The Effects of Ketogenic Diet on the Heart and Brain
Condition: Ketogenic Dieting
Study type: Interventional

Summary: 
      A ketogenic diet consists of a high intake of fats and a limited intake of carbohydrates,
      which causes an increased level of ketone bodies in the body. In recent years, it has been
      shown that the diet has cardiovascular protective effects. The investigators have also shown
      that ketone bodies act as super-gasoline for the heart. In addition, an increased level of
      ketone bodies will improve memory and comprehension in humans, possibly due to increased
      blood flow in the brain.

      The purpose of the experiment is to investigate how a ketogenic diet affects the heart and
      brain. The theory is that an increased level of ketone bodies will improve energy utilization
      in the heart by reducing oxygen deficiency in the heart as well as increasing blood flow in
      the brain.

      The study participants must go through two periods of 3 weeks, during which they must eat an
      ordinary Danish diet and a ketogenic diet, respectively. The periods end with an examination
      day, where blood samples and samples from muscle and fat tissue are taken. They will also be
      scanned with CT, PET and MRI scans to determine their body's ability to absorb sugar, fat and
      ketone bodies. The investigators expect the results to be of crucial importance for dietary
      recommendations for people at risk for cardiovascular disease and type 2 diabetes.
    

Detailed description: 
      Background:

      The ketogenic diet has long been used in the treatment of treatment-resistant epilepsy due to
      an unexplained but markedly reducing effect on the number of epileptic cases. In recent
      years, there has also been an increased focus on the potential of ketone bodies in the
      treatment of cardiovascular disease, however, the effect of a persistently elevated level of
      circulating ketone bodies (ketosis) has not been sufficiently elucidated. 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. 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 for the heart. Insulin-resistant individuals
      and 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, a
      ketogenic diet can potentially reduce the heart's need for oxygen in patients with narrowed
      coronary arteries.

      A recent study 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 (mM) 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.

      Classic ketogenic diets contain 3-4 times as many grams of fat as the total amount of
      carbohydrate and protein. The ketone substance level is increased to approximately 7 mM
      compared to ~ 0.1 mM in people who eat a "regular diet". Unfortunately, the diet requires a
      complete dedication to the diet plan and can lead to unpleasant gastrointestinal side
      effects, so there are major challenges in maintaining the diet over time.

      A modified ketogenic diet is therefore of great interest, where fat contributes approximately
      65% of the total amount of energy consumed and the circulating ketone bodies are increased to
      approximately 0.4 mM after three weeks of dietary intervention. It is not yet known how high
      ketone levels are required to achieve a clinically protective effect in the body's vital
      organs, but ketone levels are expected to reach the same level as patients treated with the
      antidiabetic drugs, sodium-glucose cotransporter (SGLT)-2 inhibitors. SGLT-2 inhibition has
      in recent studies shown impressive cardiovascular and renal protective effects in type 2
      diabetics, which is attributed by a number of researchers and clinicians to the effect on the
      elevated level of circulating ketone bodies. An increased level of ketone bodies has also
      been shown to improve cognitive function in patients with impaired cognition or mild
      Alzheimer's disease. This can potentially be explained by an increased perfusion in the blood
      vessels of the brain, which is seen in ketosis.

      Positron Emissions Tomography (PET) combined with a computed tomography (CT) scan is a
      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, as most
      substances or metabolites can be labeled by a suitable PET isotope. PET has sufficient
      spatial and temporal resolution to enable direct quantification of e.g. absorption and
      oxidation rates, and it has been successfully used by our department to assess cardiac
      efficiency, oxygen consumption , and fatty acid metabolism . The investigators are currently
      developing and validating a PET tracer for ketone bodies called 11C-Hydroxybutyrate
      (11C-3-OHB) for human studies. Once developed, the investigators will be able to detect
      changes in the biodistribution and kinetics of ketone bodies during both a ketogenic and a
      standard Western diet.

      Purpose:

      The overall aim of the project is to investigate whether a relatively simple and inexpensive
      modified ketogenic diet can be an effective non-pharmacological treatment of type 2 diabetes
      and other people at risk for ischemic heart disease. Using non-invasive imaging at PET, the
      investigators want to investigate whether the metabolism of ketones and fatty acids changes
      as well as whether blood flow increases in the heart during ketosis. Blood and tissue samples
      from skeletal muscle and adipose tissue will be examined to assess the effect of the
      ketogenic diet on insulin sensitivity in these tissues as well as the lipid composition in
      the blood. In addition, the investigators will investigate whether the improved cognitive
      function observed with ketosis is due to an increased perfusion in the brain, which can be
      detected by combining 15O-water PET with a magnetic resonance (MR) scan.

      Existing treatment for type 2 diabetes and ischemic heart disease often involves significant
      pharmacological intervention, with participants often having difficulty adhering to the
      correct treatment. This may be due to non-compliance, but also due to the possible
      interactions and side effects that pharmacological treatment may cause, especially in case of
      serious illness.

      With the project, the investigators want to utilize state-of-the-science PET/CT heart
      examinations in a clinical context. The investigators therefore hope that the project
      highlights the possibility that a relatively simple ketogenic diet may be an effective
      non-pharmacological treatment of type 2 diabetes or other individuals at risk for heart
      disease.

      Methods:

      The study will be performed as a randomized, placebo-controlled crossover study in 12 healthy
      obese participants (BMI: 28-40 kg / m2) in the age group 50-70 years. Before inclusion,
      participants will be called in for a study, which includes a conversation about health, blood
      tests, measurement of height, weight, blood pressure and ECG. Each trial participant will
      undergo two trial periods of three weeks, during which they must follow resp. a ketogenic
      diet / standard diet in random order with one week of leaching between trial periods.

      The participants will approximately once a week be contacted by telephone in both study
      periods with regard to to ensure compliance with the diet. In addition, the concentration of
      ketone bodies will be measured by the participants twice daily (7 am and 7 pm) with ketone
      strips on a hand-held glucose meter at their own home. If participants increase by <0.3 mM in
      ketone bodies after one week of ketogenic diet, they will drop out of the study without
      further follow-up.

      At the end of each trial period, trial participants will be called to a trial day of PET
      scans and metabolic studies. For 72 hours up to the test days, subjects will be asked to
      avoid alcohol and strenuous physical activity. They will have their physical activity
      monitored with an activity meter as well as blood pressure / vascular stiffness with a
      24-hour blood pressure monitor (24 hours). In addition, they will be asked to fast from kl.
      21 in the evening before all trial days. After each trial period, participants will have a
      dual energy x-ray absorptiometry (DXA) scan and an MR scan.
    

Intervention name(s): Ketogenic diet
Intervention type(s): Other
Intervention description(s): The ketogenic diet will consist of 75% fat, 20% protein and 5% carbohydrates. The diet will be standardised and matched to the energy consumption of each participant. The diet does not dictate time of consumptions. The food regime will be strictly followed every day for 3 weeks, where the investigator will contact the participants every day to secure adherence.
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: The study will be performed as a randomized, placebo-controlled crossover study in 12 healthy obese patients (BMI: 28-40 kg/m2) in the age group 50-70 years. Each participant will undergo two periods of three weeks, during which they must follow a ketogenic diet or a standard diet in random order with one week of wash out between periods. At the end of each period, a study day with Metabolic and PET examinations will be performed.
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: Ketogenic dieting; Heart metabolism; Brain perfusion