Severe diabetes, age-dependent loss of adipose tissue, and mild growth deficiency in mice lacking Akt2/PKB beta.
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.
Garofalo
Robert S
RS
Pfizer Global Research and Development, Groton, Connecticut 06357, USA. robert_s_garofalo@groton.pfizer.com
Orena
Stephen J
SJ
Rafidi
Kristina
K
Torchia
Anthony J
AJ
Stock
Jeffrey L
JL
Hildebrandt
Audrey L
AL
Coskran
Timothy
T
Black
Shawn C
SC
Brees
Dominique J
DJ
Wicks
Joan R
JR
McNeish
John D
JD
Coleman
Kevin G
KG
D000273:Adipose Tissue / Q000378:metabolism / Q000473:pathology*; D000375:Aging; D000818:Animals; D001835:Body Weight; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000473:pathology*; D005260:Female; D005822:Genetic Vectors; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D006006:Glycogen Synthase / Q000378:metabolism; D006943:Hyperglycemia / Q000235:genetics / Q000473:pathology; D006946:Hyperinsulinism / Q000235:genetics; D007150:Immunohistochemistry; D007328:Insulin / Q000097:blood / Q000378:metabolism; D007515:Islets of Langerhans / Q000473:pathology; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D009132:Muscles / Q000378:metabolism; D009929:Organ Size; D010641:Phenotype; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000096:biosynthesis / Q000235:genetics; D016133:Polymerase Chain Reaction; D020033:Protein Isoforms; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D013997:Time Factors; D014057:Tomography, X-Ray Computed
D007328:Insulin; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins; D006006:Glycogen Synthase; C494922:Akt2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D005952:Glucose-6-Phosphatase; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D005947:Glucose