Impact of L-Carnitine Infusion on Lipid Induced Insulin Resistance
试验速览
- 阶段
- 不适用
- 状态
- 终止
- 入组人数
- 17
- 试验地点
- 1
- 主要终点
- Whole body insulin sensitivity
研究概览
简要总结
Insulin resistant subjects and type 2 diabetic patients are characterized by a decreased metabolic flexibility: a reduced capability to switch from fat oxidation in the basal state to carbohydrate oxidation in the insulin-stimulated state. This metabolic inflexibility is an early hallmark in the development of diabetes. Recent evidence suggests that a low carnitine availability may limit acetylcarnitine formation, thereby reducing metabolic flexibility. Thus, when substrate flux in the muscle is high, acetyl-CoA concentrations increase, leading to inhibition of pyruvate dehydrogenase (PDH) and thereby reducing glucose oxidation. The conversion of acetyl-CoA to acetylcarnitine relieves this acetyl-CoA pressure on PDH. To provide more direct insight into the effect of carnitine in preventing metabolic inflexibility and insulin resistance and to further explore the mechanism of action is the focus of this research. Here, we hypothesize that the capacity to form acetylcarnitine may rescue lipid-induced insulin resistance. To this end, insulin resistance will be induced by lipid infusion in healthy volunteers and it will be tested whether carnitine co-infusion can alleviate insulin resistance.
详细描述
Rationale: Insulin resistant subjects and type 2 diabetic patients are characterized by a decreased metabolic flexibility: a reduced capability to switch from fat oxidation in the basal state to carbohydrate oxidation in the insulin-stimulated state. This metabolic inflexibility is an early hallmark in the development of diabetes. Recent evidence suggests that a low carnitine availability may limit acetylcarnitine formation, thereby reducing metabolic flexibility. Thus, when substrate flux in the muscle is high, acetyl-CoA concentrations increase, leading to inhibition of pyruvate dehydrogenase (PDH) and thereby reducing glucose oxidation. The conversion of acetyl-CoA to acetylcarnitine relieves this acetyl-CoA pressure on PDH. To provide more direct insight into the effect of carnitine in preventing metabolic inflexibility and insulin resistance and to further explore the mechanism of action is the focus of this research. Here, we hypothesize that the capacity to form acetylcarnitine may rescue lipid-induced insulin resistance. To this end, insulin resistance will be induced by lipid infusion in healthy volunteers and it will be tested whether carnitine co-infusion can alleviate insulin resistance.
Objective: The primary objectives are to investigate whether L-carnitine infusion may rescue lipid-induced insulin resistance and whether L-carnitine infusion is improving metabolic flexibility in the state of lipid-induced insulin resistance. Furthermore, a secondary objective is to examine the molecular pathways of carnitine and acetylcarnitine, responsible for muscle insulin sensitivity.
Study design: The current study is an interventional randomized crossover trial in which each subject serves as it owns control. Subjects will be blinded for the intervention.
Study population: n=10, healthy young (18-40 years) male subjects will be included.
Intervention (if applicable): Ten healthy subject will be subjected to the intervention of L-carnitine infusion. To investigate whether L-Carnitine infusion may rescue lipid induced insulin resistance and improve metabolic flexibility three intervention trials are included. The first trial includes lipid infusion combined with L-Carnitine infusion (=LIPID + CAR). In the second trial, L-carnitine infusion will be replaced by placebo infusion in the form of saline (= LIPID + PLAC) in order to investigate the effect of L-Carnitine. During the third trial, lipid infusion will be replaced by infusion of saline and will serve as a control for the lipid infusion (=SALINE + PLAC) and is necessary to investigate to what extend L-carnitine can rescue lipid induced insulin resistance. All three trials will be separated by at least one week. Subjects will be blinded, so no information about the infused substances will be provided to them. The three different trials will be allocated in a random order.
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
- Single (Participant)
入排标准
- 年龄范围
- 18 Years 至 40 Years（Adult）
- 性别
- Male
- 接受健康志愿者
- 是
入选标准
- •• Caucasian
- •Healthy (as determined by responsible physician based on a medical questionnaire)
- •Age: 18-40 years
- •Normal BMI: 18-25 kg/m2
- •Stable dietary habits
- •No use of medication interfering with investigated study parameters (as determined by responsible physician)
排除标准
- •Haemoglobin levels < 7.8 mmol/L
- •Uncontrolled hypertension
- •Use of anticoagulants
- •Engagement in exercise > 3 hours a week
- •Being vegetarian or vegan (because of altered whole body carnitine status)
- •Alcohol and/or drug abuse
- •Unstable body weight (weight gain or loss > 5kg in the last 3 months)
- •Significant food allergies/intolerances (seriously hampering study meals)
- •Participation in another biomedical study within 1 month before the first study visit, which would possibly hamper our study results
- •Medication use known to hamper subject's safety during the study procedures
- •Medication use known to interfere with investigated study parameters
- •Subjects with contra-indications for MRI
- •Subjects who intend to donate blood during the intervention or subjects who have donated blood less than three months before the start of the study
- •Subjects who do not want to be informed about unexpected medical findings
- •Subjects who do not want that their treating physician is informed
研究组 & 干预措施
LIPID + Carnitor
intravenous Lipid infusion (IntraLipid) combined with carnitor (L-carnitine) infusion
L-Carnitine will be administrated intravenously as continuous infusion during the 6-hour hyperinsulinemic euglycemic clamp. The administration will start with a bolus of 15mg/kg for 10 minutes. Subsequently, continuous L-carnitine infusion of 10mg/kg will start for the remaining 350 minutes.
Intralipid will be administrated intravenously as continuous infusion during the 6-hour hyperinsulinemic euglycemic clamp. The maximum dosage will not exceed 90 mL/h.
干预措施: Carnitor (Drug)
LIPID + Carnitor
intravenous Lipid infusion (IntraLipid) combined with carnitor (L-carnitine) infusion
L-Carnitine will be administrated intravenously as continuous infusion during the 6-hour hyperinsulinemic euglycemic clamp. The administration will start with a bolus of 15mg/kg for 10 minutes. Subsequently, continuous L-carnitine infusion of 10mg/kg will start for the remaining 350 minutes.
Intralipid will be administrated intravenously as continuous infusion during the 6-hour hyperinsulinemic euglycemic clamp. The maximum dosage will not exceed 90 mL/h.
干预措施: IntraLipid (Dietary Supplement)
LIPID + PLAC
Intravenous Lipid infusion (IntraLipid) combined with placebo infusion (saline)
Intralipid will be administrated intravenously as continuous infusion during the 6-hour hyperinsulinemic euglycemic clamp. The maximum dosage will not exceed 90 mL/h.
干预措施: IntraLipid (Dietary Supplement)
LIPID + PLAC
Intravenous Lipid infusion (IntraLipid) combined with placebo infusion (saline)
Intralipid will be administrated intravenously as continuous infusion during the 6-hour hyperinsulinemic euglycemic clamp. The maximum dosage will not exceed 90 mL/h.
干预措施: Placebo (Dietary Supplement)
PLAC
Infusion of saline (no IntraLipid and no carnitor)
Saline will be administrated intravenously as continuous infusion during the 6-hour hyperinsulinemic euglycemic clamp. The maximum dosage will not exceed 90 ml/h.
干预措施: Placebo (Dietary Supplement)
结局指标
主要结局
Whole body insulin sensitivity
时间窗: 6 hours
measured as GIR in µmol/kg/min during the stable period of the insulin phase of the clamp. * Peripheral insulin sensitivity measured as Rd in µmol/kg/min
Metabolic flexibility
时间窗: 6-hours
Change in RER comparing basal and insulin stimulated state during the clamp
次要结局
- glucose concentration in the blood before and during insulin stimulation(6 hours)
- free fatty acid in the blood before and during insulin stimulation(6 hours)
- Maximal acetylcarnitine concentrations after exercise(45 minutes)
- Carnitine acyltransferase (CRaT) enzyme activity (physiological parameter)(6 hours)
- Triglycerides in the blood before and during insulin stimulation(6 hours)
- Acylcarnitine profile in the muscle (physiological parameter)(6 hours)
- Lipid levels (physiological parameter)(6 hours)
- Insulin in the blood before and during insulin stimulation(6 hours)