Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Carnitine Infusion and Insulin Resistance

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02722902
Recruitment Status : Terminated (No effect of carnitine on lipid induced insulin resistance after n=8 (p=1.00))
First Posted : March 30, 2016
Last Update Posted : April 26, 2018
Sponsor:
Information provided by (Responsible Party):
Maastricht University Medical Center

Tracking Information
First Submitted Date  ICMJE February 26, 2016
First Posted Date  ICMJE March 30, 2016
Last Update Posted Date April 26, 2018
Actual Study Start Date  ICMJE May 2016
Actual Primary Completion Date June 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 31, 2016)
  • Whole body insulin sensitivity [ Time Frame: 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 [ Time Frame: 6-hours ]
    Change in RER comparing basal and insulin stimulated state during the clamp
Original Primary Outcome Measures  ICMJE
 (submitted: March 23, 2016)
  • Whole body insulin sensitivity [ Time Frame: 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 [ Time Frame: 6-hours ]
    Change in RER comparing basal and insuli stimulated state during the clamp
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 31, 2016)
  • Maximal acetylcarnitine concentrations after exercise [ Time Frame: 45 minutes ]
    Measured using 1H-MRS after 30 minutes of cycling at 70% Wmax
  • glucose concentration in the blood before and during insulin stimulation [ Time Frame: 6 hours ]
    glucose concentration in the plasma will be measured via a blood draw
  • Carnitine acyltransferase (CRaT) enzyme activity (physiological parameter) [ Time Frame: 6 hours ]
    CRaT activity will be measured in obtained muscle biopsies from the vastus Lateralis muscle using enzyme Activity Assays. Measurements will be obtained using 10 ml of sample incubated in 190 ml reaction buffer (50mM Tris-HCl, 1M EDTA, 0.45mM acetyl-CoA, 0.1mM DTNB; pH = 7.8). CrAT specific activity will be determined by measuring the rate of reduction of DTNB (412 nm) by the free CoA liberated from acetylCoA after adding 5mM L-carnitine and monitoring for 10 min
  • Acylcarnitine profile in the muscle (physiological parameter) [ Time Frame: 6 hours ]
    In muscle tissue obtained via biopsies. Acylcarnitine measurements will be performed using flow injection tandem mass spectrometry
  • Lipid levels (physiological parameter) [ Time Frame: 6 hours ]
    In muscle tissue obtained via biopsies
  • free fatty acid in the blood before and during insulin stimulation [ Time Frame: 6 hours ]
    free fatty acid concentration in the plasma will be measured via a blood draw
  • Triglycerides in the blood before and during insulin stimulation [ Time Frame: 6 hours ]
    Triglycerides wil be measured in the plasma via a blood draw
  • Insulin in the blood before and during insulin stimulation [ Time Frame: 6 hours ]
    Insulin wil be measured in the plasma via a blood draw
Original Secondary Outcome Measures  ICMJE
 (submitted: March 23, 2016)
  • Maximal acetylcarnitine concentrations after exercise [ Time Frame: 45 minutes ]
    Measured using 1H-MRS after 30 minutes of cycling at 70% Wmax
  • glucose concentration in the blood before and during insulin stimulation [ Time Frame: 6 hours ]
    glucose concentration in the plasma will be meausured via a blood draw
  • Carnitine acyltransferase (CRaT) enzym activity (physiological parameter) [ Time Frame: 6 hours ]
    CRaT activity will be measured in obtained muscle biopsies from the vastus Lateralis muscle using enzyme Activity Assays. Measurements will be obtained using 10 ml of sample incubated in 190 ml reaction buffer (50mM Tris-HCl, 1M EDTA, 0.45mM acetyl-CoA, 0.1mM DTNB; pH = 7.8). CrAT specific activity will be determined by measuring the rate of reduction of DTNB (412 nm) by the free CoA liberated from acetylCoA after adding 5mM L-carnitine and monitoring for 10 min
  • Acylcarnitine profile in the muscle (physiological parameter) [ Time Frame: 6 hours ]
    In muscle tissue obtained via biopsies. Acylcarnitine measurements will be performed using flow injection tandem mass spectrometry
  • Lipid levels (physiological parameter) [ Time Frame: 6 hours ]
    In muscle tissue obtained via biopsies
  • free fatty acid in the blood before and during insulin stimulation [ Time Frame: 6 hours ]
    free fatty acid concentration in the plasma will be meausured via a blood draw
  • Triglycerides in the blood before and during insulin stimulation [ Time Frame: 6 hours ]
    Triglycerides wil be measured in the plasma via a blood draw
  • Insulin in the blood before and during insulin stimulation [ Time Frame: 6 hours ]
    Insulin wil be measured in the plasma via a blood draw
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Carnitine Infusion and Insulin Resistance
Official Title  ICMJE Impact of L-Carnitine Infusion on Lipid Induced Insulin Resistance
Brief Summary 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.
Detailed Description

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.

Main study parameters/endpoints: The primary study endpoint is whole body insulin sensitivity, measured by the hyperinsulinemic-euglycemic clamp. Secondary endpoints are maximal acetylcarnitine concentrations after exercise, metabolic compounds in the blood and measurements regarding skeletal muscle metabolism in skeletal muscle tissue obtained by needle biopsies.

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single (Participant)
Primary Purpose: Prevention
Condition  ICMJE Glucose Intolerance
Intervention  ICMJE
  • Drug: Carnitor

    CARNITOR® (levocarnitine) is a carrier molecule in the transport of long-chain fatty acids 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.

    across the inner mitochondrial membrane.

    Other Name: L-Carnitine or Levocarnitine
  • Dietary Supplement: IntraLipid
    Lipid emulsion for infusion
  • Dietary Supplement: Placebo
    Saline will be used as placebo
    Other Name: saline
Study Arms  ICMJE
  • Experimental: 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.

    Interventions:
    • Drug: Carnitor
    • Dietary Supplement: IntraLipid
  • Placebo Comparator: 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.

    Interventions:
    • Dietary Supplement: IntraLipid
    • Dietary Supplement: Placebo
  • Placebo Comparator: 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.

    Intervention: Dietary Supplement: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: July 24, 2017)
17
Original Estimated Enrollment  ICMJE
 (submitted: March 23, 2016)
18
Actual Study Completion Date  ICMJE June 2017
Actual Primary Completion Date June 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • • Caucasian

    • Healthy (as determined by responsible physician based on a medical questionnaire)
    • Male
    • 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)

Exclusion Criteria:

  • • Female

    • 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)
    • Smoking
    • 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
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE 18 Years to 40 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Netherlands
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02722902
Other Study ID Numbers  ICMJE NL56319.068.16
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Maastricht University Medical Center
Study Sponsor  ICMJE Maastricht University Medical Center
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Vera B Schrauwen, Dr Maastricht University Medical Center
PRS Account Maastricht University Medical Center
Verification Date July 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP