BH3-only molecule Bim mediates β-cell death in IRS2 deficiency.

Abstract:

: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.

journal_name

Diabetes

journal_title

Diabetes

authors

Ren D,Sun J,Mao L,Ye H,Polonsky KS

doi

10.2337/db13-1814

subject

Has Abstract

pub_date

2014-10-01 00:00:00

pages

3378-87

issue

10

eissn

0012-1797

issn

1939-327X

pii

db13-1814

journal_volume

63

pub_type

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