Mechanisms of increased in vivo insulin sensitivity by dietary methionine restriction in mice.

Stone KP, Wanders D, Orgeron M, Cortez CC, Gettys TW
Diabetes. 2014 63 (11): 3721-33

PMID: 24947368 · PMCID: PMC4207389 · DOI:10.2337/db14-0464

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 effect of the diet on overall and tissue-specific insulin sensitivity in mice. The steady-state glucose infusion rate was threefold higher in the MR group and consistent with the 2.5- to threefold increase in 2-deoxyglucose uptake in skeletal muscle, heart, and white adipose tissue. Dietary MR enhanced suppression of hepatic glucose production by insulin, enhanced insulin-dependent Akt phosphorylation in the liver, and increased hepatic expression and circulating fibroblast growth factor 21 (FGF-21) by fourfold. 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, where it functions as a cofactor for phosphatase and tensin homolog. 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.

MeSH Terms (13)

3T3-L1 Cells Adipose Tissue Animals Deoxyglucose Fibroblast Growth Factors Hep G2 Cells Humans Insulin Resistance Liver Methionine Mice Phosphorylation Proto-Oncogene Proteins c-akt

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