Islet beta cell expression of constitutively active Akt1/PKB alpha inducesstriking hypertrophy, hyperplasia, and hyperinsulinemia

The phosphoinositide 3-kinase-Akt/PKB pathway mediates the mitogenic effect s various nutrients and growth factors in cultured cells. To study its effe cts in vivo in pancreatic islet beta cells, we created transgenic mice that expressed a constitutively active Akt1/PKB alpha linked to an Insulin gene promoter. Transgenic mice exhibited a grossly visible increase in islet ma ss, largely due to proliferation of insulin-containing beta cells. Morphome tric analysis verified a six-fold increase in beta cell mass/pancreas, a tw o-fold increase in 5-bromo-2'-deoxyuridine incorporation, a four-fold incre ase in the number of beta cells per pancreas area, and a two-fold increase in cell size in transgenic compared with wildtype mice at 5 weeks. At least part of the increase in beta cell number may be accounted for by neogenesi s, defined by criteria that include beta cells proliferating from ductular epithelium, and by a six-fold increase in the number of single and doublet beta cells scattered throughout the exocrine pancreas of the transgenic mic e. Glucose tolerance was improved, and fasting as well as fed insulin was g reater compared with wild-type mice. Glucose-stimulated insulin secretion w as maintained in transgenic mice, which were resistant to streptozotocin-in duced diabetes. We conclude that activation of the Akt1/PKB alpha pathway a ffects islet beta cell mass by alteration of size and number.