Mechanisms of Increased in Vivo Insulin Sensitivity by Dietary Methionine Restriction in Mice

  1. Thomas W. Gettys
  1. Laboratory of Nutrient Sensing and Adipocyte Signaling Pennington Biomedical Research Center, Baton Rouge, LA
  1. Corresponding Author: Thomas W. Gettys, E-mail: gettystw{at}


To understand the physiological significance of the reduction in fasting insulin produced by dietary methionine restriction (MR), hyperinsulinemic-euglycemic clamps were used to examine the impact of the diet on overall and tissue-specific insulin sensitivity in mice. The steady-state glucose infusion rate was 3-fold higher in the MR group and consistent with the 2.5- to 3-fold increase in 2-deoxyglucose uptake in skeletal muscle, heart, and white adipose tissue. Moreover, dietary MR enhanced suppression of hepatic glucose production by insulin. Dietary MR enhanced insulin-dependent Akt phosphorylation in the liver and increased hepatic expression and circulating FGF-21 by 4-fold. Limitation of media methionine recapitulated amplification of Akt phosphorylation by insulin in HepG2 cells but not in 3T3-L1 adipocytes or C2C12 myotubes. Amplification of insulin signaling in HepG2 cells by MR was associated with reduced glutathione (GSH), where it functions as a co-factor for Phosphatase and tensin homologue (PTEN). In contrast, FGF-21 but not restricting media methionine, enhanced insulin-dependent Akt phosphorylation in 3T3 L1 adipocytes. These findings provide a potential mechanism for the diet-induced increase in insulin sensitivity among tissues that involves a direct effect of methionine in liver and an indirect effect in adipose tissue through MR-dependent increases in hepatic transcription and release of FGF-21.

  • Received March 20, 2014.
  • Accepted June 13, 2014.

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