Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT05181267 |
| Other study ID # |
KETO-FAST |
| Secondary ID |
|
| Status |
Active, not recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
April 5, 2022 |
| Est. completion date |
May 2024 |
Study information
| Verified date |
May 2023 |
| Source |
University of Aarhus |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
The overall purpose of the study is to investigate whether three weeks of intermittent
fasting (alternate-day fasting, (ADF)) result in a more pronounced "metabolic shift" towards
the use of ketone bodies than three weeks of Western diet. The investigators will use
state-of-the-art PET/CT tracer techniques and well-established steady state kinetics methods
for glucose and fatty acids. The study results will provide new insights into the
physiological basis of the potential cardio-protective effects of ketone bodies during ADF
and will determine whether ADF can help prevent and treat heart failure.
Ketone bodies are produced in the liver as an alternative fuel when blood glucose levels are
low, as can be seen with various types of diets or after strenuous exercise. The energy
produced by breaking down ketone bodies has been shown to require less oxygen than breaking
down glucose and fatty acids. In a previous study, the investigators observed that ketone
bodies act as a kind of "super fuel" for the heart and improve the heart's energy
utilization. It is still unknown how high ketone levels are needed to see these
cardio-protective effects. As patients with insulin resistance and/or heart failure have a
lower glucose uptake in cardiac tissue, and as energy production by the breakdown of fatty
acids is oxygen-demanding, an elevated level of blood ketones can therefore potentially
reduce the morbidity seen in patients with type 2 diabetes and ischemic heart disease.
PET/CT is a non-invasive well-established imaging modality 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. uptake
and oxidation rates and has been successfully used by the investigators' department to assess
heart efficiency, oxygen consumption, and fatty acid metabolism. Currently, the investigators
are in the process of validating the PET tracer 11C-beta-hydroxybutyrate (11C-3-OHB) as a
radio tracer for human studies. The tracer will be able to detect changes in biodistribution
and kinetics of ketone bodies during both Western diets and ADF.
The subjects must go through two study periods of each 3 weeks in which the intervention is
western diet (no restrictions) and intermittent fasting (fasting every other day),
respectively. After both study periods, there will be an examination day with PET scans and
various laboratory examinations.
Description:
Background
Ketone bodies are produced in the liver as an alternative fuel when blood glucose levels are
low, such as during high-fat low-carb diets, prolonged calorie restriction, or after
strenuous exercise. Ketone bodies from the blood are easily absorbed by energy-consuming
tissues such as the heart and the brain, where they are oxidized to produce energy in the
form of adenosine triphosphate (ATP).
ATP production by oxidation of ketone bodies requires less oxygen per mole of ATP produced
than fatty acid oxidation, and therefore, ketone bodies have been called a "super fuel". As
patients with insulin resistance and/or heart failure are characterized by a decreased
glucose uptake into the heart tissue, and as ATP production by fatty acid oxidation is
oxygen-demanding, an elevated level of ketone bodies in the blood (hyperketonemia) therefore
has the potential to reduce myocardial ischemia-related morbidity in individuals with insulin
resistance, type 2 diabetes, and ischemic heart disease.
The investigators have previously demonstrated that the heart easily switches from glucose to
ketone body consumption when ketone body levels are rapidly increased by an infusion,
resulting in a 50% reduction in cardiac glucose consumption. In addition to the presumed
beneficial effects on oxygen consumption, the investigators also observed a marked increase
in cardiac output; findings which they subsequently confirmed with studies of heart failure
patients in which a linear dose-response relationship between the level of ketone bodies and
cardiac output was observed.
Calorie restriction (CR) is a term used for continuous energy restriction representing 30% or
more of the basic energy requirement. CR has consistently and not surprisingly been shown to
promote weight loss but also reduce the risk of cardiovascular disease. However, CR is
associated with several side effects, including decreased bone mass and bone mineral density,
and relative leukopenia, which can potentially increase the risk of infections. In addition,
individuals undergoing CR diets complain of hunger, irritability, and decreased
concentration. This results in a low, and often non-lasting, long-term success rate.
Intermittent fasting (IF) is a term that describes different dietary patterns that involve
complete or partial limitation of energy intake at different time periods and at specific
time intervals. IF has been shown to result in roughly the same beneficial effects as CR. IF
causes a weight loss, as the calorie intake on the days without fasting does not fully
compensate for the calorie deficit on days with fasting. Various forms of IF exist, including
5:2 diet, complete alternate-day fasting (ADF), modified ADF, and time-restricted feeding.
However, it is only during the 5:2 diet and the complete ADF that the fasting periods exceed
20 hours, which has major consequences for the hormonal and metabolic environment of the
fasting persons. Fasting for 20 hours or more results in low blood glucose levels and an
almost complete inhibition of insulin secretion. It stimulates ketogenesis in the liver and
lipolysis in adipose tissue with the release of fatty acids as a substrate for the formation
of ketones. This is the so-called "metabolic shift" that most individuals in the Western
world, including people on the CR diet, rarely experience. The metabolic shift during IF has
been shown to improve insulin sensitivity and to provide weight loss; even to a greater
extent than during CR. Overall, it seems that the same benefits of CR can be achieved by
exercising an IF regimen, but only the latter triggers hyperketonemia with the associated,
presumed, cardiac benefits. 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.
PET/CT 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., uptake and oxidation
rates and has been successfully used by the investigators' department to assess heart
efficiency, oxygen consumption, and fatty acid metabolism. Currently, the investigators are
in the process of validating the newly developed ketone PET tracer 11C-3-OHB as a radiotracer
for human studies. The tracer will make it possible to detect changes in biodistribution and
kinetics of ketone bodies during both Western diets and during fasting regimens such as ADF.
Purpose
The aim of the study project is to investigate whether intermittent fasting in the form of
three weeks of ADF improves insulin resistance, as well as cardiac pump function and
substrate metabolism compared to three weeks of regular Western diet. In addition, the
investigators wish to examine the perfusion in the brain, which has been shown to be
increased during ketosis. State-of-the-science PET/CT tracer techniques and well-established
steady-state kinetics methods for glucose and fatty acids will be applied. The study results
will help clarify whether ADF should be recommended in the non-pharmacological prophylaxis
and treatment of insulin resistance, type 2 diabetes, and heart failure, as well as a
possible increase in brain perfusion improving the cognitive function in these patients.
Specific aims:
1. To measure cardiac uptake and metabolism of hydroxybutyrate after ADF versus Western
diet (11C-3-OHB PET)
2. To measure myocardial perfusion and flow reserve after ADF compared to Western diet
(15O-dihydrogen monoxide (H2O) PET)
3. To determine the effect of ADF compared to Western diet on insulin sensitivity in
skeletal muscle, liver, and adipose tissue (hyperinsulinemic-euglycemic clamp)
4. To measure myocardial external efficiency (MEE) after ADF compared to Western diet
(11C-acetate PET)
5. To measure cardiac metabolism of fatty acids and glucose after ADF compared to Western
diet (11C-palmitate and fluorine-18-fluorodeoxyglucose (18F-FDG) PET, respectively)
6. To measure cerebral perfusion after ADF versus Western diet (15O-H2O PET)
7. To assess insulin signaling in skeletal muscle and adipose tissue after ADF compared to
Western diet (muscle and fat biopsies)
8. To characterize daily time-related changes in fatty acids, glucose, and ketone bodies
during three weeks of ADF
Methods
The study will be conducted as a randomized, controlled crossover study with 16
insulin-resistant subjects with overweight (BMI: 28-40 kg/m2) aged 55-70 years.
Before initiating the study, the subjects will go through a screening visit in undisturbed
surroundings at Aarhus University Hospital, where the subjects can give their informed
consent if they wish to participate in the study. Beforehand, they are informed that they
have the right to bring an attendant to the visit. After signed consent, there will be a
conversation about the subjects' health, blood samples will be taken, height, weight and
blood pressure measured, and an ECG performed. In addition, a transthoracic echocardiography
will be performed to rule out structural heart disease.
If the inclusion criteria are still met and the exclusion criteria are not, subjects will be
instructed to fast for 36 hours from 7 p.m. on day -3 as a run-in period to make sure they
can meet the time schedule for fasting. After this, they must go through two study periods of
each three weeks, where the interventions are ADF and Western diet (no restrictions),
respectively, in random order. A washout period of one week follows the first study period
before subjects cross over to the second study period. The subjects will approx. once a week
be contacted by telephone to ensure compliance to the ADF regimen.
At the start of the first study period and at the end of each study period, blood samples
will be taken, and a 24-hour urine sample will be performed, where all urine produced in one
day will be collected by the subject in a plastic can for the purpose. The urine is destroyed
after the analysis. Subjects will also be asked about risk factors for osteoporosis.
In both study periods, the concentration of ketone bodies will be measured by the subjects
twice daily (7 a.m. and 7 p.m.) with ketone strips on a hand-held glucose meter at home. If
subjects increase less than 0.3 millimolar (mM) in ketone body levels after one week of ADF
(as an expression of non-compliance with the diet), they will drop out of the study without
further follow-up. At the end of each study period, the subjects will have a ketone profile
made with 6 measurements/day over three days.
After each study period, subjects undergo an examination day with PET/CT scans and various
laboratory examinations. For 72 hours up to the examination days, subjects will be asked to
avoid alcohol and strenuous physical activity. They will have their physical activity
monitored with an activity meter (FitBit Charge 2), as well as blood pressure/vascular
stiffness with a 24-hour blood pressure monitor. In addition, they will be asked to fast from
10 p.m. the evening before both examination days.
