Effects of Intermittent Fasting on Insulin Resistance, Cardiac Metabolism, and Cerebral Perfusion
试验速览
- 阶段
- 不适用
- 状态
- 进行中（未招募）
- 入组人数
- 16
- 试验地点
- 2
- 主要终点
- Change in cardiac uptake and metabolism of hydroxybutyrate
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Prevention
- 盲法
- None
入排标准
- 年龄范围
- 55 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Age: 55-70 years
- •BMI: 28-40 kg/m2
排除标准
- •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
结局指标
主要结局
Change in cardiac uptake and metabolism of hydroxybutyrate
时间窗: 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 hydroxybutyrate after ADF versus Western diet will be measured with 11C-3-OHB PET/CT.
Change in myocardial perfusion and flow reserve
时间窗: 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 after ADF compared to Western diet will be measured with 15O-H2O PET/CT.
Change in insulin sensitivity in skeletal muscle, liver and adipose tissue
时间窗: The clamp will be performed on the study day after each 3-week study period (day 22 and 51).
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.
Change in cardiac uptake and metabolism of fatty acids
时间窗: 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 fatty acids after ADF compared to Western diet measured with 11C-palmitate PET/CT.
Change in cardiac uptake and metabolism of glucose
时间窗: 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 after ADF compared to Western diet measured with 18F-FDG PET/CT.
Change in cerebral perfusion
时间窗: 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 after ADF versus Western diet measured with 15O-H2O PET/CT.
次要结局
- 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 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).)
- 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).)
- 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).)