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TRB3: A tribbles Homolog That Inhibits Akt/PKB Activation by Insulin in Liver

Science, 6 June 2003
Vol. 300, Issue 5625, p. 1574-1577
DOI: 10.1126/science.1079817

TRB3: A tribbles Homolog That Inhibits Akt/PKB Activation by Insulin in Liver

  1. Keyong Du1,*,
  2. Stephan Herzig1,*,
  3. Rohit N. Kulkarni2,
  4. Marc Montminy1,
  1. 1 Peptide Biology Laboratories, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037—1002, USA.
  2. 2 Joslin Diabetes Center, Department of Medicine, Harvard Medical School, One Joslin Place, Boston, MA 02215, USA.
  1. To whom correspondence should be addressed. E-mail: montminy{at}
  • * These authors contributed equally to this work.


Insulin resistance is a major hallmark in the development of type II diabetes, which is characterized by the failure of insulin to promote glucose uptake in muscle and to suppress glucose production in liver. The serine-threonine kinase Akt (PKB) is a principal target of insulin signaling that inhibits hepatic glucose output when glucose is available from food. Here we show that TRB3, a mammalian homolog of Drosophila tribbles, functions as a negative modulator of Akt. TRB3 expression is induced in liver under fasting conditions, and TRB3 disrupts insulin signaling by binding directly to Akt and blocking activation of the kinase. Amounts of TRB3 RNA and protein were increased in livers of db/db diabetic mice compared with those in wild-type mice. Hepatic overexpression of TRB3 in amounts comparable to those in db/db mice promoted hyperglycemia and glucose intolerance. Our results suggest that, by interfering with Akt activation, TRB3 contributes to insulin resistance in individuals with susceptibility to type II diabetes.

    • Received for publication 28 October 2002.
    • Accepted for publication 5 May 2003.


    K. Du, S. Herzig, R. N. Kulkarni, and M. Montminy, TRB3: A tribbles Homolog That Inhibits Akt/PKB Activation by Insulin in Liver. Science 300, 1574-1577 (2003).

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    TRB3 Blocks Adipocyte Differentiation through the Inhibition of C/EBP{beta} Transcriptional Activity
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    Nelfinavir, A Lead HIV Protease Inhibitor, Is a Broad-Spectrum, Anticancer Agent that Induces Endoplasmic Reticulum Stress, Autophagy, and Apoptosis In vitro and In vivo
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    Protein-tyrosine Phosphatase 1B Deficiency Reduces Insulin Resistance and the Diabetic Phenotype in Mice with Polygenic Insulin Resistance
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    A Novel Regulatory Mechanism of the Bone Morphogenetic Protein (BMP) Signaling Pathway Involving the Carboxyl-Terminal Tail Domain of BMP Type II Receptor
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    Survival Factor Withdrawal-induced Apoptosis of TF-1 Cells Involves a TRB2-Mcl-1 Axis-dependent Pathway
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    Abnormal glucose homeostasis in adult female rat offspring after intrauterine ethanol exposure
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    Genetic Deletion of Trb3, the Mammalian Drosophila tribbles Homolog, Displays Normal Hepatic Insulin Signaling and Glucose Homeostasis
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    Large-scale phosphorylation analysis of mouse liver
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    Glucose, dexamethasone, and the unfolded protein response regulate TRB3 mRNA expression in 3T3-L1 adipocytes and L6 myotubes
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