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Science 292 (5522): 1728-1731

Copyright © 2001 by the American Association for the Advancement of Science

Insulin Resistance and a Diabetes Mellitus-Like Syndrome in Mice Lacking the Protein Kinase Akt2 (PKBbeta )

Han Cho,1 James Mu,26 Jason K. Kim,67 Joanne L. Thorvaldsen,36 Qingwei Chu,26 E. Bryan Crenshaw III,4 Klaus H. Kaestner,5 Marisa S. Bartolomei,36 Gerald I. Shulman,67 Morris J. Birnbaum26*

Glucose homeostasis depends on insulin responsiveness in target tissues, most importantly, muscle and liver. The critical initial steps in insulin action include phosphorylation of scaffolding proteins and activation of phosphatidylinositol 3-kinase. These early events lead to activation of the serine-threonine protein kinase Akt, also known as protein kinase B. We show that mice deficient in Akt2 are impaired in the ability of insulin to lower blood glucose because of defects in the action of the hormone on liver and skeletal muscle. These data establish Akt2 as an essential gene in the maintenance of normal glucose homeostasis.

1 Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
2 Department of Medicine,
3 Department of Cell and Developmental Biology,
4 Department of Neuroscience, and
5 Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
6 Howard Hughes Medical Institute and the
7 Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
*   To whom correspondence should be addressed. E-mail: birnbaum{at}mail.med.upenn.edu

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Appl1 Is Dispensable for Mouse Development, and Loss of Appl1 Has Growth Factor-selective Effects on Akt Signaling in Murine Embryonic Fibroblasts.
Y. Tan, H. You, C. Wu, D. A. Altomare, and J. R. Testa (2010)
J. Biol. Chem. 285, 6377-6389
   Abstract »    Full Text »    PDF »
The PI3K Pathway As Drug Target in Human Cancer.
K. D. Courtney, R. B. Corcoran, and J. A. Engelman (2010)
J. Clin. Oncol. 28, 1075-1083
   Abstract »    Full Text »    PDF »
Dissecting the Mechanism of Insulin Resistance Using a Novel Heterodimerization Strategy to Activate Akt.
Y. Ng, G. Ramm, and D. E. James (2010)
J. Biol. Chem. 285, 5232-5239
   Abstract »    Full Text »    PDF »
Selective Signaling by Akt2 Promotes Bone Morphogenetic Protein 2-Mediated Osteoblast Differentiation.
A. Mukherjee, E. M. Wilson, and P. Rotwein (2010)
Mol. Cell. Biol. 30, 1018-1027
   Abstract »    Full Text »    PDF »
Differential Effects of Protein Kinase B/Akt Isoforms on Glucose Homeostasis and Islet Mass.
F. Buzzi, L. Xu, R. A. Zuellig, S. B. Boller, G. A. Spinas, D. Hynx, Z. Chang, Z. Yang, B. A. Hemmings, O. Tschopp, et al. (2010)
Mol. Cell. Biol. 30, 601-612
   Abstract »    Full Text »    PDF »
Identification of a novel phosphorylation site on TBC1D4 regulated by AMP-activated protein kinase in skeletal muscle.
J. T. Treebak, E. B. Taylor, C. A. Witczak, D. An, T. Toyoda, H.-J. Koh, J. Xie, E. P. Feener, J. F. P. Wojtaszewski, M. F. Hirshman, et al. (2010)
Am J Physiol Cell Physiol 298, C377-C385
   Abstract »    Full Text »    PDF »
Subfertility Caused by Altered Follicular Development and Oocyte Growth in Female Mice Lacking PKBalpha/Akt1.
C. Brown, J. LaRocca, J. Pietruska, M. Ota, L. Anderson, S. Duncan Smith, P. Weston, T. Rasoulpour, and M. L. Hixon (2010)
Biol Reprod 82, 246-256
   Abstract »    Full Text »    PDF »
Cluster Analysis of Insulin Action in Adipocytes Reveals a Key Role for Akt at the Plasma Membrane.
Y. Ng, G. Ramm, J. G. Burchfield, A. C. F. Coster, J. Stockli, and D. E. James (2010)
J. Biol. Chem. 285, 2245-2257
   Abstract »    Full Text »    PDF »
Membrane Fatty Acid Transporters as Regulators of Lipid Metabolism: Implications for Metabolic Disease.
J. F. C. Glatz, J. J. F. P. Luiken, and A. Bonen (2010)
Physiol Rev 90, 367-417
   Abstract »    Full Text »    PDF »
Apelin is necessary for the maintenance of insulin sensitivity.
P. Yue, H. Jin, M. Aillaud, A. C. Deng, J. Azuma, T. Asagami, R. K. Kundu, G. M. Reaven, T. Quertermous, and P. S. Tsao (2010)
Am J Physiol Endocrinol Metab 298, E59-E67
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Interplay between Akt and p38 MAPK pathways in the regulation of renal tubular cell apoptosis associated with diabetic nephropathy.
M. J. Rane, Y. Song, S. Jin, M. T. Barati, R. Wu, H. Kausar, Y. Tan, Y. Wang, G. Zhou, J. B. Klein, et al. (2010)
Am J Physiol Renal Physiol 298, F49-F61
   Abstract »    Full Text »    PDF »
Regulation of Fat Cell Mass by Insulin in Drosophila melanogaster.
J. R. DiAngelo and M. J. Birnbaum (2009)
Mol. Cell. Biol. 29, 6341-6352
   Abstract »    Full Text »    PDF »
Mouse models of inherited lipodystrophy.
D. B. Savage (2009)
Dis. Model. Mech. 2, 554-562
   Abstract »    Full Text »    PDF »
Current Perspectives on Akt Akt-ivation and Akt-ions.
R. W. Matheny Jr. and M. L. Adamo (2009)
Exp Biol Med 234, 1264-1270
   Abstract »    Full Text »    PDF »
The molecular basis of insulin-stimulated glucose uptake: signalling, trafficking and potential drug targets.
S. E Leney and J. M Tavare (2009)
J. Endocrinol. 203, 1-18
   Abstract »    Full Text »    PDF »

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