Validation of 3-[11C]-OHB
Condition: Diabetes Mellitus, Type 2; Heart Failure; Healthy
MeSH terms: Diabetes Mellitus, Type 2
Study type: Interventional

Summary: 
      Ketone bodies are produced in the liver at high levels of fatty acids, and act as an
      important source of energy for the brain and heart during fasting. The energy production from
      ketone metabolism is less oxygen-demanding than both glucose and fatty acid metabolism, and
      ketone substances can therefore be a very energy-efficient substrate for the heart.
      Insulin-resistant people as well as people with heart disease have difficulty burning glucose
      in the heart due to the insulin resistant condition and are therefore dependent on other
      energy sources such as free fatty acids and ketones. Because ketones are oxygen-sparing
      compared to fatty acids, interventions that increase the level of ketone bodies can
      potentially reduce the heart's need for oxygen in patients with narrowed coronary arteries.
      PET/CT is a functional and non-invasive imaging modality and suitable for tracking the fate
      of metabolites non-invasively, as most substrates or metabolites can be labeled by a PET
      isotope.

      The purpose of this experiment is therefore to validate a new ketone tracer called
      3-[11C]-OHB. Implementation of the 3-[11C]-OHB tracer will in future allow the investigators
      to more directly estimate the impact of different levels of ketone bodies on organ functions
      by measuring tissue-specific ketone uptake, both after intravenous and oral administration.
    

Detailed description: 
      Background:

      Ketone bodies consists of 3-hydroxybutyrat, acetoacetate, and acetone. They are produced in
      the liver at high levels of fatty acids, and act as an important source of energy for the
      heart, brain and skeletal muscle during fasting. Energy production by ketone metabolism is
      less oxygen-intensive than both glucose and fatty acid metabolism, and ketone substances can
      therefore be a highly energy-efficient substrate. Insulin resistant individuals as well as
      people with heart disease have difficulty utilising glucose in the heart due to the insulin
      resistant condition and are therefore dependent on other energy sources such as free fatty
      acids and ketones. Because ketones are oxygen sparing compared to fatty acids, interventions
      that increase the level of ketone bodies can potentially reduce the heart's need for oxygen
      in patients with narrowed coronary arteries. This has led to an increased focus on the
      potential of ketone bodies in the treatment of a number of diseases, including especially
      cardiovascular disease.

      Our group has shown that ketone bodies are efficiently absorbed by the heart despite maximal
      stimulation with insulin and glucose. In the study, healthy subjects increased the level of
      circulating ketone bodies to approximately 4 millimolar with a continuous ketone infusion,
      which resulted in a 50% reduction in cardiac glucose consumption. Since the consumption of
      free fatty acids in the experiment was unchanged and the overall work of the heart was the
      same, up to 50% of the heart's energy consumption was thus covered by ketone bodies. In
      addition, the high levels of ketone bodies led to a marked increase in the blood flow to the
      heart, which could potentially further benefit patients with narrowed coronary arteries

      PET/CT is a functional and non-invasive imaging modality that is well established in
      oncological staging and treatment monitoring. The technique is also suitable for tracking the
      fate of metabolites non-invasively, as most substrates or metabolites can be labeled by a
      suitable PET isotope. PET has sufficient spatial and temporal resolution to enable direct
      quantification of e.g. uptake and oxidation rates and has been successfully used by our
      department to assess heart efficiency, oxygen consumption and fatty acid metabolism.

      Purpose With this study, the investigators want to determine the metabolism of ketone bodies
      in healthy individuals and validate a newly developed ketone PET tracer for use in humans
      called 3-[11C]-OHB. Previous studies conducted by our and others' groups have only been able
      to indirectly estimate the uptake of ketone bodies into the heart. With 3-[11C]-OHB, the
      investigators will be able to directly measure tissue-specific ketone uptake, both after
      intravenous and oral administration.

      Ihe investigators will apply state-of-the-science PET/CT tracer techniques and
      well-established models for estimating ketone metabolism (kinetics) and the radiation
      exposure of the tracer. Implementation of the 11C-3-OHB tracer in the future will allow the
      investigators to more directly estimate the impact of different levels of ketone bodies on
      organ functions, not least in the heart.

      In this study, the investigators plan specifically

        -  To investigate the biodistribution and kinetics of the tracer 3-[11C]-OHB

        -  To estimate the radiation exposure of 3-[11C]-OHB by intravenous and oral administration
           of the tracer

      Methods:

      Six healthy and overweight (BMI: 28-40 kg/m^2) aged 50-70 years will undergo two PET/CT scans
      with 3-[11C]-OHB. One scan will be performed with the injection of 200 MBq of tracer and the
      other one will be performed with the subjects orally ingestion 100 MBq of the tracer.
      Following administration of the tracer, dynamic PET scans over the whole body will be
      performed to measure the biodistribution and radiation exposure of the tracer.
    

Intervention name(s): 3-[11C]-OHB
Intervention type(s): Radiation
Intervention description(s): The PET tracer 3-[11C]-OHB is used to quantify 3-hydroxybutyrate uptake
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Other
Keywords: Ketone bodies; Whole-body biodistribution