Overexpression of IRS2 in isolated pancreatic islets causes proliferation and protects human beta-cells from hyperglycemia-induced apoptosis |
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Authors: | Mohanty S Spinas G A Maedler K Zuellig R A Lehmann R Donath M Y Trüb T Niessen M |
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Affiliation: | Division of Endocrinology and Diabetes, University Hospital of Zurich, 8091 Zurich, Switzerland. |
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Abstract: | Studies in vivo indicate that IRS2 plays an important role in maintaining functional beta-cell mass. To investigate if IRS2 autonomously affects beta-cells, we have studied proliferation, apoptosis, and beta-cell function in isolated rat and human islets after overexpression of IRS2 or IRS1. We found that beta-cell proliferation was significantly increased in rat islets overexpressing IRS2 while IRS1 was less effective. Moreover, proliferation of a beta-cell line, INS-1, was decreased after repression of Irs2 expression using RNA oligonucleotides. Overexpression of IRS2 in human islets significantly decreased apoptosis of beta-cells, induced by 33.3 mM D-glucose. However, IRS2 did not protect cultured rat islets against apoptosis in the presence of 0.5 mM palmitic acid. Overexpression of IRS2 in isolated rat islets significantly increased basal and D-glucose-stimulated insulin secretion as determined in perifusion experiments. Therefore, IRS2 is sufficient to induce proliferation in rat islets and to protect human beta-cells from D-glucose-induced apoptosis. In addition, IRS2 can improve beta-cell function. Our results indicate that IRS2 acts autonomously in beta-cells in maintenance and expansion of functional beta-cell mass in vivo. |
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Keywords: | PKB, protein kinase B FLIP, Fas-associated death domain (FADD)-like interleukin-1β-converting enzyme (FLICE inhibitory protein) cAMP, cyclic adenosine monophosphate GFP, green fluorescence protein PBS, phosphate buffered saline TBST, tris-buffered saline tween 20 MOI, multiplicity of infection pfu, plaque forming units TUNEL, terminal deoxynucleotidyltransferase (TdT)-mediated dUTP nick end labeling FFA, free fatty acids |
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