Effects of Intermittent Fasting on Insulin Resistance, Cardiac Metabolism, and Cerebral Perfusion

NCT05181267 | Completed

• 1 other identifier: KETO-FAST
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Obesity; Insulin Resistance

Keywords

intermittent fasting; ketone bodies; obesity; cardiac substrate metabolism; insulin resistance; cerebral perfusion

Outcome Measures

Primary Outcomes (6)

• Change in cardiac uptake and metabolism of hydroxybutyrate

  Change in cardiac uptake and metabolism of hydroxybutyrate after ADF versus Western diet will be measured with 11C-3-OHB PET/CT.

  The PET/CT scan will be performed on the study day after each 3-week study period (day 22 and 51).

• Change in myocardial perfusion and flow reserve

  Change in myocardial perfusion and flow reserve after ADF compared to Western diet will be measured with 15O-H2O PET/CT.

  The PET/CT scan will be performed on the study day after each 3-week study period (day 22 and 51).

• Change in insulin sensitivity in skeletal muscle, liver and adipose tissue

  Effect of ADF compared to Western diet on insulin sensitivity in skeletal muscle, liver, and adipose tissue will be measured by a hyperinsulinemic-euglycemic clamp. Subjects will undergo the clamp during the study day. The amount of infused glucose during the clamp will act as a measure of the subjects' insulin sensitivity/resistance.

  The clamp will be performed on the study day after each 3-week study period (day 22 and 51).

• Change in cardiac uptake and metabolism of fatty acids

  Change in cardiac uptake and metabolism of fatty acids after ADF compared to Western diet measured with 11C-palmitate PET/CT.

  The PET/CT scan will be performed on the study day after each 3-week study period (day 22 and 51).

• Change in cardiac uptake and metabolism of glucose

  Change in cardiac uptake and metabolism of glucose after ADF compared to Western diet measured with 18F-FDG PET/CT.

  The PET/CT scan will be performed on the study day after each 3-week study period (day 22 and 51).

• Change in cerebral perfusion

  Change in cerebral perfusion after ADF versus Western diet measured with 15O-H2O PET/CT.

  The PET/CT scan will be performed on the study day after each 3-week study period (day 22 and 51).

Secondary Outcomes (5)

• Changes in insulin signaling in skeletal muscle and adipose tissue

  The biopsies will be performed on the study day after each 3-week study period (day 22 and 51).

• Changes in circulating concentrations of free fatty acids, cholesterol, glucose, and hemoglobin

  Blood samples will be taken at the screening visit (before day -3) and on the study day after each 3-week study period (day 22 and 51).

• Changes in circulating concentrations of lactate dehydrogenase, glucagon, hydroxybutyrate, gastric inhibitory peptide, and glucagon-like peptide-1, alanine transaminase, alkaline phosphatase, and erythropoietin.

  Blood samples will be taken at the screening visit (before day -3) and on the study day after each 3-week study period (day 22 and 51).

• Changes in circulating concentrations of C-reactive protein.

  Blood samples will be taken at the screening visit (before day -3) and on the study day after each 3-week study period (day 22 and 51).

• Change in myocardial external efficiency (MEE)

  The PET/CT scan will be performed on the study day after each 3-week study period (day 22 and 51).

Study Arms (2)

Intermittent fasting

EXPERIMENTAL

Three weeks of alternate-day fasting.

Dietary Supplement: Intermittent fasting

Western diet

NO INTERVENTION

Three weeks of normal Western diet (no restrictions).

Interventions

Intermittent fasting DIETARY_SUPPLEMENT

Subjects fast from after dinner and throughout the next day, i.e., 36 hours of fasting, after which they are allowed to eat as usual until dinner the same day. Then they fast again for 36 hours, and this regimen will continue for three entire weeks.

Also known as: Alternate-day fasting

Intermittent fasting

Eligibility Criteria

• Age: 55 Years - 70 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age: 55-70 years
• BMI: 28-40 kg/m2

You may not qualify if:

• Any drug that, in the investigator's opinion, may affect the study
• HbA1c \> 48 mmol/mol
• Known heart failure, previous blood clots, or other heart disease that, in the investigator's opinion, may affect the study, including abnormal ECG and/or echocardiography with evidence of structural heart disease
• Liver disease (ALAT \> 3 x of upper normal range), renal failure (eGFR \< 60 ml/min), anaemia (Hb \< 6.5), current or previous malignant disease which, in the investigator's opinion, may affect the study
• Current alcohol abuse (\> 21 items per week)
• Blood donation within the last 3 months before the study day
• Participation in studies/examinations involving radioactive isotopes within the last 6 months
• Claustrophobia

Sponsors & Collaborators

• University of Aarhus: lead

Study Sites (1)

Aarhus University Hospital

Aarhus, Central Jutland, 8200, Denmark

Location

MeSH Terms

Conditions

Obesity; Insulin Resistance; Intermittent Fasting

Condition Hierarchy (Ancestors)

Overweight; Overnutrition; Nutrition Disorders; Nutritional and Metabolic Diseases; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases; Fasting; Feeding Behavior; Behavior

Study Officials

• Mette LG Kjærulff, MD

  Aarhus University Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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. Subjects must go through two study periods of each three weeks, where the interventions are alternate-day fasting (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. After each study period, subjects undergo a study day with PET scans and various laboratory examinations.

Study Record Dates

• First Submitted: December 1, 2021
• First Posted: January 6, 2022
• Study Start: April 5, 2022
• Primary Completion: April 18, 2024
• Study Completion: April 11, 2025
• Last Updated: April 29, 2026

Record last verified: 2026-04

Locations

DK (1)