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.
Обзор исследования
Статус
Условия
Вмешательство/лечение
Тип исследования
Регистрация (Действительный)
Фаза
- Фаза 2
- Фаза 3
Контакты и местонахождение
Места учебы
-
-
Indiana
-
Indianapolis, Indiana, Соединенные Штаты, 46202
- Indiana Clinical Research Center
-
-
Критерии участия
Критерии приемлемости
Возраст, подходящий для обучения
Принимает здоровых добровольцев
Полы, имеющие право на обучение
Описание
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
Учебный план
Как устроено исследование?
Детали дизайна
- Основная цель: Уход
- Распределение: Нерандомизированный
- Интервенционная модель: Параллельное назначение
- Маскировка: Одинокий
Оружие и интервенции
Группа участников / Армия |
Вмешательство/лечение |
|---|---|
|
Другой: Saline
12 hour saline (control) infusion prior to PET study
|
Normal saline placebo infusion for 12 hours prior to PET study
Другие имена:
|
|
Экспериментальный: 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
|
|
Экспериментальный: 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
|
|
Экспериментальный: 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
|
Что измеряет исследование?
Первичные показатели результатов
Мера результата |
Мера Описание |
Временное ограничение |
|---|---|---|
|
Myocardial Glucose Uptake.
Временное ограничение: 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
|
Вторичные показатели результатов
Мера результата |
Мера Описание |
Временное ограничение |
|---|---|---|
|
Myocardial Blood Flow
Временное ограничение: After 12 hours of GLP-1 exposure
|
Myocardial perfusion derived from acetate kinetics
|
After 12 hours of GLP-1 exposure
|
|
Myocardial Total Oxidation Rate
Временное ограничение: After 12 hours of GLP-1 exposure
|
MVO2 derived from acetate kinetics
|
After 12 hours of GLP-1 exposure
|
|
Cardiac Index
Временное ограничение: 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
Временное ограничение: 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
|
Соавторы и исследователи
Спонсор
Следователи
- Главный следователь: Kieren J Mather, MD, Indiana University
Даты записи исследования
Изучение основных дат
Начало исследования
Первичное завершение (Действительный)
Завершение исследования (Действительный)
Даты регистрации исследования
Первый отправленный
Впервые представлено, что соответствует критериям контроля качества
Первый опубликованный (Оценивать)
Обновления учебных записей
Последнее опубликованное обновление (Оценивать)
Последнее отправленное обновление, отвечающее критериям контроля качества
Последняя проверка
Дополнительная информация
Термины, связанные с этим исследованием
Ключевые слова
Дополнительные соответствующие термины MeSH
Другие идентификационные номера исследования
- 1010002497
- R21HL092799 (Грант/контракт NIH США)
Эта информация была получена непосредственно с веб-сайта clinicaltrials.gov без каких-либо изменений. Если у вас есть запросы на изменение, удаление или обновление сведений об исследовании, обращайтесь по адресу register@clinicaltrials.gov. Как только изменение будет реализовано на clinicaltrials.gov, оно будет автоматически обновлено и на нашем веб-сайте. .
Клинические исследования Здоровый
-
Drugs for Neglected DiseasesSanofiЗавершенныйПК в Healthy VolunteersФранция
-
Biotie Therapies Inc.PRA Health Sciences; Tandem Labs; Xceleron IncЗавершенныйН/Д, как Healthy VolunteersНидерланды
-
Newcastle UniversityЗавершенныйGI гликемический индекс здоровых добровольцев | Гликемическая нагрузка GL Healthy VolunteersСоединенное Королевство
-
CEN BiotechCEN Nutriment; Biovet Conseil; Amadeite SASЗавершенныйАнгедония в Healthy Volunteers