BH3-only molecule Bim mediates β-cell death in IRS2 deficiency.
Irs2-deficient mice develop type 2-like diabetes due to a reduction in β-cell mass and a failure of pancreatic islets to undergo compensatory hyperplasia in response to insulin resistance. In order to define the molecular mechanisms, we knocked down Irs2 gene expression in mouse MIN6 insulinoma cells. Insulin receptor substrate 2 (IRS2) suppression induced apoptotic cell death, which was associated with an increase in expression of the BH3-only molecule Bim. Knockdown (KD) of Bim reduced apoptotic β-cell death induced by IRS2 suppression. In Irs2-deficient mice, Bim ablation restored β-cell mass, decreased the number of TUNEL-positive cells, and restored normal glucose tolerance after glucose challenge. FoxO1 mediates Bim upregulation induced by IRS2 suppression, and FoxO1 KD partially inhibits β-cell death induced by IRS2 suppression. These results suggest that Bim plays an important role in mediating the increase in β-cell apoptosis and the reduction in β-cell mass that occurs in IRS2-deficient diabetes.
Department of Medicine, The University of Chicago, Chicago, IL.
Decheng
D
Ren
Department of Medicine, The University of Chicago, Chicago, IL.
Juan
J
Sun
Department of Medicine, The University of Chicago, Chicago, IL.
Liqun
L
Mao
Department of Medicine, The University of Chicago, Chicago, IL.
Honggang
H
Ye
Department of Medicine, The University of Chicago, Chicago, IL polonsky@bsd.uchicago.edu decheng@uchicago.edu.
Kenneth S
KS
Polonsky
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D002452:Cell Count; D016923:Cell Death / Q000502:physiology*; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D015854:Up-Regulation
D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D055504:Insulin Receptor Substrate Proteins; C526298:Irs2 protein, mouse; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins