Carnitine supplementation improves insulin sensitivity and skeletal muscle acetylcarnitine formation in patients with type 2 diabetes

Aim/Hypothesis: Recently, we reported that increasing free carnitine availability resulted in elevated skeletal muscle acetylcarnitine concentrations and restored metabolic flexibility in individuals who have impaired glucose tolerance. Metabolic flexibility is defined as the capacity to switch from predominantly fat oxidation while fasted to carbohydrate oxidation while insulin stimulated. Here we investigated if carnitine supplementation enhances the capacity of skeletal muscle to form acetylcarnitine and thereby improves insulin sensitivity and glucose homeostasis in patients with type 2 diabetes (T2DM). Methods: Thirty-two patients followed a 12-week L-carnitine treatment (2970 mg/day, orally). Insulin sensitivity was assessed by a two-step hyperinsulinemic-euglycemic clamp. In vivo skeletal muscle acetylcarnitine concentrations at rest and post-exercise (30 min, 70% W_max) and intrahepatic lipid content (IHL) were determined by proton magnetic resonance spectroscopy (¹H-MRS). All measurements were performed before and after 12 weeks of carnitine supplementation. Results: Compliance with the carnitine supplementation was good (as indicated by increased plasma-free carnitine levels (p < 0.01) and pill count (97.1 ± 0.7%)). Insulin-induced suppression of endogenous glucose production (31.9 ± 2.9 vs. 39.9 ± 3.2%, p = 0.020) and peripheral insulin sensitivity (Δ rate of glucose disappearance (ΔR_d): 10.53 ± 1.85 vs. 13.83 ± 2.02 μmol/kg/min, p = 0.005) improved after supplementation. Resting (1.18 ± 0.13 vs. 1.54 ± 0.17 mmol/kgww, p = 0.008) and post-exercise (3.70 ± 0.22 vs. 4.53 ± 0.30 mmol/kgww, p < 0.001) skeletal muscle acetylcarnitine concentrations were both elevated after carnitine supplementation. Plasma glucose (p = 0.083) and IHL (p = 0.098) tended to be reduced after carnitine supplementation. Conclusion: Carnitine supplementation improved insulin sensitivity and tended to lower IHL and fasting plasma glucose levels in patients with type 2 diabetes. Furthermore, carnitine supplementation increased acetylcarnitine concentration in muscle, which may underlie the beneficial effect on insulin sensitivity.