Regulation of pancreatic beta-cell regeneration in the normoglycemic 60% partial-pancreatectomy mouse.
beta-Cell mass is determined by a dynamic balance of proliferation, neogenesis, and apoptosis. The precise mechanisms underlying compensatory beta-cell mass (BCM) homeostasis are not fully understood. To evaluate the processes that maintain normoglycemia and regulate BCM during pancreatic regeneration, C57BL/6 mice were analyzed for 15 days following 60% partial pancreatectomy (Px). BCM increased in Px mice from 2 days onwards and was approximately 68% of the shams by 15 days, partly due to enhanced beta-cell proliferation. A transient approximately 2.8-fold increase in the prevalence of beta-cell clusters/small islets at 2 days post-Px contributed substantially to BCM augmentation, followed by an increase in the number of larger islets at 15 days. To evaluate the signaling mechanisms that may regulate this compensatory growth, we examined key intermediates of the insulin signaling pathway. We found insulin receptor substrate (IRS)2 and enhanced-activated Akt immunoreactivity in islets and ducts that correlated with increased pancreatic duodenal homeobox (PDX)1 expression. In contrast, forkhead box O1 expression was decreased in islets but increased in ducts, suggesting distinct PDX1 regulatory mechanisms in these tissues. Px animals acutely administered insulin exhibited further enhancement in insulin signaling activity. These data suggest that the IRS2-Akt pathway mediates compensatory beta-cell growth by activating beta-cell proliferation with an increase in the number of beta-cell clusters/small islets.
Peshavaria
Mina
M
University of Vermont College of Medicine, Department of Medicine, Given C331, Burlington, VT 05405, USA. mina.peshavaria@uvm.edu
Larmie
Brooke L
BL
Lausier
James
J
Satish
Basanthi
B
Habibovic
Aida
A
Roskens
Violet
V
Larock
Kyla
K
Everill
Brian
B
Leahy
Jack L
JL
Jetton
Thomas L
TL
D000199:Actins / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose; D002455:Cell Division; D056742:Cyclin D2; D016213:Cyclins / Q000378:metabolism; D015151:Immunoblotting; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000502:physiology*; D007515:Islets of Langerhans / Q000033:anatomy & histology / Q000166:cytology / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D010180:Pancreatectomy; D016133:Polymerase Chain Reaction; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D012038:Regeneration
D000199:Actins; D001786:Blood Glucose; C486196:Ccnd2 protein, mouse; D056742:Cyclin D2; D016213:Cyclins; D012313:RNA