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PMID: 12843127 Published · ppublish English Journal Article

Severe diabetes, age-dependent loss of adipose tissue, and mild growth deficiency in mice lacking Akt2/PKB beta.

The Journal of clinical investigation ·Vol. 112 ·No. 2 ·2003-07-00 ·Pages 197-208

Garofalo RS, Orena SJ, Rafidi K, Torchia AJ, Stock JL, Hildebrandt AL, Coskran T, Black SC, Brees DJ, Wicks JR, McNeish JD, Coleman KG

Abstract

The serine/threonine kinase Akt/PKB plays key roles in the regulation of cell growth, survival, and metabolism. It remains unclear, however, whether the functions of individual Akt/PKB isoforms are distinct. To investigate the function of Akt2/PKBbeta, mice lacking this isoform were generated. Both male and female Akt2/PKBbeta-null mice exhibit mild growth deficiency and an age-dependent loss of adipose tissue or lipoatrophy, with all observed adipose depots dramatically reduced by 22 weeks of age. Akt2/PKBbeta-deficient mice are insulin resistant with elevated plasma triglycerides. In addition, Akt2/PKBbeta-deficient mice exhibit fed and fasting hyperglycemia, hyperinsulinemia, glucose intolerance, and impaired muscle glucose uptake. In males, insulin resistance progresses to a severe form of diabetes accompanied by pancreatic beta cell failure. In contrast, female Akt2/PKBbeta-deficient mice remain mildly hyperglycemic and hyperinsulinemic until at least one year of age. Thus, Akt2/PKBbeta-deficient mice exhibit growth deficiency similar to that reported previously for mice lacking Akt1/PKBalpha, indicating that both Akt2/PKBbeta and Akt1/PKBalpha participate in the regulation of growth. The marked hyperglycemia and loss of pancreatic beta cells and adipose tissue in Akt2/PKBbeta-deficient mice suggest that Akt2/PKBbeta plays critical roles in glucose metabolism and the development or maintenance of proper adipose tissue and islet mass for which other Akt/PKB isoforms are unable to fully compensate.

MeSH Terms
Adipose Tissue/metabolism,pathology Aging Animals Body Weight Caspase 3 Caspases/metabolism Diabetes Mellitus, Experimental/pathology Female Genetic Vectors Glucose/metabolism Glucose Tolerance Test Glucose-6-Phosphatase/metabolism Glycogen Synthase/metabolism Hyperglycemia/genetics,pathology Hyperinsulinism/genetics Immunohistochemistry Insulin/blood,metabolism Islets of Langerhans/pathology Liver/metabolism Male Mice Mice, Transgenic Models, Genetic Muscles/metabolism Organ Size Phenotype Phosphoenolpyruvate Carboxykinase (GTP)/biosynthesis,genetics Polymerase Chain Reaction Protein Isoforms Protein Serine-Threonine Kinases Proto-Oncogene Proteins/chemistry,genetics,physiology Proto-Oncogene Proteins c-akt Time Factors Tomography, X-Ray Computed
Chemicals
Insulin Protein Isoforms Proto-Oncogene Proteins Glycogen Synthase Akt2 protein, mouse Protein Serine-Threonine Kinases Proto-Oncogene Proteins c-akt Glucose-6-Phosphatase Casp3 protein, mouse Caspase 3 Caspases Phosphoenolpyruvate Carboxykinase (GTP) Glucose
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Garofalo Robert S
Pfizer Global Research and Development, Groton, Connecticut 06357, USA. [email protected]
Orena Stephen J
Rafidi Kristina
Torchia Anthony J
Stock Jeffrey L
Hildebrandt Audrey L
Coskran Timothy
Black Shawn C
Brees Dominique J
Wicks Joan R
McNeish John D
Coleman Kevin G
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI16885
Email
[email protected]
Published
2003-07-00
Epub
2003-00-03
Pages
197-208
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC164287
Subset
IM
External Links
PubMed source DOI: 10.1172/JCI16885 PMC Full Text View journal details
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