Abnormal acyl-carnitine (AC) metabolism is implicated in muscle insulin resistance, but the effects of insulin on how plasma free fatty acids (FFA), intramyocellular triglycerides (imTG) and AC interact is unclear.
Lean (n=16) and obese (n=19) adults underwent a hyperinsulinemic-euglycemic clamp to measure muscle insulin sensitivity (Si). [U-13C]palmitate was infused before the insulin clamp to assess basal FFA incorporation into muscle lipids and changed to [2H9]palmitate during the insulin clamp. Muscle biopsies were taken before and after the clamp. Total, subsarcolemmal (SS), and intramyofibrillar (IMF) muscle imTG and AC (C4, C5, C8, C14, C16, C18, C18:1 and C18:2) concentrations and enrichment (C16-AC) were measured by LC/MS/MS.
AC concentrations in SS, IMF and total muscle were not different between lean and obese. C4, C5 and C8 species were greater in SS and the ≥C16 chain length AC’s were greater in IMF (all P<0.001). In SS and IMF, only C4 and C5-carnitine concentrations decreased (P<0.01) during hyperinsulinemia. The incorporation of plasma [U-13C]palmitate during fasting enriched imTG-palmitate to 0.034 ± 0.014 MPE and palmitoyl-carnitine to 0.03±0.02 MPE, consistent with imTG being a precursor pool for AC. There was minimal incorporation of [2H9]palmitate into imTG-palmitate during the insulin clamp. [U-13C]palmitate in imTG didn’t change during hyperinsulinemia (0.04±0.03 MPE), but [U-13C]palmitoyl-AC enrichment decreased (P<0.0001) to 0.008±0.007 MPE, indicating a shift in the precursor pool. The percent decrease in [U-13C]palmitoyl-carnitine enrichment during hyperinsulinemia correlated negatively (r=-0.43, P=0.01) with Si.
Although the IMF and SS sub-fractions of muscle have different patterns of AC, AC concentrations are not altered in obesity. Hyperinsulinemia decreases only short chain muscle AC concentrations and alters the precursor pool for palmitoyl-carnitine. The inability to shift this precursor pool is related to muscle insulin resistance.