[HTML][HTML] Islet β cell expression of constitutively active Akt1/PKBα induces striking hypertrophy, hyperplasia, and hyperinsulinemia

E Bernal-Mizrachi, W Wen, S Stahlhut… - The Journal of …, 2001 - Am Soc Clin Investig
E Bernal-Mizrachi, W Wen, S Stahlhut, CM Welling, MA Permutt
The Journal of clinical investigation, 2001Am Soc Clin Investig
The phosphoinositide 3-kinase–Akt/PKB pathway mediates the mitogenic effects various
nutrients and growth factors in cultured cells. To study its effects in vivo in pancreatic islet β
cells, we created transgenic mice that expressed a constitutively active Akt1/PKBα linked to
an Insulin gene promoter. Transgenic mice exhibited a grossly visible increase in islet mass,
largely due to proliferation of insulin-containing β cells. Morphometric analysis verified a six-
fold increase in β cell mass/pancreas, a two-fold increase in 5-bromo-2′-deoxyuridine …
The phosphoinositide 3-kinase–Akt/PKB pathway mediates the mitogenic effects various nutrients and growth factors in cultured cells. To study its effects in vivo in pancreatic islet β cells, we created transgenic mice that expressed a constitutively active Akt1/PKBα linked to an Insulin gene promoter. Transgenic mice exhibited a grossly visible increase in islet mass, largely due to proliferation of insulin-containing β cells. Morphometric analysis verified a six-fold increase in β cell mass/pancreas, a two-fold increase in 5-bromo-2′-deoxyuridine incorporation, a four-fold increase in the number of β cells per pancreas area, and a two-fold increase in cell size in transgenic compared with wild-type mice at 5 weeks. At least part of the increase in β cell number may be accounted for by neogenesis, defined by criteria that include β cells proliferating from ductular epithelium, and by a six-fold increase in the number of single and doublet β cells scattered throughout the exocrine pancreas of the transgenic mice. Glucose tolerance was improved, and fasting as well as fed insulin was greater compared with wild-type mice. Glucose-stimulated insulin secretion was maintained in transgenic mice, which were resistant to streptozotocin–induced diabetes. We conclude that activation of the Akt1/PKBα pathway affects islet β cell mass by alteration of size and number.
The Journal of Clinical Investigation