Modulation of Human Myocardial Metabolism by GLP-1 Dose Response
Condition: Type 2 Diabetes Mellitus; Healthy
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2
Study type: Interventional
Phase: Phase 2/Phase 3

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.
    


Intervention name(s): GLP-1 Low Dose; GLP-1 Mid-Range Dose; GLP-1 High Dose; Saline
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): 0.5mmol/kg/hr GLP-1 for 12 hours prior to PET study; 1.5mmol/kg/min for 12 hours prior to PET study; 4.0mmol/kg/min GLP-1 for 12 hours prior to PET study; Normal saline placebo infusion for 12 hours prior to PET study
Other intervention name(s): Normal Saline
Intervention MeSH terms: Glucagon; Glucagon-Like Peptide 1
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: Single (Participant)
Primary purpose: Treatment
Keywords: Type 2 diabetes mellitus; lean healthy control