Glucose Intolerance Clinical Trial
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.
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.
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