Enhanced expression of insulin receptor substrate-2 and activation of protein kinase B/Akt in regenerating pancreatic duct epithelium of 60 %-partial pancreatectomy rats.

AIMS/HYPOTHESIS: Early compensatory mechanisms of regeneration following partial pancreatectomy involve ductal proliferation and, subsequently, differentiation into acinar and endocrine cell types, although it is not clear how these processes are regulated. We investigated the expression and roles of insulin receptor substrate-2 (IRS-2) and protein kinase B/Akt (Akt) in pancreatic regeneration that starts with the common duct epithelium using a non-diabetic model of beta cell adaptation and mass expansion, 60 %-pancreatectomy rats.

METHODS: We used confocal immunofluorescence microscopy to study IRS-2 and Akt expression and activation in pancreatic common ducts at intervals after surgery. These proteins were studied in relation to proliferation markers and insulin immunostaining.

RESULTS: In pancreatectomized rats, a short-term increase in proliferation was observed in the common duct epithelial lining ( approximately 4-fold) compared with sham-operated control rats which correlated with about a 1.8-fold increase in IRS-2 immunoreactivity 2 days after surgery. Interspersed with proliferating cells of the common duct, evaginations were rare single and clustered insulin immunopositive cells which expressed high levels of IRS-2 immunoreactivity. Epithelium of duct evaginations from 2-day post-Px rats exhibited striking phospho-Akt staining ( approximately 3.5-fold above control rats) without any detectable changes in total Akt staining.

CONCLUSION/INTERPRETATION: Our data suggest that IRS-2 plays an important role in pancreatic regeneration and growth by mediating duct proliferation and by maintaining the differentiated beta cell. The restricted staining pattern of phospho-Akt to cells of the common duct evaginations suggests that it has a role in regulating post-mitotic events related to cell-specific gene expression or survival or both.