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.
- © 2014 by the American Diabetes Association.
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