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Prolonged Fasting Induces Peripheral Insulin Resistance, Which Is Not Ameliorated by High-Dose Salicylate

Departments of Endocrinology and Metabolism (S.N.v.d.C., G.A., H.P.S.) and Clinical Chemistry (M.T.A., E.E.), Laboratory of Endocrinology, Academic Medical Center, University of Amsterdam, 1100 DD Amsterdam; and Department of Endocrinology (J.A.R.), Leiden University Medical Center, 2300 RC Leiden, The Netherlands

Address all correspondence and requests for reprints to: S. N. van der Crabben, University Medical Center Utrecht (Wilhelmina Children’s Hospital), DBG Department of Clinical Genetics, KC04.084.2, Lundlaan 6, P.O. Box 85090, 3508 AB Utrecht, The Netherlands. E-mail: saskiananette{at}hotmail.com.

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

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

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

Setting: The study took place at the Academic Medical Center, Metabolic Research Unit.

Participants: Six healthy lean men participated.

Intervention: Intervention included 60 h of fasting with or without aspirin (6 g/d).

Main Outcome Measure: Main outcome measures included glucose and GSH metabolism.

Results: Fasting decreased insulin-mediated peripheral glucose uptake by 46% after 60 h (P = 0.03). Aspirin did not alter this effect of 60 h of fasting on insulin sensitivity (P = 0.03). GSH concentration decreased during fasting, but the fractional synthetic rate 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 IR. In contrast to type 2 diabetes mellitus, high-dose salicylate does not affect fasting-induced peripheral IR.

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