Nutrient overload, insulin resistance, and ribosomal protein S6 kinase 1, S6K1

Cell Metab. 2006 Jun;3(6):393-402. doi: 10.1016/j.cmet.2006.05.003.


Nutrient overload leads to obesity, insulin resistance, and often type 2 diabetes. Whereas increased fat intake is commonly cited as the major factor in diet-induced dysmetabolic states, increased protein consumption also contributes, through elevated circulating amino acids. Recent studies have revealed that ribosomal protein S6 kinase 1, S6K1, an effector of mTOR, is sensitive to both insulin and nutrients, including amino acids. Although S6K1 is an effector of growth, recent reports show that amino acids also negatively affect insulin signaling through mTOR/S6K1 phosphorylation of IRS1. Moreover, rather than signaling through the class 1 PI3K pathway, amino acids appear to mediate mTOR activation through class 3 PI3K, or hVps34. Consistent with this, infusion of amino acids into humans leads to S6K1 activation, inhibition of insulin-induced class 1 PI3K activation, and insulin resistance. Thus, S6K1 may mediate deleterious effects, like insulin resistance, and potentially type 2 diabetes in the face of nutrient excess.

Publication types

  • Review

MeSH terms

  • Adipose Tissue / metabolism
  • Amino Acids / metabolism*
  • Amino Acids / pharmacology
  • Animals
  • Glucose / metabolism*
  • Glucose / pharmacology
  • Homeostasis / physiology
  • Humans
  • Insulin / metabolism
  • Insulin / pharmacology
  • Insulin Resistance / physiology*
  • Muscles / metabolism
  • Nutritional Status
  • Phosphatidylinositol 3-Kinases / drug effects
  • Phosphatidylinositol 3-Kinases / metabolism
  • Ribosomal Protein S6 Kinases, 90-kDa / deficiency
  • Ribosomal Protein S6 Kinases, 90-kDa / drug effects
  • Ribosomal Protein S6 Kinases, 90-kDa / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology


  • Amino Acids
  • Insulin
  • Phosphatidylinositol 3-Kinases
  • RPS6KA1 protein, human
  • Ribosomal Protein S6 Kinases, 90-kDa
  • Glucose