Little information is available in the literature on the effect of L-carnitine to improve glucose disposal in healthy control subjects and type 2 diabetic patients. No data are reported on the pharmacological properties of acetyl-L-carnitine (ALC) in type 2 diabetes mellitus. The present study evaluates glucose uptake and oxidation rates with either ALC or placebo administration in 18 type 2 diabetic patients. On different days, each patient received both a primed-constant infusion of ALC (5 mg/kg body weight [BW] priming bolus and either 0.025, 0.1, or 1.0 mg/kg BW/min constant infusion) and a comparable placebo formulation. During the infusion period, continuous indirect calorimetric monitoring and a euglycemic-hyperinsulinemic clamp (EHC) study were performed. The total end-clamp glucose tissue uptake (M value) was significantly increased by the administration of ALC (from 3.8 to 5.2 mg/kg/min, P = .006), and the dose dependence of this effect reached borderline statistical significance (P = .037). The increase in the M/I ratio was also highly significant after ALC administration (from 3.9 to 5.8 x 10(-2) mg/kg/min/(microUI/mL, P < .001), while no statistically significant effect was attributable to the different dosages. The increase in the M value was related to increased glucose storage (highly significant effect of ALC) rather than increased glucose oxidation (no statistical significance). In conclusion, the effect of ALC on glucose disposal has no relationship to the amount administered. This could be due to an effect of ALC on the enzymes involved in both the glycolytic and gluconeogenetic pathways, and a possible reversibility of glycogen synthase inhibition in diabetic subjects.