Glucose IntoleranceNCT02722902
Carnitine Infusion and Insulin Resistance
A study testing Carnitor and IntraLipid in people with Glucose Intolerance, run by Maastricht University Medical Center at 1 site in Netherlands.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 40 years, men onlyHealthy volunteers can take part
- Conditions the study is for
- Glucose Intolerance
- What is being tested?
- Carnitor and IntraLipid
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 17 participants
- Where
- 1 siteNetherlands
- Study dates
- May 2016to Jun 2017
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 40 years
- Men only
- Healthy volunteers accepted
- Adult
Who may be able to join
- • 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)
Who cannot join
- • 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)
Show all 17Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
Netherlands1 site
Maastricht University Medical Center
Maastricht, Limburg, 6229 ER
About this study
Official title: Impact of L-Carnitine Infusion on Lipid Induced Insulin Resistance
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.
Read the 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.
- Conditions
- Glucose Intolerance
- Being tested
- Carnitor, IntraLipid, Placebo
- Keywords
- Metabolic flexibility, Insulin sensitivity
- Medical subject headings
- Glucose Intolerance, Insulin Resistance
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
CarnitorDrug
Also called L-Carnitine or Levocarnitine
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.
IntraLipidDietary supplement
Lipid emulsion for infusion
PlaceboDietary supplement
Also called saline
Saline will be used as placebo
| Study group | Role | What they receive |
|---|---|---|
| LIPID + Carnitor | Experimental | 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. Receives: Drug: Carnitor; Dietary Supplement: IntraLipid |
| LIPID + PLAC | Placebo comparator | 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. Receives: Dietary Supplement: IntraLipid; Dietary Supplement: Placebo |
| PLAC | Placebo comparator | 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. Receives: Dietary Supplement: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Whole body insulin sensitivity
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
Measured: 6 hours
Metabolic flexibility
Change in RER comparing basal and insulin stimulated state during the clamp
Measured: 6-hours
Secondary outcomes (8)
Maximal acetylcarnitine concentrations after exercise
Measured using 1H-MRS after 30 minutes of cycling at 70% Wmax
Measured: 45 minutes
glucose concentration in the blood before and during insulin stimulation
glucose concentration in the plasma will be measured via a blood draw
Measured: 6 hours
Carnitine acyltransferase (CRaT) enzyme activity (physiological parameter)
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
Measured: 6 hours
Acylcarnitine profile in the muscle (physiological parameter)
In muscle tissue obtained via biopsies. Acylcarnitine measurements will be performed using flow injection tandem mass spectrometry
Measured: 6 hours
Lipid levels (physiological parameter)
In muscle tissue obtained via biopsies
Measured: 6 hours
free fatty acid in the blood before and during insulin stimulation
free fatty acid concentration in the plasma will be measured via a blood draw
Measured: 6 hours
Triglycerides in the blood before and during insulin stimulation
Triglycerides wil be measured in the plasma via a blood draw
Measured: 6 hours
Insulin in the blood before and during insulin stimulation
Insulin wil be measured in the plasma via a blood draw
Measured: 6 hours
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 Mar 2016 (estimated)
- Study startMay 2016
- Primary completionJun 2017
- Study completionJun 2017
Why it stopped: No effect of carnitine on lipid induced insulin resistance after n=8 (p=1.00)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Glucose IntoleranceStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Single blind
- Who is masked
- Participant
- Enrolment
- 17 participants (actual)
Sponsor and investigators
- Lead sponsor
- Maastricht University Medical Center
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Vera B Schrauwen, Dr, Principal investigator, Maastricht University Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02722902
- Sponsor's protocol ID
- NL56319.068.16
- Status last verified
- Jul 2017
- First submitted
- 26 Feb 2016
- Last updated
- 26 Apr 2018
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 26 Apr 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Impact of L-Carnitine Infusion on Lipid Induced Insulin Resistance
- ClinicalTrials.gov ID
- NCT02722902
- Acronym / sponsor ID
- NL56319.068.16
- Conditions
- Glucose Intolerance
- Keywords
- Metabolic flexibility, Insulin sensitivity
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: No effect of carnitine on lipid induced insulin resistance after n=8 (p=1.00)
- Enrolment
- 17 participants (actual)
- Lead sponsor
- Maastricht University Medical CenterUniversity, hospital or other
- Study start
- May 2016 (actual)
- Primary completion
- Jun 2017 (actual)
- Study completion
- Jun 2017 (actual)
- First posted
- 30 Mar 2016 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Single blind (participant)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| LIPID + Carnitor | Experimental | Drug: Carnitor, Dietary Supplement: IntraLipidintravenous 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. |
| LIPID + PLAC | Placebo comparator | Dietary Supplement: IntraLipid, Dietary Supplement: PlaceboIntravenous 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. |
| PLAC | Placebo comparator | Dietary Supplement: PlaceboInfusion 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. |
Who may qualify
- Ages
- 18 to 40 years
- Sex
- Male only
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (7 listed)
- • Caucasian
Key exclusion criteria (17 listed)
- • Female
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| CarnitorAlso: L-Carnitine or LevocarnitineCARNITOR® (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. | Drug | LIPID + Carnitor |
| IntraLipidLipid emulsion for infusion | Dietary supplement | LIPID + Carnitor, LIPID + PLAC |
| PlaceboAlso: salineSaline will be used as placebo | Dietary supplement | LIPID + PLAC, PLAC |
Primary outcome
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
8 secondary outcomes
Maximal acetylcarnitine concentrations after exercise
Time frame: 45 minutes
glucose concentration in the blood before and during insulin stimulation
Time frame: 6 hours
Carnitine acyltransferase (CRaT) enzyme activity (physiological parameter)
Time frame: 6 hours
Acylcarnitine profile in the muscle (physiological parameter)
Time frame: 6 hours
Lipid levels (physiological parameter)
Time frame: 6 hours
free fatty acid in the blood before and during insulin stimulation
Time frame: 6 hours
Triglycerides in the blood before and during insulin stimulation
Time frame: 6 hours
Insulin in the blood before and during insulin stimulation
Time frame: 6 hours
Results and safety
The study was stopped early (reason given: No effect of carnitine on lipid induced insulin resistance after n=8 (p=1.00)). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 26 Apr 2018.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Vera B Schrauwen, Dr principal investigator
Maastricht University Medical Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Carnitor and IntraLipid in people with Glucose Intolerance, run by Maastricht University Medical Center at 1 site in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 26 Apr 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study was stopped early (reason given: No effect of carnitine on lipid induced insulin resistance after n=8 (p=1.00)). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Whole body insulin sensitivity (time frame: 6 hours). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Apr 2018.