Modulation of Human Myocardial Metabolism by GLP-1 Dose Response
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.
Aperçu de l'étude
Statut
Les conditions
Intervention / Traitement
Type d'étude
Inscription (Réel)
Phase
- Phase 2
- Phase 3
Contacts et emplacements
Lieux d'étude
-
-
Indiana
-
Indianapolis, Indiana, États-Unis, 46202
- Indiana Clinical Research Center
-
-
Critères de participation
Critère d'éligibilité
Âges éligibles pour étudier
Accepte les volontaires sains
Sexes éligibles pour l'étude
La description
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
Plan d'étude
Comment l'étude est-elle conçue ?
Détails de conception
- Objectif principal: Traitement
- Répartition: Non randomisé
- Modèle interventionnel: Affectation parallèle
- Masquage: Seul
Armes et Interventions
Groupe de participants / Bras |
Intervention / Traitement |
|---|---|
|
Autre: Saline
12 hour saline (control) infusion prior to PET study
|
Normal saline placebo infusion for 12 hours prior to PET study
Autres noms:
|
|
Expérimental: GLP-1 Low dose
GLP-1 Low Dose: 0.5 pmol/kg/min for 12 hours prior to PET study
|
0.5mmol/kg/hr GLP-1 for 12 hours prior to PET study
|
|
Expérimental: GLP-1 Mid-Range Dose
GLP-1 Mid-Range Dose: 1.5 pmol/kg/min for 12 hours prior to PET study
|
1.5mmol/kg/min for 12 hours prior to PET study
|
|
Expérimental: GLP-1 High Dose
GLP-1 High Dose: 4.0 pmol/kg/min for 12 hours prior to PET study
|
4.0mmol/kg/min GLP-1 for 12 hours prior to PET study
|
Que mesure l'étude ?
Principaux critères de jugement
Mesure des résultats |
Description de la mesure |
Délai |
|---|---|---|
|
Myocardial Glucose Uptake.
Délai: 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.
|
After 12 hours of glucagon-like peptide 1 (GLP-1) exposure
|
Mesures de résultats secondaires
Mesure des résultats |
Description de la mesure |
Délai |
|---|---|---|
|
Myocardial Blood Flow
Délai: After 12 hours of GLP-1 exposure
|
Myocardial perfusion derived from acetate kinetics
|
After 12 hours of GLP-1 exposure
|
|
Myocardial Total Oxidation Rate
Délai: After 12 hours of GLP-1 exposure
|
MVO2 derived from acetate kinetics
|
After 12 hours of GLP-1 exposure
|
|
Cardiac Index
Délai: 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.
|
After 12 hours of GLP-1 exposure
|
|
GLP-1 Concentrations
Délai: After 12 hours of GLP-1 exposure
|
Achieved GLP-1 concentrations at the end of the 12 hour treatment exposure
|
After 12 hours of GLP-1 exposure
|
Collaborateurs et enquêteurs
Parrainer
Collaborateurs
Les enquêteurs
- Chercheur principal: Kieren J Mather, MD, Indiana University
Dates d'enregistrement des études
Dates principales de l'étude
Début de l'étude
Achèvement primaire (Réel)
Achèvement de l'étude (Réel)
Dates d'inscription aux études
Première soumission
Première soumission répondant aux critères de contrôle qualité
Première publication (Estimation)
Mises à jour des dossiers d'étude
Dernière mise à jour publiée (Estimation)
Dernière mise à jour soumise répondant aux critères de contrôle qualité
Dernière vérification
Plus d'information
Termes liés à cette étude
Mots clés
Termes MeSH pertinents supplémentaires
- Troubles du métabolisme du glucose
- Maladies métaboliques
- Maladies du système endocrinien
- Diabète sucré
- Diabète sucré, Type 2
- Effets physiologiques des médicaments
- Agents gastro-intestinaux
- Les hormones
- Hormones, substituts hormonaux et antagonistes hormonaux
- Incrétines
- Glucagon
- Glucagon-Like Peptide 1
Autres numéros d'identification d'étude
- 1010002497
- R21HL092799 (Subvention/contrat des NIH des États-Unis)
Ces informations ont été extraites directement du site Web clinicaltrials.gov sans aucune modification. Si vous avez des demandes de modification, de suppression ou de mise à jour des détails de votre étude, veuillez contacter register@clinicaltrials.gov. Dès qu'un changement est mis en œuvre sur clinicaltrials.gov, il sera également mis à jour automatiquement sur notre site Web .