Acetylcarnitine and Metabolic Flexibility
Condition: Glucose Intolerance
MeSH terms: Glucose Intolerance
Study type: Interventional

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. We
      propose to test the hypothesis that metabolic inflexibility in pre-diabetic subjects and
      diabetic patients is due to a reduced capacity to form acetylcarnitines.
    

Detailed description: 
      Background: 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 low carnitine availability may limit acetylcarnitine formation, thereby reducing
      metabolic flexibility.

      Objectives: We will investigate whether subjects with impaired glucose tolerance (IGT) show a
      diminished capacity to form acetylcarnitine in the face of high substrate availability.
      Therefore, we will use a novel non-invasive 1H-Magnetic Resonance Spectroscopy (1H-MRS)
      protocol to determine in vivo, and in time, the formation of acetylcarnitine in skeletal
      muscle. Additionally, we will examine whether carnitine supplementation increases the
      capacity to form acetylcarnitine and improves metabolic flexibility and insulin sensitivity
      in IGT subjects.

      Study design: 12 subjects with IGT will be included and will be subjected to either placebo-
      or carnitine treatment (daily capsules with 2g of L-carnitine or placebo) in a randomized,
      placebo-controlled, double blind crossover design. After both interventions, acetylcarnitine
      formation after a mixed meal will be determined by 1H-MRS and meal-induced changes in fat and
      glucose oxidation by indirect calorimetry. The maximal acetylcarnitine formation will be
      measured after a cycling test via 1H-MRS. A hyperinsulinemic-euglycemic clamp will be
      performed to determine insulin sensitivity. Biopsies will be taken to measure free carnitine
      and carnitine acetyltransferase (CrAT) activity. To investigate whether differences in
      acetylcarnitine formation may be involved in variations in glucose tolerance, twelve control
      subjects, matched for BMI and age but glucose tolerant (based on oral glucose tolerance test,
      according to WHO criteria) will also be included and will undergo all measurements once
      without any intervention.
    

Intervention name(s): Carnitine supplement; Placebo
Intervention type(s): Dietary Supplement; Dietary Supplement
Intervention description(s): Carnitine supplement (oral ingestion with meals)
Total dosage of 2g carnitine per day for 36 days.
1 carnitine supplement at breakfast (500mg)
1 carnitine supplement at lunch (500mg)
2 carnitine supplements at diner (2x 500mg=1000mg)
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Prevention
Keywords: Insulin sensitivity; Metabolic flexibility