Modulation of Human Myocardial Metabolism by GLP-1 Dose Response
Status:
Completed
Trial end date:
2012-12-01
Target enrollment:
Participant gender:
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.