Context: Elevated plasma free fatty acids (FFA), excess reactive oxygen species (ROS), inflammation and gluco-counterregulatory hormones induce insulin resistance (IR) through activation of JUN NH2-terminal kinase (JNK) and nuclear factor B inhibitor kB kinase (IKK), which leads to hyperphosphorylation of the insulin receptor substrate type 1 (IRS-1). Aspirin blocks IKK and improves IR in type 2 diabetes mellitus (T2DM).

Objective: We hypothesized that high-dose aspirin would also attenuate fasting-induced insulin resistance in healthy lean subjects.

Design: Glucose and glutathione (GHS) metabolism were studied after 12 and 60h of fasting on two occasions: with and without aspirin (6 g/day).

Setting: Academic Medical Center, Metabolic Research Unit.

Participants: 6 healthy lean men.

Intervention: 60h fasting with or without aspirin ( 6 g/day).

Main outcome measure: glucose and glutathione (GSH) metabolism.

Results: Fasting decreased insulin-mediated peripheral glucose uptake (Rd) by 46% after 60h (P = 0.03). Aspirin did not alter this effect of 60h fasting on insulin sensitivity (P = 0.03) GSH concentration decreased during fasting, but the Fractional Synthetic Rate (FSR) of GSH was unaffected either with or without aspirin. Fasting did not affect inflammatory parameters, although aspirin increased soluble TNF receptors I and II.

Conclusion: prolonged fasting induces profound peripheral insulin resistance. In contrast to T2DM, high-dose salicylate does not affect fasting-induced peripheral insulin resistance.