVIATION 1.7 |
| Gender Female | 5 participants | 3 participants | 0 participants | 3 participants | 1 participants | 12 participants |
| Gender Male | 1 participants | 8 participants | 1 participants | 5 participants | 6 participants | 21 participants |
| HbA1c (%) | 5.47 % STANDARD_DEVIATION 0.4 | 5.47 % STANDARD_DEVIATION 0.4 | 7.0 % STANDARD_DEVIATION 0 | 5.56 % STANDARD_DEVIATION 0.34 | 8.40 % STANDARD_DEVIATION 3.02 | 6.48 % STANDARD_DEVIATION 1.24 |
| Region of Enrollment United States | 6 participants | 11 participants | 1 participants | 8 participants | 7 participants | 33 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 6 | 1 / 11 | 0 / 1 | 0 / 8 | 0 / 7 | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 0 / 6 | 0 / 11 | 0 / 1 | 0 / 8 | 0 / 7 | 0 / 0 | 0 / 0 |
Outcome results
Primary
Myocardial Glucose Uptake.
Myocardial glucose uptake measured using 18FDG PET, quantified using a 3-compartment model with a lumped constant of 1.0.
Time frame: After 12 hours of glucagon-like peptide 1 (GLP-1) exposure
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lean Saline | Myocardial Glucose Uptake. | 7.46 umol/min/100g | Standard Deviation 8.49 |
| Lean GLP-1 Low Dose | Myocardial Glucose Uptake. | 7.22 umol/min/100g | Standard Deviation 9.26 |
| Type 2 DM GLP-1 Low Dose | Myocardial Glucose Uptake. | 0.05 umol/min/100g | Standard Deviation 0 |
| Lean GLP-1 1.5 Pmol/kg/Min | Myocardial Glucose Uptake. | 20.89 umol/min/100g | Standard Deviation 12.47 |
| Type 2DM GLP-1 1.5 Pmol/kg/Min | Myocardial Glucose Uptake. | 5.57 umol/min/100g | Standard Deviation 19.39 |
Secondary
Cardiac Index
Impedance cardiography-derived measurement of cardiac index, assessed following 12 hour exposure to treatment condition concurrent with the PET measurements.
Time frame: After 12 hours of GLP-1 exposure
Population: Analyses performed only on the groups with relevant primary outcome data observed
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lean Saline | Cardiac Index | 3.00 L/min/m^2 | Standard Deviation 0.52 |
| Lean GLP-1 1.5 Pmol/kg/Min | Cardiac Index | 2.88 L/min/m^2 | Standard Deviation 0.31 |
| Type 2DM GLP-1 1.5 Pmol/kg/Min | Cardiac Index | 2.90 L/min/m^2 | Standard Deviation 0.51 |
Secondary
GLP-1 Concentrations
Achieved GLP-1 concentrations at the end of the 12 hour treatment exposure
Time frame: After 12 hours of GLP-1 exposure
Population: Analyses performed only on the groups with relevant primary outcome data observed
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lean Saline | GLP-1 Concentrations | 61.7 pmol/L | Standard Deviation 33.5 |
| Lean GLP-1 1.5 Pmol/kg/Min | GLP-1 Concentrations | 302.1 pmol/L | Standard Deviation 149.1 |
| Type 2DM GLP-1 1.5 Pmol/kg/Min | GLP-1 Concentrations | 307.8 pmol/L | Standard Deviation 86.2 |
Secondary
Myocardial Blood Flow
Myocardial perfusion derived from acetate kinetics
Time frame: After 12 hours of GLP-1 exposure
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lean Saline | Myocardial Blood Flow | 34.66 ml/min/100g | Standard Deviation 4.6 |
| Lean GLP-1 Low Dose | Myocardial Blood Flow | 44.44 ml/min/100g | Standard Deviation 9.17 |
| Type 2 DM GLP-1 Low Dose | Myocardial Blood Flow | 47.61 ml/min/100g | Standard Deviation 0 |
| Lean GLP-1 1.5 Pmol/kg/Min | Myocardial Blood Flow | 35.30 ml/min/100g | Standard Deviation 7.35 |
| Type 2DM GLP-1 1.5 Pmol/kg/Min | Myocardial Blood Flow | 51.19 ml/min/100g | Standard Deviation 19.39 |
Secondary
Myocardial Total Oxidation Rate
MVO2 derived from acetate kinetics
Time frame: After 12 hours of GLP-1 exposure
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lean Saline | Myocardial Total Oxidation Rate | 15.25 ml/min/100g | Standard Deviation 2.39 |
| Lean GLP-1 Low Dose | Myocardial Total Oxidation Rate | 30.21 ml/min/100g | Standard Deviation 14.32 |
| Type 2 DM GLP-1 Low Dose | Myocardial Total Oxidation Rate | 65.30 ml/min/100g | Standard Deviation 0 |
| Lean GLP-1 1.5 Pmol/kg/Min | Myocardial Total Oxidation Rate | 18.57 ml/min/100g | Standard Deviation 3.78 |
| Type 2DM GLP-1 1.5 Pmol/kg/Min | Myocardial Total Oxidation Rate | 59.85 ml/min/100g | Standard Deviation 30.47 |