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Science 1 June 2001:
Vol. 292. no. 5522, pp. 1728 - 1731
DOI: 10.1126/science.292.5522.1728
Prev | Table of Contents

Reports

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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   Abstract »    Full Text »    PDF »
Skeletal Muscle-Selective Knockout of LKB1 Increases Insulin Sensitivity, Improves Glucose Homeostasis, and Decreases TRB3.
H.-J. Koh, D. E. Arnolds, N. Fujii, T. T. Tran, M. J. Rogers, N. Jessen, Y. Li, C. W. Liew, R. C. Ho, M. F. Hirshman, et al. (2006)
Mol. Cell. Biol. 26, 8217-8227
   Abstract »    Full Text »    PDF »
Only Akt1 Is Required for Proliferation, while Akt2 Promotes Cell Cycle Exit through p21 Binding.
L. Heron-Milhavet, C. Franckhauser, V. Rana, C. Berthenet, D. Fisher, B. A. Hemmings, A. Fernandez, and N. J. C. Lamb (2006)
Mol. Cell. Biol. 26, 8267-8280
   Abstract »    Full Text »    PDF »
Chronic Protein Kinase B (PKB/c-akt) Activation Leads to Apoptosis Induced by Oxidative Stress-Mediated Foxo3a Transcriptional Up-regulation..
A. G.M. van Gorp, K. M. Pomeranz, K. U. Birkenkamp, R. C-Y. Hui, E. W-F. Lam, and P. J. Coffer (2006)
Cancer Res. 66, 10760-10769
   Abstract »    Full Text »    PDF »
Life with a Single Isoform of Akt: Mice Lacking Akt2 and Akt3 Are Viable but Display Impaired Glucose Homeostasis and Growth Deficiencies.
B. Dummler, O. Tschopp, D. Hynx, Z.-Z. Yang, S. Dirnhofer, and B. A. Hemmings (2006)
Mol. Cell. Biol. 26, 8042-8051
   Abstract »    Full Text »    PDF »
Role of Akt2 in contraction-stimulated cell signaling and glucose uptake in skeletal muscle.
K. Sakamoto, D. E. Arnolds, N. Fujii, H. F. Kramer, M. F. Hirshman, and L. J. Goodyear (2006)
Am J Physiol Endocrinol Metab 291, E1031-E1037
   Abstract »    Full Text »    PDF »
Akt2 Regulates Cardiac Metabolism and Cardiomyocyte Survival.
B. DeBosch, N. Sambandam, C. Weinheimer, M. Courtois, and A. J. Muslin (2006)
J. Biol. Chem. 281, 32841-32851
   Abstract »    Full Text »    PDF »
Quantitative Analysis of Anti-apoptotic Function of Akt in Akt1 and Akt2 Double Knock-out Mouse Embryonic Fibroblast Cells under Normal and Stressed Conditions.
X. Liu, Y. Shi, M. J. Birnbaum, K. Ye, R. De Jong, T. Oltersdorf, V. L. Giranda, and Y. Luo (2006)
J. Biol. Chem. 281, 31380-31388
   Abstract »    Full Text »    PDF »
Control of MyoD Function during Initiation of Muscle Differentiation by an Autocrine Signaling Pathway Activated by Insulin-like Growth Factor-II.
E. M. Wilson and P. Rotwein (2006)
J. Biol. Chem. 281, 29962-29971
   Abstract »    Full Text »    PDF »
Bradykinin Augments Insulin-Stimulated Glucose Transport in Rat Adipocytes via Endothelial Nitric Oxide Synthase-Mediated Inhibition of Jun NH2-Terminal Kinase..
K. M. Beard, H. Lu, K. Ho, and I. G. Fantus (2006)
Diabetes 55, 2678-2687
   Abstract »    Full Text »    PDF »
Insulin Signaling Diverges into Akt-dependent and -independent Signals to Regulate the Recruitment/Docking and the Fusion of GLUT4 Vesicles to the Plasma Membrane.
E. Gonzalez and T. E. McGraw (2006)
Mol. Biol. Cell 17, 4484-4493
   Abstract »    Full Text »    PDF »
Insulin resistance and increased pancreatic {beta}-cell proliferation in mice expressing a mutant insulin receptor (P1195L)..
J Ogino, K Sakurai, K Yoshiwara, Y. Suzuki, N Ishizuka, N Seki, Y. Suzuki, H Koseki, T Shirasawa, N Hashimoto, et al. (2006)
J. Endocrinol. 190, 739-747
   Abstract »    Full Text »    PDF »
Mesangial Cell Hypertrophy by High Glucose Is Mediated by Downregulation of the Tumor Suppressor PTEN..
L. Mahimainathan, F. Das, B. Venkatesan, and G. G. Choudhury (2006)
Diabetes 55, 2115-2125
   Abstract »    Full Text »    PDF »
Repletion of Atypical Protein Kinase C following RNA Interference-mediated Depletion Restores Insulin-stimulated Glucose Transport.
M. P. Sajan, J. Rivas, P. Li, M. L. Standaert, and R. V. Farese (2006)
J. Biol. Chem. 281, 17466-17473
   Abstract »    Full Text »    PDF »
Exercise-Induced Phosphorylation of the Novel Akt Substrates AS160 and Filamin A in Human Skeletal Muscle.
A. Deshmukh, V. G. Coffey, Z. Zhong, A. V. Chibalin, J. A. Hawley, and J. R. Zierath (2006)
Diabetes 55, 1776-1782
   Abstract »    Full Text »    PDF »
Kinetic Mechanism of AKT/PKB Enzyme Family.
X. Zhang, S. Zhang, H. Yamane, R. Wahl, A. Ali, J. A. Lofgren, and R. L. Kendall (2006)
J. Biol. Chem. 281, 13949-13956
   Abstract »    Full Text »    PDF »
Akt Signaling and Growth of the Heart.
K. Walsh (2006)
Circulation 113, 2032-2034
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Akt1 Is Required for Physiological Cardiac Growth.
B. DeBosch, I. Treskov, T. S. Lupu, C. Weinheimer, A. Kovacs, M. Courtois, and A. J. Muslin (2006)
Circulation 113, 2097-2104
   Abstract »    Full Text »    PDF »
Insulin Resistance and Atherosclerosis.
J. Nigro, N. Osman, A. M. Dart, and P. J. Little (2006)
Endocr. Rev. 27, 242-259
   Abstract »    Full Text »    PDF »
AKT1 Provides an Essential Survival Signal Required for Differentiation and Stratification of Primary Human Keratinocytes.
B. R. Thrash, C. W. Menges, R. H. Pierce, and D. J. McCance (2006)
J. Biol. Chem. 281, 12155-12162
   Abstract »    Full Text »    PDF »
Selective Deletion of Pten in Pancreatic {beta} Cells Leads to Increased Islet Mass and Resistance to STZ-Induced Diabetes..
B. L. Stiles, C. Kuralwalla-Martinez, W. Guo, C. Gregorian, Y. Wang, J. Tian, M. A. Magnuson, and H. Wu (2006)
Mol. Cell. Biol. 26, 2772-2781
   Abstract »    Full Text »    PDF »
PKB{alpha} is required for adipose differentiation of mouse embryonic fibroblasts.
A. Baudry, Z.-Z. Yang, and B. A. Hemmings (2006)
J. Cell Sci. 119, 889-897
   Abstract »    Full Text »    PDF »


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