Description

Strain Information

Type Congenic; Mutant Strain; Targeted Mutation; Mating System +/+ sibling x Heterozygote         (Female x Male) Species laboratory mouse   Donating Investigator Morris Birnbaum,   Un of Pennsylvania Schl of Medicine

Description
Mice homozygous for this Akt2 (thymoma viral proto-oncogene 2) mutant allele are viable and fertile. Homozygotes develop insulin resistance, hyperglycemia, impaired glucose tolerance, abnormal glucose uptake in muscle tissue, increased pancreatic beta-cell mass, and diabetes.

In an attempt to offer alleles on well-characterized or multiple genetic backgrounds, alleles are frequently moved to a genetic background different from that on which an allele was first characterized. It should be noted that the phenotype could vary from that originally described. We will modify the strain description if necessary as published results become available.

Development
This mutation was created by Dr. Morris Birnbaum (University of Pennsylvania) by flanking exons 4-5 of the targeted gene with loxP sites. The targeting vector was electroporated into 129P2/OlaHsd-derived E14 embryonic stem (ES) cells, and the chimeric males were bred with C57BL/6 females. Mutant mice were then bred to cre transgenic mice to remove exons 4-5 and bred for an unknown number of generations. These mutant mice on a mixed (approximately 80% C57BL/6J) background were then shipped to Dr. Jan Breslow at The Rockefeller University. Dr. Breslow's lab crossed these mice to another mutant strain and further backcrossed to C57BL/6J for approximately 7 generations prior to arrival at The Jackson Laboratory (as Stock No. 006952). The donating investigators report that 102/104 microsatellite markers indicate C57BL/6J background; the only exceptions are D7Mit21 and D7Mit294. The Y chromosome may not have been fixed to the C57BL/6J genetic background. Upon arrival, some Stock No. 006952 mice were bred to C57BL/6J to isolate the Akt2 mutant allele; generating this single mutant congenic strain (Stock No. 006966).

Control Information

	Control
	Wild-type from the colony
	000664 C57BL/6J
Considerations for Choosing Controls

Related Strains

Strains carrying   Akt2^tm1.1Mbb allele

006952

B6.Cg-Akt2tm1.1Mbb Ldlrtm1Her/J

View Strains carrying   Akt2^tm1.1Mbb     (1 strain)

Additional Web Information

Congenic Nomenclature

Phenotype

Phenotype Information

Related Disease (OMIM) Terms

Diabetes Mellitus, Noninsulin-Dependent; NIDDM

Mammalian Phenotype Terms assigned by genotype

The following phenotype information may relate to a genetic background differing from this JAX^® Mice strain.

Akt2^tm1.1Mbb/Akt2^tm1.1Mbb

        involves: 129P2/OlaHsd * C57BL/6

• homeostasis/metabolism phenotype
• hyperglycemia (MGI Ref ID J:71491)
  • homozygotes develop into adulthood without apparent growth defects but exhibit a mild but significant fasting hyperglycemia, which is more pronounced during fed states
• impaired glucose tolerance (MGI Ref ID J:71491)
  • in response to oral glucose load, 2-mo-old homozygotes display a mild glucose intolerance, with increased blood glucose levels at all time points measured
• increased circulating insulin level (MGI Ref ID J:71491)
  • homozygotes develop inadequate compensatory hyperinsulinemia
• insulin resistance (MGI Ref ID J:71491)
  • in response to i.p. administration of insulin, homozygotes display significantly elevated blood glucose levels relative to wild-type mice at all time points measured (at 60 min; 70.8 ± 7.9 mg/dl vs 22.3 ± 1.1 mg/dl, respectively)
  • in euglycemic-hyperinsulinemic clamp expts, homozygotes exhibit peripheral insulin resistance along with complete failure of insulin to suppress hepatic glucose output
  • notably, circulating free fatty acid concentrations remain normal
• muscle phenotype
• abnormal muscle cell glucose uptake (MGI Ref ID J:71491)
  • in euglycemic-hyperinsulinemic clamp studies, 2-5-mo-old homozygotes show a ~50% reduction in total body insulin-dependent glucose disposal relative to wild-type mice
  • insulin-stimulated hexose uptake into the glycolytic extensor digitorum longus (EDL) muscle is severely blunted in the presence of 0.33 nM insulin; however, no impairment is noted upon exposure of the mutant EDL to a higher insulin concentration (13.3 nM)
  • insulin-stimulated deoxyglucose uptake into the oxidative soleus muscle is not significantly impaired at either an intermediate or maximal concentration of insulin
• endocrine/exocrine gland phenotype
• increased pancreatic beta cell number (MGI Ref ID J:71491)
  • pancreata from 2- to 3-month-old male homozygotes respond to insulin resistance with an increase in islet mass (~4-fold) and number (~2-fold) relative to wild-type mice
• adipose tissue phenotype
• abnormal adipocyte glucose uptake (MGI Ref ID J:71491)
  • in euglycemic-hyperinsulinemic clamp studies, insulin-stimulated hexose uptake is mildly impaired in mutant adipocytes
• digestive/alimentary phenotype
• increased pancreatic beta cell number (MGI Ref ID J:71491)
  • pancreata from 2- to 3-month-old male homozygotes respond to insulin resistance with an increase in islet mass (~4-fold) and number (~2-fold) relative to wild-type mice

Akt2^tm1.1Mbb/Akt2^tm1.1Mbb

        Background Not Specified

• normal phenotype
• no abnormal phenotype detected (MGI Ref ID J:135903)
  • no abnormalities in T cell development are observed

Research Applications

This mouse can be used to support research in many areas including:

Diabetes and Obesity Research
Hyperglycemia
Insulin Resistance
Type 2 Diabetes (NIDDM)

Research Tools
Diabetes and Obesity Research
Metabolism Research

Genes & Alleles

Gene & Allele Information

Allele Symbol		Akt2tm1.1Mbb
Allele Name		targeted mutation 1.1, Morris J Birnbaum
Common Name(s)		Akt2 KO; Akt2-;
Mutation Made By		Morris Birnbaum,   Un of Pennsylvania Schl of Medicine
Strain of Origin		129P2/OlaHsd
ES Cell Line Name		E14
ES Cell Line Strain		129P2/OlaHsd
Gene Symbol and Name		Akt2, thymoma viral proto-oncogene 2
Chromosome		7
Gene Common Name(s)		2410016A19Rik; AW554154; PKB; PKBB; PKBBETA; PRKBB; RAC-BETA; RIKEN cDNA 2410016A19 gene; expressed sequence AW554154;
Molecular Note		This allele is a derivative of Akt2tm1Mbb. Cre-mediated recombination in vivo under the control of a 6 kb 5'-flanking sequence from the Pou3f4 gene excised the floxed exons 4 and 5 in the germline. The excision of exons 4 and 5 results in a frameshift mutation that would lead to a premature termination even if the remaining exon 3 were to splice to exon 6. Exon 5 encodes the lysine residue necessary for catalytic activity. Western blot analyses using a polyclonal antibody did not detect protein in liver, muscle, and isolated adipocytes from homozygous mice. [MGI Ref ID J:71491]

Genotyping

Genotyping Information

Genotyping Protocols

Akt2^tm1.1Mbb, STD PCR, vers. 1

Helpful Links

Optimizing PCR Protocols

References

References

Selected Reference(s)

Cho H; Mu J; Kim JK; Thorvaldsen JL; Chu Q; Crenshaw EB rd; Kaestner KH; Bartolomei MS; Shulman GI; Birnbaum MJ. 2001. Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB beta). Science 292(5522):1728-31. [PubMed: 11387480]  [MGI Ref ID J:71491]

Additional References

Akt2^tm1.1Mbb related

Ackah E; Yu J; Zoellner S; Iwakiri Y; Skurk C; Shibata R; Ouchi N; Easton RM; Galasso G; Birnbaum MJ; Walsh K; Sessa WC. 2005. Akt1/protein kinase Balpha is critical for ischemic and VEGF-mediated angiogenesis. J Clin Invest 115(8):2119-2127. [PubMed: 16075056]  [MGI Ref ID J:100143]

Boxer RB; Stairs DB; Dugan KD; Notarfrancesco KL; Portocarrero CP; Keister BA; Belka GK; Cho H; Rathmell JC; Thompson CB; Birnbaum MJ; Chodosh LA. 2006. Isoform-specific requirement for Akt1 in the developmental regulation of cellular metabolism during lactation. Cell Metab 4(6):475-90. [PubMed: 17141631]  [MGI Ref ID J:129773]

DeBosch B; Sambandam N; Weinheimer C; Courtois M; Muslin AJ. 2006. Akt2 regulates cardiac metabolism and cardiomyocyte survival. J Biol Chem 281(43):32841-51. [PubMed: 16950770]  [MGI Ref ID J:117383]

Easton RM; Cho H; Roovers K; Shineman DW; Mizrahi M; Forman MS; Lee VM; Szabolcs M; de Jong R; Oltersdorf T; Ludwig T; Efstratiadis A; Birnbaum MJ. 2005. Role for Akt3/protein kinase Bgamma in attainment of normal brain size. Mol Cell Biol 25(5):1869-78. [PubMed: 15713641]  [MGI Ref ID J:96823]

Juntilla MM; Wofford JA; Birnbaum MJ; Rathmell JC; Koretzky GA. 2007. Akt1 and Akt2 are required for {alpha}beta thymocyte survival and differentiation. Proc Natl Acad Sci U S A 104(29):12105-10. [PubMed: 17609365]  [MGI Ref ID J:123155]

Kramer HF; Witczak CA; Fujii N; Jessen N; Taylor EB; Arnolds DE; Sakamoto K; Hirshman MF; Goodyear LJ. 2006. Distinct signals regulate AS160 phosphorylation in response to insulin, AICAR, and contraction in mouse skeletal muscle. Diabetes 55(7):2067-76. [PubMed: 16804077]  [MGI Ref ID J:111856]

Li D; August S; Woulfe DS. 2008. GSK3beta is a negative regulator of platelet function and thrombosis. Blood 111(7):3522-30. [PubMed: 18218855]  [MGI Ref ID J:133503]

Li G; Anderson RE; Tomita H; Adler R; Liu X; Zack DJ; Rajala RV. 2007. Nonredundant role of Akt2 for neuroprotection of rod photoreceptor cells from light-induced cell death. J Neurosci 27(1):203-11. [PubMed: 17202487]  [MGI Ref ID J:117208]

Mao C; Tili EG; Dose M; Haks MC; Bear SE; Maroulakou I; Horie K; Gaitanaris GA; Fidanza V; Ludwig T; Wiest DL; Gounari F; Tsichlis PN. 2007. Unequal contribution of Akt isoforms in the double-negative to double-positive thymocyte transition. J Immunol 178(9):5443-53. [PubMed: 17442925]  [MGI Ref ID J:135903]

Maroulakou IG; Oemler W; Naber SP; Tsichlis PN. 2007. Akt1 ablation inhibits, whereas Akt2 ablation accelerates, the development of mammary adenocarcinomas in mouse mammary tumor virus (MMTV)-ErbB2/neu and MMTV-polyoma middle T transgenic mice. Cancer Res 67(1):167-77. [PubMed: 17210696]  [MGI Ref ID J:117336]

McCurdy CE; Cartee GD. 2005. Akt2 is essential for the full effect of calorie restriction on insulin-stimulated glucose uptake in skeletal muscle. Diabetes 54(5):1349-56. [PubMed: 15855319]  [MGI Ref ID J:105199]

Sakamoto K; Arnolds DE; Fujii N; Kramer HF; Hirshman MF; Goodyear LJ. 2006. Role of Akt2 in contraction-stimulated cell signaling and glucose uptake in skeletal muscle. Am J Physiol Endocrinol Metab 291(5):E1031-7. [PubMed: 16803855]  [MGI Ref ID J:113860]

Southgate RJ; Bruce CR; Carey AL; Steinberg GR; Walder K; Monks R; Watt MJ; Hawley JA; Birnbaum MJ; Febbraio MA. 2005. PGC-1alpha gene expression is down-regulated by Akt- mediated phosphorylation and nuclear exclusion of FoxO1 in insulin-stimulated skeletal muscle. FASEB J 19(14):2072-4. [PubMed: 16203862]  [MGI Ref ID J:104633]

Wofford JA; Wieman HL; Jacobs SR; Zhao Y; Rathmell JC. 2008. IL-7 promotes Glut1 trafficking and glucose uptake via STAT5-mediated activation of Akt to support T-cell survival. Blood 111(4):2101-11. [PubMed: 18042802]  [MGI Ref ID J:131334]

Woulfe D; Jiang H; Morgans A; Monks R; Birnbaum M; Brass LF. 2004. Defects in secretion, aggregation, and thrombus formation in platelets from mice lacking Akt2. J Clin Invest 113(3):441-50. [PubMed: 14755341]  [MGI Ref ID J:87588]

Yin H; Stojanovic A; Hay N; Du X. 2008. The role of Akt in the signaling pathway of the glycoprotein Ib-IX induced platelet activation. Blood 111(2):658-65. [PubMed: 17914025]  [MGI Ref ID J:130112]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Room Number           AX11

Colony Maintenance

Breeding & Husbandry	When maintaining a live colony, heterozygous or homozygous mice can be bred. Homozygous mice may have impaired fecundity as a result of diabetic phenotype.
Diet Information	LabDiet® 5K52/5K67

Purchasing information

Pricing, Supply Level & Notes, Controls, General Terms & Conditions

Pricing

Control Information

	Control
	Wild-type from the colony
	000664 C57BL/6J
Considerations for Choosing Controls
USA, Canada and Mexico - Control Pricing Information for Genetically Engineered Mutant Strains.
International - Control Pricing Information for Genetically Engineered Mutant Strains.

General Terms and Conditions

View JAX^® Mice & Services Conditions of Use.

Effective September 26, 2007: License Requirements for Strains using Cre-lox Technology only apply in Canada, see Licenses for Strains using Cre-lox Technology.

For additional Licensing and Use Restrictions view the link(s) below:
- Use of MICE by companies or for-profit entities requires a license prior to shipping.

The Jackson Laboratory's Genotype Promise

The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX^® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX^® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX^® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project.

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