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

J Clin Invest. 2003 Jul;112(2):197-208. doi: 10.1172/JCI16885. Epub 2003 Jul 3.

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
  • Adipose Tissue / 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
  • Hyperglycemia / pathology
  • Hyperinsulinism / genetics
  • Immunohistochemistry
  • Insulin / blood
  • Insulin / metabolism
  • Islets of Langerhans / pathology
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Transgenic
  • Models, Genetic
  • Muscles / metabolism
  • Organ Size
  • Phenotype
  • Phosphoenolpyruvate Carboxykinase (GTP) / biosynthesis
  • Phosphoenolpyruvate Carboxykinase (GTP) / genetics
  • Polymerase Chain Reaction
  • Protein Isoforms
  • Protein-Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / chemistry
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / physiology*
  • Proto-Oncogene Proteins c-akt
  • Time Factors
  • Tomography, X-Ray Computed

Substances

  • 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