Acute Nutritional Ketosis in VLCAD Deficiency: Testing the Metabolic Base for Therapeutic Use
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 5
- 试验地点
- 4
- 主要终点
- Change of ATP concentration in millimolar
研究概览
简要总结
To test if a ketone-ester based drink can boost muscle mitochondrial function in vivo in patients with VLCADD in order to establish a rational basis for therapeutic use in this disorder.
详细描述
Exertional rhabdomyolysis is a common symptom in very long-chain acylCoA dehydrogenase deficient (VLCADD) patients. Failing muscle ATP homeostasis, due to impaired fatty acid oxidation, is the most likely cause. Therefore, supplementation with an alternative energy substrate to boost ATP homeostasis, such as an exogenous ketone ester (KE) drink, could be a therapeutic option. Previous results suggest that KE is preferentially oxidized in the tricyclic acid (TCA) cycle and improves physical endurance in athletes. Our primary objective is to test if KE boosts muscular ATP homeostasis in VLCADD patients to establish a rational basis for therapeutic use.
VLCADD patients will be included in a randomized, blinded, placebo controlled, 2-way cross-over trial. Prior to each test, patients receive a KE drink or an isocaloric carbohydrate equivalent, and completed a 35 min cycling test on an upright bicycle, followed by 10 minutes of supine cycling inside a MR scanner. The protocol will be repeated after at least one week with the opposite drink.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Other
- 盲法
- Double (Participant, Outcomes Assessor)
盲法说明
Double (Participant, Outcomes Assessor)
入排标准
- 年龄范围
- 16 Years 至 65 Years（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Confirmed VLCADD by genetic profiling
排除标准
- •contraindications for MRI studies (assessed by standardised questionnaire as previously used in METC 08-267/K; see UMCG section F METC documents)
- •inability to perform bicycle exercise.
- •recent episode of rhabdomyolysis, or treatment for acute renal failure in the past 2 months.
- •intercurrent illness which may influence exercise tolerance (anaemia, musculoskeletal injury, or other undiagnosed illness under investigation).
- •known coronary artery disease, positive history for angina, or changes on ECG suggestive of previous ischaemia without a negative stress test.
- •insulin-dependent diabetes mellitus.
- •loss of, or an inability to give informed consent.
- •pregnancy or current breastfeeding, or females not taking the oral contraceptive pill (this is due to the variability in hormonal patterns and substrate levels with different parts of the menstrual cycle).
- •any other cause which in the opinion of the investigators, may affect the volunteers ability to participate in the study.
研究组 & 干预措施
ketone ester drink
Oral intake of ketone ester drink muscle biopsy exercise muscle biopsy Magnetic Resonance imaging
干预措施: ketone ester drink (Dietary Supplement)
ketone ester drink
Oral intake of ketone ester drink muscle biopsy exercise muscle biopsy Magnetic Resonance imaging
干预措施: exercise (Behavioral)
ketone ester drink
Oral intake of ketone ester drink muscle biopsy exercise muscle biopsy Magnetic Resonance imaging
干预措施: muscle biopsy (Procedure)
ketone ester drink
Oral intake of ketone ester drink muscle biopsy exercise muscle biopsy Magnetic Resonance imaging
干预措施: Magnetic Resonance Imaging (Diagnostic Test)
carbohydrate drink
Oral intake of isocaloric carbohydrate drinkmuscle biopsy exercise muscle biopsy Magnetic Resonance imaging
干预措施: exercise (Behavioral)
carbohydrate drink
Oral intake of isocaloric carbohydrate drinkmuscle biopsy exercise muscle biopsy Magnetic Resonance imaging
干预措施: muscle biopsy (Procedure)
carbohydrate drink
Oral intake of isocaloric carbohydrate drinkmuscle biopsy exercise muscle biopsy Magnetic Resonance imaging
干预措施: Magnetic Resonance Imaging (Diagnostic Test)
结局指标
主要结局
Change of ATP concentration in millimolar
时间窗: During session 2 and 3: continuous measurements from t=75 minutes until t=85 minutes
steady-state in vivo intramuscular concentration of ATP metabolites during rest and exercise.
Change of PCr concentration in millimolar
时间窗: During session 2 and 3: continuous measurements from t=75 minutes until t=85 minutes
steady-state in vivo intramuscular concentration of ATP metabolites during rest and exercise.
Change of Pi concentration in millimolar
时间窗: During session 2 and 3: continuous measurements from t=75 minutes until t=85 minutes
steady-state in vivo intramuscular concentration of ATP metabolites during rest and exercise.
次要结局
- completion of 10 minute supine bicycling bout at FATMAX in scanner(Session 2 and 3, 10 minutes)
- VCO2 in milliliter per minute per kilogram(During session 1, 15 minutes During Session 2 + 3: 35 minutes)
- optional: glycolysis intermediates in muscle tissue (units is ratio of metabolite peak/ internal standard) and will be expressed as fold change from baseline(Session 2+3: before and after exercise, 20 minutes per session)
- optional: parameters for metabolism and mitochondrial function in muscle (AMPK, PPAR gamma, PGC1a, and GLUT4). All expressed as protein content as % of control.(Session 2+3: before and after exercise, 20 minutes per session)
- Changes in blood metabolites: glucose in millimol per liter(Session 2 and 3, 265 minutes per session)
- Changes in blood metabolites: insulin in picomol per liter(Session 2 and 3, 265 minutes per session)
- Changes in blood metabolites: creatine kinase in units per liter(Session 2 and 3, 265 minutes per session)
- optional: TCA intermediates in muscle tissue (units is ratio of metabolite peak/ internal standard) and will be expressed as fold change from baseline(Session 2+3: before and after exercise, 20 minutes per session)
- optional: acylcarnitines in muscle tissue (units is ratio of metabolite peak/ internal standard) and will be expressed as fold change from baseline(Session 2+3: before and after exercise, 20 minutes per session)
- optional: mitochondrial density based on ATPase, COX-SDH, SDH and NADH staining (intensity per microgram per minute).(Session 2+3: before and after exercise, 20 minutes per session)
- optional: muscle fiber type composition based on myosin heavy chain profiling. Type I, IIa, IIx fibres will be expressed as % of total fibres.(Session 2+3: before and after exercise, 20 minutes per session)
- kinetic rate constant of ATP synthesis in Hertz(session 2 and 3, 10 minutes each time)
- HR in beats per minute(During session 1, 15 minutes During Session 2 + 3: 35 minutes)
- Changes in blood metabolites: free fatty acids in millimol per liter(Session 2 and 3, 265 minutes per session)
- Changes in blood metabolites: total cholesterol in millimol per liter(Session 2 and 3, 265 minutes per session)
- Changes in blood metabolites: HDL cholesterol in millimol per liter(Session 2 and 3, 265 minutes per session)
- Changes in blood metabolites: acylcarnitines in micromol per liter(Session 2 and 3, 265 minutes per session)
- weight in kilogram(1 minute during screening visit)
- BMI in kg/m^2(1 minute during screening visit)
- intramuscular concentration of H+ in millimolar(session 2 and 3, 10 minutes each time)
- completion of 35 minute upright bicycling bout at FATMAX(Session 2 and 3, 35 minutes)
- Changes in blood metabolites: triglycerides in millimol per liter(Session 2 and 3, 265 minutes per session)
- Changes in blood metabolites: LDL cholesterol in millimol per liter(Session 2 and 3, 265 minutes per session)
- optional: mitochondrial density based on as citrate synthase activity expressed as absorbance/s/mg.(Session 2+3: before and after exercise, 20 minutes per session)
- optional: glycogen content of muscle based on Periodic acid-Schiff (PAS) staining (intensity per millimeter^2)(Session 2+3: before and after exercise, 20 minutes per session)
- VO2 in milliliter per minute per kilogram(During session 1, 15 minutes During Session 2 + 3: 35 minutes)
- Changes in blood metabolites: D-betahydroxybutyrate in millimol per liter(Session 2 and 3, 265 minutes per session)
- Changes in blood metabolites: lactate in millimol per liter(Session 2 and 3, 265 minutes per session)
- Subjective exertion(During Session 2 + 3, assessed during blood sampling, 265 minutes per session)
- height in meters(1 minute during screening visit)
- optional: D-betahydroxybutyrate in muscle tissue (units is ratio of metabolite peak/ internal standard) and will be expressed as fold change from baseline(Session 2+3: before and after exercise, 20 minutes per session)
- optional: capillary density in muscle tissue based on CD31 staining (capillaries per millimeter^2)(Session 2+3: before and after exercise, 20 minutes per session)
- optional: lipid accumulation based on Oil-Red-O staining (intensity of staining, and percentage positive-stained cells).(Session 2+3: before and after exercise, 20 minutes per session)
- optional: muscle fiber type composition based on ATPase staining (intensity/ug/min). Type I, IIa, IIx fibres will be expressed as % of total fibres.(Session 2+3: before and after exercise, 20 minutes per session)
- optional: glycogen content of muscle measured as glucose released after enzymatic digestion with amyloglucosidase expressed as micromol per gram wet muscle weight.(Session 2+3: before and after exercise, 20 minutes per session)
研究者
dr. J.A.L. Jeneson
Principal Investigator
University Medical Center Groningen