Document Detail


The type 2 diabetes associated gene Ide is required for insulin secretion and suppression of α-synuclein levels in β-cells.
MedLine Citation:
PMID:  23349488     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Genome wide association studies have identified several type 2 diabetes (T2D) risk loci linked to impaired β-cell function. The identity and function of the causal genes in these susceptibility loci remain, however, elusive. The HHEX/IDE T2D locus is associated with decreased insulin secretion in response to oral glucose stimulation in humans. Here we have assessed β-cell function in Ide knock-out (KO) mice. We find that glucose stimulated insulin secretion (GSIS) is decreased in Ide KO mice due to impaired replenishment of the releasable pool of granules and that the Ide gene is haploinsufficient. We also show that autophagic flux and microtubule content is reduced in β-cells of Ide KO mice. One important cellular role for IDE involves the neutralization of amyloidogenic proteins and we find that α-synuclein and IDE levels are inversely correlated in β-cells of Ide KO mice and T2D patients. Moreover, we provide evidence that both gain- and loss-of-function of α-synuclein in β-cells in vivo not only impair GSIS but also autophagy. Together, these data identify the Ide gene as a regulator of GSIS, suggest a molecular mechanism for β-cell degeneration as a consequence of Ide deficiency, and additionally corroborates and extends a previously established important role for α-synuclein in β-cell function.
Authors:
Pär Steneberg; Lisandro Bernardo; Sara Edfalk; Fredrik Backlund; Lisa Lundberg; Claes-Gran Stenson; Helena Edlund
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-1-24
Journal Detail:
Title:  Diabetes     Volume:  -     ISSN:  1939-327X     ISO Abbreviation:  Diabetes     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-1-25     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0372763     Medline TA:  Diabetes     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Umeå University, UCMM, Umeå, Sweden.
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