Carnitine Infusion and Insulin Resistance

NCT02722902 | Terminated DMC

• 1 other identifier: NL56319.068.16
• Study Type: interventional
• Target: 17
• Locations: 1 country
• Sites: 1

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.

Conditions

Glucose Intolerance

Keywords

Metabolic flexibility; Insulin sensitivity

Outcome Measures

Primary Outcomes (2)

• 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

  6 hours

• Metabolic flexibility

  Change in RER comparing basal and insulin stimulated state during the clamp

  6-hours

Secondary Outcomes (8)

• Maximal acetylcarnitine concentrations after exercise

  45 minutes

• glucose concentration in the blood before and during insulin stimulation

  6 hours

• Carnitine acyltransferase (CRaT) enzyme activity (physiological parameter)

  6 hours

• Acylcarnitine profile in the muscle (physiological parameter)

  6 hours

• Lipid levels (physiological parameter)

  6 hours

Study Arms (3)

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.

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.

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.

Dietary Supplement: Placebo

Interventions

Carnitor DRUG

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.

Also known as: L-Carnitine or Levocarnitine

LIPID + Carnitor

IntraLipid DIETARY_SUPPLEMENT

Lipid emulsion for infusion

LIPID + Carnitor; LIPID + PLAC

Placebo DIETARY_SUPPLEMENT

Saline will be used as placebo

Also known as: saline

LIPID + PLAC; PLAC

Eligibility Criteria

• Age: 18 Years - 40 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• Maastricht University Medical Center: lead

Study Sites (1)

Maastricht University Medical Center

Maastricht, Limburg, 6229 ER, Netherlands

Location

MeSH Terms

Conditions

Glucose Intolerance; Insulin Resistance

Interventions

Carnitine; soybean oil, phospholipid emulsion; Sodium Chloride

Condition Hierarchy (Ancestors)

Hyperglycemia; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Hyperinsulinism

Intervention Hierarchy (Ancestors)

Trimethyl Ammonium Compounds; Quaternary Ammonium Compounds; Amines; Organic Chemicals; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Study Officials

• Vera B Schrauwen, Dr

  Maastricht University Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: PREVENTION
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 26, 2016
• First Posted: March 30, 2016
• Study Start: May 1, 2016
• Primary Completion: June 1, 2017
• Study Completion: June 1, 2017
• Last Updated: April 26, 2018

Record last verified: 2017-07

Locations

NL (1)