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

Ernesto Bernal Mizrachi, W. Wen, S. Stahlhut, C. M. Welling, M. A. Permutt

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)1631-1638
Number of pages8
JournalJournal of Clinical Investigation
Volume108
Issue number11
DOIs
StatePublished - 2001
Externally publishedYes

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Hyperinsulinism
Islets of Langerhans
Hypertrophy
Transgenic Mice
Hyperplasia
Insulin
Pancreas
Cell Count
Glucose
Exocrine Pancreas
1-Phosphatidylinositol 4-Kinase
Experimental Diabetes Mellitus
Bromodeoxyuridine
Cell Size
Cultured Cells
Fasting
Intercellular Signaling Peptides and Proteins
Epithelium
Food
Genes

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Islet β cell expression of constitutively active Akt1/PKBα induces striking hypertrophy, hyperplasia, and hyperinsulinemia. / Bernal Mizrachi, Ernesto; Wen, W.; Stahlhut, S.; Welling, C. M.; Permutt, M. A.

In: Journal of Clinical Investigation, Vol. 108, No. 11, 2001, p. 1631-1638.

Research output: Contribution to journalArticle

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